28595140	Most reward studies focus on the reinforcement of simple tasks or stimulus-response rules. However, recent theories (re)emphasized that cognitive control representations should adhere to the same reinforcement learning principles as do more basic stimulus and response representations. This study focused on the act of switching between different tasks, and investigated the effects of disproportionally rewarding task alternations or repetitions in a cued task switching paradigm on subsequent voluntary task switching behavior (i.e., when participants could choose which task to perform). The results show that subjects who were more rewarded for task alternations (relative to those more rewarded for repetitions) showed more task switching behavior. Moreover, this increased task switching behavior also came with a cost, with participants more rewarded for task repetitions showing a better task focus (i.e., smaller task-rule congruency effects). These results demonstrate that reward can reinforce more abstract control representations, beyond low-level stimulus or response representations.
28594633	Despite preliminary evidence that individuals with borderline personality disorder (BPD) demonstrate deficits in learning from corrective feedback, no studies have examined the influence of emotional state on these learning deficits in BPD. This laboratory study examined the influence of negative emotions on learning among participants with BPD (n = 17), compared with clinical (past-year mood/anxiety disorder; n = 20) and healthy (n = 23) controls. Participants completed a reinforcement learning task before and after a negative emotion induction. The learning task involved presenting pairs of stimuli with probabilistic feedback in the training phase, and subsequently assessing accuracy for choosing previously rewarded stimuli or avoiding previously punished stimuli. ANOVAs and ANCOVAs revealed no significant between-group differences in overall learning accuracy. However, there was an effect of group in the ANCOVA for postemotion induction high-conflict punishment learning accuracy, with the BPD group showing greater decrements in learning accuracy than controls following the negative emotion induction.
28592258	Novice drivers are at relatively high risk of road traffic injury. There is good evidence that Graduated Driving Licensing (GDL) schemes reduce collisions rates, by reducing exposure to risk and by extending learning periods. Legislation for a proposed scheme in Northern Ireland was passed in 2016, providing an opportunity for future evaluation of the full public health impacts of a scheme in a European context within a natural experiment. This qualitative study was designed to inform the logic model for such an evaluation, and provide baseline qualitative data on the role of private cars in health and wellbeing.Nine group interviews with young people aged 16-23 (N = 43) and two group interviews with parents of young people (N = 8) were conducted in a range of settings in Northern Ireland in 2015. Data were analysed using thematic content analysis.	Informal car-pooling within and beyond households led to routine expectations of lift provision and uptake. Experiences of risky driving situations were widespread. In rural areas, extensive use of farm vehicles for transport needs meant many learner drivers had both early driving experience and expectations that legislation may have to be locally adapted to meet social needs. Cars were used as a site for socialising, as well as essential means of transport. Alternative modes (public transport, walking and cycling) were held in low esteem, even where available. Recall of other transport-related public health messages and parents' existing use of GDL-type restrictions suggested GDL schemes were acceptable in principle. There was growing awareness and use of in-car technologies (telematics) used by insurance companies to reward good driving.	Key issues to consider in evaluating the broader public health impact of GDL will include: changes in injury rates for licensed car occupants and other populations and modes; changes in exposure to risk in the licensed and general population; and impact on transport exclusion. We suggest an important pathway will be change in social norms around offering and accepting lifts and to risk-taking. The growing adoption of in-car telematics will have implications for future GDL programmes and for evaluation.	
28591584	Natural and drug rewards increase the motivational valence of stimuli in the environment that, through Pavlovian learning mechanisms, become conditioned stimuli that directly motivate behavior in the absence of the original unconditioned stimulus. While the hippocampus has received extensive attention for its role in learning and memory processes, less is known regarding its role in drug-reward associations. We used in vivo Ca2+ imaging in freely moving mice during the formation of nicotine preference behavior to examine the role of the dorsal-CA1 region of the hippocampus in encoding contextual reward-seeking behavior. We show the development of specific neuronal ensembles whose activity encodes nicotine-reward contextual memories and that are necessary for the expression of place preference. Our findings increase our understanding of CA1 hippocampal function in general and as it relates to reward processing by identifying a critical role for CA1 neuronal ensembles in nicotine place preference.
28585192	Ribosomal s6 kinase 2 is a growth factor activated serine/threonine kinase and member of the ERK signaling pathway. Mutations in the Rsk2 gene cause Coffin-Lowry syndrome, a rare syndromic form of intellectual disability. The Rsk2 KO mouse model was shown to have learning and memory defects. We focused on the investigation of the emotional behavioral phenotype of Rsk2 KO mice mainly in the IntelliCage. They exhibited an anti-depressive, sucrose reward seeking phenotype and showed reduced anxiety. Spontaneous activity was increased in some conventional tests. However, KO mice did not show defects in place learning, working memory and motor impulsivity. In addition, we found changes of the monoaminergic system in HPLC and qRT-PCR experiments. Taken together, RSK2 not only plays a role in cognitive processes but also in emotional and reward-related behaviors.
28585020	In this functional magnetic resonance imaging (fMRI) study we examined neural processing of infant faces associated with a happy or a sad temperament in nulliparous women. We experimentally manipulated adult perception of infant temperament in a probabilistic learning task. In this task, participants learned about an infant's temperament through repeated pairing of the infant face with positive or negative facial expressions and vocalizations. At the end of the task, participants were able to differentiate between "mostly sad" infants who cried often and "mostly happy" infants who laughed often. Afterwards, brain responses to neutral faces of infants with a happy or a sad temperament were measured with fMRI and compared to brain responses to neutral infants with no temperament association. Our findings show that a brief experimental manipulation of temperament can change brain responses to infant signals. We found increased amygdala connectivity with frontal regions and the visual cortex, including the occipital fusiform gyrus, during the perception of infants with a happy temperament. In addition, amygdala connectivity was positively related to the post-manipulation ratings of infant temperament, indicating that amygdala connectivity is involved in the encoding of the rewarding value of an infant with a happy temperament.
28585018	Prior research has shown that the ratio between resting-state theta (4-7 Hz)-beta (13-30 Hz) oscillations in the electroencephalogram (EEG) is associated with reward- and punishment-related feedback learning and risky decision making. However, it remains unclear whether the theta/beta EEG ratio is also an electrophysiological index for poorer behavioral adaptation when reward and punishment contingencies change over time. The aim of the present study was to investigate whether resting-state theta (4-7 Hz)-beta (13-30 Hz) EEG ratio correlated with reversal learning. A 4-min resting-state EEG was recorded and a gambling task with changing reward-punishment contingencies was administered in 128 healthy volunteers. Results showed an inverse relationship between theta/beta EEG ratio and reversal learning. Our findings replicate and extend previous findings by showing that higher midfrontal theta/beta EEG ratios are associated with poorer reversal learning and behavioral adaptive responses under changing environmental demands.
28584955	Recent studies of visual search suggest that learning about valued outcomes (rewards and punishments) influences the likelihood that distractors will capture spatial attention and slow search for a target, even when those value-related distractors have never themselves been the targets of search. In the present study, we demonstrated a related effect in the context of temporal, rather than spatial, selection. Participants were presented with a temporal stream of pictures in a fixed central location and had to identify the orientation of a rotated target picture. Response accuracy was reduced if the rotated target was preceded by a "valued" distractor picture that signaled that a correct response to the target would be rewarded (and an incorrect response punished), relative to a distractor picture that did not signal reward or punishment. This effect of signal value on response accuracy was short-lived, being most prominent with a short lag between distractor and target. Impairment caused by a valued distractor was observed if participants were explicitly instructed regarding its relation to reward/punishment (Exps. 1, 3, and 4), or if they could learn this relationship only via trial-by-trial experience (Exp. 2). These findings show that the influence of signal value on attentional capture extends to temporal selection, and also demonstrate that value-related distractors can interfere with the conscious perception of subsequent target information.
28584929	Drug addiction can be described as aberrant allocation of effort toward acquiring drug, despite associated costs. It is unclear if this behavioral pattern results from an overvaluation of reward or to an altered sensitivity to costs.Present experiments assessed reward sensitivity and effortful choice in rats following 1 week of withdrawal from methamphetamine (mAMPH).	Rats were treated with either saline or an escalating dose mAMPH regimen, then tested after a week without the drug. In experiment 1, rats were given a free choice between water and various concentrations of sucrose solution to assess general reward sensitivity. In experiment 2, rats were presented with a choice between lever-pressing for sucrose pellets on a progressive ratio schedule or consuming freely-available chow.	In experiment 1, we found no differences in sucrose preference between mAMPH- and saline-pretreated rats. In experiment 2, when selecting between two options, mAMPH-pretreated rats engaged in less lever-pressing for sucrose pellets (p < 0.01) and switched from this preferred reward to the chow sooner than saline-pretreated rats (p < 0.05). This effect was not consistent with general reward devaluation or loss of motivation.	These findings demonstrate that mAMPH exposure and withdrawal lead to steeper discounting of reward value by effort, an effect that is consistent with the effect of mAMPH on discounting by delay, and which may reflect an underlying shared mechanism.	
28581478	How does experience inform decisions? In episodic sampling, decisions are guided by a few episodic memories of past choices. This process can yield choice patterns similar to model-free reinforcement learning; however, samples can vary from trial to trial, causing decisions to vary. Here we show that context retrieved during episodic sampling can cause choice behavior to deviate sharply from the predictions of reinforcement learning. Specifically, we show that, when a given memory is sampled, choices (in the present) are influenced by the properties of other decisions made in the same context as the sampled event. This effect is mediated by fMRI measures of context retrieval on each trial, suggesting a mechanism whereby cues trigger retrieval of context, which then triggers retrieval of other decisions from that context. This result establishes a new avenue by which experience can guide choice and, as such, has broad implications for the study of decisions.
28580231	Hormones and neuropeptides represent biological correlates of internal homeostatic signals detected and integrated in the hypothalamus, which establishes a robust functional connection with the ventral tegmental area (VTA). The hypothalamus-VTA connection determines the ability of these signals to influence central dopaminergic neurotransmission and, therefore, their ability to increase responsiveness to their reward-associated stimuli and to establish appropriate associative learning. The hypothalamus also provides the main source of the multiple neuropeptides that are released in the VTA. With volume transmission of neuropeptides and hormones, extrasynaptic receptors within the VTA provide a fine-tune mechanism, which depends on the ability of molecularly different G protein-coupled receptors (GPCRs) to form heteromers. GPCR heteromer is defined as a macromolecular complex composed of at least two different receptor units (protomers) with biochemical properties that are demonstrably different from those of its individual components. GPCR heteromers can provide unique allosteric properties to specific ligands, which provides new avenues for drug development. We have identified specific GPCR heteromers in the VTA that integrate orexin and CRF neurotransmission and opioid and galanin neurotransmission, which play a very significant role in the modulation of dopaminergic neuronal activity and which can constitute targets for the treatment of loss of control of food intake and substance use disorders.

28579691	The role of prediction error (PE) in driving learning is well-established in fields such as classical and instrumental conditioning, reward learning and procedural memory; however, its role in human one-shot declarative encoding is less clear. According to one recent hypothesis, PE reflects the divergence between two probability distributions: one reflecting the prior probability (from previous experiences) and the other reflecting the sensory evidence (from the current experience). Assuming unimodal probability distributions, PE can be manipulated in three ways: (1) the distance between the mode of the prior and evidence, (2) the precision of the prior, and (3) the precision of the evidence. We tested these three manipulations across five experiments, in terms of peoples' ability to encode a single presentation of a scene-item pairing as a function of previous exposures to that scene and/or item. Memory was probed by presenting the scene together with three choices for the previously paired item, in which the two foil items were from other pairings within the same condition as the target item. In Experiment 1, we manipulated the evidence to be either consistent or inconsistent with prior expectations, predicting PE to be larger, and hence memory better, when the new pairing was inconsistent. In Experiments 2a-c, we manipulated the precision of the priors, predicting better memory for a new pairing when the (inconsistent) priors were more precise. In Experiment 3, we manipulated both visual noise and prior exposure for unfamiliar faces, before pairing them with scenes, predicting better memory when the sensory evidence was more precise. In all experiments, the PE hypotheses were supported. We discuss alternative explanations of individual experiments, and conclude the Predictive Interactive Multiple Memory Signals (PIMMS) framework provides the most parsimonious account of the full pattern of results.

28575505	Having a depressed mother is one of the strongest predictors for developing depression in adolescence. Given the role of aberrant reward processing in the onset and maintenance of depression, we examined the association between mothers' and their daughters' neural response to the anticipation of reward and loss. Fifteen non-depressed mothers with a history of recurrent depression and their never-disordered daughters, and 23 mothers without past or current depression and their never-disordered daughters, underwent fMRI while performing the monetary incentive delay (MID) task. To assess mother-daughter concordance, we first identified ROIs involved in the anticipation of reward and loss across all mother-daughter pairs. Within each of these ROIs, we examined the association between mothers' and daughters' neural response, and the interaction between group status and mothers' neural response in predicting daughters' neural response. We found a significant association between mothers' and daughters' putamen response to the anticipation of loss, regardless of mother's depression history. Furthermore, pubertal stage moderated the association between mother-daughter putamen concordance. Our findings suggest a unique role of the putamen in the maternal transmission of reward learning and have important implications for understanding disorders characterized by disturbances in reward learning and processing, such as major depression.
28575424	The lateral habenula plays a central role in reward and punishment processing and has been suggested to drive the cardinal symptom of anhedonia in depression. This hypothesis is largely based on observations of habenula hypermetabolism in animal models of depression, but the activity of habenula and its relationship with clinical symptoms in patients with depression remains unclear. High-resolution functional magnetic resonance imaging (fMRI) and computational modelling were used to investigate the activity of the habenula during a probabilistic reinforcement learning task with rewarding and punishing outcomes in 21 unmedicated patients with major depression and 17 healthy participants. High-resolution anatomical scans were also acquired to assess group differences in habenula volume. Healthy individuals displayed the expected activation in the left habenula during receipt of punishment and this pattern was confirmed in the computational analysis of prediction error processing. In depressed patients, there was a trend towards attenuated left habenula activation to punishment, while greater left habenula activation was associated with more severe depressive symptoms and anhedonia. We also identified greater habenula volume in patients with depression, which was associated with anhedonic symptoms. Habenula dysfunction may contribute to abnormal response to punishment in patients with depression, and symptoms such as anhedonia.
28572059	The attention system is shaped by reward history, such that learned reward cues involuntarily draw attention. Recent research has begun to uncover the neural mechanisms by which learned reward cues compete for attention, implicating dopamine (DA) signaling within the dorsal striatum. How these elevated priority signals develop in the brain during the course of learning is less well understood, as is the relationship between value-based attention and the experience of reward during learning. We hypothesized that the magnitude of the striatal DA response to reward during learning contributes to the development of a learned attentional bias towards the cue that predicted it, and examined this hypothesis using positron emission tomography with [11C]raclopride. We measured changes in dopamine release for rewarded versus unrewarded visual search for color-defined targets as indicated by the density and distribution of the available D2/D3 receptors. We then tested for correlations of individual differences in this measure of reward-related DA release to individual differences in the degree to which previously reward-associated but currently task-irrelevant stimuli impair performance in an attention task (i.e., value-driven attentional bias), revealing a significant relationship in the right anterior caudate. The degree to which reward-related DA release was right hemisphere lateralized was also predictive of later attentional bias. Our findings provide support for the hypothesis that value-driven attentional bias can be predicted from reward-related DA release during learning.
28561735	The lateral habenula (LHb) is believed to encode negative motivational values. It remains unknown how LHb neurons respond to various stressors and how learning shapes their responses. Here, we used fiber-photometry and electrophysiology to track LHb neuronal activity in freely-behaving mice. Bitterness, pain, and social attack by aggressors intensively excite LHb neurons. Aversive Pavlovian conditioning induced activation by the aversion-predicting cue in a few trials. The experience of social defeat also conditioned excitatory responses to previously neutral social stimuli. In contrast, fiber photometry and single-unit recordings revealed that sucrose reward inhibited LHb neurons and often produced excitatory rebound. It required prolonged conditioning and high reward probability to induce inhibition by reward-predicting cues. Therefore, LHb neurons can bidirectionally process a diverse array of aversive and reward signals. Importantly, their responses are dynamically shaped by learning, suggesting that the LHb participates in experience-dependent selection of behavioral responses to stressors and rewards.
28559955	A human's, or lower insects', behavior is dominated by its nervous system. Each stable behavior has its own inner steps and control rules, and is regulated by a neural circuit. Understanding how the brain influences perception, thought, and behavior is a central mandate of neuroscience. The phototactic flight of insects is a widely observed deterministic behavior. Since its movement is not stochastic, the behavior should be dominated by a neural circuit. Based on the basic firing characteristics of biological neurons and the neural circuit's constitution, we designed a plausible neural circuit for this phototactic behavior from logic perspective. The circuit's output layer, which generates a stable spike firing rate to encode flight commands, controls the insect's angular velocity when flying. The firing pattern and connection type of excitatory and inhibitory neurons are considered in this computational model. We simulated the circuit's information processing using a distributed PC array, and used the real-time average firing rate of output neuron clusters to drive a flying behavior simulation. In this paper, we also explored how a correct neural decision circuit is generated from network flow view through a bee's behavior experiment based on the reward and punishment feedback mechanism. The significance of this study: firstly, we designed a neural circuit to achieve the behavioral logic rules by strictly following the electrophysiological characteristics of biological neurons and anatomical facts. Secondly, our circuit's generality permits the design and implementation of behavioral logic rules based on the most general information processing and activity mode of biological neurons. Thirdly, through computer simulation, we achieved new understanding about the cooperative condition upon which multi-neurons achieve some behavioral control. Fourthly, this study aims in understanding the information encoding mechanism and how neural circuits achieve behavior control. Finally, this study also helps establish a transitional bridge between the microscopic activity of the nervous system and macroscopic animal behavior.
28559954	In this paper, an improved and much stronger RNH-QL method based on RBF network and heuristic Q-learning was put forward for route searching in a larger state space. Firstly, it solves the problem of inefficiency of reinforcement learning if a given problem's state space is increased and there is a lack of prior information on the environment. Secondly, RBF network as weight updating rule, reward shaping can give an additional feedback to the agent in some intermediate states, which will help to guide the agent towards the goal state in a more controlled fashion. Meanwhile, with the process of Q-learning, it is accessible to the underlying dynamic knowledge, instead of the need of background knowledge of an upper level RBF network. Thirdly, it improves the learning efficiency by incorporating the greedy exploitation strategy to train the neural network, which has been testified by the experimental results.
28559801	The striatum is an input channel of the basal ganglia and is well known to be involved in reward-based decision making and learning. At the macroscopic level, the striatum has been postulated to contain parallel functional modules, each of which includes neurons that perform similar computations to support selection of appropriate actions for different task contexts. At the single-neuron level, however, recent studies in monkeys and rodents have revealed heterogeneity in neuronal activity even within restricted modules of the striatum. Looking for generality in the complex striatal activity patterns, here we briefly survey several types of striatal activity, focusing on their usefulness for mediating behaviors. In particular, we focus on two types of behavioral tasks: reward-based tasks that use salient sensory cues and manipulate outcomes associated with the cues; and perceptual decision tasks that manipulate the quality of noisy sensory cues and associate all correct decisions with the same outcome. Guided by previous insights on the modular organization and general selection-related functions of the basal ganglia, we relate striatal activity patterns on these tasks to two types of computations: implementation of selection and evaluation. We suggest that a parsing with the selection/evaluation categories encourages a focus on the functional commonalities revealed by studies with different animal models and behavioral tasks, instead of a focus on aspects of striatal activity that may be specific to a particular task setting. We then highlight several questions in the selection-evaluation framework for future explorations.
28559792	We describe a low-cost system designed to document bodily movement and neural activity and deliver rewards to monkeys behaving freely in their home cage. An important application is to studying brain-machine interface (BMI) systems during free behavior, since brain signals associated with natural movement can differ significantly from those associated with more commonly used constrained conditions. Our approach allows for short-latency (<500 ms) reward delivery and behavior monitoring using low-cost off-the-shelf components. This system interfaces existing untethered recording equipment with a custom hub that controls a cage-mounted feeder. The behavior monitoring system uses a depth camera to provide real-time, easy-to-analyze, gross movement data streams. In a proof-of-concept experiment we demonstrate robust learning of neural activity using the system over 14 behavioral sessions.
28559307	Rewards are known to influence neural activity associated with both motor preparation and execution. This influence can be exerted directly upon the primary motor (M1) and somatosensory (S1) cortical areas via the projections from reward-sensitive dopaminergic neurons of the midbrain ventral tegmental areas. However, the neurophysiological manifestation of reward-related signals in M1 and S1 are not well understood. Particularly, it is unclear how the neurons in these cortical areas multiplex their traditional functions related to the control of spatial and temporal characteristics of movements with the representation of rewards. To clarify this issue, we trained rhesus monkeys to perform a center-out task in which arm movement direction, reward timing, and magnitude were manipulated independently. Activity of several hundred cortical neurons was simultaneously recorded using chronically implanted microelectrode arrays. Many neurons (9-27%) in both M1 and S1 exhibited activity related to reward anticipation. Additionally, neurons in these areas responded to a mismatch between the reward amount given to the monkeys and the amount they expected: A lower-than-expected reward caused a transient increase in firing rate in 60-80% of the total neuronal sample, whereas a larger-than-expected reward resulted in a decreased firing rate in 20-35% of the neurons. Moreover, responses of M1 and S1 neurons to reward omission depended on the direction of movements that led to those rewards. These observations suggest that sensorimotor cortical neurons corepresent rewards and movement-related activity, presumably to enable reward-based learning.
28559224	Behavioral economics has stimulated renewed interest in financial health incentives worldwide. The Carrot Rewards app was developed as part of a public-private partnership to reward Canadians with loyalty points (eg, movies and groceries) for downloading the app, referring friends, and completing an average of 1 to 2 educational health quizzes per week ("micro-learning"), with long-term objectives of increasing health knowledge and encouraging healthy behaviors.The main objective of this study was to evaluate uptake of a loyalty points-based mHealth app during the exclusive 3-month launch period in British Columbia (BC), Canada. The secondary aims were to describe the health and sociodemographic characteristics of users, as well as participation levels (eg, proportion of quizzes completed and friends referred).	The app was promoted via loyalty program email campaigns (1.64 million emails). Number of downloads and registrations (users enter age, gender, and valid BC postal code to register) were collected. Additional sociodemographics were inferred by linking postal codes with census data at the local health area (LHA) level. Health risk assessments were also deployed. Participation levels were collected over 3 months and descriptive data were presented.	In 3 months, 67,464 individuals downloaded the app; in its first week, Carrot Rewards was the most downloaded health app in Canada. Among valid users (n=57,885; at least one quiz completed), the majority were female (62.96%; 36,446/57,885) and aged 18 to 34 years (54.34%; 31,459/57,885). More than half of the users (52.40%; 30,332/57,885) resided in LHAs where the median personal income was below the provincial average (Can $28,765). Furthermore, 64.42% (37,291/57,885) of users lived in metropolitan (ie, urban) LHAs, compared with 56.17% of the general BC population. The most prevalent risk factors were "not" meeting physical activity guidelines (72.70%; 31,765/43,692) and "not" getting the flu shot last year (67.69%; 30,286/44,739). Regarding participation, 60.05% (34,761/57,885) of users were classified as "very high" engagers (>75% quiz completion rate).	Early results suggest that loyalty points may promote mHealth app uptake. The app was downloaded by younger females especially, and BC residents from higher and lower income regions were equally represented. Loyalty points appear to have driven participation throughout the inaugural 3-month period (ie, quiz completion).	
28555096	HIGHLIGHTS Blockade of dopamine D1 receptors in ACC suppressed instrumental learning when overt responding was required.Covert learning through observation was not impaired.After treatment with a dopamine antagonist, instrumental learning recovered but not the rat's pretreatment level of effort tolerance.ACC dopamine is not necessary for acquisition of task-relevant cues during learning, but regulates energy expenditure and effort based decision. Dopamine activity in anterior cingulate cortex (ACC) is essential for various aspects of instrumental behavior, including learning and effort based decision making. To dissociate learning from physical effort, we studied both observational (covert) learning, and trial-and-error (overt) learning. If ACC dopamine activity is required for task acquisition, its blockade should impair both overt and covert learning. If dopamine is not required for task acquisition, but solely for regulating the willingness to expend effort for reward, i.e., effort tolerance, blockade should impair overt learning but spare covert learning. Rats learned to push a lever for food rewards either with or without prior observation of an expert conspecific performing the same task. Before daily testing sessions, the rats received bilateral ACC microinfusions of SCH23390, a dopamine D1 receptor antagonist, or saline-control infusions. We found that dopamine blockade suppressed overt responding selectively, leaving covert task acquisition through observational learning intact. In subsequent testing sessions without dopamine blockade, rats recovered their overt-learning capacity but not their pre-treatment level of effort tolerance. These results suggest that ACC dopamine is not required for the acquisition of conditioned behaviors and that apparent learning impairments could instead reflect a reduced level of willingness to expend effort due to cortical dopamine blockade.
28554687	Many mammalian species, including humans, exhibit social behavior and form complex social groups. Mechanistic studies in animal models have revealed important roles for the endocannabinoid signaling system, comprising G protein-coupled cannabinoid receptors and their endogenous lipid-derived agonists, in the control of neural processes that underpin social anxiety and social reward, two key aspects of social behavior. An emergent insight from these studies is that endocannabinoid signaling in specific circuits of the brain is context dependent and selectively recruited. These insights open new vistas on the neural basis of social behavior and social impairment.
28552600	Recent rodent studies have demonstrated that parental cocaine exposure can influence offspring behavior, supporting the idea that environmental insults can impact subsequent generations. However, studies on the effects of paternal cocaine exposure are limited and multiple inconsistencies exist. In the current study, we behaviorally characterize the effects of paternal cocaine exposure in a C57BL/6J intergenerational mouse model. Male sires were administered cocaine hydrochloride (20mg/kg) or saline (0.01mL/g) once a day for 75days, and bred with drug naïve females twenty-four hours after the final injection. Offspring, separated by sex, were tested in a battery of behaviors. We found that paternal cocaine exposure altered sensitivity to the rewarding and stimulant effects of psychostimulants and natural reward (sucrose) in female offspring; female cocaine-sired offspring showed blunted cocaine preference using cocaine conditioned place preference (CPP) at a low dose (5mg/kg), but displayed similar preference at a higher dose (10mg/kg) compared to saline-sired controls. Additionally, cocaine-sired female offspring exhibited higher psychomotor sensitivity to cocaine (10mg/kg) and amphetamine (2mg/kg) and consumed more sucrose. Cocaine-sired males exhibited increased psychomotor effects of cocaine and amphetamine. Male offspring also displayed an anxiety-like phenotype. No effect of paternal cocaine exposure was observed on depressive-like, learning and memory or social behavior in male or female offspring. Collectively, our findings show that paternal, chronic cocaine exposure induces intergenerational behavioral effects in male and female offspring with greatest impact on sensitivity to psychostimulants and sucrose in females.
28549647	Judgement bias tests of animal affect and hence welfare assume that the animal's responses to ambiguous stimuli, which may herald positive or negative outcomes, are under instrumental control and reflect 'optimism' or 'pessimism' about what will happen. However, Pavlovian control favours responses (e.g. approach or withdrawal) according to the valence associated with a stimulus, rather than the anticipated response outcomes. Typically, positive contexts promote action and approach whilst negative contexts promote inhibition or withdrawal. The prevalence of Go-for-reward (Go-pos) and NoGo-to-avoid-punishment (NoGo-neg) judgement bias tasks reflects this Pavlovian influence. A Pavlovian increase or decrease in activity or vigour has also been argued to accompany positive or negative affective states, and this may interfere with instrumental Go or NoGo decisions under ambiguity based on anticipated decision outcomes. One approach to these issues is to develop counter-balanced Go-pos/NoGo-neg and Go-neg/NoGo-pos tasks. Here we implement such tasks in Sprague Dawley rats and C57BL/6J mice using food and air-puff as decision outcomes. We find striking species/strain differences with rats achieving criterion performance on the Go-pos/NoGo-neg task but failing to learn the Go-neg/NoGo-pos task, in line with predictions, whilst mice do exactly the opposite. Pavlovian predispositions may thus differ between species, for example reflecting foraging and predation ecology and/or baseline activity rates. Learning failures are restricted to cues predicting a negative outcome; use of a more powerful air-puff stimulus may thus allow implementation of a fully counter-balanced task. Rats and mice achieve criterion faster than in comparable automated tasks and also show the expected generalisation of responses across ambiguous tones. A fully counter-balanced task thus offers a potentially rapidly implemented and automated method for assessing animal welfare, identifying welfare problems and areas for welfare improvement and 3Rs Refinement, and assessing the effectiveness of refinements.
28542639	L-Lactate (LL) is an essential cellular metabolite which can be used to generate energy. In addition, accumulating evidence suggests that LL is used for inter-cellular signalling. Some LL-sensitive receptors have been identified but we recently proposed that there may be yet another unknown G-protein coupled receptor (GPCR) sensitive to LL in the brain. Olfactory receptors (ORs) represent the largest family of GPCRs and some of them are expressed outside the olfactory system, including brain, making them interesting candidates for non-olfactory LL signalling. One of the "ectopically" expressed ORs, Olfr78 in mice (Olr59 in rats and OR51E2 in humans), reportedly can be activated by LL. This implies that both rodents and humans should be able to detect the LL odour. Surprisingly, this has never been demonstrated. Here we show that mice can detect the odour of LL in odour detection and habituation-dishabituation tasks, and discriminate it from peppermint and vanilla odours. Behaviour of the Olfr78 null mice and wildtype mice in odour detection task was not different, indicating that rodents are equipped with more than one LL-sensitive OR. Rats were also able to use the smell of LL as a cue in an odour-reward associative learning task. When presented to humans, more than 90% of participants detected a smell of LL in solution. Interestingly, LL was perceived differently than acetate or propionate-LL was preferentially reported as a pleasant sweet scent while acetate and propionate were perceived as repulsive sour/acid smells. Subjective perception of LL smell was different in men and women. Taken together, our data demonstrate that both rodents and humans are able to detect the odour of LL. Moreover, in mice, LL perception is not purely mediated by Olfr78. Discovery of further LL-sensitive OR might shed the light on their contribution to LL signalling in the body.
28541078	The orbitofrontal cortex (OFC) has long been implicated in the ability to use the current value of expected outcomes to guide behavior. More recently, this specific role has been conceptualized as a special case of a more general function that OFC plays in constructing a "cognitive map" of the behavioral task space by labeling the current task state and learning relationships among task states. Here, we have used single unit recording data from 2 prior studies to examine whether and how information relating different states within and across trials is represented in medial versus lateral OFC in rats. Using a hierarchical clustering analysis, we examined how neurons from each area represented information about differently valued trial types, defined by the cue-outcome pairings, versus how those same neurons represented information about similar epochs between these different trial types, such as the stimulus sample, delay, and reward consumption epochs. This analysis revealed that ensembles in the lateral OFC (lOFC) group states according to trial epoch, whereas those in the medial OFC (mOFC) organize the same states by trial type. These results suggest that the lOFC and mOFC construct cognitive maps that emphasize different features of the behavioral landscape, with lOFC tracking events based on local similarities, irrespective of their values and mOFC tracking more distal or higher order relationships relevant to value. (PsycINFO Database Record
28541056	Animal social learning is typically studied experimentally by the presentation of artificial foraging tasks. Although productive, results are often variable even for the same species. We present and test the hypothesis that one cause of variation is that spatial distance between rewards and the means of reward release causes conflicts for participants' attentional focus. We investigated whether spatial contiguity between a visible reward and the means of release would affect behavioral responses that evidence social learning, testing 21 brown capuchins (Sapajus apella), a much-studied species with variant evidence for social learning, and one hundred eighty 2- to 4-year-old human children (Homo sapiens), a benchmark species known for a strong social learning disposition. Participants were presented with a novel transparent apparatus where a reward was either proximal or distal to a demonstrated means of releasing it. A distal reward location decreased attention toward the location of the demonstration and impaired subsequent success in gaining rewards. Generally, the capuchins produced the alternative method to that demonstrated, whereas children copied the method demonstrated, although a distal reward location reduced copying in younger children. We conclude that some design features in common social learning tasks may significantly degrade the evidence for social learning. We have demonstrated this for 2 different primates but suggest that it is a significant factor to control for in social learning research across all taxa. (PsycINFO Database Record
28539425	Visual attentional selection is influenced by the value of objects. Previous studies have demonstrated that reward-associated items lead to rapid distraction and associated behavioral costs, which are difficult to override with top-down control. However, it has not been determined whether a perceptually competitive environment could render the reward-driven distraction more susceptible to top-down suppression. Here, we trained both genders of human subjects to associate two orientations with high and low magnitudes of reward. After training, we collected fMRI data while the subjects performed a categorical visual search task. The item in the reward-associated orientation served as the distractor, and the relative physical salience between the target and distractor was carefully controlled to modulate the degree of perceptual competition. The behavioral results showed faster searches in the presence of high, relative to low, reward-associated distractors. However, this effect was evident only if the physical salience of the distractor was higher than that of the target, indicating a context-dependent suppression effect of reward salience that relied on high perceptual competition. By analyzing the fMRI data in primary visual cortex, we found that the behavioral pattern of results could be predicted by the suppressed channel responses tuned to the reward-associated orientation in the distractor location, accompanied by increased responses in the midbrain dopaminergic region. Our results suggest that the learned salience of a reward plays a flexible role in solving perceptual competition, enabling the neural system to adaptively modulate the perceptual representation for behavioral optimization.SIGNIFICANCE STATEMENT The predictiveness principle in learning theory suggests that the stimulus with high predictability of reward receives priority in attentional selection. This selection bias leads to difficulties in changing approach behaviors, and thus becomes an important factor related to psychiatric disorders with attentional deficits. Here, we demonstrated that such principle is adaptively implemented in attentional suppression in visual search. We showed that the learned salience induced the suppression of the reward-associated distractor if its competition with the target was strong and could not be readily solved. This behavioral pattern was accompanied by increased midbrain fMRI activity and weakened sensory representation of the reward-associated distractor in V1. Our findings provided direct evidence that our brain flexibly uses learned regularities in attentional control.
28539420	Instrumental learning is a fundamental process through which agents optimize their choices, taking into account various dimensions of available options such as the possible reward or punishment outcomes and the costs associated with potential actions. Although the implication of dopamine in learning from choice outcomes is well established, less is known about its role in learning the action costs such as effort. Here, we tested the ability of patients with Parkinson's disease (PD) to maximize monetary rewards and minimize physical efforts in a probabilistic instrumental learning task. The implication of dopamine was assessed by comparing performance ON and OFF prodopaminergic medication. In a first sample of PD patients (n = 15), we observed that reward learning, but not effort learning, was selectively impaired in the absence of treatment, with a significant interaction between learning condition (reward vs effort) and medication status (OFF vs ON). These results were replicated in a second, independent sample of PD patients (n = 20) using a simplified version of the task. According to Bayesian model selection, the best account for medication effects in both studies was a specific amplification of reward magnitude in a Q-learning algorithm. These results suggest that learning to avoid physical effort is independent from dopaminergic circuits and strengthen the general idea that dopaminergic signaling amplifies the effects of reward expectation or obtainment on instrumental behavior.SIGNIFICANCE STATEMENT Theoretically, maximizing reward and minimizing effort could involve the same computations and therefore rely on the same brain circuits. Here, we tested whether dopamine, a key component of reward-related circuitry, is also implicated in effort learning. We found that patients suffering from dopamine depletion due to Parkinson's disease were selectively impaired in reward learning, but not effort learning. Moreover, anti-parkinsonian medication restored the ability to maximize reward, but had no effect on effort minimization. This dissociation suggests that the brain has evolved separate, domain-specific systems for instrumental learning. These results help to disambiguate the motivational role of prodopaminergic medications: they amplify the impact of reward without affecting the integration of effort cost.
28539416	The infralimbic cortex (IL) mediates extinction learning and the active suppression of cocaine-seeking behavior. However, the precise temporal relationship among IL activity, lever pressing, and extinction learning is unclear. To address this issue, we used activity-guided optogenetics in male Sprague Dawley rats to silence IL pyramidal neurons optically for 20 s immediately after unreinforced lever presses during early extinction training after cocaine self-administration. Optical inhibition of the IL increased active lever pressing during shortened extinction sessions, but did not alter the retention of the extinction learning as assessed in ensuing extinction sessions with no optical inhibition. During subsequent cued reinstatement sessions, rats that had previously received optical inhibition during the extinction sessions showed increased cocaine-seeking behavior. These findings appeared to be specific to inhibition during the post-lever press period because IL inhibition given in a noncontingent, pseudorandom manner during extinction sessions did not produce the same effects. Illumination alone (i.e., with no opsin expression) and food-seeking control experiments also failed to produce the same effects. In another experiment, IL inhibition after lever presses during cued reinstatement sessions increased cocaine seeking during those sessions. Finally, inhibition of the prelimbic cortex immediately after unreinforced lever presses during shortened extinction sessions decreased lever pressing during these sessions, but had no effect on subsequent reinstatement. These results indicate that IL activity immediately after unreinforced lever presses is necessary for normal extinction of cocaine seeking, suggesting that critical encoding of the new contingencies between a lever press and a cocaine reward occurs during that period.SIGNIFICANCE STATEMENT The infralimbic cortex (IL) contributes to the extinction of cocaine-seeking behavior, but the precise relationship among IL activity, lever pressing during extinction, and extinction learning has not been elucidated using traditional methods. Using a closed-loop optogenetic approach, we found that selective inhibition of the IL immediately after unreinforced lever pressing impaired within-session extinction learning and promoted the subsequent cued reinstatement of cocaine seeking. These studies suggest that IL activity immediately after the instrumental response during extinction learning of cocaine seeking encodes information required for such learning and that altering such activity produces long-lasting changes in subsequent measures of cocaine craving/relapse.
28536513	Neuronal firing in the substantia nigra (SN) immediately following reward is thought to play a crucial role in human reinforcement learning. As in Ramayya et al. (2014a) we applied microstimulation in the SN of patients undergoing deep brain stimulation (DBS) for the treatment of Parkinson's disease as they engaged in a two-alternative reinforcement learning task. We obtained microelectrode recordings to assess the proximity of the electrode tip to putative dopaminergic and GABAergic SN neurons and applied stimulation to assess the functional importance of these neuronal populations for learning. We found that the proximity of SN microstimulation to putative GABAergic neurons predicted the degree of stimulation-related changes in learning. These results extend previous work by supporting a specific role for SN GABA firing in reinforcement learning. Stimulation near these neurons appears to dampen the reinforcing effect of rewarding stimuli.
28536046	Learning of prediction error (PE), including reward PE and risk PE, is crucial for updating the prediction in reinforcement learning (RL). Neurobiological and computational models of RL have reported extensive brain activations related to PE. However, the occurrence of PE does not necessarily predict updating the prediction, e.g., in a probability-known event. Therefore, the brain regions specifically engaged in updating the prediction remain unknown. Here, we conducted two functional magnetic resonance imaging (fMRI) experiments, the probability-unknown Iowa Gambling Task (IGT) and the probability-known risk decision task (RDT). Behavioral analyses confirmed that PEs occurred in both tasks but were only used for updating the prediction in the IGT. By comparing PE-related brain activations between the two tasks, we found that the rostral anterior cingulate cortex/ventral medial prefrontal cortex (rACC/vmPFC) and the posterior cingulate cortex (PCC) activated only during the IGT and were related to both reward and risk PE. Moreover, the responses in the rACC/vmPFC and the PCC were modulated by uncertainty and were associated with reward prediction-related brain regions. Electric brain stimulation over these regions lowered the performance in the IGT but not in the RDT. Our findings of a distributed neural circuit of PE processing suggest that the rACC/vmPFC and the PCC play a key role in updating the prediction through PE processing during decision making.
28521266	Although impaired reward processing in depression has been well-documented, the exact nature of that deficit remains poorly understood. To investigate the link between depression and the neural mechanisms of reward processing, we examined individual differences in personality.We recorded the electroencephalogram from healthy college students engaged in a probabilistic reinforcement learning task. Participants also completed several personality questionnaires that assessed traits related to reward sensitivity, motivation, and depression. We examined whether behavioral measures of reward learning and event-related potential components related to outcome processing and reward anticipation-namely, the cue and feedback-related reward positivity (RewP) and the stimulus preceding negativity (SPN)-would link these personality traits to depression.	Participants who scored high in reward sensitivity produced a relatively larger feedback-RewP. By contrast, participants who scored high in depression learned the contingencies for infrequently rewarded cue-response combinations relatively poorly, exhibited a larger SPN, and produced a smaller feedback-RewP, especially to outcomes following cue-response combinations that were frequently rewarded.	These results point to a primary deficit in reward valuation in individuals who score high in depression, with secondary consequences that impact reward learning and anticipation.	Despite recent evidence arguing for an anticipatory deficit in depression, impaired reward valuation as a primary deficit should be further examined in clinical samples.	
28512323	Many plants defend themselves against herbivores by chemical deterrents in their tissues and the presence of such substances in floral nectar means that pollinators often encounter them when foraging. The effect of such substances on the foraging behaviour of pollinators is poorly understood. Using artificial flowers in tightly-controlled laboratory settings, we examined the effects of the alkaloid nicotine on bumblebee foraging performance. We found that bumblebees confronted simultaneously with two equally rewarded nicotine-containing and nicotine-free flower types are deterred only by unnaturally high nicotine concentrations. This deterrence disappears or even turns into attraction at lower nectar-relevant concentrations. The alkaloid has profound effects on learning in a dose-dependent manner. At a high natural dose, bees learn the colour of a nicotine-containing flower type more swiftly than a flower type with the same caloric value but without nicotine. Furthermore, after experiencing flowers containing nicotine in any tested concentration, increasing numbers of bumblebees stay more faithful to these flowers, even if they become a suboptimal choice in terms of reward. These results demonstrate that alkaloids enhance pollinator flower constancy, opening new perspectives in co-evolutionary process between plants and pollinators.
28512009	Appetitive Pavlovian conditioning plays a crucial role in the pathogenesis of drug addiction and conditioned reward cues can trigger craving and relapse even after long phases of abstinence. Promising preclinical work showed that the NMDA-receptor partial agonist D-cycloserine (DCS) facilitates Pavlovian extinction learning of fear and drug cues. Furthermore, DCS-augmented exposure therapy seems to be beneficial in various anxiety disorders, while the supposed working mechanism of DCS during human appetitive or aversive extinction learning is still not confirmed. To test the hypothesis that DCS administration before extinction training improves extinction learning, healthy adults (n=32) underwent conditioning, extinction, and extinction recall on three successive days in a randomized, double-blind, placebo-controlled fMRI design. Monetary wins and losses served as unconditioned stimuli during conditioning to probe appetitive and aversive learning. An oral dose of 50mg of DCS or placebo was administered 1h before extinction training and DCS effects during extinction recall were evaluated on a behavioral and neuronal level. We found attenuated amygdala activation in the DCS compared to the placebo group during recall of the extinguished appetitive cue, along with evidence for enhanced functional amygdala-vmPFC coupling in the DCS group. While the absence of additional physiological measures of conditioned responses during recall in this study prevent the evaluation of a behavioral DCS effect, our neuronal findings are in accordance with recent theories linking successful extinction recall in humans to modulatory top-down influences from the vmPFC that inhibit amygdala activation. Our results should encourage further translational studies concerning the usefulness of DCS to target maladaptive Pavlovian reward associations.
28508125	Biases in judgement of ambiguous stimuli, as measured in a judgement bias task, have been proposed as a measure of the valence of affective states in animals. We recently suggested a list of criteria for behavioural tests of emotion, one of them stating that responses on the task used to assess emotionality should not be confounded by, among others, differences in learning capacity, i.e. must not simply reflect the cognitive capacity of an animal. We performed three independent studies in which pigs acquired a spatial holeboard task, a free choice maze which simultaneously assesses working memory and reference memory. Next, pigs learned a conditional discrimination between auditory stimuli predicting a large or small reward, a prerequisite for assessment of judgement bias. Once pigs had acquired the conditional discrimination task, optimistic responses to previously unheard ambiguous stimuli were measured in the judgement bias task as choices indicating expectation of the large reward. We found that optimism in the judgement bias task was independent of all three measures of learning and memory indicating that the performance is not dependent on the pig's cognitive abilities. These results support the use of biases in judgement as proxy indicators of emotional valence in animals.
28506437	Stress is widely known to alter behavioral responses to rewards and punishments. It is believed that stress may precipitate these changes through modulation of corticostriatal circuitry involved in reinforcement learning and motivation, although the intervening mechanisms remain unclear. One candidate is inflammation, which can rapidly increase following stress and can disrupt dopamine-dependent reward pathways.Here, in a sample of 88 healthy female participants, we first assessed the effect of an acute laboratory stress paradigm on levels of plasma interleukin-6 (IL-6), a cytokine known to be both responsive to stress and elevated in depression. In a second laboratory session, we examined the effects of a second laboratory stress paradigm on reward prediction error (RPE) signaling in the ventral striatum.	We show that individual differences in stress-induced increases in IL-6 (session 1) were associated with decreased ventral striatal RPE signaling during reinforcement learning (session 2), though there was no main effect of stress on RPE. Furthermore, changes in IL-6 following stress predicted intraindividual variability in perceived stress during a 4-month follow-up period.	Taken together, these data identify a novel link between IL-6 and striatal RPEs during reinforcement learning in the context of acute psychological stress, as well as future appraisal of stressful life events.	
28505470	Elevated brain reward and attention region response, and weaker inhibitory region response to high-calorie food images have been found to predict future weight gain. These findings suggest that an intervention that reduces reward and attention region response and increases inhibitory control region response to such foods might reduce overeating. We conducted a randomized pilot experiment that tested the hypothesis that a multi-faceted food response and attention training with personalized high- and low-calorie food images would produce changes in behavioral and neural responses to food images and body fat compared to a control training with non-food images among community-recruited overweight/obese adults. Compared to changes observed in controls, completing the intervention was associated with significant reductions in reward and attention region response to high-calorie food images (Mean Cohen's d = 1.54), behavioral evidence of learning, reductions in palatability ratings and monetary valuation of high-calorie foods (p = 0.009, d's = 0.92), and greater body fat loss over a 4-week period (p = 0.009, d = 0.90), though body fat effects were not significant by 6-month follow-up. Results suggest that this multifaceted response and attention training intervention was associated with reduced reward and attention region responsivity to food cues, and a reduction in body fat. Because this implicit training treatment is both easy and inexpensive to deliver, and does not require top-down executive control that is necessary for negative energy balance obesity treatment, it may prove useful in treating obesity if future studies can determine how to create more enduring effects.
28504638	Catecholamines modulate the impact of motivational cues on action. Such motivational biases have been proposed to reflect cue-based, 'Pavlovian' effects. Here, we assess whether motivational biases may also arise from asymmetrical instrumental learning of active and passive responses following reward and punishment outcomes. We present a novel paradigm, allowing us to disentangle the impact of reward and punishment on instrumental learning from Pavlovian response biasing. Computational analyses showed that motivational biases reflect both Pavlovian and instrumental effects: reward and punishment cues promoted generalized (in)action in a Pavlovian manner, whereas outcomes enhanced instrumental (un)learning of chosen actions. These cue- and outcome-based biases were altered independently by the catecholamine enhancer melthylphenidate. Methylphenidate's effect varied across individuals with a putative proxy of baseline dopamine synthesis capacity, working memory span. Our study uncovers two distinct mechanisms by which motivation impacts behaviour, and helps refine current models of catecholaminergic modulation of motivated action.
28504254	The intake of water is important for the survival of all animals and drinking water can be used as a reward in thirsty animals. Here we found that thirsty Drosophila melanogaster can associate drinking water with an odour to form a protein-synthesis-dependent water-reward long-term memory (LTM). Furthermore, we found that the reinforcement of LTM requires water-responsive dopaminergic neurons projecting to the restricted region of mushroom body (MB) β' lobe, which are different from the neurons required for the reinforcement of learning and short-term memory (STM). Synaptic output from α'β' neurons is required for consolidation, whereas the output from γ and αβ neurons is required for the retrieval of LTM. Finally, two types of MB efferent neurons retrieve LTM from γ and αβ neurons by releasing glutamate and acetylcholine, respectively. Our results therefore cast light on the cellular and molecular mechanisms responsible for processing water-reward LTM in Drosophila.
28496402	Corticostriatal circuits through the orbitofrontal cortex (OFC) play key roles in complex human behaviors such as evaluation, affect regulation and reward-based decision-making. Importantly, the medial and lateral OFC (mOFC and lOFC) circuits have functionally and anatomically distinct connectivity profiles which differentially contribute to the various aspects of goal-directed behavior. OFC corticostriatal circuits have been consistently implicated across a wide range of psychiatric disorders, including major depressive disorder (MDD), obsessive compulsive disorder (OCD), and substance use disorders (SUDs). Furthermore, psychiatric disorders related to OFC corticostriatal dysfunction can be addressed via conventional and novel neurostimulatory techniques, including deep brain stimulation (DBS), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). Such techniques elicit changes in OFC corticostriatal activity, resulting in changes in clinical symptomatology. Here we review the available literature regarding how disturbances in mOFC and lOFC corticostriatal functioning may lead to psychiatric symptomatology in the aforementioned disorders, and how psychiatric treatments may exert their therapeutic effect by rectifying abnormal OFC corticostriatal activity. First, we review the role of OFC corticostriatal circuits in reward-guided learning, decision-making, affect regulation and reappraisal. Second, we discuss the role of OFC corticostriatal circuit dysfunction across a wide range of psychiatric disorders. Third, we review available evidence that the therapeutic mechanisms of various neuromodulation techniques may directly involve rectifying abnormal activity in mOFC and lOFC corticostriatal circuits. Finally, we examine the potential of future applications of therapeutic brain stimulation targeted at OFC circuitry; specifically, the role of OFC brain stimulation in the growing field of individually-tailored therapies and personalized medicine in psychiatry.
28495976	Salt appetite, in which animals can immediately seek out salt when under a novel state of sodium deprivation, is a classic example of how homeostatic systems interface with learned associations to produce an on-the-fly updating of motivated behavior. Neural activity in the ventral pallidum (VP) has been shown to encode changes in the value of salt under such conditions, both the value of salt itself (Tindell et al., 2006) and the motivational value of its predictive cues (Tindell et al., 2009; Robinson and Berridge, 2013). However, it is not known whether the VP is necessary for salt appetite in terms of seeking out salt or consuming salt following sodium depletion. Here, we used a conditioned place-preference procedure to investigate the effects of optogenetically inhibiting the VP on context-driven salt seeking and the consumption of salt following deprivation. Male rats learned to associate one context with sucrose and another context with less-desirable salt. Following sodium depletion, and in the absence of either sucrose or salt, we found that inhibiting the VP selectively reduced the elevation in time spent in the salt-paired context. VP inhibition had minimal effects on the consumption of salt once it was made available. To our knowledge, this is the first evidence that the VP or any brain region is necessary for the ability to use contextual cues to guide salt seeking. These results highlight a dissociation between deficit-driven reward seeking and reward consumption to replenish those deficits, with the former process being particularly sensitive to on-line VP activity.SIGNIFICANCE STATEMENT Salt appetite, in which rats will immediately seek out a once-undesirable concentrated salt solution after being depleted of bodily sodium despite never having tasted salt as a positive reward, is a phenomenon showing how animals can update their motivational goals without any new learning or conditioning. This salt-seeking behavior is also observed when the animal is presented with salt-paired cues. The neural circuitry necessary for context-driven salt-seeking behavior is unknown. We used a novel conditioned place preference procedure to show that optogenetic inhibition of the ventral pallidum (VP), a region known for processing reward, impairs context-driven salt seeking and has minimal effects on the consumption of salt itself following sodium depletion. These results highlight the importance of the VP in context-driven reward-seeking behavior.
28495493	Influential models of schizophrenia suggest that patients experience incoming stimuli as excessively novel and motivating, with important consequences for hallucinatory experience and delusional belief. However, whether schizophrenia patients exhibit excessive novelty value and whether this interferes with adaptive behaviour has not yet been formally tested. Here, we employed a three-armed bandit task to investigate this hypothesis. Schizophrenia patients and healthy controls were first familiarised with a group of images and then asked to repeatedly choose between familiar and unfamiliar images associated with different monetary reward probabilities. By fitting a reinforcement-learning model we were able to estimate the values attributed to familiar and unfamiliar images when first presented in the context of the decision-making task. In line with our hypothesis, we found increased preference for newly introduced images (irrespective of whether these were familiar or unfamiliar) in patients compared to healthy controls and this to correlate with severity of hallucinatory experience. In addition, we found a correlation between value assigned to novel images and task performance, suggesting that excessive novelty value may interfere with optimal learning in patients, putatively through the disruption of the mechanisms regulating exploration versus exploitation. Our results suggest excessive novelty value in patients, whereby even previously seen stimuli acquire higher value as the result of their exposure in a novel context - a form of 'hyper novelty' which may explain why patients are often attracted by familiar stimuli experienced as new.
28491495	Substance-dependent individuals often lack the ability to adjust decisions flexibly in response to the changes in reward contingencies. Prediction errors (PEs) are thought to mediate flexible decision-making by updating the reward values associated with available actions. In this study, we explored whether the neurobiological correlates of PEs are altered in alcohol dependence. Behavioral, and functional magnetic resonance imaging (fMRI) data were simultaneously acquired from 34 abstinent alcohol-dependent patients (ADP) and 26 healthy controls (HC) during a probabilistic reward-guided decision-making task with dynamically changing reinforcement contingencies. A hierarchical Bayesian inference method was used to fit and compare learning models with different assumptions about the amount of task-related information subjects may have inferred during the experiment. Here, we observed that the best-fitting model was a modified Rescorla-Wagner type model, the "double-update" model, which assumes that subjects infer the knowledge that reward contingencies are anti-correlated, and integrate both actual and hypothetical outcomes into their decisions. Moreover, comparison of the best-fitting model's parameters showed that ADP were less sensitive to punishments compared to HC. Hence, decisions of ADP after punishments were loosely coupled with the expected reward values assigned to them. A correlation analysis between the model-generated PEs and the fMRI data revealed a reduced association between these PEs and the BOLD activity in the dorsolateral prefrontal cortex (DLPFC) of ADP. A hemispheric asymmetry was observed in the DLPFC when positive and negative PE signals were analyzed separately. The right DLPFC activity in ADP showed a reduced correlation with positive PEs. On the other hand, ADP, particularly the patients with high dependence severity, recruited the left DLPFC to a lesser extent than HC for processing negative PE signals. These results suggest that the DLPFC, which has been linked to adaptive control of action selection, may play an important role in cognitive inflexibility observed in alcohol dependence when reinforcement contingencies change. Particularly, the left DLPFC may contribute to this impaired behavioral adaptation, possibly by impeding the extinction of the actions that no longer lead to a reward.
28490322	Patients with traumatic brain injury often have balance and attentive disorders. Video game therapy (VGT) has been proposed as a new intervention to improve mobility and attention through a reward-learning approach. In this pilot randomized, controlled trial, we tested the effects of VGT, compared with a balance platform therapy (BPT), on balance, mobility and selective attention in chronic traumatic brain injury patients.We enrolled chronic traumatic brain injury patients (n = 21) that randomly received VGT or BPT for 3 sessions per week for 6 weeks. The clinical outcome measures included: i) the Community Balance & Mobility Scale (CB&M); ii) the Unified Balance Scale (UBS); iii) the Timed Up and Go test (TUG); iv) static balance and v) selective visual attention evaluation (Go/Nogo task).	Both groups improved in CB&M scores, but only the VGT group increased on the UBS and TUG with a between-group significance (p < 0.05). Selective attention improved significantly in the VGT group (p < 0.01).	Video game therapy is an option for the management of chronic traumatic brain injury patients to ameliorate balance and attention deficits.	
28488135	Operant-conditioning boxes are widely used in animal training, allowing researchers to shape specific behaviors through reinforcements and/or punishments. Commercially available devices are expensive and run with proprietary software and hardware, hampering adaptations for the specific needs of an experiment. Therefore, many low-cost and open-source devices have recently been developed, but there are still few options for studying auditory behaviors. To overcome this problem, we developed a device based on a computer and an Arduino Mega 2560 board, named OBAT (Operant Box for Auditory Tasks), designed to present two different auditory stimuli to small primates. It has three modules: sound delivery, response bars, and reward system. We estimate that OBAT is at least 4-10 times cheaper than commercially available operant-conditioning boxes. Data from a behavioral pilot test ensured that the device can be used to train a marmoset in an auditory discrimination task. In addition, despite its low cost, accuracy tests showed that the OBAT operates with a high temporal precision. All schematics and software source code are available so that other groups can easily replicate the experiment or adapt the device to their own needs.
28488062	The incentive-sensitization theory posits that drug addiction results from altered learning and motivational processes that stem from drug-induced changes in the brain's reward circuitry. Although it is generally accepted that problematic drug use results from these neuroadaptations, less research has focused on how these neural changes affect the incentive-motivational properties of naturally rewarding stimuli such as sex. The present set of experiments was conducted to investigate (1) dose-dependent effects of preexposure to chronic cocaine on sexual conditioning and (2) how prior cocaine exposure affects the extinction of sexually conditioned behavior in male Japanese quail. In Experiment 1, male quail were exposed to saline or to cocaine (5, 10, or 20 mg/kg ip) for 10 days, and their locomotor activity was measured. After a washout period, ten sexual-conditioning trials were conducted in which a light (CS) was presented prior to the presentation of a female quail (US) and approach to the light was measured. The results showed that cocaine dose-dependently enhanced sexually conditioned approach behavior and copulation. Experiment 2 was procedurally similar to Experiment 1, except that the quail received either saline or 10 mg/kg cocaine (ip) and 24 extinction trials were conducted. During extinction, no female was presented after the CS. The results showed that preexposure to cocaine delayed extinction. Therefore, cocaine may dose-dependently increase the strength of sexual conditioning, and this may subsequently increase resistance to extinction. These findings and their possible mechanisms are explored.
28486526	When an otherwise inconspicuous stimulus is learned to predict a reward, this stimulus will automatically capture visual attention. This learned attentional bias is not specific to the precise object previously associated with reward, but can be observed for different stimuli that share a defining feature with the reward cue. Under certain circumstances, value-driven attentional biases can even transfer to new contexts in which the reward cues were not previously experienced, and can also be evident for different exemplars of a stimulus category, suggesting some degree of tolerance in the scope of the underlying bias. Whether a match to a reward-predictive feature is necessary to support value-driven attention, or whether similar-looking features also receive some degree of elevated priority following associative reward learning, remains an open question. Here, I examine the impact of learned associations between reward and red- and green-colored stimuli on the processing of other colors. The findings show that even though other colors experienced during training were non-predictive with respect to reward, the speed with which targets possessing these colors were identified in a subsequent test phase was affected by their similarity to the high-value color. Thus, value-driven attentional biases for stimulus features are imprecise, as would be predicted by a sensory gain model of value-driven attention.
28484738	The demonstration of the ability of rodents to navigate in virtual reality (VR) has made it an important behavioral paradigm for studying spatially modulated neuronal activity in these animals. However, their behavior in such simulated environments remains poorly understood. Here, we show that encoding and retrieval of goal location memory in mice head-fixed in VR depends on the postsynaptic scaffolding protein Shank2 and the dorsal hippocampus. In our newly developed virtual cued goal location task, a head-fixed mouse moves from one end of a virtual linear track to seek rewards given at a target location along the track. The mouse needs to visually recognize the target location and stay there for a short period of time to receive the reward. Transient pharmacological blockade of fast glutamatergic synaptic transmission in the dorsal hippocampus dramatically and reversibly impaired performance of this task. Encoding and updating of virtual cued goal location memory was impaired in mice deficient in the postsynaptic scaffolding protein Shank2, a mouse model of autism that exhibits impaired spatial learning in a real environment. These results highlight the crucial roles of the dorsal hippocampus and postsynaptic protein complexes in spatial learning and navigation in VR.
28484422	Psychotic symptoms frequently occur in Parkinson's disease (PD), but their pathophysiology is poorly understood. According to the National Institute of Health RDoc programme, the pathophysiological basis of neuropsychiatric symptoms may be better understood in terms of dysfunction of underlying domains of neurocognition in a trans-diagnostic fashion. Abnormal cortico-striatal reward processing has been proposed as a key domain contributing to the pathogenesis of psychotic symptoms in schizophrenia. This theory has received empirical support in the study of schizophrenia spectrum disorders and preclinical models of psychosis, but has not been tested in the psychosis associated with PD. We, therefore, investigated brain responses associated with reward expectation and prediction error signaling during reinforcement learning in PD-associated psychosis. An instrumental learning task with monetary gains and losses was conducted during an fMRI study in PD patients with (n = 12), or without (n = 17), a history of psychotic symptoms, along with a sample of healthy controls (n = 24). We conducted region of interest analyses in the ventral striatum (VS), ventromedial prefrontal and posterior cingulate cortices, and whole-brain analyses. There was reduced activation in PD patients with a history of psychosis, compared to those without, in the posterior cingulate cortex and the VS during reward anticipation (p < 0.05 small volume corrected). The results suggest that cortical and striatal abnormalities in reward processing, a putative pathophysiological mechanism of psychosis in schizophrenia, may also contribute to the pathogenesis of psychotic symptoms in PD. The finding of posterior cingulate dysfunction is in keeping with prior results highlighting cortical dysfunction in the pathogenesis of PD psychosis.
28481915	Reinforcement learning tasks are often used to assess participants' tendency to learn more from the positive or more from the negative consequences of one's action. However, this assessment often requires comparison in learning performance across different task conditions, which may differ in the relative salience or discriminability of the stimuli associated with more and less rewarding outcomes, respectively. To address this issue, in a first set of studies, participants were subjected to two versions of a common probabilistic learning task. The two versions differed with respect to the stimulus (Hiragana) characters associated with reward probability. The assignment of character to reward probability was fixed within version but reversed between versions. We found that performance was highly influenced by task version, which could be explained by the relative perceptual discriminability of characters assigned to high or low reward probabilities, as assessed by a separate discrimination experiment. Participants were more reliable in selecting rewarding characters that were more discriminable, leading to differences in learning curves and their sensitivity to reward probability. This difference in experienced reinforcement history was accompanied by performance biases in a test phase assessing ability to learn from positive vs. negative outcomes. In a subsequent large-scale web-based experiment, this impact of task version on learning and test measures was replicated and extended. Collectively, these findings imply a key role for perceptual factors in guiding reward learning and underscore the need to control stimulus discriminability when making inferences about individual differences in reinforcement learning.
28481903	Delay discounting-often referred to as hyperbolic discounting in the financial literature-is defined by a consistent preference for smaller, immediate rewards over larger, delayed rewards, and by failure of future consequences to curtail current consummatory behaviors. Previous research demonstrates (1) excessive delay discounting among individuals with attention-deficit/hyperactivity disorder (ADHD), (2) common neural substrates of delay discounting and hyperactive-impulsive symptoms of ADHD, and (3) associations between delay discounting and both debt burden and high interest rate borrowing. This study extends prior research by examining associations between ADHD symptoms, delay discounting, and an array of previously unevaluated financial outcomes among 544 individuals (mean age 35 years). Controlling for age, income, sex, education, and substance use, ADHD symptoms were associated with delay discounting, late credit card payments, credit card balances, use of pawn services, personal debt, and employment histories (less time spent at more jobs). Consistent with neural models of reward processing and associative learning, more of these relations were attributable to hyperactive-impulsive symptoms than inattentive symptoms. Implications for financial decision-making and directions for future research are discussed.
28480973	The Monty Hall Dilemma (MHD) poses a counterintuitive probabilistic problem to the players of this game. In the MHD task, a participant chooses one of three options where only one contains a reward. After one of the unchosen options (always no reward) is disclosed, the participant is asked to make a final decision: either change to the remaining option or stick with their first choice. Although the probability of winning if they change is higher (2/3) compared to sticking with their first choice (1/3), most people stick with their original selection and often lose. In accordance with previous research, repetitive exposure to the MHD task increases the change behavior without any obvious understanding of the mathematical reasons why changing increases their chance of being rewarded. We recorded the stimulus-preceding negativity (SPN), an ERP that might reflect the informative value of the feedback. In the second half of the task, feedback was predicted to be less informative because learning had taken place. Indeed, the SPN amplitude became smaller over the frontal region. Also, the SPN amplitude was larger for change than for stick trials. These results suggest that learning in the MHD might be manifest in affective-motivational anticipation as indicated by the SPN.
28480967	The spatial location of objects is processed in egocentric and allocentric reference frames, the early temporal dynamics of which have remained relatively unexplored. Previous experiments focused on ERP components related only to egocentric navigation. Thus, we designed a virtual reality experiment to see whether allocentric reference frame-related ERP modulations can also be registered. Participants collected reward objects at the end of the west and east alleys of a cross maze, and their ERPs to the feedback objects were measured. Participants made turn choices from either the south or the north alley randomly in each trial. In this way, we were able to discern place and response coding of object location. Behavioral results indicated a strong preference for using the allocentric reference frame and a preference for choosing the rewarded place in the next trial, suggesting that participants developed probabilistic expectations between places and rewards. We also found that the amplitude of the P1 was sensitive to the allocentric place of the reward object, independent of its value. We did not find evidence for egocentric response learning. These results show that early ERPs are sensitive to the location of objects during navigation in an allocentric reference frame.
28475063	Functional Electrical Stimulation (FES) employs neuroprostheses to apply electrical current to the nerves and muscles of individuals paralyzed by spinal cord injury (SCI) to restore voluntary movement. Neuroprosthesis controllers calculate stimulation patterns to produce desired actions. To date, no existing controller is able to efficiently adapt its control strategy to the wide range of possible physiological arm characteristics, reaching movements, and user preferences that vary over time. Reinforcement learning (RL) is a control strategy that can incorporate human reward signals as inputs to allow human users to shape controller behavior. In this study, ten neurologically intact human participants assigned subjective numerical rewards to train RL controllers, evaluating animations of goal-oriented reaching tasks performed using a planar musculoskeletal human arm simulation. The RL controller learning achieved using human trainers was compared with learning accomplished using human-like rewards generated by an algorithm; metrics included success at reaching the specified target; time required to reach the target; and target overshoot. Both sets of controllers learned efficiently and with minimal differences, significantly outperforming standard controllers. Reward positivity and consistency were found to be unrelated to learning success. These results suggest that human rewards can be used effectively to train RL-based FES controllers.
28472677	Behavioural training through positive reinforcement techniques is a well-recognised refinement to laboratory animal welfare. Behavioural neuroscience research requires subjects to be trained to perform repetitions of specific behaviours for food/fluid reward. Some animals fail to perform at a sufficient level, limiting the amount of data that can be collected and increasing the number of animals required for each study.We have implemented automated positive reinforcement training systems (comprising a button press task with variable levels of difficulty using LED cues and a fluid reward) at the breeding facility and research facility, to compare performance across these different settings, to pre-screen animals for selection and refine training protocols.	Animals learned 1- and 4-choice button tasks within weeks of home enclosure training, with some inter-individual differences. High performance levels (∼200-300 trials per 60min session at ∼80% correct) were obtained without food or fluid restriction. Moreover, training quickly transferred to a laboratory version of the task. Animals that acquired the task at the breeding facility subsequently performed better both in early home enclosure sessions upon arrival at the research facility, and also in laboratory sessions.	Automated systems at the breeding facility may be used to pre-screen animals for suitability for behavioural neuroscience research. In combination with conventional training, both the breeding and research facility systems facilitate acquisition and transference of learning.	Automated systems have the potential to refine training protocols and minimise requirements for food/fluid control.	
28472335	Q-learning is a method of reinforcement learning that employs backwards stage-wise estimation to identify sequences of actions that maximize some long-term reward. The method can be applied to sequential multiple-assignment randomized trials to develop personalized adaptive treatment strategies (ATSs) - longitudinal practice guidelines highly tailored to time-varying attributes of individual patients. Sometimes, the basis for choosing which ATSs to include in a sequential multiple-assignment randomized trial (or randomized controlled trial) may be inadequate. Non-randomized data sources may inform the initial design of ATSs, which could later be prospectively validated. We illustrate challenges in using non-randomized data for this purpose with a case study from the Center for International Blood and Marrow Transplant Research registry (1995-2007) aimed at 1) determining if the sequence of therapeutic classes used in graft-versus-host disease prophylaxis and in refractory graft-versus-host disease is associated with improved survival and 2) identifying donor and patient factors to guide individualized immunosuppressant selections over time. We discuss how to communicate the potential benefit from following an ATS at the population and subgroup levels, and how to evaluate its robustness to modeling assumptions. This worked example may serve as a model for developing ATSs from registries and cohorts in oncology and other fields requiring sequential treatment decisions.
28471221	Reward cues can be perceived as highly attractive stimuli because of their acquired motivational properties. However, because the motivational value of reward changes after reward receipt, a debated question is whether the attentional salience of reward cues changes accordingly. In Experiment 1, thirsty participants learned 3 cue-reward associations involving different contingencies. Then, while thirsty, participants performed a visual-search task under extinction, during which the previous reward cues appeared as irrelevant stimuli containing target and distractor items. Experiment 2 was identical to Experiment 1, except that participants drank ad libitum before the visual-search task. In Experiment 3, instead, participants quenched their thirst at the beginning of the learning session. The results of Experiment 1 showed that attention was preferentially deployed toward the cue that best predicted the reward in the previous conditioning phase. Crucially, Experiment 2 revealed that the attentional bias persisted despite reward devaluation. By contrast, no attentional bias was found in Experiment 3. The novelty of our study is that the attentional salience of a reward cue can outlast reward devaluation, suggesting that some incentive properties of the cue can become independent from those of the reward. (PsycINFO Database Record
28469564	Larval Drosophila offer a study case for behavioral neurogenetics that is simple enough to be experimentally tractable, yet complex enough to be worth the effort. We provide a detailed, hands-on manual for Pavlovian odor-reward learning in these animals. Given the versatility of Drosophila for genetic analyses, combined with the evolutionarily shared genetic heritage with humans, the paradigm has utility not only in behavioral neurogenetics and experimental psychology, but for translational biomedicine as well. Together with the upcoming total synaptic connectome of the Drosophila nervous system and the possibilities of single-cell-specific transgene expression, it offers enticing opportunities for research. Indeed, the paradigm has already been adopted by a number of labs and is robust enough to be used for teaching in classroom settings. This has given rise to a demand for a detailed, hands-on manual directed at newcomers and/or at laboratory novices, and this is what we here provide. The paradigm and the present manual have a unique set of features: The paradigm is cheap, easy, and robust;The manual is detailed enough for newcomers or laboratory novices;It briefly covers the essential scientific context;It includes sheets for scoring, data analysis, and display;It is multilingual: in addition to an English version we provide German, French, Japanese, Spanish and Italian language versions as well.The present manual can thus foster science education at an earlier age and enable research by a broader community than has been the case to date.
28464964	Olfaction is a key sense routing foraging behaviour in parasitoids. Preferences for food, mate and host stimuli can be innate in parasitic wasps. Alternatively, learning-mediated mechanisms play a crucial role. Females of the braconid parasitoid Psyttalia concolor exploit olfactory cues arising from tephritid hosts and related microhabitats. However, little is known on the olfactory stimuli routing males searching for mates. In this study, we focused on the attractiveness of Bactrocera oleae-induced olive volatiles towards P. concolor males. Furthermore, we evaluated learning occurrence in virgin males, when trained for selected unattractive volatile organic compounds (VOCs) associated with mate rewards. (E)-β-Ocimene, α-pinene and limonene attracted virgin males in Y-tube bioassays. Unattractive VOCs evoked positive chemotaxis after associative learning training. P. concolor males exposed to VOCs during a successful or unsuccessful mating, showed short-term preference for these VOCs (<1 h). However, memory consolidation was strictly dependent on reward value. Indeed, males experiencing a successful mating showed a fast consolidation into protein dependent long-term memory, appearing after 24 h. On the other hand, males experiencing a less valuable training experience (i.e. unsuccessful courtship), did not show consolidated memory after 24 h. Overall, our findings suggest that P. concolor virgin males may exploit VOCs from the host microhabitat to boost their mate searching activity, thus their reproductive success. However, since learning is a costly process, P. concolor males retained durable memories just in presence of a valuable reward, thus avoiding maladaptive behaviours.
28461214	Much human behavior is driven by rewards. Preclinical neurophysiological and clinical positron emission tomography (PET) studies have implicated striatal phasic dopamine (DA) release as a primary modulator of reward processing. However, the relationship between experimental reward-induced striatal DA release and responsiveness to naturalistic rewards, and therefore functional relevance of these findings, has been elusive. We therefore combined, for the first time, a DA D2/3 receptor [18F]fallypride PET during a probabilistic reinforcement learning (RL) task with a six day ecological momentary assessments (EMA) of reward-related behavior in the everyday life of 16 healthy volunteers. We detected significant reward-induced DA release in the bilateral putamen, caudate nucleus and ventral striatum, the extent of which was associated with better behavioral performance on the RL task across all regions. Furthermore, individual variability in the extent of reward-induced DA release in the right caudate nucleus and ventral striatum modulated the tendency to be actively engaged in a behavior if the active engagement was previously deemed enjoyable. This study suggests a link between striatal reward-related DA release and ecologically relevant reward-oriented behavior, suggesting an avenue for the inquiry into the DAergic basis of optimal and impaired motivational drive.
28450078	Adolescence has traditionally been viewed as a period of vulnerability to increased risk-taking and adverse outcomes, which have been linked to neurobiological maturation of the frontostriatal reward system. However, growing research on the role of developmental changes in the adolescent frontostriatal system in facilitating learning will provide a more nuanced view of adolescence. In this review, we discuss the implications of existing research on this topic for learning during adolescence, and suggest that the very neural changes that render adolescents vulnerable to social pressure and risky decision making may also stand to play a role in scaffolding the ability to learn from rewards and from performance-related feedback.
28446872	Despite their small size, insect brains are able to produce robust and efficient navigation in complex environments. Specifically in social insects, such as ants and bees, these navigational capabilities are guided by orientation directing vectors generated by a process called path integration. During this process, they integrate compass and odometric cues to estimate their current location as a vector, called the home vector for guiding them back home on a straight path. They further acquire and retrieve path integration-based vector memories globally to the nest or based on visual landmarks. Although existing computational models reproduced similar behaviors, a neurocomputational model of vector navigation including the acquisition of vector representations has not been described before. Here we present a model of neural mechanisms in a modular closed-loop control-enabling vector navigation in artificial agents. The model consists of a path integration mechanism, reward-modulated global learning, random search, and action selection. The path integration mechanism integrates compass and odometric cues to compute a vectorial representation of the agent's current location as neural activity patterns in circular arrays. A reward-modulated learning rule enables the acquisition of vector memories by associating the local food reward with the path integration state. A motor output is computed based on the combination of vector memories and random exploration. In simulation, we show that the neural mechanisms enable robust homing and localization, even in the presence of external sensory noise. The proposed learning rules lead to goal-directed navigation and route formation performed under realistic conditions. Consequently, we provide a novel approach for vector learning and navigation in a simulated, situated agent linking behavioral observations to their possible underlying neural substrates.
28443814	Two theoretical studies reveal how networks of neurons may behave during reward-based learning.
28442362	In the present study we investigated whether stimulation of muscarinic acetylcholine (mACh) receptors in the ventral tegmental area (VTA) plays a role in the acquisition of food-based conditioned approach learning. Rats were exposed to 3 (in Experiment 1) or 7 (in Experiment 2) conditioning sessions in which 30, randomly presented light (CS) presentations were paired with delivery of food pellets (US), followed by one session with no light or food and finally one CS-only test session with only light stimulus presentations. Bilateral microinjections of scopolamine (a mACh receptor antagonist) were made either prior to each conditioning session (Experiment 1; to test effects on acquisition) or prior to the CS-only test (Experiment 2; to test effects on performance of the learned response). Scopolamine produced a dose-related significant reduction in the acquisition of conditioned approach but had no effect on its performance. These results suggest that mACh receptor stimulation in the VTA plays a necessary role in the acquisition of reward-related learning.
28441518	The goal of this article is to investigate how human participants allocate their limited time to decisions with different properties. We report the results of two behavioral experiments. In each trial of the experiments, the participant must accumulate noisy information to make a decision. The participants received positive and negative rewards for their correct and incorrect decisions, respectively. The stimulus was designed such that decisions based on more accumulated information were more accurate but took longer. Therefore, the total outcome that a participant could achieve during the limited experiments' time depended on her "decision threshold", the amount of information she needed to make a decision. In the first experiment, two types of trials were intermixed randomly: hard and easy. Crucially, the hard trials were associated with smaller positive and negative rewards than the easy trials. A cue presented at the beginning of each trial would indicate the type of the upcoming trial. The optimal strategy was to adopt a small decision threshold for hard trials. The results showed that several of the participants did not learn this simple strategy. We then investigated how the participants adjusted their decision threshold based on the feedback they received in each trial. To this end, we developed and compared 10 computational models for adjusting the decision threshold. The models differ in their assumptions on the shape of the decision thresholds and the way the feedback is used to adjust the decision thresholds. The results of Bayesian model comparison showed that a model with time-varying thresholds whose parameters are updated by a reinforcement learning algorithm is the most likely model. In the second experiment, the cues were not presented. We showed that the optimal strategy is to use a single time-decreasing decision threshold for all trials. The results of the computational modeling showed that the participants did not use this optimal strategy. Instead, they attempted to detect the difficulty of the trial first and then set their decision threshold accordingly.
28441114	Dopamine neurons facilitate learning by calculating reward prediction error, or the difference between expected and actual reward. Despite two decades of research, it remains unclear how dopamine neurons make this calculation. Here we review studies that tackle this problem from a diverse set of approaches, from anatomy to electrophysiology to computational modeling and behavior. Several patterns emerge from this synthesis: that dopamine neurons themselves calculate reward prediction error, rather than inherit it passively from upstream regions; that they combine multiple separate and redundant inputs, which are themselves interconnected in a dense recurrent network; and that despite the complexity of inputs, the output from dopamine neurons is remarkably homogeneous and robust. The more we study this simple arithmetic computation, the knottier it appears to be, suggesting a daunting (but stimulating) path ahead for neuroscience more generally.
28436980	Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral nucleus of the amygdala (BLA) and prelimbic (PL) medial prefrontal cortex have been implicated in reward-seeking and fear-related responses, but how information flows between these reciprocally connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task wherein competing shock- and sucrose-predictive cues were simultaneously presented. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, BLA neurons optogenetically identified as projecting to PL more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally photostimulation of the BLA→PL projection increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. Therefore, the BLA→PL circuit is critical in governing the selection of behavioral responses in the face of competing signals.
28436832	Adversity impacts many aspects of psychological and physical development including reward-based learning and decision-making. Mechanisms relating adversity and reward processing in children, however, remain unclear. Here, we show that adversity is associated with potentiated learning from positive outcomes and impulsive decision-making, but unrelated to learning from negative outcomes. We then show via functional magnetic resonance imaging that the link between adversity and reward processing is partially mediated by differences in ventral striatal response to rewards. The findings suggest that early-life adversity is associated with alterations in the brain's sensitivity to rewards accounting, in part, for the link between adversity and altered reward processing in children.
28434586	The periaqueductal gray (PAG) has been commonly recognized as a downstream site in neural networks for the expression of a variety of behaviors and is thought to provide stereotyped responses. However, a growing body of evidence suggests that the PAG may exert more complex modulation of a number of behavioral responses and work as a unique hub supplying primal emotional tone to influence prosencephalic sites mediating complex aversive and appetitive responses. Of particular relevance, we review how the PAG is involved in influencing complex forms of defensive responses, such as circa-strike and risk assessment responses in animals. In addition, we discuss putative dorsal PAG ascending paths that are likely to convey information related to threatening events to cortico-hippocampal-amygdalar circuits involved in the processing of fear learning. Finally, we discuss the evidence supporting the role of the PAG in reward seeking and note that the lateral PAG is part of the circuitry related to goal-oriented responses mediating the motivation to hunt and perhaps drug seeking behavior.
28430545	The aim of this study was to determine how monetary motivations influence decision making of humans performing as security analysts and hackers in a cybersecurity game.Cyberattacks are increasing at an alarming rate. As cyberattacks often cause damage to existing cyber infrastructures, it is important to understand how monetary rewards may influence decision making of hackers and analysts in the cyber world. Currently, only limited attention has been given to this area.	In an experiment, participants were randomly assigned to three between-subjects conditions ( n = 26 for each condition): equal payoff, where the magnitude of monetary rewards for hackers and defenders was the same; rewarding hacker, where the magnitude of monetary reward for hacker's successful attack was 10 times the reward for analyst's successful defense; and rewarding analyst, where the magnitude of monetary reward for analyst's successful defense was 10 times the reward for hacker's successful attack. In all conditions, half of the participants were human hackers playing against Nash analysts and half were human analysts playing against Nash hackers.	Results revealed that monetary rewards for human hackers and analysts caused a decrease in attack and defend actions compared with the baseline. Furthermore, rewarding human hackers for undetected attacks made analysts deviate significantly from their optimal behavior.	If hackers are rewarded for their undetected attack actions, then this causes analysts to deviate from optimal defend proportions. Thus, analysts need to be trained not become overenthusiastic in defending networks.	Applications of our results are to networks where the influence of monetary rewards may cause information theft and system damage.	
28426971	Value-based decision making often involves integration of reward outcomes over time, but this becomes considerably more challenging if reward assignments on alternative options are probabilistic and non-stationary. Despite the existence of various models for optimally integrating reward under uncertainty, the underlying neural mechanisms are still unknown. Here we propose that reward-dependent metaplasticity (RDMP) can provide a plausible mechanism for both integration of reward under uncertainty and estimation of uncertainty itself. We show that a model based on RDMP can robustly perform the probabilistic reversal learning task via dynamic adjustment of learning based on reward feedback, while changes in its activity signal unexpected uncertainty. The model predicts time-dependent and choice-specific learning rates that strongly depend on reward history. Key predictions from this model were confirmed with behavioral data from non-human primates. Overall, our results suggest that metaplasticity can provide a neural substrate for adaptive learning and choice under uncertainty.
28421669	Fairness perception and equality during social interactions frequently elicit affective arousal and affect decision making. By integrating the dictator game and a probabilistic gambling task, this study aimed to investigate the effects of a negative experience induced by perceived unfairness on decision making using behavioral, model fitting, and electrophysiological approaches. Participants were randomly assigned to the neutral, harsh, or kind groups, which consisted of various asset allocation scenarios to induce different levels of perceived unfairness. The monetary gain was subsequently considered the initial asset in a negatively rewarded, probabilistic gambling task in which the participants were instructed to maintain as much asset as possible. Our behavioral results indicated that the participants in the harsh group exhibited increased levels of negative emotions but retained greater total game scores than the participants in the other two groups. Parameter estimation of a reinforcement learning model using a Bayesian approach indicated that these participants were more loss aversive and consistent in decision making. Data from simultaneous ERP recordings further demonstrated that these participants exhibited larger feedback-related negativity to unexpected outcomes in the gambling task, which suggests enhanced reward sensitivity and signaling of reward prediction error. Collectively, our study suggests that a negative experience may be an advantage in the modulation of reward-based decision making.
28417291	Surprises are important sources of learning. Cognitive scientists often refer to surprises as "reward prediction errors," a parameter that captures discrepancies between expectations and actual outcomes. Here, we integrate neurophysiological and functional magnetic resonance imaging (fMRI) results addressing the processing of reward prediction errors and how they might be altered in drug addiction and Parkinson's disease.By increasing phasic dopamine responses, drugs might accentuate prediction error signals, causing increases in fMRI activity in mesolimbic areas in response to drugs. Chronic substance dependence, by contrast, has been linked with compromised dopaminergic function, which might be associated with blunted fMRI responses to pleasant non-drug stimuli in mesocorticolimbic areas. In Parkinson's disease, dopamine replacement therapies seem to induce impairments in learning from negative outcomes. The present review provides a holistic overview of reward prediction errors across different pathologies and might inform future clinical strategies targeting impulsive/compulsive disorders.	
28416630	Avoiding unfavorable situations is a vital skill and a constant task for any animal. Situations can be unfavorable because they feature something that the animal wants to escape from, or because they do not feature something that it seeks to obtain. We investigate whether the microbehavioral mechanisms by which these two classes of aversion come about are shared or distinct. We find that larval Drosophila avoid odors either previously associated with a punishment, or previously associated with the lack of a reward. These two classes of conditioned aversion are found to be strikingly alike at the microbehavioral level. In both cases larvae show more head casts when oriented toward the odor source than when oriented away, and direct fewer of their head casts toward the odor than away when oriented obliquely to it. Thus, conditioned aversion serving two qualitatively different functions-escape from a punishment or search for a reward-is implemented by the modulation of the same microbehavioral features. These features also underlie conditioned approach, albeit with opposite sign. That is, the larvae show conditioned approach toward odors previously associated with a reward, or with the lack of a punishment. In order to accomplish both these classes of conditioned approach the larvae show fewer head casts when oriented toward an odor, and direct more of their head casts toward it when they are headed obliquely. Given that the Drosophila larva is a genetically tractable model organism that is well suited to study simple circuits at the single-cell level, these analyses can guide future research into the neuronal circuits underlying conditioned approach and aversion, and the computational principles of conditioned search and escape.
28416452	Facial expressions of emotion have an undeniable processing advantage over neutral faces, discernible both at behavioral level and in emotion-related modulations of several event-related potentials (ERPs). Recently it was proposed that also inherently neutral stimuli might gain salience through associative learning mechanisms. The present study investigated whether acquired motivational salience leads to processing advantages similar to biologically determined origins of inherent emotional salience by applying an associative learning paradigm to human face processing. Participants (N=24) were trained to categorize neutral faces to salience categories by receiving different monetary outcomes. ERPs were recorded in a subsequent test phase consisting of gender decisions on previously associated faces, as well as on familiarized and novel faces expressing happy, angry or no emotion. Previously reward-associated faces boosted the P1 component, indicating that acquired reward-associations modulate early sensory processing in extrastriate visual cortex. However, ERP modulations to emotional - primarily angry - expressions expanded to subsequent processing stages, as reflected in well-established emotion-related ERPs. The present study offers new evidence that motivational salience associated to inherently neutral stimuli can sharpen sensory encoding but does not obligatorily lead to preferential processing at later stages.
28415138	In neuroeconomics, valuation refers to the process of assigning values to states and actions on the basis of the animal's current representation of the environment, while reward processing corresponds to processing the feedback received from the environment to update the values of states and actions. In this article, we review the brain circuits associated with valuation and reward processing and argue that these are fundamental processes critical to many cognitive functions. Specifically, we focus on the role of valuation and reward processing in attention, memory, decision making, and learning. Next, the extant neuroimaging literature on a number of psychiatric disorders is reviewed (i.e., addiction, pathological gambling, schizophrenia, and mood disorders), and an argument is made that associated deficits in cognitive functions can be explained in terms of abnormal valuation and reward processing. The review concludes with the impact of this framework in clinical settings and prescriptions for future research, in particular with regard to the conversions of qualitatively different valuation systems into a system of common currency.
28413988	Alzheimer&amp;#039;s dementia is characterized by significant cortical and subcortical atrophy, causing diverse neuropsychological deficits. According to the somatic marker hypothesis, the areas responsible for generating the somatic markers that anticipate the consequences of a decision and thereby optimize the process would be affected in these patients.The aim of this experiment is to study the decision-making processes in Alzheimer type dementia patients to determine potential deficits in these processes as a result of the disease, aside from the cognitive impairment that is typical of aging. In addition, we wish to determine the defining characteristics of decision-making in these patients, on the basis of the prospect valence-learning parameters.	We evaluated 30 patients with Alzheimer's disease and a control group of 30 healthy subjects. A short version of the Iowa Gambling Task was used.	The results showed that patients made less advantageous choices than did controls. Group differences were quantitative and qualitative, as significant differences in cognitive mechanisms identified in the prospect valence-learning decisions were observed. These results are consistent with evidence from neuroimaging studies as well as with work carried out with amnesic patients.	That problems in our patients' decision-making could be due to the characteristic memory deficits of this disease, which prevents them from establishing new stimulus-reward relationships and eliminating previously learned responses as a result of the parietal and temporal atrophy they present.	
28413776	Risk-taking is purported to be central to addictive behaviors. However, for Internet gaming disorder (IGD), a condition conceptualized as a behavioral addiction, the neural processes underlying impaired decision-making (risk evaluation and outcome processing) related to gains and losses have not been systematically investigated. Forty-one males with IGD and 27 healthy comparison (HC) male participants were recruited, and the cups task was used to identify neural processes associated with gain- and loss-related risk- and outcome-processing in IGD. During risk evaluation, the IGD group, compared to the HC participants, showed weaker modulation for experienced risk within the bilateral dorsolateral prefrontal cortex (DLPFC) (t = - 4.07; t = - 3.94; PFWE  < 0.05) and inferior parietal lobule (IPL) (t = - 4.08; t = - 4.08; PFWE  < 0.05) for potential losses. The modulation of the left DLPFC and bilateral IPL activation were negatively related to addiction severity within the IGD group (r = - 0.55; r = - 0.61; r = - 0.51; PFWE  < 0.05). During outcome processing, the IGD group presented greater responses for the experienced reward within the ventral striatum, ventromedial prefrontal cortex, and orbitofrontal cortex (OFC) (t = 5.04, PFWE  < 0.05) for potential gains, as compared to HC participants. Within the IGD group, the increased reward-related activity in the right OFC was positively associated with severity of IGD (r = 0.51, PFWE  < 0.05). These results provide a neurobiological foundation for decision-making deficits in individuals with IGD and suggest an imbalance between hypersensitivity for reward and weaker risk experience and self-control for loss. The findings suggest a biological mechanism for why individuals with IGD may persist in game-seeking behavior despite negative consequences, and treatment development strategies may focus on targeting these neural pathways in this population.
28411561	The current study examined whether cognitive control moderates the association between (non-drug) reward-modulated attentional capture and use of alcohol and other drugs (AOD).Participants were 66 university students who completed an assessment including questions about AOD use, a visual search task to measure value-modulated attentional capture, and a goal-directed selective attention task as a measure of cognitive control.	The association between the effect of value-modulated attentional capture and illicit drug use was moderated by level of cognitive control. Among participants with lower levels of cognitive control, value-modulated attentional capture was associated with illicit drug use. This was not the case among participants with higher levels of cognitive control, who instead showed a significant association between illicit drug use and self-reported impulsivity, as well as alcohol use.	These results provide support for models that view addictive behaviours as resulting from interaction and competition between automatic and more reflective processes. That is, the mechanisms that ultimately drive addictive behaviour may differ between people low or high in cognitive control. This has important implications for understanding the development and maintenance of substance use disorders and potentially their treatment and prevention.	
28410153	Individuals with Internet addiction (IA) show loss of control and recurring maladaptive Internet use. This condition has negative consequences and causes significant psychosocial distress. Here, we review neurobiological changes in four key paradigms in cognitive domain in IA including reward processing, impulsivity, cue reactivity, and decision-making. IA is associated with alterations in prefrontal-cingulate region activation during the inhibition of inappropriate responses. Such patterns are also observed in cue-reactivity paradigm tasks, suggesting a relationship with loss of control and deficits in the control of cue-eliciting behavior. Individuals with IA exhibit heightened reward prediction, devalue negative outcomes and have a higher risk-taking propensity under ambiguous situations. In conclusion, addictive use of the Internet is associated with deficits in cognitive-emotional processing, aberrant sensitivity to rewards and Internet-related cues, poor impulse control, and impaired decision-making. There is a need to examine neural underpinnings of these aberrant behaviors and neurobiological-cognitive perspective in IA.
28408878	It is widely accepted that the basal ganglia (BG) play a key role in action selection and reinforcement learning. However, despite considerable number of studies, the BG architecture and function are not completely understood. Action selection and reinforcement learning are facilitated by the activity of dopaminergic neurons, which encode reward prediction errors when reward outcomes are higher or lower than expected. The BG are thought to select proper motor responses by gating appropriate actions, and suppressing inappropriate ones. The direct striato-nigral (GO) and the indirect striato-pallidal (NOGO) pathways have been suggested to provide the functions of BG in the two-pathway concept. Previous models confirmed the idea that these two pathways can mediate the behavioral choice, but only for a relatively small number of potential behaviors. Recent studies have provided new evidence of BG involvement in motor adaptation tasks, in which adaptation occurs in a non-error-based manner. In such tasks, there is a continuum of possible actions, each represented by a complex neuronal activity pattern. We extended the classical concept of the two-pathway BG by creating a model of BG interacting with a movement execution system, which allows for an arbitrary number of possible actions. The model includes sensory and premotor cortices, BG, a spinal cord network, and a virtual mechanical arm performing 2D reaching movements. The arm is composed of 2 joints (shoulder and elbow) controlled by 6 muscles (4 mono-articular and 2 bi-articular). The spinal cord network contains motoneurons, controlling the muscles, and sensory interneurons that receive afferent feedback and mediate basic reflexes. Given a specific goal-oriented motor task, the BG network through reinforcement learning constructs a behavior from an arbitrary number of basic actions represented by cortical activity patterns. Our study confirms that, with slight modifications, the classical two-pathway BG concept is consistent with results of previous studies, including non-error based motor adaptation experiments, pharmacological manipulations with BG nuclei, and functional deficits observed in BG-related motor disorders.
28407554	Depression and schizophrenia are two of the most serious psychiatric disorders. They share similar symptoms but the pathology-specific commonalities and differences remain unknown. This study was conducted to acquire a full picture of the functional alterations in schizophrenia and depression patients.The resting-state fMRI data from 20 patients with schizophrenia, 20 patients with depression and 20 healthy control subjects were collected. A data-driven approach that included local functional connectivity density (FCD) analysis combined with multivariate pattern analysis (MVPA) was used to compare the three groups.	Based on the results of the MVPA, the local FCD value in the orbitofrontal cortex (OFC) can differentiate depression patients from schizophrenia patients. The patients with depression had a higher local FCD value in the medial and anterior parts of the OFC than the subjects in the other two groups, which suggested altered abstract and reward reinforces processing in depression patients. Subsequent functional connectivity analysis indicated that the connection in the prefrontal cortex was significantly lower in people with schizophrenia compared to people with depression and healthy controls.	The systematically different medications for schizophrenia and depression may have different effects on functional connectivity.	These results suggested that the resting-state functional connectivity pattern in the prefrontal cortex may be a transdiagnostic difference between depression and schizophrenia patients.	
28407527	Adaptive decision-making requires that feedback about decision outcomes is adequately processed. Recent studies have shown that fronto-central event-related potentials (ERPs) are sensitive to feedback valence and can be used as an index of feedback processing. The present study investigated whether the processes involved in feedback evaluation are affected by top-down mechanisms driven by knowledge about feedback validity. In a simple decision task, participants had to make use of feedback to learn which one of two stimuli was associated with a reward in a later test phase. Feedback stimuli were followed by a cue indicating whether feedback was valid or invalid. Prior to each block, participants were informed about the frequency of valid feedback in this block. An effect of feedback validity was obtained not only for learning but also for fronto-central ERPs. While high-validity feedback was associated with a fronto-central valence effect, this effect was absent for low-validity feedback. This indicates that processes involved in feedback evaluation are affected by prior knowledge about feedback validity via top-down processes.
28406677	Stimuli with intrinsic emotional value, like emotional faces, and stimuli associated with reward and punishment are often prioritized in visual awareness relative to neutral stimuli. Recently, Anderson, Siegel, Bliss-Moreau, and Barrett (2011) demonstrated that simply associating a face with affective knowledge can also influence visual awareness. Using a binocular rivalry task (BR), where a face was shown to one eye and a house to the other, they found that faces paired with negative versus neutral and positive behaviors dominated visual awareness. We were interested in whether faces associated with negative information would also be capable of reaching awareness more quickly in the first place. To test this, we set out to replicate Anderson and colleagues' finding and to examine whether it would extend to breaking continuous flash suppression (b-CFS), a technique where a dynamic mask shown to one eye initially suppresses the stimulus shown to the other eye. Participants completed a learning task followed by BR and b-CFS tasks, in counterbalanced order. Across both tasks, faces associated with negative behaviors were treated no differently from faces associated with neutral or positive behaviors. However, faces associated with any type of behavior were prioritized in awareness over novel faces. These findings indicate that while familiarity influences conscious perception, the influence of affective person knowledge on visual awareness is more circumscribed than previously thought. (PsycINFO Database Record
28406662	Motivational and hedonic impairments are core features of a variety of types of psychopathology. An important aspect of motivational function is reinforcement learning (RL), including implicit (i.e., outside of conscious awareness) and explicit (i.e., including explicit representations about potential reward associations) learning, as well as both positive reinforcement (learning about actions that lead to reward) and punishment (learning to avoid actions that lead to loss). Here we present data from paradigms designed to assess both positive and negative components of both implicit and explicit RL, examine performance on each of these tasks among individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis, and examine their relative relationships to specific symptom domains transdiagnostically. None of the diagnostic groups differed significantly from controls on the implicit RL tasks in either bias toward a rewarded response or bias away from a punished response. However, on the explicit RL task, both the individuals with schizophrenia and schizoaffective disorder performed significantly worse than controls, but the individuals with bipolar did not. Worse performance on the explicit RL task, but not the implicit RL task, was related to worse motivation and pleasure symptoms across all diagnostic categories. Performance on explicit RL, but not implicit RL, was related to working memory, which accounted for some of the diagnostic group differences. However, working memory did not account for the relationship of explicit RL to motivation and pleasure symptoms. These findings suggest transdiagnostic relationships across the spectrum of psychotic disorders between motivation and pleasure impairments and explicit RL. (PsycINFO Database Record
28403383	Withdrawal from nicotine is an important contributor to smoking relapse. Understanding how reward-based decision making is affected by abstinence and by pharmacotherapies such as nicotine replacement therapy and varenicline tartrate may aid cessation treatment.To independently assess the effects of nicotine dependence and stimulation of the nicotinic acetylcholine receptor on the ability to interpret valence information (reward sensitivity) and subsequently alter behavior as reward contingencies change (cognitive flexibility) in a probabilistic reversal learning task.	Nicotine-dependent smokers and nonsmokers completed a probabilistic reversal learning task during acquisition of functional magnetic resonance imaging (fMRI) in a 2-drug, double-blind placebo-controlled crossover design conducted from January 21, 2009, to September 29, 2011. Smokers were abstinent from cigarette smoking for 12 hours for all sessions. In a fully Latin square fashion, participants in both groups underwent MRI twice while receiving varenicline and twice while receiving a placebo pill, wearing either a nicotine or a placebo patch. Imaging analysis was performed from June 15, 2015, to August 10, 2016.	A well-established computational model captured effects of smoking status and administration of nicotine and varenicline on probabilistic reversal learning choice behavior. Neural effects of smoking status, nicotine, and varenicline were tested for on MRI contrasts that captured reward sensitivity and cognitive flexibility.	The study included 24 nicotine-dependent smokers (12 women and 12 men; mean [SD] age, 35.8 [9.9] years) and 20 nonsmokers (10 women and 10 men; mean [SD] age, 30.4 [7.2] years). Computational modeling indicated that abstinent smokers were biased toward response shifting and that their decisions were less sensitive to the available evidence, suggesting increased impulsivity during withdrawal. These behavioral impairments were mitigated with nicotine and varenicline. Similarly, decreased mesocorticolimbic activity associated with cognitive flexibility in abstinent smokers was restored to the level of nonsmokers following stimulation of nicotinic acetylcholine receptors (familywise error-corrected P < .05). Conversely, neural signatures of decreased reward sensitivity in smokers (vs nonsmokers; familywise error-corrected P < .05) in the dorsal striatum and anterior cingulate cortex were not mitigated by nicotine or varenicline.	There was a double dissociation between the effects of chronic nicotine dependence on neural representations of reward sensitivity and acute effects of stimulation of nicotinic acetylcholine receptors on behavioral and neural signatures of cognitive flexibility in smokers. These chronic and acute pharmacologic effects were observed in overlapping mesocorticolimbic regions, suggesting that available pharmacotherapies may alleviate deficits in the same circuitry for certain mental computations but not for others.	
28397140	Parkinson's disease (PD) is associated with procedural learning deficits. Nonetheless, studies have demonstrated that reward-related learning is comparable between patients with PD and controls (Bódi et al., Brain, 132(9), 2385-2395, 2009; Frank, Seeberger, & O'Reilly, Science, 306(5703), 1940-1943, 2004; Palminteri et al., Proceedings of the National Academy of Sciences of the United States of America, 106(45), 19179-19184, 2009). However, because these studies do not separate the effect of reward from the effect of practice, it is difficult to determine whether the effect of reward on learning is distinct from the effect of corrective feedback on learning. Thus, it is unknown whether these group differences in learning are due to reward processing or learning in general. Here, we compared the performance of medicated PD patients to demographically matched healthy controls (HCs) on a task where the effect of reward can be examined separately from the effect of practice. We found that patients with PD showed significantly less reward-related learning improvements compared to HCs. In addition, stronger learning of rewarded associations over unrewarded associations was significantly correlated with smaller skin-conductance responses for HCs but not PD patients. These results demonstrate that when separating the effect of reward from the effect of corrective feedback, PD patients do not benefit from reward.
28396213	Loss aversion is the tendency to prefer avoiding losses over acquiring gains of the same amount. To shed light on the spatio-temporal processes underlying loss aversion, we analysed the associations between individual loss aversion and electrophysiological responses to loss and gain outcomes in a monetary gamble task. Electroencephalographic feedback-related negativity (FRN) was computed in 29 healthy participants as the difference in electrical potentials between losses and gains. Loss aversion was evaluated using non-linear parametric fitting of choices in a separate gamble task. Loss aversion correlated positively with FRN amplitude (233-263ms) at electrodes covering the lower face. Feedback related potentials were modelled by five equivalent source dipoles. From these dipoles, stronger activity in a source located in the orbitofrontal cortex was associated with loss aversion. The results suggest that loss aversion implemented during risky decision making is related to a valuation process in the orbitofrontal cortex, which manifests during learning choice outcomes.
28393399	Anorexia Nervosa (AN) is a serious disorder, with a mortality rate the highest of any psychiatric illness. It is notoriously challenging to treat and mechanisms of illness are not well understood. Reward system abnormalities have been proposed across theoretical models of the persistence of AN. Feedback learning is an important component of how reward systems shape behavior and we hypothesized that individuals with AN would show poorer learning from feedback.We administered the acquired equivalence task to measure both learning from incremental feedback and generalization of that learning to novel stimuli. Participants were individuals with AN (n = 36) before and after intensive weight restoration treatment and healthy comparison participants (HC, n = 26) tested twice. Performance was assessed as accuracy during the Learning and Test phases, for both trained and novel stimuli. The relationship between task performance and eating disorder severity at baseline was also assessed.	Both before and after treatment, individuals with AN showed reduced learning from feedback in the Learning phase (F3,180  = 2.75, p = .048) and lower accuracy during the Test phase (F1,60  = 4.29, p = .043), as compared with HC. Individuals with AN did not differ from HC in accuracy for novel stimuli (F1,60  = 1.04, p = .312), indicating no deficit in generalization. Decreased acquisition of feedback learning was associated with longer illness duration and with greater eating disorder symptom severity at baseline.	Individuals with AN show reduced learning from feedback or reinforcement, which may contribute to difficulties in changing maladaptive behaviors.	
28390863	The phasic dopamine reward prediction error response is a major brain signal underlying learning, approach and decision making. This dopamine response consists of two components that reflect, initially, stimulus detection from physical impact and, subsequenttly, reward valuation; dopamine activations by punishers reflect physical impact rather than aversiveness. The dopamine reward signal is distinct from earlier reported and recently confirmed phasic changes with behavioural activation. Optogenetic activation of dopamine neurones in monkeys causes value learning and biases economic choices. The dopamine reward signal conforms to formal economic utility and thus constitutes a utility prediction error signal. In these combined ways, the dopamine reward prediction error signal constitutes a potential neuronal substrate for the crucial economic decision variable of utility.
28389249	Over the past years, evidence has accumulated that obesity is intimately linked to the integrity of the fronto-striatal system of the human brain. However, the nature and causality of this relationship remains elusive. The fronto-striatal system is responsible for higher order cognitive functions such as learning, working memory, decision-making and cognitive control. Further, it determines the individual propensity to actively seek out rewards in the environment or to avoid possibly punishing situations. One of the major neurotransmitters of this system is dopamine. Recently, we suggested that markers of obesity are linked to markers of the dopaminergic system in an inverted u-shaped manner, with profound differences between individuals with moderate and severe obesity. Cross-sectional observations of dopamine-associated functions such as general reward sensitivity and anticipation support this hypothesis. Because of the fundamental role of the dopaminergic system in cognitive domains such as learning, prediction formation, cognitive control, and working memory, obesity-associated changes in this system affect cognition beyond food contexts. Taken together, the reviewed literature suggest either a dynamic relationship between the dopaminergic system and markers of obesity during the development of obesity, possibly based on processes of neuroplasticity, or different endophenotypes in individuals with overweight/moderate obesity and severe obesity.
28384481	Individual differences in dopaminergic tone underlie tendencies to learn from reward versus punishment. These effects are well documented in Parkinson's patients, who vacillate between low and high tonic dopaminergic states as a function of medication. Yet very few studies have investigated the influence of higher-level cognitive states known to affect downstream dopaminergic learning in Parkinson's patients. A dopamine-dependent cognitive influence over learning would provide a candidate mechanism for declining cognitive integrity and motivation in Parkinson's patients. In this report we tested the influence of two high-level cognitive states (cost of conflict and value of volition) that have recently been shown to cause predictable learning biases in healthy young adults as a function of dopamine receptor subtype and dopaminergic challenge. It was hypothesized that Parkinson's patients OFF medication would have an enhanced cost of conflict and a decreased value of volition, and that these effects would be remediated or reversed ON medication. Participants included N = 28 Parkinson's disease patients who were each tested ON and OFF dopaminergic medication and 28 age- and sex-matched controls. The expected cost of conflict effect was observed in Parkinson's patients OFF versus ON medication, but only in those that were more recently diagnosed (<5 years). We found an unexpected effect in the value of volition task: medication compromised the ability to learn from difficult a-volitional (instructed) choices. This novel finding was also enhanced in recently diagnosed patients. The difference in learning biases ON versus OFF medication between these two tasks was strongly correlated, bolstering the idea that they tapped into a common underlying imbalance in dopaminergic tone that is particularly variable in earlier stage Parkinsonism. The finding that these decision biases are specific to earlier but not later stage disease may offer a chance for future studies to quantify phenotypic expressions of idiosyncratic disease progression.
28383956	Learning to choose adaptively when faced with uncertain and variable outcomes is a central challenge for decision makers. This study examines repeated choice in dynamic probability learning tasks in which outcome probabilities changed either as a function of the choices participants made or independently of those choices. This presence/absence of sequential choice-outcome dependencies was implemented by manipulating a single task aspect between conditions: the retention/withdrawal of reward across individual choice trials. The study addresses how people adapt to these learning environments and to what extent they engage in 2 choice strategies often contrasted as paradigmatic examples of striking violation of versus nominal adherence to rational choice: diversification and persistent probability maximizing, respectively. Results show that decisions approached adaptive choice diversification and persistence when sufficient feedback was provided on the dynamic rules of the probabilistic environments. The findings of divergent behavior in the 2 environments indicate that diversified choices represented a response to the reward retention manipulation rather than to the mere variability of outcome probabilities. Choice in both environments was well accounted for by the generalized matching law, and computational modeling-based strategy analyses indicated that adaptive choice arose mainly from reliance on reinforcement learning strategies. (PsycINFO Database Record
28383111	According to reinforcement learning theory, dopamine-dependent anticipatory processes play a critical role in learning from action outcomes such as feedback or reward. To better understand outcome anticipation, we examined variation in slow cortical potentials and assessed their changes over the course of motor-skill acquisition. Healthy young adults learned a series of precisely timed, key press sequences. Feedback was delivered at a delay of either 2.5 or 8 s, to encourage use of either the striatally mediated, habit learning system or the hippocampus-dependent, episodic memory system, respectively. During the 2.5-s delay, the stimulus-preceding negativity (SPN) was shown to decline in amplitude across trials, confirming previous results from a perceptual categorization task (Morís, Luque, & Rodríguez-Fornells, 2013). This falsifies the hypothesis that SPN reflects specific outcome predictions, on the assumption that the ability to make such predictions should improve as a task is mastered. An SPN was also evident during the 8-s delay, but it increased in amplitude across trials. At the conclusion of the 8-s but not the 2.5-s prefeedback interval, a reversed-polarity lateralized readiness potential (LRP) was noted. It was suggested that this might indicate maintenance of an action representation for comparison with the feedback display. If so, this would constitute the first direct psychophysiological evidence for a popular hypothetical construct in quantitative models of reinforcement learning, the so-called eligibility trace.
28382893	Adolescents' snack choices could be altered by increasing the reinforcing value (RV) of healthy snacks compared with unhealthy snacks. This study assessed whether the RV of fruit increased by linking it to a reward and if this increased RV was comparable with the RV of unhealthy snacks alone. Moderation effects of sex, hunger, BMI z-scores and sensitivity to reward were also explored. The RV of snacks was assessed in a sample of 165 adolescents (15·1 (sd 1·5) years, 39·4 % boys and 17·4 % overweight) using a computerised food reinforcement task. Adolescents obtained points for snacks through mouse clicks (responses) following progressive ratio schedules of increasing response requirements. Participants were (computer) randomised to three experimental groups (1:1:1): fruit (n 53), fruit+reward (n 60) or unhealthy snacks (n 69). The RV was evaluated as total number of responses and breakpoint (schedule of terminating food reinforcement task). Multilevel regression analyses (total number of responses) and Cox's proportional hazard regression models (breakpoint) were used. The total number of responses made were not different between fruit+reward and fruit (b -473; 95 % CI -1152, 205, P=0·17) or unhealthy snacks (b410; 95 % CI -222, 1043, P=0·20). The breakpoint was slightly higher for fruit than fruit+reward (HR 1·34; 95 % CI 1·00, 1·79, P=0·050), whereas no difference between unhealthy snacks and fruit+reward (HR 0·86; 95 % CI 0·62, 1·18, P=0·34) was observed. No indication of moderation was found. Offering rewards slightly increases the RV of fruit and may be a promising strategy to increase healthy food choices. Future studies should however, explore if other rewards, could reach larger effect sizes.
28378414	Opioid addiction has devastating health and socio-economic consequences, and current pharmacotherapy is limited and often accompanied by side effects, thus novel treatment is warranted. Traditionally, the neurohypophyseal peptide oxytocin (OT) is known for its effects on mediating reward, social affiliation and bonding, stress and learning and memory. There is now strong evidence that OT is a possible candidate for the treatment of drug addiction and depression-addiction co-morbidities. This review summarizes and critically discusses the preclinical evidence surrounding the consequences of pharmacological manipulation of the oxytocinergic system on opioid addiction-related processes, as well as the effects of opioids on the OT system at different stages of the addiction cycle. The mechanisms underlying the effects of OT on opioid addiction, including OT' interaction with the monoaminergic, glutamatergic, opioidergic systems and its effect on the amygdala, the hypothalamic-pituitary-adrenal axis and on memory consolidation of traumatic memories, are also reviewed. We also review clinical evidence on the effects of intranasal OT administration on opioid-dependent individuals and discuss the therapeutic potential along with the limitations that accompany OT-based pharmacotherapies. Review of these studies clearly indicates that the OT system is profoundly affected by opioid use and abstinence and points towards the OT system as an important target for developing pharmacotherapies for the treatment of opioid addiction and co-existing affective disorders, thereby preventing relapse. Therefore, there is a clear need for clinical studies assessing the efficacy of OT-based pharmacotherapies in opioid addiction.
28377451	The effects of motor learning, such as motor adaptation, in stroke rehabilitation are often transient, thus mandating approaches that enhance the amount of learning and retention. Previously, we showed in young individuals that reward and punishment feedback have dissociable effects on motor adaptation, with punishment improving adaptation and reward enhancing retention. If these findings were able to generalise to patients with stroke, they would provide a way to optimise motor learning in these patients. Therefore, we tested this in 45 patients with chronic stroke allocated in three groups.Patients performed reaching movements with their paretic arm with a robotic manipulandum. After training (day 1), day 2 involved adaptation to a novel force field. During the adaptation phase, patients received performance-based feedback according to the group they were allocated: reward, punishment or no feedback (neutral). On day 3, patients readapted to the force field but all groups now received neutral feedback.	All patients adapted, with reward and punishment groups displaying greater adaptation and readaptation than the neutral group, irrespective of demographic, cognitive or functional differences. Remarkably, the reward and punishment groups adapted to similar degree as healthy controls. Finally, the reward group showed greater retention.	This study provides, for the first time, evidence that reward and punishment can enhance motor adaptation in patients with stroke. Further research on reinforcement-based motor learning regimes is warranted to translate these promising results into clinical practice and improve motor rehabilitation outcomes in patients with stroke.	
28375688	A large body of research has shown that learning about relationships between neutral stimuli and events of significance-rewards or punishments-influences the extent to which people attend to those stimuli in future. However, different accounts of this influence differ in terms of the critical variable that is proposed to determine learned changes in attention. We describe two experiments using eye-tracking with a rewarded visual search procedure to investigate whether attentional capture is influenced by the predictiveness of stimuli (i.e., the extent to which they provide information about upcoming events) or by their absolute associative value (that is, the expected incentive value of the outcome that a stimulus predicts). Results demonstrated a clear influence of associative value on the likelihood that stimuli will capture eye-movements, but the evidence for a distinct influence of predictiveness was less compelling. The results of these experiments can be reconciled within a simple account under which attentional prioritization is a monotonic function of the expected, subjective value of the reward that is signalled by a stimulus.
28374660	Depression is one of the most common and debilitating non-motor symptoms of Parkinson's disease (PD). The neurocognitive mechanisms underlying depression in PD are unclear and treatment is often suboptimal.We investigated the role of striatal dopamine in reversal learning from reward and punishment by combining a controlled medication withdrawal procedure with functional magnetic resonance imaging in 22 non-depressed PD patients and 19 PD patients with past or present depression.	PD patients with a depression (history) exhibited impaired reward v. punishment reversal learning as well as reduced reward v. punishment-related BOLD signal in the striatum (putamen) compared with non-depressed PD patients. No effects of dopaminergic medication were observed.	The present findings demonstrate that impairments in reversal learning from reward v. punishment and associated striatal signalling depend on the presence of (a history of) depression in PD.	
28374264	Pretest sucrose affects a dopamine-modulated response of bumblebees to an ambiguous cue to reward as well as a response to a simulated attack (Perry, Baciadonna, & Chittka, Science, 353(6307), 1529-1531, 2016). The contribution of the study lies in opening the door to research on the inner experience of insects, the learning and motivational mechanisms of their behavior, and the evolutionary analysis of emotions.
28373714	The hypothesis of strategic motives postulates that offering fairly in the Ultimatum Game (UG) is to avoid rejection and receive money. In this fMRI study, we used a modified UG to elucidate how proposers reached decisions of offering fairly and to what extent they considered offering selfishly with different stakes. We had proposers choose between a fair and a selfish offer with different degrees of selfishness and stake sizes. Proposers were less likely and spent more time choosing the fair offer over a slightly-selfish offer than a very selfish offer independent of stakes. Such choices evoked greater activation in the dorsal anterior cingulate cortices that typically involve in allocation of cognitive control for cost/benefit decision making. Choosing a fair offer in higher stakes evoked greater activation in the anterior cingulate gyrus (ACCg) and the areas that previously have been implicated in reward and theory of mind. Furthermore, choosing a slightly selfish offer over a fair offer evoked greater activation in the anterior cingulate sulcus, ACCg, ventral tegmental area (or substantia nigra) and anterior insular cortex signalling the higher gain and implying higher rejection risk. In conclusion, our findings favoured the hypothesis that proposers offer fairly based on the strategic motives.
28373651	During decisions, animals balance goal achievement and effort management. Despite physical exercise and fatigue significantly affecting the levels of effort that an animal exerts to obtain a reward, their role in effort-based choice and the underlying neurochemistry are incompletely known. In particular, it is unclear whether fatigue influences decision (cost-benefit) strategies flexibly or only post-decision action execution and learning. To answer this question, we trained mice on a T-maze task in which they chose between a high-cost, high-reward arm (HR), which included a barrier, and a low-cost, low-reward arm (LR), with no barrier. The animals were parametrically fatigued immediately before the behavioural tasks by running on a treadmill. We report a sharp choice reversal, from the HR to LR arm, at 80% of their peak workload (PW), which was temporary and specific, as the mice returned to choose the HC when the animals were successively tested at 60% PW or in a two-barrier task. These rapid reversals are signatures of flexible choice. We also observed increased subcortical dopamine levels in fatigued mice: a marker of individual bias to use model-based control in humans. Our results indicate that fatigue levels can be incorporated in flexible cost-benefits computations that improve foraging efficiency.
28373569	In natural behavior, animals have access to multiple sources of information, but only a few of these sources are relevant for learning and actions. Beyond choosing an appropriate action, making good decisions entails the ability to choose the relevant information, but fundamental questions remain about the brain's information sampling policies. Recent studies described the neural correlates of seeking information about a reward, but it remains unknown whether, and how, neurons encode choices of instrumental information, in contexts in which the information guides subsequent actions. Here we show that parietal cortical neurons involved in oculomotor decisions encode, before an information sampling saccade, the reduction in uncertainty that the saccade is expected to bring for a subsequent action. These responses were distinct from the neurons' visual and saccadic modulations and from signals of expected reward or reward prediction errors. Therefore, even in an instrumental context when information and reward gains are closely correlated, individual cells encode decision variables that are based on informational factors and can guide the active sampling of action-relevant cues.
28366865	Glucocorticoid stress hormones are known to enhance the consolidation of hippocampus-dependent spatial and contextual memory. Recent findings indicate that glucocorticoids also enhance the consolidation of procedural memory that relies on the dorsal striatum. The dorsal striatum can be functionally subdivided into the dorsolateral striatum (DLS), which is primarily implicated in shaping procedural memories, and the dorsomedial striatum (DMS), which is engaged in spatial memory. Here, we investigated the hypothesis that posttraining glucocorticoid administration into the DLS promotes the formation of a procedural memory that will normally take place only with extensive training. Male Wistar rats were trained to find a reward in a cross maze that can be solved through either place or response learning. Rats received four trials per day for 5days, a probe trial on Day 6, further training on Days 7-13, and an additional probe trial on Day 14. On Days 2-4 of training, they received posttraining infusions of corticosterone (10 or 30ng) or vehicle into either the DLS or DMS. Rats treated with vehicle into either the DLS or DMS displayed place learning on Day 6 and response learning on Day 14, indicating a shift in control of learned behavior toward a habit-like procedural strategy with extended training. Rats administered corticosterone (10ng) into the DLS displayed response learning on both Days 6 and 14, indicating an accelerated shift to response learning. In contrast, corticosterone administered posttraining into the DMS did not significantly alter the shift from place to response learning. These findings indicate that glucocorticoid administration into the DLS enhances memory consolidation of procedural learning and thereby influences the timing of the switch from the use of spatial/contextual memory to habit-like procedural memory to guide behavior.
28346515	Gender differences in feedback processing have been observed among adolescents and adults through event-related potentials. However, information on whether and how this feedback processing is affected by feedback valence, feedback type, and individual sensitivity in reward/punishment among children remains minimal. In this study, we used a guessing game task coupled with electroencephalography to investigate gender differences in feedback processing, in which feedback to reward and punishment was presented in the context of monetary and social conditions. Results showed that boys were less likely to switch their response after punishment, had generally less feedback-related negativity (FRN) amplitude, and longer FRN latency in monetary and punishment conditions than girls. Moreover, FRN for monetary punishment, which is related to individual difference in reward sensitivity, was observed only in girls. The study provides gender-specific evidence for the neural processing of feedback, which may offer educational guidance for appropriate feedback for girls and boys.
28346121	Recent research suggests that the mere act of retrieving a memory can temporarily make that memory vulnerable to disruption. This process of "reconsolidation" will typically restabilize the neural representation of the memory and foster its long-term storage. However, the process of reconsolidating the memory takes time to complete, and during this limited time window, the original memory may be modified either by the presentation of new information or with pharmacological agents. Such findings have prompted rising interest in using disruption during reconsolidation as a clinical intervention for anxiety, posttraumatic stress, and substance use disorders. However, "boundary conditions" on memory reconsolidation may pose significant obstacles to clinical translation. The aim of this article is to critically examine the nature of these boundary conditions, their neurobiological substrates, and the potential effect they may have on disruption of reconsolidation as a clinical intervention. These boundary conditions also highlight potential constraints on the reconsolidation phenomenon and suggest a limited role for memory updating consistent with evolutionary accounts of associative learning for threat and reward. We conclude with suggestions for future research needed to elucidate the precise conditions under which reconsolidation disruption may be clinically useful.
28344546	In recent years there has been an increase in the number of portable low-cost electroencephalographic (EEG) systems available to researchers. However, to date the validation of the use of low-cost EEG systems has focused on continuous recording of EEG data and/or the replication of large system EEG setups reliant on event-markers to afford examination of event-related brain potentials (ERP). Here, we demonstrate that it is possible to conduct ERP research without being reliant on event markers using a portable MUSE EEG system and a single computer. Specifically, we report the results of two experiments using data collected with the MUSE EEG system-one using the well-known visual oddball paradigm and the other using a standard reward-learning task. Our results demonstrate that we could observe and quantify the N200 and P300 ERP components in the visual oddball task and the reward positivity (the mirror opposite component to the feedback-related negativity) in the reward-learning task. Specifically, single sample t-tests of component existence (all p's < 0.05), computation of Bayesian credible intervals, and 95% confidence intervals all statistically verified the existence of the N200, P300, and reward positivity in all analyses. We provide with this research paper an open source website with all the instructions, methods, and software to replicate our findings and to provide researchers with an easy way to use the MUSE EEG system for ERP research. Importantly, our work highlights that with a single computer and a portable EEG system such as the MUSE one can conduct ERP research with ease thus greatly extending the possible use of the ERP methodology to a variety of novel contexts.
28344152	Food cravings can reflect an intense trait-like emotional-motivational desire to eat palatable food, often resulting in the failure of weight loss efforts. Studies have linked trait-based food-cravings to increased risk of overeating. However, little is known about resting-state neural mechanisms that underlie food cravings. We investigated this issue using resting-state functional magnetic resonance imaging (fMRI) to test the extent to which spontaneous neural activity occurs in regions implicated in emotional memory and reward motivation associated with food cravings. Spontaneous regional activity patterns correlating to food cravings were assessed among 65 young healthy women using regional homogeneity analysis to assess temporal synchronization of spontaneous activity. Analyses indicated that women with higher scores on the Food Cravings Questionnaire displayed increased local functional homogeneity in brain regions involved in emotional memory and visual attention processing (i.e., parahippocampal gyrus and fusiform gyrus) but not reward. In view of parahippocampal gyrus involvement in hedonic learning and incentive memory encoding, this study suggests that trait-based food cravings are encoded by emotional memory circuits.
28343270	Elasmobranch fishes (sharks, skates, and rays) have been hypothesized to use the geomagnetic field as a cue for orienting and navigating across a wide range of spatial scales. Magnetoreception has been demonstrated in many invertebrate and vertebrate taxa, including elasmobranchs, but this sensory modality and the cognitive abilities of cartilaginous fishes are poorly studied. Wild caught yellow stingrays, Urobatis jamaicensis (N = 8), underwent conditioning to associate a magnetic stimulus with a food reward in order to elicit foraging behaviors. Behavioral conditioning consisted of burying magnets and non-magnetic controls at random locations within a test arena and feeding stingrays as they passed over the hidden magnets. The location of the magnets and controls was changed for each trial, and all confounding sensory cues were eliminated. The stingrays learned to discriminate the magnetic stimuli within a mean of 12.6 ± 0.7 SE training sessions of four trials per session. Memory probes were conducted at intervals between 90 and 180 days post-learning criterion, and six of eight stingrays completed the probes with a ≥75% success rate and minimum latency to complete the task. These results show the fastest rate of learning and longest memory window for any batoid (skate or ray) to date. This study demonstrates that yellow stingrays, and possibly other elasmobranchs, can use a magnetic stimulus as a geographic marker for the location of resources and is an important step toward understanding whether these fishes use geomagnetic cues during spatial navigation tasks in the natural environment.
28343269	In an ever-changing environment, the ability to adapt choices to new conditions is essential for daily living and ultimately, for survival. Behavioural flexibility allows animals to maximise survival and reproduction in novel settings by adjusting their behaviour based on specific information and feedback acquired in their current environments. However, a growing body of evidence indicates that an individual's personality type can limit the extent to which the individual might behave flexibly, by influencing the way an individual pays attention to novelty and how much information it collects and stores, which in turn affects the individual's decision-making and learning process. In this study, the behavioural flexibility of a generalist predator, the Chimango Caracara, Milvago chimango, was analysed using the reversal learning paradigm, focusing on the comparison between age classes, and the relation of learning flexibility with a personality trait, the level of neophobia. Due to the low number of male individuals captured, this study was carried out only with female birds. The results showed that age had no significant effect either on the acquisition of a stimulus-reward association, or on the capacity of reversing this previously learned association. Reversal of the response was a harder task for these birds in comparison with the initial acquisition process. The individual's performances in the learning tasks seemed to be uncorrelated with each other, suggesting that they involve different neural mechanisms. Contrary to the general pattern observed in the majority of previous work on personality and cognition in non-human animals, the level of neophobia did not correlate with the initial associative learning performance in both adults and juveniles, yet it showed a significant negative relationship with reversal learning ability, mainly in the regressive phase of this task, for the two age classes. Our results suggest that the predatory and generalist lifestyle of female individuals of M. chimango along with the selective pressures of the environment of the individuals studied might play a critical role in the degree and direction of the linkage between novelty response and learning flexibility observed in this study.
28341268	Humans often attempt to influence one another's behavior using rewards and punishments. How does this work? Psychologists have often assumed that "evaluative feedback" influences behavior via standard learning mechanisms that learn from environmental contingencies. On this view, teaching with evaluative feedback involves leveraging learning systems designed to maximize an organism's positive outcomes. Yet, despite its parsimony, programs of research predicated on this assumption, such as ones in developmental psychology, animal behavior, and human-robot interaction, have had limited success. We offer an explanation by analyzing the logic of evaluative feedback and show that specialized learning mechanisms are uniquely favored in the case of evaluative feedback from a social partner. Specifically, evaluative feedback works best when it is treated as communicating information about the value of an action rather than as a form of reward to be maximized. This account suggests that human learning from evaluative feedback depends on inferences about communicative intent, goals and other mental states-much like learning from other sources, such as demonstration, observation and instruction. Because these abilities are especially developed in humans, the present account also explains why evaluative feedback is far more widespread in humans than non-human animals.
28338882	The tribal character of the affective link between football fans and their teams is a well-recognized phenomenon. Other forms of love such as romantic or maternal attachment have previously been studied from a neuroimaging point of view. Here we aimed to investigate the neural basis of this tribal form of love, which implies both the feeling of belongingness and rivalry against opposing teams. A pool of 56 participants was submitted to an fMRI experimental design involving the presentation of winning and losing football moments of their loved, rival or neutral teams. We found recruitment of amygdala and reward regions, including the ventral tegmental area (VTA) and substantia nigra (SN), as well as other limbic regions involved in emotional cognition, for 'positive vs neutral' and 'positive vs negative' conditions. The latter contrast was correlated with neuropsychological scores of fanaticism in the amygdala and regions within the reward system, as the VTA and SN. The observation of increased response patterns in critical components of the reward system, in particular for positive content related to the loved team, suggests that this kind of non-romantic love reflects a specific arousal and motivational state, which is biased for emotional learning of positive outcomes.
28334960	According to current concepts, major depressive disorder is strongly related to dysfunctional neural processing of motivational information, entailing impairments in reinforcement learning. While computational modelling can reveal the precise nature of neural learning signals, it has not been used to study learning-related neural dysfunctions in unmedicated patients with major depressive disorder so far. We thus aimed at comparing the neural coding of reward and punishment prediction errors, representing indicators of neural learning-related processes, between unmedicated patients with major depressive disorder and healthy participants. To this end, a group of unmedicated patients with major depressive disorder (n = 28) and a group of age- and sex-matched healthy control participants (n = 30) completed an instrumental learning task involving monetary gains and losses during functional magnetic resonance imaging. The two groups did not differ in their learning performance. Patients and control participants showed the same level of prediction error-related activity in the ventral striatum and the anterior insula. In contrast, neural coding of reward prediction errors in the medial orbitofrontal cortex was reduced in patients. Moreover, neural reward prediction error signals in the medial orbitofrontal cortex and ventral striatum showed negative correlations with anhedonia severity. Using a standard instrumental learning paradigm we found no evidence for an overall impairment of reinforcement learning in medication-free patients with major depressive disorder. Importantly, however, the attenuated neural coding of reward in the medial orbitofrontal cortex and the relation between anhedonia and reduced reward prediction error-signalling in the medial orbitofrontal cortex and ventral striatum likely reflect an impairment in experiencing pleasure from rewarding events as a key mechanism of anhedonia in major depressive disorder.
28334633	Optimal intertemporal decisions arise from the balance between an emotional-visceral component, signaling the need for immediate gratification, and a rational, long-term oriented component. Alexithymia, a personality construct characterized by amplified sensitivity to internal bodily signals of arousal, may result in enhanced activation of the emotional-visceral component over the cognitive-rational one. To test this hypothesis, participants with high- and low-alexithymia level were compared at an intertemporal decision-making task, and their choice behavior correlated with their interoceptive sensitivity. We show that high-alexithymic tend to behave more impatiently than low-alexithymic in intertemporal decisions, particularly when the sooner reward is immediately available. Moreover, the greater their sensitivity to their own visceral sensations, the greater the impatience. Together, these results suggest a disproportionate valuation of reward available immediately in high alexithymia, possibly reflecting heightened perception of bodily physiological signals, which ultimately would bias their intertemporal decision-making.
28334611	Our motor outputs are constantly re-calibrated to adapt to systematic perturbations. This motor adaptation is thought to depend on the ability to form a memory of a systematic perturbation, often called an internal model. However, the mechanisms underlying the formation, storage, and expression of such models remain unknown. Here, we developed a mouse model to study forelimb adaptation to force field perturbations. We found that temporally precise photoinhibition of somatosensory cortex (S1) applied concurrently with the force field abolished the ability to update subsequent motor commands needed to reduce motor errors. This S1 photoinhibition did not impair basic motor patterns, post-perturbation completion of the action, or their performance in a reward-based learning task. Moreover, S1 photoinhibition after partial adaptation blocked further adaptation, but did not affect the expression of already-adapted motor commands. Thus, S1 is critically involved in updating the memory about the perturbation that is essential for forelimb motor adaptation.
28334609	Basolateral amygdala (BLA) principal cells are capable of driving and antagonizing behaviors of opposing valence. BLA neurons project to the central amygdala (CeA), which also participates in negative and positive behaviors. However, the CeA has primarily been studied as the site for negative behaviors, and the causal role for CeA circuits underlying appetitive behaviors is poorly understood. Here, we identify several genetically distinct populations of CeA neurons that mediate appetitive behaviors and dissect the BLA-to-CeA circuit for appetitive behaviors. Protein phosphatase 1 regulatory subunit 1B+ BLA pyramidal neurons to dopamine receptor 1+ CeA neurons define a pathway for promoting appetitive behaviors, while R-spondin 2+ BLA pyramidal neurons to dopamine receptor 2+ CeA neurons define a pathway for suppressing appetitive behaviors. These data reveal genetically defined neural circuits in the amygdala that promote and suppress appetitive behaviors analogous to the direct and indirect pathways of the basal ganglia. VIDEO ABSTRACT.
28334608	The prevailing view is that striatal parvalbumin (PV)-positive interneurons primarily function to downregulate medium spiny projection neuron (MSN) activity via monosynaptic inhibitory signaling. Here, by combining in vivo neural recordings and optogenetics, we unexpectedly find that both suppressing and over-activating PV cells attenuates spontaneous MSN activity. To account for this, we find that, in addition to monosynaptic coupling, PV-MSN interactions are mediated by a competing disynaptic inhibitory circuit involving a variety of neuropeptide Y-expressing interneurons. Next we use optogenetic and chemogenetic approaches to show that dorsolateral striatal PV interneurons influence the initial expression of reward-conditioned responses but that their contribution to performance declines with experience. Consistent with this, we observe with large-scale recordings in behaving animals that the relative contribution of PV cells on MSN activity diminishes with training. Together, this work provides a possible mechanism by which PV interneurons modulate striatal output and selectively enhance performance early in learning.
28333486	Transitive inference (TI) is a classic learning paradigm for which the relative contributions of experienced rewards and representation-based inference have been debated vigorously, particularly regarding the notion that animals are capable of logic and reasoning. Rhesus macaque subjects and human participants performed a TI task in which, prior to learning a 7-item list (ABCDEFG), a block of trials presented exclusively the pair FG. Contrary to the expectation of associative models, the high prior rate of reward for F did not disrupt subsequent learning of the entire list. Monkeys (who each completed many sessions with novel stimuli) learned to anticipate that novel stimuli should be preferred over F. We interpret this as evidence of a task representation of TI that generalizes beyond learning about specific stimuli. Humans (who were task-naïve) showed a transitory bias to F when it was paired with novel stimuli, but very rapidly unlearned that bias. Performance with respect to the remaining stimuli was consistent with past reports of TI in both species. These results are difficult to reconcile with any account that assigns the strength of association between individual stimuli and rewards. Instead, they support sophisticated cognitive processes in both species, albeit with some species differences. (PsycINFO Database Record
28326050	Many of the decisions we make in our everyday lives are sequential and entail sparse rewards. While sequential decision-making has been extensively investigated in theory (e.g., by reinforcement learning models) there is no systematic experimental paradigm to test it. Here, we developed such a paradigm and investigated key components of reinforcement learning models: the eligibility trace (i.e., the memory trace of previous decision steps), the external reward, and the ability to exploit the statistics of the environment's structure (model-free vs. model-based mechanisms). We show that the eligibility trace decays not with sheer time, but rather with the number of discrete decision steps made by the participants. We further show that, unexpectedly, neither monetary rewards nor the environment's spatial regularity significantly modulate behavioral performance. Finally, we found that model-free learning algorithms describe human performance better than model-based algorithms.
28324169	The thalamus provides a massive input to the striatum, but despite accumulating evidence, the functions of this system remain unclear. It is known, however, that the centromedian (CM) and parafascicular (Pf) nuclei of the thalamus can strongly influence particular striatal neuron subtypes, notably including the cholinergic interneurons of the striatum (CINs), key regulators of striatal function. Here, we highlight the thalamostriatal system through the CM-Pf to striatal CINs. We consider how, by virtue of the direct synaptic connections of the CM and PF, their neural activity contributes to the activity of CINs and striatal projection neurons (SPNs). CM-Pf neurons are strongly activated at sudden changes in behavioral context, such as switches in action-outcome contingency or sequence of behavioral requirements, suggesting that their activity may represent change of context operationalized as associability. Striatal CINs, on the other hand, acquire and loose responses to external events associated with particular contexts. In light of this physiological evidence, we propose a hypothesis of the CM-Pf-CINs system, suggesting that it augments associative learning by generating an associability signal and promotes reinforcement learning guided by reward prediction error signals from dopamine-containing neurons. We discuss neuronal circuit and synaptic organizations based on in vivo/in vitro studies that we suppose to underlie our hypothesis. Possible implications of CM-Pf-CINs dysfunction (or degeneration) in brain diseases are also discussed by focusing on Parkinson's disease.
28321184	It is now clearly established that complex interactions between genes and environment are involved in multiple aspects of neuropsychiatric disorders, from determining an individual's vulnerability to onset, to influencing its response to therapeutic intervention. In this perspective, it appears crucial to better understand how the organism reacts to environmental stimuli and provide a coordinated and adapted response. In the central nervous system, neuronal plasticity and neurotransmission are among the major processes integrating such complex interactions between genes and environmental stimuli. In particular, immediate early genes (IEGs) are critical components of these interactions as they provide the molecular framework for a rapid and dynamic response to neuronal activity while opening the possibility for a lasting and sustained adaptation through regulation of the expression of a wide range of genes. As a result, IEGs have been tightly associated with neuronal activity as well as a variety of higher order processes within the central nervous system such as learning, memory and sensitivity to reward. The immediate early gene and transcription factor early growth response 1 (EGR1) has thus been revealed as a major mediator and regulator of synaptic plasticity and neuronal activity in both physiological and pathological conditions. In this review article, we will focus on the role of EGR1 in the central nervous system. First, we will summarize the different factors influencing its activity. Then, we will analyze the amount of data, including genome-wide, that has emerged in the recent years describing the wide variety of genes, pathways and biological functions regulated directly or indirectly by EGR1. We will thus be able to gain better insights into the mechanisms underlying EGR1's functions in physiological neuronal activity. Finally, we will discuss and illustrate the role of EGR1 in pathological states with a particular interest in cognitive functions and neuropsychiatric disorders.
28321129	The human brain contains approximately 60 billion cerebellar granule cells, which outnumber all other brain neurons combined. Classical theories posit that a large, diverse population of granule cells allows for highly detailed representations of sensorimotor context, enabling downstream Purkinje cells to sense fine contextual changes. Although evidence suggests a role for the cerebellum in cognition, granule cells are known to encode only sensory and motor context. Here, using two-photon calcium imaging in behaving mice, we show that granule cells convey information about the expectation of reward. Mice initiated voluntary forelimb movements for delayed sugar-water reward. Some granule cells responded preferentially to reward or reward omission, whereas others selectively encoded reward anticipation. Reward responses were not restricted to forelimb movement, as a Pavlovian task evoked similar responses. Compared to predictable rewards, unexpected rewards elicited markedly different granule cell activity despite identical stimuli and licking responses. In both tasks, reward signals were widespread throughout multiple cerebellar lobules. Tracking the same granule cells over several days of learning revealed that cells with reward-anticipating responses emerged from those that responded at the start of learning to reward delivery, whereas reward-omission responses grew stronger as learning progressed. The discovery of predictive, non-sensorimotor encoding in granule cells is a major departure from the current understanding of these neurons and markedly enriches the contextual information available to postsynaptic Purkinje cells, with important implications for cognitive processing in the cerebellum.
28320846	Reinforcement learning (RL) in simple instrumental tasks is usually modeled as a monolithic process in which reward prediction errors (RPEs) are used to update expected values of choice options. This modeling ignores the different contributions of different memory and decision-making systems thought to contribute even to simple learning. In an fMRI experiment, we investigated how working memory (WM) and incremental RL processes interact to guide human learning. WM load was manipulated by varying the number of stimuli to be learned across blocks. Behavioral results and computational modeling confirmed that learning was best explained as a mixture of two mechanisms: a fast, capacity-limited, and delay-sensitive WM process together with slower RL. Model-based analysis of fMRI data showed that striatum and lateral prefrontal cortex were sensitive to RPE, as shown previously, but, critically, these signals were reduced when the learning problem was within capacity of WM. The degree of this neural interaction related to individual differences in the use of WM to guide behavioral learning. These results indicate that the two systems do not process information independently, but rather interact during learning.SIGNIFICANCE STATEMENT Reinforcement learning (RL) theory has been remarkably productive at improving our understanding of instrumental learning as well as dopaminergic and striatal network function across many mammalian species. However, this neural network is only one contributor to human learning and other mechanisms such as prefrontal cortex working memory also play a key role. Our results also show that these other players interact with the dopaminergic RL system, interfering with its key computation of reward prediction errors.
28316564	Background: The ventral tegmental area (VTA), containing mesolimbic and mesocortical dopaminergic neurons, is implicated in processes involving reward, addiction, reinforcement, and learning, which are associated with a variety of neuropsychiatric disorders. Electrical stimulation of the VTA or the medial forebrain bundle and its projection target the nucleus accumbens (NAc) is reported to improve depressive symptoms in patients affected by severe, treatment-resistant major depressive disorder (MDD) and depressive-like symptoms in animal models of depression. Here we sought to determine the neuromodulatory effects of VTA deep brain stimulation (DBS) in a normal large animal model (swine) by combining neurochemical measurements with functional magnetic resonance imaging (fMRI). Methods: Animals (n = 8 swine) were implanted with a unilateral DBS electrode targeting the VTA. During stimulation (130 Hz frequency, 0.25 ms pulse width, and 3 V amplitude), fMRI was performed. Following fMRI, fast-scan cyclic voltammetry in combination with carbon fiber microelectrodes was performed to quantify VTA-DBS-evoked dopamine release in the ipsilateral NAc. In a subset of swine, the blood oxygen level-dependent (BOLD) percent change evoked by stimulation was performed at increasing voltages (1, 2, and 3 V). Results: A significant increase in VTA-DBS-evoked BOLD signal was found in the following regions: the ipsilateral dorsolateral prefrontal cortex, anterior and posterior cingulate, insula, premotor cortex, primary somatosensory cortex, and striatum. A decrease in the BOLD signal was also observed in the contralateral parahippocampal cortex, dorsolateral and anterior prefrontal cortex, insula, inferior temporal gyrus, and primary somatosensory cortex (Bonferroni-corrected < 0.001). During neurochemical measurements, stimulation time-locked changes in dopamine release were recorded in the NAc, confirming that mesolimbic dopaminergic neurons were stimulated by DBS. In the parametric study, BOLD signal changes were positively correlated with stimulation amplitude. Conclusions: In this study, the modulation of the neural circuitry associated with VTA-DBS was characterized in a large animal. Our findings suggest that VTA-DBS could affect the activity of neural systems and brain regions implicated in reward, mood regulation, and in the pathophysiology of MDD. In addition, we showed that a combination of fMRI and electrochemically-based neurochemical detection platform is an effective investigative tool for elucidating the circuitry involved in VTA-DBS.
28316265	To understand the cognitive effects of alpha-synuclein polymorphism, we employed a drift diffusion model (DDM) to analyze reward- and punishment-guided probabilistic learning task data of participants with the rare alpha-synuclein gene duplication and age- and education-matched controls. Overall, the DDM analysis showed that, relative to controls, asymptomatic alpha-synuclein gene duplication carriers had significantly increased learning from negative feedback, while they tended to show impaired learning from positive feedback. No significant differences were found in response caution, response bias, or motor/encoding time. We here discuss the implications of these computational findings to the understanding of the neural mechanism of alpha-synuclein gene duplication.
28315981	Psychopathic traits are a manifestation of a personality pathology that comprises a core affective-interpersonal dysfunction (callous-unemotional traits) and an impulsive-antisocial behavioral component. Of particular importance, psychopathic traits are associated with the perpetration of some of the most severe acts of violence, and they appear to indicate a subset of youth at risk for earlier onset, greater frequency, and persistence of violent offending. Although these youth represent a minority of the population, they commit a significant proportion of the violence in the general community. In our review, we highlight evidence of a unique neurobiological predisposition that underlies the core affective deficits and describe contemporary accounts for the developmental processes leading to the antisocial behavior associated with psychopathy. Current evidence suggests that, for this subset of youth, the structure and function of neural circuitry supporting emotion processing, reward learning, decision making, and the development of emotion related to empathy may be crucial to understanding why they are at risk for violence. In particular, a reward dominant pattern of neurobehavioral conditioning may explain how these youth progress to some of the most severe and persistent forms of violence. However, this pattern of conditioning may also be essential to the primary prevention of such deleterious behavior. We suspect that effective strategies to prevent such violence may ultimately be informed by understanding these affective and motivational mechanisms.
28315693	Drugs of abuse increase the frequency and magnitude of brief (1-3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release - possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse.
28314439	Chronic substance use can disrupt the reward function of the anterior cingulate cortex (ACC), biasing the ACC to favor goal-directed behaviors that converge on drug use. Here we used multimodal neuroimaging methods to ask whether modulating reward-related signaling in the ACC can reverse the atypical valuation of nondrug and drug rewards in abstinent smokers.We first recorded functional magnetic resonance imaging data from 20 moderately dependent cigarette smokers (mean age = 25 years; no history of neuropsychiatric disorders), following an overnight period of abstinence, to identify regions of the left dorsal lateral prefrontal cortex associated with the anticipation of drug-related rewards (cigarette puff). Next, we recorded the reward positivity-an electrophysiological signal believed to index sensitivity of the ACC to rewards-while participants engaged in two feedback tasks to gain either monetary or cigarette rewards. Lastly, guided by functional magnetic resonance imaging data, a robotic arm positioned a repetitive transcranial magnetic stimulation coil over a subject-specific dorsal lateral prefrontal cortex target, and 50 repetitive transcranial magnetic stimulation pulses were delivered at 10 Hz (excitatory stimulation) immediately before each block of 10 trials of the money condition and at 1 Hz (inhibitory stimulation) before each block of 10 trials of the cigarette condition.	Our findings show that abstained smokers exhibited a heightened reward positivity to cigarette rewards relative to monetary rewards, and by applying excitatory or inhibitory repetitive transcranial magnetic stimulation to a subject-specific frontal-cingulate reward pathway, this pattern of results was reversed.	By modulating how the brain links value to drug and nondrug rewards, novel brain-based treatments may finally be on the horizon.	
28303403	Dopamine neurons in the ventral tegmental area (VTA) are a critical part of the neural circuits that underlie reward learning and motivation. Dopamine neurons send dense projections throughout the brain and recent observations suggest that both the intrinsic properties and the functional output of dopamine neurons are dependent on projection target and are subject to neuromodulatory influences. Lateral hypothalamic hypocretin (also termed orexin) neurons project to the VTA and contain both hypocretin and dynorphin peptides in the same dense core vesicles suggesting they may be co-released. Hypocretin peptides act at excitatory Gαq protein-coupled receptors and dynorphin acts at inhibitory Gαi/o protein-coupled receptors, which are both expressed on subpopulations of dopamine neurons. This review describes a role for neuromodulation of dopamine neurons and the influence on motivated behaviour in response to natural and drug rewards.
28303097	Massive Multiple Online Role-Playing Games (MMORPGs) have increased in popularity among children, juveniles, and adults since MMORPGs' appearance in this digital age. MMORPGs can be applied to enhancing language learning, which is drawing researchers' attention from different fields and many studies have validated MMORPGs' positive effect on language learning. However, there are few studies on the underlying behavioral or neural mechanism of such effect. This paper reviews the educational application of the MMORPGs based on relevant macroscopic and microscopic studies, showing that gamers' overall language proficiency or some specific language skills can be enhanced by real-time online interaction with peers and game narratives or instructions embedded in the MMORPGs. Mechanisms underlying the educational assistant role of MMORPGs in second language learning are discussed from both behavioral and neural perspectives. We suggest that attentional bias makes gamers/learners allocate more cognitive resources toward task-related stimuli in a controlled or an automatic way. Moreover, with a moderating role played by activation of reward circuit, playing the MMORPGs may strengthen or increase functional connectivity from seed regions such as left anterior insular/frontal operculum (AI/FO) and visual word form area to other language-related brain areas.
28301764	Abnormal reward processing is a prominent transdiagnostic feature of psychopathology. The present review provides a framework for considering the different aspects of reward processing and their assessment, and highlights recent insights from the field of neuroeconomics that may aid in understanding these processes. Although altered reward processing in psychopathology has often been treated as a general hypo- or hyperresponsivity to reward, increasing data indicate that a comprehensive understanding of reward dysfunction requires characterization within more specific reward-processing domains, including subjective valuation, discounting, hedonics, reward anticipation and facilitation, and reinforcement learning. As such, more nuanced models of the nature of these abnormalities are needed. We describe several processing abnormalities capable of producing the types of selective alterations in reward-related behavior observed in different forms of psychopathology, including (mal)adaptive scaling and anchoring, dysfunctional weighting of reward and cost variables, competition between valuation systems, and reward prediction error signaling.
28298263	Deep brain stimulation (DBS) has been applied as an effective therapy for treating Parkinson's disease or essential tremor. Several open-loop DBS control strategies have been developed for clinical experiments, but they are limited by short battery life and inefficient therapy. Therefore, many closed-loop DBS control systems have been designed to tackle these problems by automatically adjusting the stimulation parameters via feedback from neural signals, which has been reported to reduce the power consumption. However, when the association between the biomarkers of the model and stimulation is unclear, it is difficult to develop an optimal control scheme for other DBS applications, i.e., DBS-enhanced instrumental learning. Furthermore, few studies have investigated the effect of closed-loop DBS control for cognition function, such as instrumental skill learning, and have been implemented in simulation environments. In this paper, we proposed a proof-of-principle design for a closed-loop DBS system, cognitive-enhancing DBS (ceDBS), which enhanced skill learning based on in vivo experimental data. The ceDBS acquired local field potential (LFP) signal from the thalamic central lateral (CL) nuclei of animals through a neural signal processing system. A strong coupling of the theta oscillation (4-7 Hz) and the learning period was found in the water reward-related lever-pressing learning task. Therefore, the theta-band power ratio, which was the averaged theta band to averaged total band (1-55 Hz) power ratio, could be used as a physiological marker for enhancement of instrumental skill learning. The on-line extraction of the theta-band power ratio was implemented on a field-programmable gate array (FPGA). An autoregressive with exogenous inputs (ARX)-based predictor was designed to construct a CL-thalamic DBS model and forecast the future physiological marker according to the past physiological marker and applied DBS. The prediction could further assist the design of a closed-loop DBS controller. A DBS controller based on a fuzzy expert system was devised to automatically control DBS according to the predicted physiological marker via a set of rules. The simulated experimental results demonstrate that the ceDBS based on the closed-loop control architecture not only reduced power consumption using the predictive physiological marker, but also achieved a desired level of physiological marker through the DBS controller.
28297663	Dopamine neurons in the ventral tegmental area (VTA) were previously found to express vesicular glutamate transporter 2 (VGLUT2) and to co-transmit glutamate in the ventral striatum (VStr). This capacity may play an important role in reinforcement learning. Although it is known that activation of the VTA-VStr dopamine system readily reinforces behavior, little is known about the role of glutamate co-transmission in such reinforcement. By combining electrode recording and optogenetics, we found that stimulation of VTA dopamine neurons in vivo evoked fast excitatory responses in many VStr neurons of adult mice. Whereas conditional knockout of the gene encoding VGLUT2 in dopamine neurons largely eliminated fast excitatory responses, it had little effect on the acquisition of conditioned responses reinforced by dopamine neuron activation. Therefore, glutamate co-transmission appears dispensable for acquisition of conditioned responding reinforced by DA neuron activation.
28288832	Associative learning can enable environmental cues to signal food and stimulate feeding, independent of physiological hunger. Two forebrain regions necessary in cue driven feeding, the basolateral area of the amygdala and the medial prefrontal cortex, communicate via extensive, topographically organized connections. The basolateral nucleus (BLA) sends extensive projections to the prelimbic cortex (PL), and our aim here was to determine if this pathway was selectively recruited during cue-food associative learning. The anterior and posterior basolateral nuclei are recruited during different phases of cue-food learning, and thus we examined whether distinct pathways that originate in these nuclei and project to the PL are differently recruited during early and late stages of learning. To accomplish this we used neuroanatomical tract tracing combined with the detection of Fos induction. To identify projecting neurons within the BLA, prior to training, rats received a retrograde tracer, Fluoro-Gold (FG) into the PL. Rats were given either one or ten sessions of tone-food presentations (Paired group) or tone-only presentations (Control group). The Paired group learned the tone-food association quickly and robustly and had greater Fos induction within the anterior and posterior BLA during early and late learning compared to the Control group. Notably, the Paired group had more double-labeled neurons (FG + Fos) during late training compared to the Control group, specifically in the anterior BLA. This demonstrates selective recruitment of the anterior BLA-PL pathway by late cue-food learning. These findings indicate plasticity and specificity in the BLA-PL pathways across cue-food associative learning.
28285994	Central to the organization of behavior is the ability to predict the values of outcomes to guide choices. The accuracy of such predictions is honed by a teaching signal that indicates how incorrect a prediction was ("reward prediction error," RPE). In several reinforcement learning contexts, such as Pavlovian conditioning and decisions guided by reward history, this RPE signal is provided by midbrain dopamine neurons. In many situations, however, the stimuli predictive of outcomes are perceptually ambiguous. Perceptual uncertainty is known to influence choices, but it has been unclear whether or how dopamine neurons factor it into their teaching signal. To cope with uncertainty, we extended a reinforcement learning model with a belief state about the perceptually ambiguous stimulus; this model generates an estimate of the probability of choice correctness, termed decision confidence. We show that dopamine responses in monkeys performing a perceptually ambiguous decision task comply with the model's predictions. Consequently, dopamine responses did not simply reflect a stimulus' average expected reward value but were predictive of the trial-to-trial fluctuations in perceptual accuracy. These confidence-dependent dopamine responses emerged prior to monkeys' choice initiation, raising the possibility that dopamine impacts impending decisions, in addition to encoding a post-decision teaching signal. Finally, by manipulating reward size, we found that dopamine neurons reflect both the upcoming reward size and the confidence in achieving it. Together, our results show that dopamine responses convey teaching signals that are also appropriate for perceptual decisions.
28285820	Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn't reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons or optogenetic manipulation of dopamine concentration alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions, and they have important implications for neurological disorders, including Parkinson's disease and substance dependence.
28284949	The mechanisms by which dopaminergic neurotransmission in the nucleus accumbens (NAc) is involved in incentive learning produced by rewarding stimuli remain unclear. Recently, Wnt signalling has been implicated in synaptic plasticity and learning and memory. Functional interactions between Wnt and dopamine (DA) signalling has been demonstrated using in vitro and tissue physiology approaches, however there remains a lack of in vivo research into the involvement of Wnt in DA-mediated learning in behaving animals. The present study assessed the role of Wnt signalling in DA-mediated incentive learning using the conditioned place preference (CPP) paradigm. We hypothesized that inhibition of Wnt with intra-NAc microinjections of Wnt palmitoylation inhibitor IWP-2 will dose-dependently block the acquisition and expression of amphetamine (AMPH)-induced CPP in rats. Intra-NAc IWP-2 (0.001, 0.05, 1.0 but not 0.0001μg/0.5μl/side) prior to conditioning with AMPH (20.0μg/0.5μl/side) blocked acquisition of CPP. Intra-NAc IWP-2 (0.05, 0.5, 1.0 but not 0.001μg/0.5μl/side) during test following conditioning with AMPH blocked expression but at a higher dose than was need to block acquisition. Sensitization of locomotor activity to AMPH was observed during conditioning and this effect was blocked in groups given IWP-2 prior to AMPH. However, intra-NAc IWP-2 during conditioning did not block the locomotor stimulant effects of AMPH. These results implicate Wnt in DA-mediated incentive learning and suggest that Wnt signalling may be more important for the acquisition of CPP then for its expression. However, mechanisms by which Wnt and DA signalling pathways interact to influence DA-mediated reward-related learning remain to be elucidated.
28284947	Adolescence is a critical period in brain development. During this critical period the seeking for hedonic activities is increased, and their activity signals are stronger than the regulatory signals of judgment and reasoning. We recently reported that alteration of ErbB signaling during this period led to elevated striatal dopamine levels and reduced preference for sweetness without affecting locomotor activity and exploratory behavior. In the current study, we extend our findings and explore whether inhibition of the ErbB pathway during adolescence or adulthood also affects alcohol preference (hedonic "liking"), avoidance learning, and motivational reward "wanting". We demonstrated that chronic administration of the pan-ErbB kinase inhibitor JNJ28871063 (JNJ) to adolescent mice, but not to adult mice, reduced alcohol preference compared with the saline-injected group, without affecting avoidance learning as measured by increasing concentrations of quinine in the bitter avoidance test. Adolescent JNJ-treated mice continue to demonstrate less alcohol preference in adulthood compared with their saline-injected controls. In addition, adolescent JNJ-treated mice and their saline-injected controls did not differ in the time they spent in the food-condition chamber, and in their preference for social odor. In contrast to adolescent JNJ- treated mice, blocking the pathway during adulthood alter the preference to natural reward. These data support our initial findings that interruption of the ErbB pathway during adolescence emerges in a reduced hedonic capacity that persists into adulthood, without disturbing avoidance and reward learning. In addition, this paper provides a further behavioral role of the ErbB signaling pathway in the reward system, and suggests a different time period for the involvement of the pathway in the "liking" and the "wanting" components of the system.
28283562	Amotivation is a common phenotype of major depressive disorder and schizophrenia, which are clinically distinct disorders. Effective treatment targets and strategies can be discovered by examining the dopaminergic reward network function underlying amotivation between these disorders. We conducted an fMRI study in healthy human participants and medicated patients with depression and schizophrenia using an effort-based reinforcement task. We examined regional activations related to reward type (positive and negative reinforcement), effort level, and their composite value, as well as resting-state functional connectivities within the meso-striatal-prefrontal pathway. We found that integrated reward and effort values of low effort-positive reinforcement and high effort-negative reinforcement were behaviorally anticipated and represented in the putamen and medial orbitofrontal cortex activities. Patients with schizophrenia and depression did not show anticipation-related and work-related reaction time reductions, respectively. Greater amotivation severity correlated with smaller work-related putamen activity changes according to reward type in schizophrenia and effort level in depression. Patients with schizophrenia showed feedback-related putamen hyperactivity of low effort compared with healthy controls and depressed patients. The strength of medial orbitofrontal-striatal functional connectivity predicted work-related reaction time reduction of high effort negative reinforcement in healthy controls and amotivation severity in both patients with schizophrenia and those with depression. Patients with depression showed deficient medial orbitofrontal-striatal functional connectivity compared with healthy controls and patients with schizophrenia. These results indicate that amotivation in depression and schizophrenia involves different pathophysiology in the prefrontal-striatal circuitry.SIGNIFICANCE STATEMENT Amotivation is present in both depression and schizophrenia. However, treatment involves the use of drugs that enhance serotonin activity in depression and inhibit serotonin and dopamine activity in schizophrenia. Understanding how motivation processed in the mesocorticolimbic and nigostriatal pathways is affected in depression and schizophrenia is important in discovering treatment targets and strategies for amotivation. To our knowledge, this is the first study to compare patients with depression and schizophrenia in a common functional construct. By using an effort-based reinforcement task and examining resting-state functional connectivity in the dopaminergic network, we propose that difference in striato-orbitofrontal dysfunction in effort-based reinforcement between depression and schizophrenia may be related to differences in the extent of functional dysconnectivity in the dopaminergic pathway.
28283558	The mesolimbic dopamine pathway receives inputs from numerous regions of the brain as part of a neural system that detects rewarding stimuli and coordinates a behavioral response. The capacity to simultaneously map and molecularly define the components of this complex multisynaptic circuit would thus advance our understanding of the determinants of motivated behavior. To accomplish this, we have constructed pseudorabies virus (PRV) strains in which viral propagation and fluorophore expression are activated only after exposure to Cre recombinase. Once activated in Cre-expressing neurons, the virus serially labels chains of presynaptic neurons. Dual injection of GFP and mCherry tracing viruses simultaneously illuminates nigrostriatal and mesolimbic circuitry and shows no overlap, demonstrating that PRV transmission is confined to synaptically connected neurons. To molecularly profile mesolimbic dopamine neurons and their presynaptic inputs, we injected Cre-conditional GFP virus into the NAc of (anti-GFP) nanobody-L10 transgenic mice and immunoprecipitated translating ribosomes from neurons infected after retrograde tracing. Analysis of purified RNA revealed an enrichment of transcripts expressed in neurons of the dorsal raphe nuclei and lateral hypothalamus that project to the mesolimbic dopamine circuit. These studies identify important inputs to the mesolimbic dopamine pathway and further show that PRV circuit-directed translating ribosome affinity purification can be broadly applied to identify molecularly defined neurons comprising complex, multisynaptic circuits.SIGNIFICANCE STATEMENT The mesolimbic dopamine circuit integrates signals from key brain regions to detect and respond to rewarding stimuli. To further define this complex multisynaptic circuit, we constructed a panel of Cre recombinase-activated pseudorabies viruses (PRVs) that enabled retrograde tracing of neural inputs that terminate on Cre-expressing neurons. Using these viruses and Retro-TRAP (translating ribosome affinity purification), a previously reported molecular profiling method, we developed a novel technique that provides anatomic as well as molecular information about the neural components of polysynaptic circuits. We refer to this new method as PRV-Circuit-TRAP (PRV circuit-directed TRAP). Using it, we have identified major projections to the mesolimbic dopamine circuit from the lateral hypothalamus and dorsal raphe nucleus and defined a discrete subset of transcripts expressed in these projecting neurons, which will allow further characterization of this important pathway. Moreover, the method we report is general and can be applied to the study of other neural circuits.
28281665	The clinical diagnosis and symptoms of major depressive disorder (MDD) have been closely associated with impairments in reward processing. In particular, various studies have shown blunted neural and behavioral responses to the experience of reward in depression. However, little is known about whether depression affects individuals' valuation of potential rewards during decision-making, independent from reward experience. To address this question, we used a gambling task and a model-based analytic approach to measure two types of individual sensitivity to reward values in participants with MDD: 'risk preference,' indicating how objective values are subjectively perceived, and 'inverse temperature,' determining the degree to which subjective value differences between options influence participants' choices. On both of these measures of value sensitivity, participants with MDD were comparable to non-psychiatric controls. In addition, both risk preference and inverse temperature were stable over four laboratory visits and comparable between the groups at each visit. Neither valuation measure varied with severity of clinical symptoms in MDD. These data suggest intact and stable value processing in MDD during risky decision-making.
28280884	Mood disorders can be triggered by stress and are characterized by deficits in reward processing, including disrupted reward learning (the ability to modulate behavior according to past rewards). Reward learning is regulated by the anterior cingulate cortex (ACC) and striatal circuits, both of which are implicated in the pathophysiology of mood disorders.Here, we assessed in rats the effects of a potent stressor (social defeat) on reward learning and gene expression in the ACC, ventral tegmental area (VTA), and striatum.	Adult male Wistar rats were trained on an operant probabilistic reward task (PRT) and then exposed to 3 days of social defeat before assessment of reward learning. After testing, the ACC, VTA, and striatum were dissected, and expression of genes previously implicated in stress was assessed.	Social defeat blunted reward learning (manifested as reduced response bias toward a more frequently rewarded stimulus) and was associated with increased nociceptin/orphanin FQ (N/OFQ) peptide mRNA levels in the striatum and decreased Fos mRNA levels in the VTA. Moreover, N/OFQ peptide and nociceptin receptor mRNA levels in the ACC, VTA and striatum were inversely related to reward learning.	The behavioral findings parallel previous data in humans, suggesting that stress similarly disrupts reward learning in both species. Increased striatal N/OFQ mRNA in stressed rats characterized by impaired reward learning is consistent with accumulating evidence that antagonism of nociceptin receptors, which bind N/OFQ, has antidepressant-like effects. These results raise the possibility that nociceptin systems represent a molecular substrate through which stress produces reward learning deficits in mood disorders.	
28279781	Impulsivity is an important personality trait that affects people's lives every day. Because of the complicated structures and various measurements of impulsivity, the conclusion that whether there were gender differences on impulsivity remained controversial. In our study, we used delay discounting and probability discounting to measure impulsive choice and employed stop signal reaction time task (SSRT) to measure impulsive action within the same subjects. No inherent gender differences were found, either on impulsive choice or on impulsive action. However, after adding a working memory (WM) task, we found an interaction between gender and WM: males made more impulsive choices in the delay discounting task, but females remained no change, and this only occurred when the reward amount was large; in the SSRT, the males showed better inhibitory control under the WM load condition, but females did not. These results demonstrate that gender difference does not exist on impulsivity biologically, but the increased working memory load could affect the gender's sense of delay gratification and the ability of inhibitory control differently. These findings can contribute to the studies of gender differences on impulsivity and draw attention to the need for further research that gender factors should be considered more carefully when exploring the effects of working memory.
28279753	Midbrain dopamine neurons play critical roles in reward- and aversion-driven associative learning. However, it is not clear whether they do this by a common mechanism or by separate mechanisms that can be dissociated. In the present study we addressed this question by testing whether a partial lesion of the dopamine neurons of the rat SNc has comparable effects on conditioned place preference (CPP) learning and conditioned place aversion (CPA) learning. Partial lesions of dopamine neurons in the rat substantia nigra pars compacta (SNc) induced by bilateral intranigral infusion of 6-hydroxydopamine (6-OHDA, 3μg/side) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 200μg/side) impaired learning of conditioned place aversion (CPA) without affecting conditioned place preference (CPP) learning. Control experiments demonstrated that these lesions did not impair motor performance and did not alter the hedonic value of the sucrose and quinine. The number of dopamine neurons in the caudal part of the SNc positively correlated with the CPP scores of the 6-OHDA rats and negatively correlated with CPA scores of the SHAM rats. In addition, the CPA scores of the 6-OHDA rats positively correlated with the tissue content of striatal dopamine. Insomuch as reward-driven learning depends on an increase in dopamine release by nigral neurons, these findings show that this mechanism is functional even in rats with a partial lesion of the SNc. On the other hand, if aversion-driven learning depends on a reduction of extracellular dopamine in the striatum, the present study suggests that this mechanism is no longer functional after the partial SNc lesion.
28275359	Phasic activity of midbrain dopamine neurons is currently thought to encapsulate the prediction-error signal described in Sutton and Barto's (1981) model-free reinforcement learning algorithm. This phasic signal is thought to contain information about the quantitative value of reward, which transfers to the reward-predictive cue after learning. This is argued to endow the reward-predictive cue with the value inherent in the reward, motivating behavior toward cues signaling the presence of reward. Yet theoretical and empirical research has implicated prediction-error signaling in learning that extends far beyond a transfer of quantitative value to a reward-predictive cue. Here, we review the research which demonstrates the complexity of how dopaminergic prediction errors facilitate learning. After briefly discussing the literature demonstrating that phasic dopaminergic signals can act in the manner described by Sutton and Barto (1981), we consider how these signals may also influence attentional processing across multiple attentional systems in distinct brain circuits. Then, we discuss how prediction errors encode and promote the development of context-specific associations between cues and rewards. Finally, we consider recent evidence that shows dopaminergic activity contains information about causal relationships between cues and rewards that reflect information garnered from rich associative models of the world that can be adapted in the absence of direct experience. In discussing this research we hope to support the expansion of how dopaminergic prediction errors are thought to contribute to the learning process beyond the traditional concept of transferring quantitative value.
28274677	Irritability, defined as an increased propensity to exhibit increased anger relative to one's peers, is a common clinical problem in youth. Irritability can be conceptualized as aberrant responses to frustration (where frustration is the emotional response to blocked goal attainment) and/or aberrant 'approach' responses to threat. Irritable youth show hyper-reactivity to threat mediated by dysfunction in amygdala, medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), insula, striatum, and association cortex. Irritable youth also show abnormalities in reward learning, cognitive control, and responses to frustration. These abnormalities are mediated by circuitry that includes the inferior frontal gyrus (iFG), striatum, ACC, and parietal cortex. Effective treatments for irritability are lacking, but pathophysiological research could lead to more precisely targeted interventions.
28270751	The introduction of allosteric receptor-receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses. Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription factors which can lead to the formation of specific adapter proteins. The observation of the GPCR heterodimer network (GPCR-HetNet) indicated that the allosteric receptor-receptor interactions dramatically increase GPCR diversity and biased recognition and signaling leading to enhanced specificity in signaling. Dysfunction of the GPCR heteroreceptor complexes can lead to brain disease. The findings of serotonin (5-HT) hetero and isoreceptor complexes in the brain over the last decade give new targets for drug development in major depression. Neuromodulation of neuronal networks in depression via 5-HT, galanin peptides and zinc involve a number of GPCR heteroreceptor complexes in the raphe-hippocampal system: GalR1-5-HT1A, GalR1-5-HT1A-GPR39, GalR1-GalR2, and putative GalR1-GalR2-5-HT1A heteroreceptor complexes. The 5-HT1A receptor protomer remains a receptor enhancing antidepressant actions through its participation in hetero- and homoreceptor complexes listed above in balance with each other. In depression, neuromodulation of neuronal networks in the raphe-hippocampal system and the cortical regions via 5-HT and fibroblast growth factor 2 involves either FGFR1-5-HT1A heteroreceptor complexes or the 5-HT isoreceptor complexes such as 5-HT1A-5-HT7 and 5-HT1A-5-HT2A. Neuromodulation of neuronal networks in cocaine use disorder via dopamine (DA) and adenosine signals involve A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complexes in the dorsal and ventral striatum. The excitatory modulation by A2AR agonists of the ventral striato-pallidal GABA anti-reward system via targeting the A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complex holds high promise as a new way to treat cocaine use disorders. Neuromodulation of neuronal networks in schizophrenia via DA, adenosine, glutamate, 5-HT and neurotensin peptides and oxytocin, involving A2AR-D2R, D2R-NMDAR, A2AR-D2R-mGluR5, D2R-5-HT2A and D2R-oxytocinR heteroreceptor complexes opens up a new world of D2R protomer targets in the listed heterocomplexes for treatment of positive, negative and cognitive symptoms of schizophrenia.
28270567	Predicting future reward is paramount to performing an optimal action. Although a number of brain areas are known to encode such predictions, a detailed account of how the associated representations evolve over time is lacking. Here, we address this question using human magnetoencephalography (MEG) and multivariate analyses of instantaneous activity in reconstructed sources. We overtrained participants on a simple instrumental reward learning task where geometric cues predicted a distribution of possible rewards, from which a sample was revealed 2000 ms later. We show that predicted mean reward (i.e., expected value), and predicted reward variability (i.e., economic risk), are encoded distinctly. Early on, representations of mean reward are seen in parietal and visual areas, and later in frontal regions with orbitofrontal cortex emerging last. Strikingly, an encoding of reward variability emerges simultaneously in parietal/sensory and frontal sources and later than mean reward encoding. An orbitofrontal variability encoding emerged around the same time as that seen for mean reward. Crucially, cross-prediction showed that mean reward and variability representations are distinct and also revealed that instantaneous representations become more stable over time. Across sources, the best fitting metric for variability signals was coefficient of variation (rather than SD or variance), but distinct best metrics were seen for individual brain regions. Our data demonstrate how a dynamic encoding of probabilistic reward prediction unfolds in the brain both in time and space.SIGNIFICANCE STATEMENT Predicting future reward is paramount to optimal behavior. To gain insight into the underlying neural computations, we investigate how reward representations in the brain arise over time. Using magnetoencephalography, we show that a representation of predicted mean reward emerges early in parietal/sensory regions and later in frontal cortex. In contrast, predicted reward variability representations appear in most regions at the same time, and slightly later than for mean reward. For both features, representations dynamically change >1000 ms before stabilizing. The best metric for encoding variability is coefficient of variation, with heterogeneity in this encoding seen between brain areas. The results provide novel insights into the emergence of predictive reward representations.
28270566	Cognitive impairments, uncontrolled drinking, and neuropathological cortical changes characterize alcohol use disorder. Dysfunction of the orbitofrontal cortex (OFC), a critical cortical subregion that controls learning, decision-making, and prediction of reward outcomes, contributes to executive cognitive function deficits in alcoholic individuals. Electrophysiological and quantitative synaptomics techniques were used to test the hypothesis that heavy drinking produces neuroadaptations in the macaque OFC. Integrative bioinformatics and reverse genetic approaches were used to identify and validate synaptic proteins with novel links to heavy drinking in BXD mice. In drinking monkeys, evoked firing of OFC pyramidal neurons was reduced, whereas the amplitude and frequency of postsynaptic currents were enhanced compared with controls. Bath application of alcohol reduced evoked firing in neurons from control monkeys, but not drinking monkeys. Profiling of the OFC synaptome identified alcohol-sensitive proteins that control glutamate release (e.g., SV2A, synaptogyrin-1) and postsynaptic signaling (e.g., GluA1, PRRT2) with no changes in synaptic GABAergic proteins. Western blot analysis confirmed the increase in GluA1 expression in drinking monkeys. An exploratory analysis of the OFC synaptome found cross-species genetic links to alcohol intake in discrete proteins (e.g., C2CD2L, DIRAS2) that discriminated between low- and heavy-drinking monkeys. Validation studies revealed that BXD mouse strains with the D allele at the C2cd2l interval drank less alcohol than B allele strains. Thus, by profiling of the OFC synaptome, we identified changes in proteins controlling glutamate release and postsynaptic signaling and discovered several proteins related to heavy drinking that have potential as novel targets for treating alcohol use disorder.SIGNIFICANCE STATEMENT Clinical research identified cognitive deficits in alcoholic individuals as a risk factor for relapse, and alcoholic individuals display deficits on cognitive tasks that are dependent upon the orbitofrontal cortex (OFC). To identify neurobiological mechanisms that underpin OFC dysfunction, this study used electrophysiology and integrative synaptomics in a translational nonhuman primate model of heavy alcohol consumption. We found adaptations in synaptic proteins that control glutamatergic signaling in chronically drinking monkeys. Our functional genomic exploratory analyses identified proteins with genetic links to alcohol and cocaine intake across mice, monkeys, and humans. Future work is necessary to determine whether targeting these novel targets reduces excessive and harmful levels of alcohol drinking.
28268958	Encoding of reward valence has been shown in various brain regions, including deep structures such as the substantia nigra as well as cortical structures such as the orbitofrontal cortex. While the correlation between these signals and reward valence have been shown in aggregated data comprised of many trials, little work has been done investigating the feasibility of decoding reward valence on a single trial basis. Towards this goal, one non-human primate (macaca radiata) was trained to grip and hold a target level of force in order to earn zero, one, two, or three juice rewards. The animal was informed of the impending result before reward delivery by means of a visual cue. Neural data was recorded from primary somatosensory cortex (S1) during these experiments and firing rate histograms were created following the appearance of the visual cue and used as input to a variety of classifiers. Reward valence was decoded with high levels of accuracy from S1 both in the post-cue and post-reward periods. Additionally, the proportion of units showing significant changes in their firing rates was influenced in a predictable way based on reward valence. The existence of a signal within S1 cortex that encodes reward valence could have utility for implementing reinforcement learning algorithms for brain machine interfaces. The ability to decode this reward signal in real time with limited data is paramount to the usability of such a signal in practical applications.
28268275	Intermittent feedback control for stabilizing human upright stance is a promising strategy, alternative to the standard time-continuous stiffness control. Here we show that such an intermittent controller can be established naturally through reinforcement learning. To this end, we used a single inverted pendulum model of the upright posture and a very simple reward function that gives a certain amount of punishments when the inverted pendulum falls or changes its position in the state space. We found that the acquired feedback controller exhibits hallmarks of the intermittent feedback control strategy, namely the action of the feedback controller is switched-off intermittently when the state of the pendulum is located near the stable manifold of the unstable saddle-type upright equilibrium of the inverted pendulum with no active control: this action provides an opportunity to exploit transiently converging dynamics toward the unstable upright position with no help of the active feedback control. We then speculate about a possible physiological mechanism of such reinforcement learning, and suggest that it may be related to the neural activity in the pedunculopontine tegmental nucleus (PPN) of the brainstem. This hypothesis is supported by recent evidence indicating that PPN might play critical roles for generation and regulation of postural tonus, reward prediction, as well as postural instability in patients with Parkinson's disease.
28268267	Consistent repetitions of an action lead to plastic change in the motor cortex and cause shift in the direction of future movements. This process is known as use-dependent plasticity (UDP), one of the basic forms of the motor memory. We have recently demonstrated in a physiological study that success-related reinforcement signals could modulate the strength of UDP. We tested this idea by developing a computational approach that modeled the shift in the direction of future action as a change in preferred direction of population activity of neurons in the primary motor cortex. The rate of the change follows a modified temporal difference reinforcement learning algorithm, in which the learning policy is based on comparison between what reward the population experiences on a particular trial, and what it had expected on the basis of its previous learning. By using this model, we were able to characterize the nature of learning and retention of UDP. Exploring the relationship between reinforcement and UDP constitutes a crucial step toward understanding the basic blocks involved in the formation of motor memories.
28267655	The purpose of the present study was to investigate the cognitive processes underlying texting while driving. A sample of 120 college students completed a survey to assess how frequently they send and read a text message while driving. Based on this information, students were assigned to one of two groups: 20 students who frequently text while driving and 20 matched-control students who infrequently text while driving but were similar in gender, age, years of education, and years driving. The groups were compared on the extent to which they differed in self-reported measures of executive function and impulsivity. The groups were also compared on a behavioral measure of impulsivity: the extent to which they discounted hypothetical monetary rewards as a function of the delay. For this measure, the students made repeated choices between smaller monetary rewards available immediately and larger rewards available after delays ranging from 1 week to 6 months. The results show that the group of students who frequently text while driving showed (a) significantly lower levels of executive function and (b) higher levels of self-reported impulsivity, although the groups did not differ significantly on the behavioral measure of impulsivity. These results support a general conclusion that drivers with lower levels of executive function and higher levels of impulsivity are more likely to text while driving.
28267151	Dopamine signaling is essential for reward learning and fear-related learning, and thought to be involved in neuropsychiatric diseases. However, the molecular mechanisms underlying the regulation of dopamine responsiveness is unclear. Here we show the critical roles of Notch/RBP-J signaling in the regulation of dopamine responsiveness in the striatum. Notch/RBP-J signaling regulates various neural cell fate specification, and neuronal functions in the adult central nervous system. Conditional deletion of RBP-J specifically in neuronal cells causes enhanced response to apomorphine, a non-selective dopamine agonist, and SKF38393, a D1 agonist, and impaired dopamine-dependent instrumental avoidance learning, which is corrected by SCH23390, a D1 antagonist. RBP-J deficiency drastically reduced dopamine release in the striatum and caused a subtle decrease in the number of dopaminergic neurons. Lentivirus-mediated gene transfer experiments showed that RBP-J deficiency in the striatum was sufficient for these deficits. These findings demonstrated that Notch/RBP-J signaling regulates dopamine responsiveness in the striatum, which may explain the mechanism whereby Notch/RBP-J signaling affects an individual's susceptibility to neuropsychiatric disease.
28263413	The anteromedial part of the bed nucleus of the stria terminalis (amBNST) is a limbic structure innervating the ventral tegmental area (VTA) that is remarkably constant across species. The amBNST modulates fear and anxiety, and activation of VTA dopamine (DA) neurons by amBNST afferents seems to be the way by which stress controls motivational states associated with reward or aversion. Because fear learning and anxiety states can be expressed differently between rats and mice, we compared the functional connectivity between amBNST and the VTA-DA neurons in both species using consistent methodological approaches. Using a combination of in vivo electrophysiological, neuroanatomical tracing and laser capture approaches we explored the BNST influences on VTA-DA neuron activity. First, we characterised in rats the molecular phenotype of the amBNST neurons projecting to the VTA. We found that this projection is complex, including both GABAergic and glutamatergic neurons. Then, VTA injections of a conventional retrograde tracer, the β-sub-unit of the cholera toxin (CTB), revealed a stronger BNST-VTA projection in mice than in rats. Finally, electrical stimulations of the BNST during VTA-DA neuron recording demonstrated a more potent excitatory influence of the amBNST on VTA-DA neuron activity in rats than in mice. These data illustrate anatomically, but also functionally, a significant difference between rats and mice in the amBNST-VTA pathway. More generally, together with previous findings, our research highlights the importance of species differences for the interpretation and the generalisation of research data.
28263301	Midbrain dopamine neurons signal reward prediction error (RPE), or actual minus expected reward. The temporal difference (TD) learning model has been a cornerstone in understanding how dopamine RPEs could drive associative learning. Classically, TD learning imparts value to features that serially track elapsed time relative to observable stimuli. In the real world, however, sensory stimuli provide ambiguous information about the hidden state of the environment, leading to the proposal that TD learning might instead compute a value signal based on an inferred distribution of hidden states (a 'belief state'). Here we asked whether dopaminergic signaling supports a TD learning framework that operates over hidden states. We found that dopamine signaling showed a notable difference between two tasks that differed only with respect to whether reward was delivered in a deterministic manner. Our results favor an associative learning rule that combines cached values with hidden-state inference.
28261137	Many advances have been made over the last decades in describing, on the one hand, the link between reward-based learning and decision-making, and on the other hand, the link between impulsivity and decision-making. However, the association between reward-based learning and impulsivity remains poorly understood. In this study, we evaluated the association between individual differences in loss-minimizing and gain-maximizing behavior in a learning-based probabilistic decision-making task and individual differences in cognitive impulsivity. We found that low cognitive impulsivity was associated both with a better performance minimizing losses and maximizing gains during the task. These associations remained significant after controlling for mathematical skills and gender as potential confounders. We discuss potential mechanisms through which cognitive impulsivity might interact with reward-based learning and decision-making.
28261071	Anticipation and delivery of rewards improves memory formation, but little effort has been made to disentangle their respective contributions to memory enhancement. Moreover, it has been suggested that the effects of reward on memory are mediated by dopaminergic influences on hippocampal plasticity. Yet, evidence linking memory improvements to actual reward computations reflected in the activity of the dopaminergic system, i.e., prediction errors and expected values, is scarce and inconclusive. For example, different previous studies reported that the magnitude of prediction errors during a reinforcement learning task was a positive, negative, or non-significant predictor of successfully encoding simultaneously presented images. Individual sensitivities to reward and punishment have been found to influence the activation of the dopaminergic reward system and could therefore help explain these seemingly discrepant results. Here, we used a novel associative memory task combined with computational modeling and showed independent effects of reward-delivery and reward-anticipation on memory. Strikingly, the computational approach revealed positive influences from both reward delivery, as mediated by prediction error magnitude, and reward anticipation, as mediated by magnitude of expected value, even in the absence of behavioral effects when analyzed using standard methods, i.e., by collapsing memory performance across trials within conditions. We additionally measured trait estimates of reward and punishment sensitivity and found that individuals with increased reward (vs. punishment) sensitivity had better memory for associations encoded during positive (vs. negative) prediction errors when tested after 20 min, but a negative trend when tested after 24 h. In conclusion, modeling trial-by-trial fluctuations in the magnitude of reward, as we did here for prediction errors and expected value computations, provides a comprehensive and biologically plausible description of the dynamic interplay between reward, dopamine, and associative memory formation. Our results also underline the importance of considering individual traits when assessing reward-related influences on memory.
28260249	Models of attention often distinguish among attention subtypes, with classic models separating orienting, switching, and sustaining functions. Compared with other forms of attention, the neurophysiological basis of sustaining attention has received far less notice, yet it is known that momentary failures of sustained attention can have far-ranging negative effects in healthy individuals, and lasting sustained attention deficits are pervasive in clinical populations. In recent years, however, there has been increased interest in characterizing moment-to-moment fluctuations in sustained attention, in addition to the overall vigilance decrement, and understanding how these neurocognitive systems change over the life span and across various clinical populations. The use of novel neuroimaging paradigms and statistical approaches has allowed for better characterization of the neural networks supporting sustained attention and has highlighted dynamic interactions within and across multiple distributed networks that predict behavioral performance. These advances have also provided potential biomarkers to identify individuals with sustained attention deficits. These findings have led to new theoretical models explaining why sustaining focused attention is a challenge for individuals and form the basis for the next generation of sustained attention research, which seeks to accurately diagnose and develop theoretically driven treatments for sustained attention deficits that affect a variety of clinical populations.
28259655	The brain reward system is known to be the neuroanatomical basis of addictive behaviors. Systemic, cognitive and functional consequences of crack-cocaine addiction are clinically evident, but the neuroanatomical underpinnigs are not yet well understood. We aim to assess the neuroanatomical differences between crack-cocaine patients and paired healthy controls. Fifteen crack-cocaine patients recently discharged from the Addiction Unit of the Hospital de Clínicas de Porto Alegre and fifteen controls matched for gender, age, education and handedness were scanned using a Philips Achieva 1.5T MRI equipment. All subjects had negative positive tests at admission and patients had at least 15days of detoxification. Active neurologic, inflammatory, cardiovascular or systemic comorbidities were excluded. Subcortical structure volumes were determined using Freesurfer v5.1. Controls had greater volumes in the left accumbens (t=3.604, df=28, p=0.001) compared to patients. Right accumbens volumes were also greater in controls (t=2.098, df=28, p=0.045). Groups did not differ regarding intracranial volumes (p=0.514). This preliminary and innovative data on crack-cocaine dependence suggests that there is a volumetric reduction of the accumbens, a region that has a significant role in motivation, pleasure, reward and reinforcement learning, and it could play a central role in the pathophysiology of this drug addiction. Therefore, these findings may contribute to understand some behavioral and cognitive deficits in this population.
28255941	Identifying potential risk factors for problem gambling (PG) is of primary importance for planning preventive and therapeutic interventions. We illustrate a new approach based on the combination of standard logistic regression and an innovative method of supervised data mining (Logic Learning Machine or LLM). Data were taken from a pilot cross-sectional study to identify subjects with PG behaviour, assessed by two internationally validated scales (SOGS and Lie/Bet). Information was obtained from 251 gamblers recruited in six betting establishments. Data on socio-demographic characteristics, lifestyle and cognitive-related factors, and type, place and frequency of preferred gambling were obtained by a self-administered questionnaire. The following variables associated with PG were identified: instant gratification games, alcohol abuse, cognitive distortion, illegal behaviours and having started gambling with a relative or a friend. Furthermore, the combination of LLM and LR indicated the presence of two different types of PG, namely: (a) daily gamblers, more prone to illegal behaviour, with poor money management skills and who started gambling at an early age, and (b) non-daily gamblers, characterised by superstitious beliefs and a higher preference for immediate reward games. Finally, instant gratification games were strongly associated with the number of games usually played. Studies on gamblers habitually frequently betting shops are rare. The finding of different types of PG by habitual gamblers deserves further analysis in larger studies. Advanced data mining algorithms, like LLM, are powerful tools and potentially useful in identifying risk factors for PG.
28250186	While numerous studies have demonstrated that infants and adults preferentially orient to social stimuli, it remains unclear as to what drives such preferential orienting. It has been suggested that the learned association between social cues and subsequent reward delivery might shape such social orienting. Using a novel, spontaneous indication of reinforcement learning (with the use of a gaze contingent reward-learning task), we investigated whether children and adults' orienting towards social and non-social visual cues can be elicited by the association between participants' visual attention and a rewarding outcome. Critically, we assessed whether the engaging nature of the social cues influences the process of reinforcement learning. Both children and adults learned to orient more often to the visual cues associated with reward delivery, demonstrating that cue-reward association reinforced visual orienting. More importantly, when the reward-predictive cue was social and engaging, both children and adults learned the cue-reward association faster and more efficiently than when the reward-predictive cue was social but non-engaging. These new findings indicate that social engaging cues have a positive incentive value. This could possibly be because they usually coincide with positive outcomes in real life, which could partly drive the development of social orienting.
28248958	The ability to make optimal decisions depends on evaluating the expected rewards associated with different potential actions. This process is critically dependent on the fidelity with which reward value information can be maintained in the nervous system. Here we directly probe the fidelity of value representation following a standard reinforcement learning task. The results demonstrate a previously-unrecognized bias in the representation of value: extreme reward values, both low and high, are stored significantly more accurately and precisely than intermediate rewards. The symmetry between low and high rewards pertained despite substantially higher frequency of exposure to high rewards, resulting from preferential exploitation of more rewarding options. The observed variation in fidelity of value representation retrospectively predicted performance on the reinforcement learning task, demonstrating that the bias in representation has an impact on decision-making. A second experiment in which one or other extreme-valued option was omitted from the learning sequence showed that representational fidelity is primarily determined by the relative position of an encoded value on the scale of rewards experienced during learning. Both variability and guessing decreased with the reduction in the number of options, consistent with allocation of a limited representational resource. These findings have implications for existing models of reward-based learning, which typically assume defectless representation of reward value.
28245532	The mushroom bodies (MBs) are insect brain regions important for sensory integration, learning, and memory. In adult worker honey bees (Apis mellifera), the volume of neuropil associated with the MBs is larger in experienced foragers compared with hive bees and less experienced foragers. In addition, the characteristic synaptic structures of the calycal neuropils, the microglomeruli, are larger but present at lower density in 35-day-old foragers relative to 1-day-old workers. Age- and experience-based changes in plasticity of the MBs are assumed to support performance of challenging tasks, but the behavioral consequences of brain plasticity in insects are rarely examined. In this study, foragers were recruited from a field hive to a patch comprising two colors of otherwise identical artificial flowers. Flowers of one color contained a sucrose reward mimicking nectar; flowers of the second were empty. Task difficulty was adjusted by changing flower colors according to the principle of honey bee color vision space. Microglomerular volume and density in the lip (olfactory inputs) and collar (visual inputs) compartments of the MB calyces were analyzed using anti-synapsin I immunolabeling and laser scanning confocal microscopy. Foragers displayed significant variation in microglomerular volume and density, but no correlation was found between these synaptic attributes and foraging performance. © 2017 Wiley Periodicals, Inc. Develop Neurobiol, 2017.
28245497	High performance in well-practiced, everyday tasks-driving, sports, gaming-suggests a kind of procedural attention that can allocate processing resources to behaviorally relevant information in an unsupervised manner. Here we show that training can lead to a new, automatic attentional selection rule that operates in the absence of bottom-up, salience-driven triggers and willful top-down selection. Taking advantage of the fact that attention modulates motion aftereffects, observers were presented with a bivectorial display with overlapping, iso-salient red and green dot fields moving to the right and left, respectively, while distracted by a demanding auditory two-back memory task. Before training, since the motion vectors canceled each other out, no net motion aftereffect (MAE) was found. However, after 3 days (0.5 hr/day) of training, during which observers practiced selectively attending to the red, rightward field, a significant net MAE was observed-even when top-down selection was again distracted. Further experiments showed that these results were not due to perceptual learning, and that the new rule targeted the motion, and not the color of the target dot field, and global, not local, motion signals; thus, the new rule was: "select the rightward field." This study builds on recent work on selection history-driven and reward-driven biases, but uses a novel paradigm where the allocation of visual processing resources are measured passively, offline, and when the observer's ability to execute top-down selection is defeated.
28245495	Our state of arousal fluctuates from moment to moment-fluctuations that can have profound impacts on behavior. Arousal has been proposed to play a powerful, widespread role in the brain, influencing processes as far ranging as perception, memory, learning, and decision making. Although arousal clearly plays a critical role in modulating behavior, the mechanisms underlying this modulation remain poorly understood. To address this knowledge gap, we examined the modulatory role of arousal on one of the cornerstones of visual perception: contrast perception. Using a reward-driven paradigm to manipulate arousal state, we discovered that elevated arousal state substantially enhances visual sensitivity, incurring a multiplicative modulation of contrast response. Contrast defines vision, determining whether objects appear visible or invisible to us, and these results indicate that one of the consequences of decreased arousal state is an impaired ability to visually process our environment.
28240742	DNA methyltransferases (Dnmts) - epigenetic writers catalyzing the transfer of methyl-groups to cytosine (DNA methylation) - regulate different aspects of memory formation in many animal species. In honeybees, Dnmt activity is required to adjust the specificity of olfactory reward memories and bees' relearning capability. The physiological relevance of Dnmt-mediated DNA methylation in neural networks, however, remains unknown. Here, we investigated how Dnmt activity impacts neuroplasticity in the bees' primary olfactory center, the antennal lobe (AL) an equivalent of the vertebrate olfactory bulb. The AL is crucial for odor discrimination, an indispensable process in forming specific odor memories. Using pharmacological inhibition, we demonstrate that Dnmt activity influences neural network properties during memory formation in vivo. We show that Dnmt activity promotes fast odor pattern separation in trained bees. Furthermore, Dnmt activity during memory formation increases both the number of responding glomeruli and the response magnitude to a novel odor. These data suggest that Dnmt activity is necessary for a form of homoeostatic network control which might involve inhibitory interneurons in the AL network.
28240598	For brain-machine interfaces (BMI) to be used in activities of daily living by paralyzed individuals, the BMI should be as autonomous as possible. One of the challenges is how the feedback is extracted and utilized in the BMI. Our long-term goal is to create autonomous BMIs that can utilize an evaluative feedback from the brain to update the decoding algorithm and use it intelligently in order to adapt the decoder. In this study, we show how to extract the necessary evaluative feedback from a biologically realistic (synthetic) source, use both the quantity and the quality of the feedback, and how that feedback information can be incorporated into a reinforcement learning (RL) controller architecture to maximize its performance.Motivated by the perception-action-reward cycle (PARC) in the brain which links reward for cognitive decision making and goal-directed behavior, we used a reward-based RL architecture named Actor-Critic RL as the model. Instead of using an error signal towards building an autonomous BMI, we envision to use a reward signal from the nucleus accumbens (NAcc) which plays a key role in the linking of reward to motor behaviors. To deal with the complexity and non-stationarity of biological reward signals, we used a confidence metric which was used to indicate the degree of feedback accuracy. This confidence was added to the Actor's weight update equation in the RL controller architecture. If the confidence was high (>0.2), the BMI decoder used this feedback to update its parameters. However, when the confidence was low, the BMI decoder ignored the feedback and did not update its parameters. The range between high confidence and low confidence was termed as the 'ambiguous' region. When the feedback was within this region, the BMI decoder updated its weight at a lower rate than when fully confident, which was decided by the confidence. We used two biologically realistic models to generate synthetic data for MI (Izhikevich model) and NAcc (Humphries model) to validate proposed controller architecture.	In this work, we show how the overall performance of the BMI was improved by using a threshold close to the decision boundary to reject erroneous feedback. Additionally, we show the stability of the system improved when the feedback was used with a threshold.	The result of this study is a step towards making BMIs autonomous. While our method is not fully autonomous, the results demonstrate that extensive training times necessary at the beginning of each BMI session can be significantly decreased. In our approach, decoder training time was only limited to 10 trials in the first BMI session. Subsequent sessions used previous session weights to initialize the decoder. We also present a method where the use of a threshold can be applied to any decoder with a feedback signal that is less than perfect so that erroneous feedback can be avoided and the stability of the system can be increased.	
28239676	Midbrain dopaminergic neurons code a computational quantity, reward prediction error (RPE), which has been causally related to learning. Recently, this insight has been leveraged to link phenomenological and biological levels of understanding in psychiatric disorders, such as schizophrenia. However, results have been mixed, possibly due to small sample sizes. Here we present results from two studies with relatively large Ns to assess VS RPE in schizophrenia.In the current study we analyzed data from two independent studies, involving a total of 87 chronic medicated schizophrenia patients and 61 controls. Subjects completed a probabilistic reinforcement-learning task in conjunction with fMRI scanning. We fit each participant's choice behavior to a Q-learning model and derived trial-wise RPEs. We then modeled BOLD signal data with parametric regressor functions using these values to determine whether patient and control groups differed in prediction-error-related BOLD signal modulations.	Both groups demonstrated robust VS RPE BOLD activations. Interestingly, these BOLD activation patterns did not differ between groups in either study. This was true when we included all participants in the analysis, as well as when we excluded participants whose data was not sufficiently fit by the models.	These data demonstrate the utility of computational methods in isolating/testing underlying mechanisms of interest in psychiatric disorders. Importantly, similar VS RPE signal encoding across groups suggests that this mechanism does not drive task deficits in these patients. Deficits may instead stem from aberrant prefrontal/parietal circuits associated with maintenance and selection of goal-relevant information.	
28236171	The anterior cingulate cortex (ACC) is commonly associated with cognitive control and decision making, but its specific function is highly debated. To explore a recent theory that the ACC learns the reward values of task contexts (Holroyd & McClure in Psychological Review, 122, 54-83, 2015; Holroyd & Yeung in Trends in Cognitive Sciences, 16, 122-128, 2012), we recorded the event-related brain potentials (ERPs) from participants as they played a novel gambling task. The participants were first required to select from among three games in one "virtual casino," and subsequently they were required to select from among three different games in a different virtual casino; unbeknownst to them, the payoffs for the games were higher in one casino than in the other. Analysis of the reward positivity, an ERP component believed to reflect reward-related signals carried to the ACC by the midbrain dopamine system, revealed that the ACC is sensitive to differences in the reward values associated with both the casinos and the games inside the casinos, indicating that participants learned the values of the contexts in which rewards were delivered. These results highlight the importance of the ACC in learning the reward values of task contexts in order to guide action selection.
28232794	Rats fed high fat diets have been shown to be impaired in hippocampal-dependent behavioral tasks, such as spatial recognition in the Y-maze and reference memory in the Morris water maze (MWM). It is clear from previous studies, however, that motivation and reward factor into the memory deficits associated with obesity and high-fat diet consumption, and that the prefrontal cortex and striatum and neurotransmitter dopamine play important roles in cognitive performance. In this series of studies we extend our research to investigate the effect of a high fat diet on striatal neurochemistry and performance in the delayed spatial win-shift radial arm maze task, a paradigm highly reliant on dopamine-rich brain regions, such as the striatum after high fat diet consumption. Memory performance, neuronal activation and brain dopaminergic levels were compared in rats fed a "Western" (21% fat, 0.15% cholesterol) chow diet compared to normal diet (6% fat, 0.15% cholesterol)-fed controls. Twelve weeks of dietary manipulation produced an increase in weight in western diet-fed rats, but did not affect learning and performance in the delayed spatial win-shift radial arm maze task. Concurrently, there was an observed decrease in dopamine levels in the striatum and a reduction of dopamine turnover in the hippocampus in western diet-fed rats. In a separate cohort of rats Fos levels were measured after rats had been placed in a novel arena and allowed to explore freely. In normal rats, this exposure to a unique environment did not affect neuronal activation. In contrast, rats fed a western diet were found to have significantly increased Fos expression in the striatum, but not prefrontal cortex or hippocampus. Our study demonstrates that while western diet consumption in rats produces weight gain and brain neuronal and neurotransmitter changes, it did not affect performance in the delayed spatial win-shift paradigm in the radial arm maze. We conclude that modeling the cognitive decline-obesity relationship is complex with considerations, of type of memory, behavioral task and dietary intervention (fat, fat and sugar, sugar, and cafeteria diets) all adding to our overall understanding.
28232788	Motor imagery (MI) activates the sensorimotor system independent of actual movements and might be facilitated by neurofeedback. Knowledge on the interaction between feedback modality and the involved frequency bands during MI-related brain self-regulation is still scarce. Previous studies compared the cortical activity during the MI task with concurrent feedback (MI with feedback condition) to cortical activity during the relaxation task where no feedback was provided (relaxation without feedback condition). The observed differences might, therefore, be related to either the task or the feedback. A proper comparison would necessitate studying a relaxation condition with feedback and a MI task condition without feedback as well. Right-handed healthy subjects performed two tasks, i.e., MI and relaxation, in alternating order. Each of the tasks (MI vs. relaxation) was studied with and without feedback. The respective event-driven oscillatory activity, i.e., sensorimotor desynchronization (during MI) or synchronization (during relaxation), was rewarded with contingent feedback. Importantly, feedback onset was delayed to study the task-related cortical activity in the absence of feedback provision during the delay period. The reward modality was alternated every 15 trials between proprioceptive and visual feedback. Proprioceptive input was superior to visual input to increase the range of task-related spectral perturbations in the α- and β-band, and was necessary to consistently achieve MI-related sensorimotor desynchronization (ERD) significantly below baseline. These effects occurred in task periods without feedback as well. The increased accuracy and duration of learned brain self-regulation achieved in the proprioceptive condition was specific to the β-band. MI-related operant learning of brain self-regulation is facilitated by proprioceptive feedback and mediated in the sensorimotor β-band.
28232576	We explored bees' behavioral flexibility in a task that required transporting a small ball to a defined location to gain a reward. Bees were pretrained to know the correct location of the ball. Subsequently, to obtain a reward, bees had to move a displaced ball to the defined location. Bees that observed demonstration of the technique from a live or model demonstrator learned the task more efficiently than did bees observing a "ghost" demonstration (ball moved via magnet) or without demonstration. Instead of copying demonstrators moving balls over long distances, observers solved the task more efficiently, using the ball positioned closest to the target, even if it was of a different color than the one previously observed. Such unprecedented cognitive flexibility hints that entirely novel behaviors could emerge relatively swiftly in species whose lifestyle demands advanced learning abilities, should relevant ecological pressures arise.
28231717	Anorexia nervosa is a psychiatric disorder of unknown etiology. Understanding associations between behavior and neurobiology is important in treatment development. Using a novel monetary reward task during functional magnetic resonance brain imaging, the authors tested how brain reward learning in adolescent anorexia nervosa changes with weight restoration.Female adolescents with anorexia nervosa (N=21; mean age, 16.4 years [SD=1.9]) underwent functional MRI (fMRI) before and after treatment; similarly, healthy female control adolescents (N=21; mean age, 15.2 years [SD=2.4]) underwent fMRI on two occasions. Brain function was tested using the reward prediction error construct, a computational model for reward receipt and omission related to motivation and neural dopamine responsiveness.	Compared with the control group, the anorexia nervosa group exhibited greater brain response 1) for prediction error regression within the caudate, ventral caudate/nucleus accumbens, and anterior and posterior insula, 2) to unexpected reward receipt in the anterior and posterior insula, and 3) to unexpected reward omission in the caudate body. Prediction error and unexpected reward omission response tended to normalize with treatment, while unexpected reward receipt response remained significantly elevated. Greater caudate prediction error response when underweight was associated with lower weight gain during treatment. Punishment sensitivity correlated positively with ventral caudate prediction error response.	Reward system responsiveness is elevated in adolescent anorexia nervosa when underweight and after weight restoration. Heightened prediction error activity in brain reward regions may represent a phenotype of adolescent anorexia nervosa that does not respond well to treatment. Prediction error response could be a neurobiological marker of illness severity that can indicate individual treatment needs.	
28228742	Children suffering from attention-deficit hyperactivity disorder (ADHD) often also display impaired learning and memory. Previous research has documented aberrant reward processing in ADHD as well as impaired sleep-dependent consolidation of declarative memory. We investigated whether sleep also fosters the consolidation of behavior learned by probabilistic reward and whether ADHD patients with a comorbid disorder of social behavior show deficits in this memory domain, too. A group of 17 ADHD patients with comorbid disorders of social behavior aged 8-12 years and healthy controls matched for age, IQ, and handedness took part in the experiment. During the encoding task, children worked on a probabilistic learning task acquiring behavioral preferences for stimuli rewarded most often. After a 12-hr retention interval of either sleep at night or wakefulness during the day, a reversal task was presented where the contingencies were reversed. Consolidation of rewarded behavior is indicated by greater resistance to reversal learning. We found that healthy children consolidate rewarded behavior better during a night of sleep than during a day awake and that the sleep-dependent consolidation of rewarded behavior by trend correlates with non-REM sleep but not with REM sleep. In contrast, children with ADHD and comorbid disorders of social behavior do not show sleep-dependent consolidation of rewarded behavior. Moreover, their consolidation of rewarded behavior does not correlate with sleep. The results indicate that dysfunctional sleep in children suffering from ADHD and disorders of social behavior might be a crucial factor in the consolidation of behavior learned by reward.
28225752	The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species. In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus. While connectivity among these structures contributes to appetitive behaviours, how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control reward-seeking behaviour through the opposing activities of projection-specific cell populations.
28225034	The laboratory study of how humans and other animals trade-off value and time has a long and storied history, and is the subject of a vast literature. However, despite a long history of study, there is no agreed upon mechanistic explanation of how intertemporal choice preferences arise. Several theorists have recently proposed model-based reinforcement learning as a candidate framework. This framework describes a suite of algorithms by which a model of the environment, in the form of a state transition function and reward function, can be converted on-line into a decision. The state transition function allows the model-based system to make decisions based on projected future states, while the reward function assigns value to each state, together capturing the necessary components for successful intertemporal choice. Empirical work has also pointed to a possible relationship between increased prospection and reduced discounting. In the current paper, we look for direct evidence of a relationship between temporal discounting and model-based control in a large new data set (n = 168). However, testing the relationship under several different modeling formulations revealed no indication that the two quantities are related.
28220089	"Distress disorders," which include generalized anxiety disorder and major depression are often highly comorbid with each other and appear to be characterized by common temperamental features that reflect heightened sensitivity to underlying motivational systems related to threat/safety and reward/loss. Further, individuals with distress disorders tend to utilize self-referential processes (e.g., worry, rumination, self-criticism) in a maladaptive attempt to respond to motivationally relevant distress, often resulting in suboptimal contextual learning. Despite the success of cognitive behavioral therapies for emotional disorders, a sizable subgroup of patients with distress disorders fail to evidence adequate treatment response. Emotion Regulation Therapy (ERT) is a theoretically derived, evidence based, treatment that integrates principles (e.g., skills training, exposure) from traditional and contemporary therapies with findings from basic and translational affective science to offer a framework for improving intervention by focusing on the motivational responses and corresponding regulatory characteristics of individuals with high levels of chronic distress. Open and randomized controlled trials have demonstrated preliminary support for the utility of ERT as reflected by strong effect sizes comparable to and exceeding established intervention approaches. In addition, pilot findings support the role of underlying proposed mechanisms in this efficacious response. This article presents the functional model associated with ERT and describes the proposed mechanisms of the treatment. Additionally, a clinical case is presented, allowing the reader to gain a greater applied understanding of the different components of the ERT model and treatment.
28215543	Emotional eating, or eating in response to negative emotions rather than internal hunger cues, has been related to many maladaptive eating patterns that contribute to weight gain and obesity. The parent feeding practice of use of food as a reward is positively associated with children emotionally overeating, yet, little is known as to the potential behavioral mechanism linking these behaviors. The current study examined the mediating role of child self-regulation of eating in the relationship between parental use of food as a reward and child emotional overeating. Parents of preschool aged children (n = 254) completed online questionnaires targeting parent feeding practices, child eating behaviors, and child self-regulation in eating. Mediation was assessed with Hayes' PROCESS macros in SPSS. Results demonstrated that the relationship between parental use of food as a reward and child emotional overeating was partially mediated by child self-regulation in eating, even after controlling for parent and child gender, household income, and race/ethnicity. In summary, parental use of food as a reward leads to children's diminished ability to regulate intake, which then leads to increased emotional over eating. Results of this study have implications for both the prevention of disordered eating behaviors and childhood obesity prevention programs, suggesting the need to assist children in learning how to self-regulate in the presence of food.
28213812	We are called upon to make decisions, large and small, many times a day. Whether in the voting booth, the stock exchange, or the cafeteria line, we identify potential options, estimate and compare their subjective values, and make a choice. Decision-making has only recently become a focus for cognitive neuroscience. The last two decades have seen rapid progress in our understanding of the brain basis of at least some aspects of this rather complex aspect of cognition. This work has provided fresh perspectives on poorly understood brain regions, such as orbitofrontal cortex and ventral striatum. It has led to interesting interdisciplinary exchanges with diverse fields, notably economics, but also ecology and political science, among others. The novel perspectives arising from these exchanges have begun to be related to better understood aspects of cognition. In particular, it is increasingly clear that decision-making is tightly interlinked with learning and memory. Key early insights in decision neuroscience came from what were essentially reinforcement learning tasks. Recent work has made similar links to aspects of declarative memory. Indeed, decision-making can be seen as the link between memory of the past and future actions. This chapter reviews selected topics in decision neuroscience, with a particular focus on the links to learning and memory, and a particular emphasis on regions within prefrontal cortex.
28213443	Cues that predict the availability of food rewards influence motivational states and elicit food-seeking behaviors. If a cue no longer predicts food availability, then animals may adapt accordingly by inhibiting food-seeking responses. Sparsely activated sets of neurons, coined "neuronal ensembles," have been shown to encode the strength of reward-cue associations. Although alterations in intrinsic excitability have been shown to underlie many learning and memory processes, little is known about these properties specifically on cue-activated neuronal ensembles. We examined the activation patterns of cue-activated orbitofrontal cortex (OFC) and nucleus accumbens (NAc) shell ensembles using wild-type and Fos-GFP mice, which express green fluorescent protein (GFP) in activated neurons, after appetitive conditioning with sucrose and extinction learning. We also investigated the neuronal excitability of recently activated, GFP+ neurons in these brain areas using whole-cell electrophysiology in brain slices. Exposure to a sucrose cue elicited activation of neurons in both the NAc shell and OFC. In the NAc shell, but not the OFC, these activated GFP+ neurons were more excitable than surrounding GFP- neurons. After extinction, the number of neurons activated in both areas was reduced and activated ensembles in neither area exhibited altered excitability. These data suggest that learning-induced alterations in the intrinsic excitability of neuronal ensembles is regulated dynamically across different brain areas. Furthermore, we show that changes in associative strength modulate the excitability profile of activated ensembles in the NAc shell.SIGNIFICANCE STATEMENT Sparsely distributed sets of neurons called "neuronal ensembles" encode learned associations about food and cues predictive of its availability. Widespread changes in neuronal excitability have been observed in limbic brain areas after associative learning, but little is known about the excitability changes that occur specifically on neuronal ensembles that encode appetitive associations. Here, we reveal that sucrose cue exposure recruited a more excitable ensemble in the nucleus accumbens, but not orbitofrontal cortex, compared with their surrounding neurons. This excitability difference was not observed when the cue's salience was diminished after extinction learning. These novel data provide evidence that the intrinsic excitability of appetitive memory-encoding ensembles is regulated differentially across brain areas and adapts dynamically to changes in associative strength.
28212944	Though commonly used as a treatment for ADHD, the psychostimulant methylphenidate (MPH) is also misused and abused in adolescence in both clinical and general populations. Although MPH acts via pathways activated by other drugs of abuse, the short- and long-term effects of MPH on reward processing in learning and decision-making are not clearly understood. We examined the effect of adolescent MPH treatment on a battery of reward-directed behaviors both in adolescence during its administration and in adulthood after its discontinuation. We further measured whether MPH had lasting effects on dopamine receptor mRNA expression in orbitofrontal cortex (OFC) that may correspond with behavior. Long-Evans rats were injected with MPH (0, 1, 2.5, or 5mg/kg IP) twice daily from middle to late adolescence (PD38-57). During adolescence, the high dose of MPH reduced preference for large rewards in a Reward Magnitude Discrimination task, but did not affect preference for smaller-sooner rewards in a Delay Discounting task. In adulthood, after discontinuation of MPH, animals previously treated with the moderate dose of MPH showed improved acquisition, but not reversal, in a Reversal Learning task. MPH exposure did not increase preference for large-risky rewards in a Risk task in adulthood. We then quantified mRNA expression of D1, D2, and D3 receptors in the OFC using qPCR. MPH increased mRNA expression of dopamine D3 receptor subtype, but not D1 or D2. Overall, these results indicate that MPH has both immediate and lasting effects on reward-dependent learning and decisions, as well as dopaminergic function in rodents.
28210998	When predictive of extrinsic reward as targets, stimuli rapidly acquire the ability to automatically capture attention. Attentional biases for former targets of visual search also can develop without reward feedback but typically require much longer training. These learned biases towards former targets often are conceptualized within a single framework and might differ merely in degree. That is, both are the result of the reinforcement of selection history, with extrinsic reward for correct report of the target providing greater reinforcement than correct report alone. A direct test of this shared mechanisms hypothesis is lacking, however. Recent evidence demonstrates that depressed individuals present with blunted value-driven attentional biases. Based on the shared mechanisms hypothesis, we predicted that depressed individuals would similarly show blunted attentional biases for former targets following unrewarded training. To the contrary, however, we found that the effects of selection history on attention were robust and equivalent between individuals experiencing depressive symptoms and control participants, whereas attentional capture by previously reward-associated stimuli was blunted in depressed individuals. Our results suggest a qualitative distinction between the effects of reward history and the effects of selection history on attention, with depressive symptoms impairing the former while leaving the latter unaffected.
28210781	Environmental challenges during adolescence, such as drug exposure, can cause enduring behavioral and molecular changes that contribute to life-long maladaptive behaviors, including addiction. Selectively bred high-responder (bHR) and low-responder (bLR) rats represent a unique model for assessing the long-term impact of adolescent environmental manipulations, as they inherently differ on a number of addiction-related traits. bHR rats are considered "addiction-prone," whereas bLR rats are "addiction-resilient," at least under baseline conditions. Moreover, relative to bLRs, bHR rats are more likely to attribute incentive motivational value to reward cues, or to "sign-track."We utilized bHR and bLR rats to determine whether adolescent cocaine exposure can alter their inborn behavioral and neurobiological profiles, with a specific focus on Pavlovian conditioned approach behavior (i.e., sign- vs. goal-tracking) and hippocampal neurogenesis.	bHR and bLR rats were administered cocaine (15 mg/kg) or saline for 7 days during adolescence (postnatal day, PND 33-39) and subsequently tested for Pavlovian conditioned approach behavior in adulthood (PND 62-75), wherein an illuminated lever (conditioned stimulus) was followed by the response-independent delivery of a food pellet (unconditioned stimulus). Behaviors directed toward the lever and the food cup were recorded as sign- and goal-tracking, respectively. Hippocampal cell genesis was evaluated on PND 77 by immunohistochemistry.	Adolescent cocaine exposure impaired hippocampal cell genesis (proliferation and survival) and enhanced the inherent propensity to goal-track in adult bLR, but not bHR, rats.	Adolescent cocaine exposure elicits long-lasting changes in stimulus-reward learning and enduring deficits in hippocampal neurogenesis selectively in adult bLR rats.	
28209979	The ability to make decisions and act quickly without hesitation can be advantageous in many settings. However, when persistently expressed, impulsive decisions and actions are considered risky, maladaptive and symptomatic of such diverse brain disorders as attention-deficit hyperactivity disorder, drug addiction and affective disorders. Over the past decade, rapid progress has been made in the identification of discrete neural networks that underlie different forms of impulsivity - from impaired response inhibition and risky decision making to a profound intolerance of delayed rewards. Herein, we review what is currently known about the neural and psychological mechanisms of impulsivity, and discuss the relevance and application of these new insights to various neuropsychiatric disorders.
28209978	Many accounts of reward-based choice argue for distinct component processes that are serial and functionally localized. In this Opinion article, we argue for an alternative viewpoint, in which choices emerge from repeated computations that are distributed across many brain regions. We emphasize how several features of neuroanatomy may support the implementation of choice, including mutual inhibition in recurrent neural networks and the hierarchical organization of timescales for information processing across the cortex. This account also suggests that certain correlates of value are emergent rather than represented explicitly in the brain.
28207733	To make good decisions, humans need to learn about and integrate different sources of appetitive and aversive information. While serotonin has been linked to value-based decision-making, its role in learning is less clear, with acute manipulations often producing inconsistent results. Here, we show that when the effects of a selective serotonin reuptake inhibitor (SSRI, citalopram) are studied over longer timescales, learning is robustly improved. We measured brain activity with functional magnetic resonance imaging (fMRI) in volunteers as they performed a concurrent appetitive (money) and aversive (effort) learning task. We found that 2 weeks of citalopram enhanced reward and effort learning signals in a widespread network of brain regions, including ventromedial prefrontal and anterior cingulate cortex. At a behavioral level, this was accompanied by more robust reward learning. This suggests that serotonin can modulate the ability to learn via a mechanism that is independent of stimulus valence. Such effects may partly underlie SSRIs' impact in treating psychological illnesses. Our results highlight both a specific function in learning for serotonin and the importance of studying its role across longer timescales.
28202786	Learning to optimally predict rewards requires agents to account for fluctuations in reward value. Recent work suggests that individuals can efficiently learn about variable rewards through adaptation of the learning rate, and coding of prediction errors relative to reward variability. Such adaptive coding has been linked to midbrain dopamine neurons in nonhuman primates, and evidence in support for a similar role of the dopaminergic system in humans is emerging from fMRI data. Here, we sought to investigate the effect of dopaminergic perturbations on adaptive prediction error coding in humans, using a between-subject, placebo-controlled pharmacological fMRI study with a dopaminergic agonist (bromocriptine) and antagonist (sulpiride). Participants performed a previously validated task in which they predicted the magnitude of upcoming rewards drawn from distributions with varying SDs. After each prediction, participants received a reward, yielding trial-by-trial prediction errors. Under placebo, we replicated previous observations of adaptive coding in the midbrain and ventral striatum. Treatment with sulpiride attenuated adaptive coding in both midbrain and ventral striatum, and was associated with a decrease in performance, whereas bromocriptine did not have a significant impact. Although we observed no differential effect of SD on performance between the groups, computational modeling suggested decreased behavioral adaptation in the sulpiride group. These results suggest that normal dopaminergic function is critical for adaptive prediction error coding, a key property of the brain thought to facilitate efficient learning in variable environments. Crucially, these results also offer potential insights for understanding the impact of disrupted dopamine function in mental illness.SIGNIFICANCE STATEMENT To choose optimally, we have to learn what to expect. Humans dampen learning when there is a great deal of variability in reward outcome, and two brain regions that are modulated by the brain chemical dopamine are sensitive to reward variability. Here, we aimed to directly relate dopamine to learning about variable rewards, and the neural encoding of associated teaching signals. We perturbed dopamine in healthy individuals using dopaminergic medication and asked them to predict variable rewards while we made brain scans. Dopamine perturbations impaired learning and the neural encoding of reward variability, thus establishing a direct link between dopamine and adaptation to reward variability. These results aid our understanding of clinical conditions associated with dopaminergic dysfunction, such as psychosis.
28198813	Patients with anorexia nervosa (AN) are characterised by increased self-control, cognitive rigidity and impairments in set-shifting, but the underlying neural mechanisms are poorly understood. Here we used functional magnetic resonance imaging (fMRI) to elucidate the neural correlates of behavioural adaptation to changes in reward contingencies in young acutely ill AN patients. Thirty-six adolescent/young adult, non-chronic female AN patients and 36 age-matched healthy females completed a well-established probabilistic reversal learning task during fMRI. We analysed hemodynamic responses in empirically-defined regions of interest during positive feedback and negative feedback not followed/followed by behavioural adaptation and conducted functional connectivity analyses. Although overall task performance was comparable between groups, AN showed increased shifting after receiving negative feedback (lose-shift behaviour) and altered dorsal anterior cingulate cortex (dACC) responses as a function of feedback. Specifically, patients had increased dACC responses (which correlated with perfectionism) and task-related coupling with amygdala preceding behavioural adaption. Given the generally preserved task performance in young AN, elevated dACC responses specifically during behavioural adaption is suggestive of increased monitoring for the need to adjust performance strategies. Higher dACC-amygdala coupling and increased adaptation after negative feedback underlines this interpretation and could be related to intolerance of uncertainty which has been suggested for AN.
28197758	A great deal of our goal-directed behaviour depends on stimulus-response (S-R) associations, which can be established through conditioning or explicit instructions. For conditioned and reward maximizing behaviour, it has been shown that redundant information will no longer be taken into account once those associations have been formed ("blocking effect"). Following from this, new aspects will not be included in a pre-established association unless they improve behaviour. Opposing this, influential action control theories state that all kinds of information may be taken into account during action selection, thus denying the possibility of blocking redundant "surplus" information from non-conditioned goal-directed behaviour. We probed these contradicting predictions by asking two groups of healthy young adults to perform a redundant and a non-redundant version of a stop-change task in a counter-balanced order. Using behavioural and electrophysiological data, we demonstrate that contradicting current theories, blocking seems to be a general mechanism which also applies to non-conditioned goal-directed behaviour. Specifically, we show that the complexity of response selection processes associated with medial frontal cortical activity is altered by blocking. This was reflected by faster responses and smaller central P3 amplitudes originating in the ACC (BA24/BA32). Preceding attentional processes were not affected. Contradicting current views, our ability to ignore information that hampers an expedient unfolding of goal-directed behaviour is quite limited. Prior experiences have a much larger influence on which input we consider for response formation. This offers a functional explanation for why it can be hard to alter (inefficient) behaviour once it has been established.
28196108	Post-traumatic stress disorder (PTSD) can develop following exposure to a traumatic event. Re-experiencing, which includes intrusive memories or flashbacks of the trauma, is a core symptom cluster of PTSD. From an associative learning perspective, this cluster may be attributed to cues associated with the trauma, which have come to elicit symptoms in a variety of situations encountered in daily life due to a tendency to overgeneralize. Consistent with this, prior studies have indicated that both individuals with clinically diagnosed with PTSD, and those with self-reported symptoms who may not meet full diagnostic criteria, show changes in generalization. Building on prior research, the current study examined whether PTSD symptom burden, but also gender, veteran status, and combat experience-all associated with PTSD vulnerability-modulate learning and generalization in a computer-based task. Participants were presented with stimulus compounds consisting of a foreground and background that could be predictive of reward, punishment or no outcome. Learning was followed by a generalization test where these components were recombined to form novel configurations. An interaction between PTSD symptom burden and gender was found where females with more severe PTSD symptoms showed no evidence of sensitivity to the background. This result is consistent with increased generalization, and may indicate a decrease in the ability to process cue configurations leading to re-experiencing in a variety of situations. Further work is indicated to help elucidate the cognitive processes driving gender differences that may confer vulnerability to PTSD.
28194005	Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.Molecular Psychiatry advance online publication, 14 February 2017; doi:10.1038/mp.2017.7.
28193692	Recent research has shown that perceptual processing of stimuli previously associated with high-value rewards is automatically prioritized even when rewards are no longer available. It has been hypothesized that such reward-related modulation of stimulus salience is conceptually similar to an "attentional habit." Recording event-related potentials in humans during a reinforcement learning task, we show strong evidence in favor of this hypothesis. Resistance to outcome devaluation (the defining feature of a habit) was shown by the stimulus-locked P1 component, reflecting activity in the extrastriate visual cortex. Analysis at longer latencies revealed a positive component (corresponding to the P3b, from 550-700 ms) sensitive to outcome devaluation. Therefore, distinct spatiotemporal patterns of brain activity were observed corresponding to habitual and goal-directed processes. These results demonstrate that reinforcement learning engages both attentional habits and goal-directed processes in parallel. Consequences for brain and computational models of reinforcement learning are discussed.SIGNIFICANCE STATEMENT The human attentional network adapts to detect stimuli that predict important rewards. A recent hypothesis suggests that the visual cortex automatically prioritizes reward-related stimuli, driven by cached representations of reward value; that is, stimulus-response habits. Alternatively, the neural system may track the current value of the predicted outcome. Our results demonstrate for the first time that visual cortex activity is increased for reward-related stimuli even when the rewarding event is temporarily devalued. In contrast, longer-latency brain activity was specifically sensitive to transient changes in reward value. Therefore, we show that both habit-like attention and goal-directed processes occur in the same learning episode at different latencies. This result has important consequences for computational models of reinforcement learning.
28193686	Foraging animals balance the need to seek food and energy against the accompanying dangers of injury and predation. To do so, they rely on learning systems encoding reward and danger. Whereas much is known about these separate learning systems, little is known about how they interact to shape and guide behavior. Here we show a key role for the rat paraventricular nucleus of the thalamus (PVT), a nucleus of the dorsal midline thalamus, in this interaction. First, we show behavioral competition between reward and danger: the opportunity to seek food reward negatively modulates expression of species-typical defensive behavior. Then, using a chemogenetic approach expressing the inhibitory hM4Di designer receptor exclusively activated by a designer drug in PVT neurons, we show that the PVT is central to this behavioral competition. Chemogenetic PVT silencing biases behavior toward either defense or reward depending on the experimental conditions, but does not consistently favor expression of one over the other. This bias could not be attributed to changes in fear memory retrieval, learned safety, or memory interference. Rather, our results demonstrate that the PVT is essential for balancing conflicting behavioral tendencies toward danger and reward, enabling adaptive responding under this basic selection pressure.SIGNIFICANCE STATEMENT Among the most basic survival problems faced by animals is balancing the need to seek food and energy against the accompanying dangers of injury and predation. Although much is known about the brain mechanisms that underpin learning about reward and danger, little is known about how these interact to solve basic survival problems. Here we show competition between defensive (to avoid predatory detection) and approach (to obtain food) behavior. We show that the paraventricular thalamus, a nucleus of the dorsal midline thalamus, is integral to this behavioral competition. The paraventricular thalamus balances the competing behavioral demands of danger and reward, enabling adaptive responding under this selection pressure.
28192860	Pride is an important, self-conscious emotion composed of two distinct conceptual facets: arrogant, egotistic "hubristic pride," and pro-social, achievement-oriented "authentic pride." However, little is known about the neural basis of the two facets of pride. Here, we investigated the association between spontaneous brain activity and these two facets of pride in resting state.We measured 276 participants on authentic and hubristic pride. The fractional amplitude of low-frequency fluctuations (fALFF) was used to identify pride-related regions.	The results revealed individual differences in authentic pride were associated with the fALFF in the bilateral superior temporal gyrus (STG), which has been implicated in social processing. In contrast, individual differences in hubristic pride were associated with the fALFF in the left orbitofrontal cortex (OFC) and posterior cingulate cortex (PCC), which have been implicated in self-referential and reward processing.	Together, our results provide initial evidence for the distinct neural substrates for authentic and hubristic pride.	
28191003	The primary goal of the present study was to investigate how positive and negative feedback may differently facilitate learning throughout development. In addition, the role of motivation as a modulating factor was examined. Participants (children, adolescents, and adults) completed two forms of the guess and application task (GAT). Feedback from the Cool-GAT task has low motivational salience because there are no consequences, while feedback from the Hot-GAT task has high motivational salience as it pertains to receiving a reward. The results indicated that negative feedback leads to a reduction in learning compared to positive feedback. The effect of negative feedback was greater in adolescent participants compared to children and adults in the Hot-GAT task, suggesting an interaction between age and motivation level on learning. Further analysis indicated that greater risk was associated with a greater reduction in learning from negative feedback and again, the reduction was greatest in adolescents. In summary, the current study supports the idea that learning from positive feedback and negative feedback differs throughout development. In a rule-based learning task, when associative learning is primarily in practice, participants learned less from negative feedback. This reduction is amplified during adolescence when task-elicited motivation is high.
28190083	Tobacco has a higher rate of dependence than other drugs of abuse. However, the psychopharmacological effects of nicotine are incongruent with the tenacity of tobacco addiction since nicotine does not produce robust euphoria in humans or self-administration in rodents. A potential explanation is that nicotine amplifies the salience of other stimuli that have some incentive value, which could influence the initiation and persistence of smoking. However, the neural mechanisms of this process are unknown.One way that nicotine may amplify the salience of other stimuli is by enhancing reward prediction errors. We hypothesized that nicotine would enhance the neural response to unexpected (relative to expected) rewards compared to placebo.	Twenty-three nonsmokers underwent two fMRI scans, following nicotine (1 mg) or placebo administration, while performing an outcome expectation task. In the task, a pair of cues was associated with either a subsequent reward (the image of a $100 bill) or a nonreward (the image of a blurry rectangle). On 20% of trials, the cue was followed by an unexpected outcome.	Although nicotine did not affect the magnitude of prediction errors relative to placebo, nicotine did increase BOLD activation in the anterior insula/inferior frontal gyrus and decrease activation in the caudate across all outcome types (including both rewards and nonrewards).	The insula and caudate could play a role in the initial effects of nicotine in nonsmokers, and these changes in baseline may be the mechanism that underlies how nicotine amplifies the salience of nondrug stimuli.	
28188587	Reward-related learning, including that associated with drugs of abuse, is largely mediated by the dopaminergic mesolimbic pathway. Mesolimbic neurophysiology and motivated behavior, in turn, are modulated by the circadian timing system which generates ∼24-h rhythms in cellular activity. Both drug taking and seeking and mesolimbic dopaminergic neurotransmission can vary widely over the day. Moreover, circadian clock genes are expressed in ventral tegmental area dopaminergic cells and in mesolimbic target regions where they can directly modulate reward-related neurophysiology and behavior. There also exists a reciprocal influence between drug taking and circadian timing as the administration of drugs of abuse can alter behavioral rhythms and circadian clock gene expression in mesocorticolimbic structures. These interactions suggest that manipulations of the circadian timing system may have some utility in the treatment of substance abuse disorders. Here, the literature on bidirectional interactions between the circadian timing system and drug taking is briefly reviewed, and potential chronotherapeutic considerations for the treatment of addiction are discussed.
28180079	Antisocial behavior (AB), including aggression, violence, and theft, is thought be underpinned by abnormal functioning in networks of the brain critical to emotion processing, behavioral control, and reward-related learning. To better understand the abnormal functioning of these networks, research has begun to investigate the structural connections between brain regions implicated in AB using diffusion tensor imaging (DTI), which assesses white-matter tract microstructure. This systematic review integrates findings from 22 studies that examined the relationship between white-matter microstructure and AB across development. In contrast to a prior hypothesis that AB is associated with greater diffusivity specifically in the uncinate fasciculus, findings suggest that adult AB is associated with greater diffusivity across a range of white-matter tracts, including the uncinate fasciculus, inferior fronto-occipital fasciculus, cingulum, corticospinal tract, thalamic radiations, and corpus callosum. The pattern of findings among youth studies was inconclusive with both higher and lower diffusivity found across association, commissural, and projection and thalamic tracts.
28179180	Large animal models of human neurological disorders are advantageous compared to rodent models due to their neuroanatomical complexity, longevity and their ability to be maintained in naturalised environments. Some large animal models spontaneously develop behaviours that closely resemble the symptoms of neural and psychiatric disorders. The horse is an example of this; the domestic form of this species consistently develops spontaneous stereotypic behaviours akin to the compulsive and impulsive behaviours observed in human neurological disorders such as Tourette's syndrome. The ability to non-invasively probe normal and abnormal equine brain function through cognitive testing may provide an extremely useful methodological tool to assess brain changes associated with certain human neurological and psychiatric conditions.An automated operant system with the ability to present visual and auditory stimuli as well as dispense salient food reward was developed. To validate the system, ten horses were trained and tested using a standard cognitive task (three choice serial reaction time task (3-CSRTT)).	All animals achieved total learning criterion and performed six probe sessions. Learning criterion was met within 16.30±0.79 sessions over a three day period. During six probe sessions, level of performance was maintained at 80.67±0.57% (mean±SEM) accuracy.	This is the first mobile fully automated system developed to examine cognitive function in the horse.	A fully-automated operant system for mobile cognitive function of a large animal model has been designed and validated. Horses pose an interesting complementary model to rodents for the examination of human neurological dysfunction.	
28177160	Animals including humans execute motor behavior to reach their goals. For this purpose, they must choose correct strategies according to environmental conditions and shape many parameters of their movements, including their serial order and timing. To investigate the neurobiology underlying such skills, we used a multi-sensor equipped, motor-driven running wheel with adjustable sequences of foothold pegs on which mice ran to obtain water reward. When the peg patterns changed from a familiar pattern to a new pattern, the mice had to learn and implement new locomotor strategies in order to receive reward. We found that the accuracy of stepping and the achievement of water reward improved with the new learning after changes in the peg-pattern, and c-Fos expression levels assayed after the first post-switch session were high in both dorsolateral striatum and motor cortex, relative to post-switch plateau levels. Combined in situ hybridization and immunohistochemistry of striatal sections demonstrated that both enkephalin-positive (indirect pathway) neurons and substance P-positive (direct pathway) neurons were recruited specifically after the pattern switches, as were interneurons expressing neuronal nitric oxide synthase. When we blocked N-methyl-D-aspartate (NMDA) receptors in the dorsolateral striatum by injecting the NMDA receptor antagonist, D-2-amino-5-phosphonopentanoic acid (AP5), we found delays in early post-switch improvement in performance. These findings suggest that the dorsolateral striatum is activated on detecting shifts in environment to adapt motor behavior to the new context via NMDA-dependent plasticity, and that this plasticity may underlie forming and breaking skills and habits as well as to behavioral difficulties in clinical disorders.
28176352	Successful avoidance of a threatening event may negatively reinforce the behavior due to activation of brain structures involved in reward processing. Here, we further investigated the learning-related properties of avoidance using feedback-related negativity (FRN). The FRN is modulated by violations of an intended outcome (prediction error, PE), that is, the bigger the difference between intended and actual outcome, the larger the FRN amplitude is. Twenty-eight participants underwent an operant conditioning paradigm, in which a behavior (button press) allowed them to avoid a painful electric shock. During two learning blocks, participants could avoid an electric shock in 80% of the trials by pressing one button (avoidance button), or by not pressing another button (punishment button). After learning, participants underwent two test blocks, which were identical to the learning ones except that no shocks were delivered. Participants pressed the avoidance button more often than the punishment button. Importantly, response frequency increased throughout the learning blocks but it did not decrease during the test blocks, indicating impaired extinction and/or habit formation. In line with a PE account, FRN amplitude to negative feedback after correct responses (i.e., unexpected punishment) was significantly larger than to positive feedback (i.e., expected omission of punishment), and it increased throughout the blocks. Highly anxious individuals showed equal FRN amplitudes to negative and positive feedback, suggesting impaired discrimination. These results confirm the role of negative reinforcement in motivating behavior and learning, and reveal important differences between high and low anxious individuals in the processing of prediction errors.
28176215	Findings from an increasingly large number of studies have been used to argue that attentional capture can be dependent on the learned value of a stimulus, or value-driven. However, under certain circumstances attention can be biased to select stimuli that previously served as targets, independent of reward history. Value-driven attentional capture, as studied using the training phase-test phase design introduced by Anderson and colleagues, is widely presumed to reflect the combined influence of learned value and selection history. However, the degree to which attentional capture is at all dependent on value learning in this paradigm has recently been questioned. Support for value-dependence can be provided through one of two means: (1) greater attentional capture by prior targets following rewarded training than following unrewarded training, and (2) greater attentional capture by prior targets previously associated with high compared to low value. Using a variant of the original value-driven attentional capture paradigm, Sha and Jiang (Attention, Perception, and Psychophysics, 78, 403-414, 2016) failed to find evidence of either, and raised criticisms regarding the adequacy of evidence provided by prior studies using this particular paradigm. To address this disparity, here we provided a stringent test of the value-dependence hypothesis using the traditional value-driven attentional capture paradigm. With a sufficiently large sample size, value-dependence was observed based on both criteria, with no evidence of attentional capture without rewards during training. Our findings support the validity of the traditional value-driven attentional capture paradigm in measuring what its name purports to measure.
28174533	Motivation can have invigorating effects on behavior via dopaminergic neuromodulation. While this relationship has mainly been established in theoretical models and studies in younger subjects, the impact of structural declines of the dopaminergic system during healthy aging remains unclear. To investigate this issue, we used electroencephalography (EEG) in healthy young and elderly humans in a reward-learning paradigm. Specifically, scene images were initially encoded by combining them with cues predicting monetary reward (high vs. low reward). Subsequently, recognition memory for the scenes was tested. As a main finding, we can show that response times (RTs) during encoding were faster for high reward predicting images in the young but not elderly participants. This pattern was resembled in power changes in the theta-band (4-7 Hz). Importantly, analyses of structural MRI data revealed that individual reward-related differences in the elderlies' response time could be predicted by the structural integrity of the dopaminergic substantia nigra (SN; as measured by magnetization transfer (MT)). These findings suggest a close relationship between reward-based invigoration, theta oscillations and age-dependent changes of the dopaminergic system.
28170057	El desarrollo de modelos animales de refuerzo y adicción a las drogas es imprescindible para el avance en el conocimiento de las bases biológicas de este trastorno y la identificación de nuevas dianas terapéuticas. En función del componente del refuerzo que deseemos estudiar podemos servirnos de un tipo de modelos animales u otros. Podemos utilizar modelos de refuerzo basados en el efecto hedónico primario que produce el consumo de la sustancia adictiva, como los modelos de autoadministración (AA) y autoestimulación eléctrica intracraneal (AEIC), o modelos basados en el componente relacionado con el aprendizaje asociativo y la capacidad cognitiva de realizar predicciones sobre la obtención del refuerzo en el futuro, como el modelo de condicionamiento de preferencia de lugar (CPL). En los últimos años los modelos han incorporado modificaciones metodológicas para incluir el estudio de los procesos de extinción, reinstauración y reconsolidación o para modelar aspectos concretos de la conducta adictiva como puede ser la motivación para consumir la droga, el consumo compulsivo o la búsqueda de la droga bajo situaciones de castigo. Otros modelos interrelacionan diferentes componentes del refuerzo o modelan la motivación voluntaria por consumir (modelos de “two-bottle choice” o “drinking in the dark”). En definitiva, las innovaciones en estos modelos contribuyen al avance en el conocimiento científico de los diferentes factores que llevan a tomar una droga y a desarrollar un consumo compulsivo, ofreciendo una vía para identificar futuros tratamientos para la adicción.The development of animal models of drug reward and addiction is an essential factor for progress in understanding the biological basis of this disorder and for the identification of new therapeutic targets. Depending on the component of reward to be studied, one type of animal model or another may be used. There are models of reinforcement based on the primary hedonic effect produced by the consumption of the addictive substance, such as the self-administration (SA) and intracranial self-stimulation (ICSS) paradigms, and there are models based on the component of reward related to associative learning and cognitive ability to make predictions about obtaining reward in the future, such as the conditioned place preference (CPP) paradigm. In recent years these models have incorporated methodological modifications to study extinction, reinstatement and reconsolidation processes, or to model specific aspects of addictive behavior such as motivation to consume drugs, compulsive consumption or drug seeking under punishment situations. There are also models that link different reinforcement components or model voluntary motivation to consume (two-bottle choice, or drinking in the dark tests). In short, innovations in these models allow progress in scientific knowledge regarding the different aspects that lead individuals to consume a drug and develop compulsive consumption, providing a target for future treatments of addiction.	
28169427	Previous research indicated that the skin conductance response of the autonomic nervous system in the Concealed Information Test (CIT) is typically increased in subjects who are financially and otherwise incentivized to defeat the CIT (the paradoxical "motivational impairment" effect). This is not the case for RT-based CITs, nor P300 tests based on the three-stimulus protocol for detection of cognitive malingering (although these are not the same as CITs). The present report is the first attempt to study the effect of financial motivation on the P300-based Complex Trial Protocol using both episodic and semantic memory probe and irrelevant stimuli. The Test of Memory Malingering (TOMM) was used to validate behavioral differences between the two groups we created by offering one (paid) group but not another (unpaid) group a financial reward for beating our tests. Group behavioral differences on the TOMM did confirm group manipulations. Probe-minus-irrelevant P300 differences did not differ between groups, although as previously, semantic memory-evoked P300s were larger than episodic memory-evoked P300s.
28168198	This study aimed to explore the associations of occupational stressors (extrinsic effort, reward, and overcommitment), perceived organizational support (POS), and psychological capital (PsyCap) and its components (self-efficacy, hope, resilience, and optimism) with work engagement and the mediating roles of PsyCap and its components among Chinese female nurses within the framework of the job demands-resources (JD-R) model. A cross-sectional sample (1,330) completed the Utrecht Work Engagement Scale, Effort-Reward Imbalance Scale, Survey of POS, and PsyCap Questionnaire, and effective respondents were 1,016 (76.4%). Hierarchical regression analysis and Preacher and Hayes' asymptotic and resampling strategies were used. Extrinsic effort was negatively associated with vigor, dedication, and absorption, while POS, PsyCap, and hope were positively associated with them. Reward and overcommitment were positively associated with dedication and absorption. Optimism was positively associated with vigor and dedication. Optimism mediated the associations of extrinsic effort, reward, and POS with vigor and dedication. PsyCap and hope mediated the associations of POS with vigor, dedication, and absorption. There is a low level of work engagement among Chinese female nurses. Extrinsic effort could reduce work engagement, while reward, overcommitment, POS, PsyCap, hope, and optimism could enhance work engagement. Hospital managers should develop the PsyCap of female nurses through controlling occupational stressors and establishing supportive organizational climate to enhance their work engagement.
28167910	EM-based policy search methods estimate a lower bound of the expected return from the histories of episodes and iteratively update the policy parameters using the maximum of a lower bound of expected return, which makes gradient calculation and learning rate tuning unnecessary. Previous algorithms like Policy learning by Weighting Exploration with the Returns, Fitness Expectation Maximization, and EM-based Policy Hyperparameter Exploration implemented the mechanisms to discard useless low-return episodes either implicitly or using a fixed baseline determined by the experimenter. In this paper, we propose an adaptive baseline method to discard worse samples from the reward history and examine different baselines, including the mean, and multiples of SDs from the mean. The simulation results of benchmark tasks of pendulum swing up and cart-pole balancing, and standing up and balancing of a two-wheeled smartphone robot showed improved performances. We further implemented the adaptive baseline with mean in our two-wheeled smartphone robot hardware to test its performance in the standing up and balancing task, and a view-based approaching task. Our results showed that with adaptive baseline, the method outperformed the previous algorithms and achieved faster, and more precise behaviors at a higher successful rate.
28167200	The ability to utilize numerical information can be adaptive in a number of ecological contexts including foraging, mating, parental care, and anti-predator strategies. Numerical abilities of mammals and birds have been studied both in natural conditions and in controlled laboratory conditions using a variety of approaches. During the last decade this ability was also investigated in some fish species. Here we reviewed the main methods used to study this group, highlighting the strengths and weaknesses of each of the methods used. Fish have only been studied under laboratory conditions and among the methods used with other species, only two have been systematically used in fish-spontaneous choice tests and discrimination learning procedures. In the former case, the choice between two options is observed in a biologically relevant situation and the degree of preference for the larger/smaller group is taken as a measure of the capacity to discriminate the two quantities (e.g., two shoals differing in number). In discrimination learning tasks, fish are trained to select the larger or the smaller of two sets of abstract objects, typically two-dimensional geometric figures, using food or social companions as reward. Beyond methodological differences, what emerges from the literature is a substantial similarity of the numerical abilities of fish with those of other vertebrates studied.
28161360	Animals use cues from their environment to orient in space and to navigate their surroundings. Geometry is a cue whose informational content may originate from the metric properties of a given environment, and its use has been demonstrated in the laboratory in nearly every species of animal tested. However, it is not clear whether geometric information, used by animals typically tested in small, rectangular boxes, is directly relevant to animals in their natural environment. Here we present the first data that confirm the use of geometric cues by a free-living animal in the wild. We trained rufous hummingbirds to visit a rectangular array of four artificial flowers, one of which was rewarded. In some trials a conspicuous landmark cued the reward. Following array translocation and rotation, we presented hummingbirds with three tests. When trained and tested with the landmark, or when trained and tested without it, hummingbirds failed to show geometric learning. However, when trained with a landmark but tested without it, hummingbirds produced the classic geometric response, showing that they had learned the geometric relationships (distance and direction) of several non-reward visual elements of the environment. While it remains that the use of geometry to relocate a reward may be an experimental artefact, its use is not confined to the laboratory.
28158896	Children who experience early adversity often develop emotion regulatory problems, but little is known about the mechanisms that mediate this relation. We tested whether general associative learning processes contribute to associations between adversity, in the form of child maltreatment, and negative behavioral outcomes.Eighty-one participants between 12 and 17 years of age were recruited for this study and completed a probabilistic learning Task. Forty-one of these participants had been exposed to physical abuse, a form of early adversity. Forty additional participants without any known history of maltreatment served as a comparison group. All participants (and their parents) also completed portions of the Youth Life Stress Interview to understand adolescent's behavior. We calculated measures of associative learning, and also constructed mathematical models of learning.	We found that adolescents exposed to high levels of adversity early in their lives had lower levels of associative learning than comparison adolescents. In addition, we found that impaired associative learning partially explained the higher levels of behavioral problems among youth who suffered early adversity. Using mathematical models, we also found that two components of learning were specifically affected in children exposed to adversity: choice variability and biases in their beliefs about the likelihood of rewards in the environment.	Participants who had been exposed to early adversity were less able than their peers to correctly learn which stimuli were likely to result in reward, even after repeated feedback. These individuals also used information about known rewards in their environments less often. In addition, individuals exposed to adversity made decisions early in the learning process as if rewards were less consistent and occurred more at random. These data suggest one mechanism through which early life experience shapes behavioral development.	
28158309	Learning based on networks of real neurons, and learning based on biologically inspired models of neural networks, have yet to find general learning rules leading to widespread applications. In this paper, we argue for the existence of a principle allowing to steer the dynamics of a biologically inspired neural network. Using carefully timed external stimulation, the network can be driven towards a desired dynamical state. We term this principle "Learning by Stimulation Avoidance" (LSA). We demonstrate through simulation that the minimal sufficient conditions leading to LSA in artificial networks are also sufficient to reproduce learning results similar to those obtained in biological neurons by Shahaf and Marom, and in addition explains synaptic pruning. We examined the underlying mechanism by simulating a small network of 3 neurons, then scaled it up to a hundred neurons. We show that LSA has a higher explanatory power than existing hypotheses about the response of biological neural networks to external simulation, and can be used as a learning rule for an embodied application: learning of wall avoidance by a simulated robot. In other works, reinforcement learning with spiking networks can be obtained through global reward signals akin simulating the dopamine system; we believe that this is the first project demonstrating sensory-motor learning with random spiking networks through Hebbian learning relying on environmental conditions without a separate reward system.
28158199	The relationship between personality and learning abilities has become a growing field of interest. Studies have mainly focused on the relationship with performance, such as the speed of acquisition. In this study, we hypothesised that personality could in part also be related to a certain predisposition of an individual to switch more easily from a goal-directed process to a habit process during learning. To identify these processes, we conducted a contingency degradation protocol. This study investigated 1/ whether in general horses are able to adjust their response according to the contingency between their action and the reward, 2/ whether there are any relationships between certain personality profiles and a predisposition to switch more rapidly to habitual processes, and 3/ whether emotional states experienced during the learning procedure play a role in this switching. Personality tests were conducted on 29 horses, followed by a degradation contingency protocol. Overall, results show that horses were sensitive to contingency degradation between their action and the reward. Nevertheless, there was inter-individual variability: the horses presenting high fearfulness, and to a lesser extent low sensory sensitivity and low gregariousness were less sensitive to the degradation, demonstrating that they were more likely to switch to a habitual process. Contrary to our expectations, the emotional state experienced during the procedure did not seem to explain this switching. We conclude that personality is not only related to learning performance, but also in part to the process involved during learning, independently of the emotion experienced during the process. This study provides new theoretical knowledge on cognitive skills in ungulates.

28148725	A previous study revealed that, although monkeys with bilateral lesions of either the orbitofrontal cortex (OFC) or the amygdala could learn an action-outcome task, they could not adapt their choices in response to devalued outcomes. Specifically, they could not adjust their choice between two actions after the value of the outcome associated with one of the actions had decreased. Here, we investigated whether OFC needs to interact functionally with the amygdala in mediating such choices. Rhesus monkeys were trained to make two mutually exclusive actions on a touch-sensitive screen: "tap" and "hold." Taps led to the availability of one kind of food outcome; holds produced a different food. On each trial, monkeys could choose either a tap or a hold to earn the corresponding food reward. After consuming one of the two foods to satiety, monkeys were then tested on their ability to adapt their choices in response to the updated relative valuation of the two predicted outcomes. Whereas intact (control) monkeys shifted their choices toward the action associated with the higher value (nonsated) food, monkeys with crossed surgical disconnection of the amygdala and OFC did not. These findings demonstrate that amygdala-OFC interactions are necessary for choices among actions based on the updated value of predicted outcomes and they also have a bearing on the idea that OFC specializes in stimulus- or object-based choices in contrast to action- or response-based choices.SIGNIFICANCE STATEMENT Dysfunctional interactions between orbitofrontal cortex (OFC) and the amygdala underlie several mental health disorders, often related to value-based decision making. Understanding the underlying neural circuitry may help to develop therapies for those suffering from mood and anxiety disorders and provide insight into addiction. Here, we investigated whether the amygdala must interact with OFC to make adaptive choices. Monkeys learned to perform two different actions, "tap" for one kind of food reward and "hold" for another, and then one of the two foods was devalued temporarily. Intact monkeys shifted their choice to whichever action produced the higher-value food; monkeys with crossed surgical disconnection of OFC and the amygdala did not. Therefore, OFC and the amygdala must interact functionally to mediate adaptive choices.
28146250	A relapse into nicotine addiction during abstinence often occurs after the reactivation of nicotine reward memories, either by acute exposure to nicotine (a smoking episode) or by smoking-associated conditioned stimuli (CS). Preclinical studies suggest that drug reward memories can undergo memory reconsolidation after being reactivated, during which they can be weakened or erased by pharmacological or behavioral manipulations. However, translational clinical studies using CS-induced memory retrieval-reconsolidation procedures to decrease drug craving reported inconsistent results.To develop and test an unconditioned stimulus (UCS)-induced retrieval-reconsolidation procedure to decrease nicotine craving among people who smoke.	A translational rat study and human study in an academic outpatient medical center among 96 male smokers (aged 18- 45 years) to determine the association of propranolol administration within the time window of memory reconsolidation (after retrieval of the nicotine-associated memories by nicotine UCS exposure) with relapse to nicotine-conditioned place preference (CPP) and operant nicotine seeking in rats, and measures of preference to nicotine-associated CS and nicotine craving among people who smoke.	The study rats were injected noncontingently with the UCS (nicotine 0.15 mg/kg, subcutaneous) in their home cage, and the human study participants administered a dose of propranolol (40 mg, per os; Zhongnuo Pharma).	Nicotine CPP and operant nicotine seeking in rats, and preference and craving ratings for newly learned and preexisting real-life nicotine-associated CS among people who smoke.	Sixty-nine male smokers completed the experiment and were included for statistical analysis: 24 in the group that received placebo plus 1 hour plus UCS, 23 who received propranolol plus 1 hour plus UCS, and 22 who received UCS plus 6 hours plus propranolol. In rat relapse models, propranolol injections administered immediately after nicotine UCS-induced memory retrieval inhibited subsequent nicotine CPP and operant nicotine seeking after short (CPP, d = 1.72, 95% CI, 0.63-2.77; operant seeking, d = 1.61, 95% CI, 0.59-2.60) or prolonged abstinence (CPP, d = 1.46, 95% CI, 0.42-2.47; operant seeking: d = 1.69, 95% CI, 0.66-2.69), as well as nicotine priming-induced reinstatement of nicotine CPP (d = 1.28, 95% CI, 0.27-2.26) and operant nicotine seeking (d = 1.61, 95% CI, 0.59-2.60) after extinction. Among the smokers, oral propranolol administered prior to nicotine UCS-induced memory retrieval decreased subsequent nicotine preference induced by newly learned nicotine CS (CS1, Cohen d = 0.61, 95% CI, 0.02-1.19 and CS2, d = 0.69, 95% CI, 0.10-1.28, respectively), preexisting nicotine CS (d = 0.57, 95% CI, -0.02 to 1.15), and nicotine priming (CS1, d = 0.82, 95% CI, 0.22-1.41 and CS2, d = 0.78, 95% CI, 0.18-1.37, respectively; preexisting nicotine CS, d = 0.92, 95% CI, 0.31-1.52), as well as nicotine craving induced by the preexisting nicotine CS (d = 0.64, 95% CI, 0.05-1.22), and nicotine priming (d = 1.15, 95% CI, 0.52-1.76).	In rat-to-human translational study, a novel UCS-induced memory retrieval-reconsolidation interference procedure inhibited nicotine craving induced by exposure to diverse nicotine-associated CS and nicotine itself. This procedure should be studied further in clinical trials.	
28146248	Disrupted reward processing, mainly driven by striatal dysfunction, is a key characteristic of addictive behaviors. However, functional magnetic resonance imaging (fMRI) studies have reported conflicting results, with both hypoactivations and hyperactivations during anticipation and outcome notification of monetary rewards in addiction.To determine the nature and direction of reward-processing disruptions during anticipation and outcome notification of monetary rewards in individuals with addiction using image-based meta-analyses of fMRI studies.	Relevant publications were identified searching PubMed (inclusion until March 2015) using the following terms: reward, fMRI, substance use, cocaine, cannabis, opiates, alcohol, nicotine, smokers, gambling, gamblers, gaming, and gamers. Authors of included articles were contacted to obtain statistical fMRI maps.	Inclusion criteria: reward task involving monetary reward anticipation and/or outcome; participants showing addictive behaviors; and healthy control group. Exclusion criteria: participants aged younger than 18 years; recreational substance use or gambling; participants at risk for addictive behaviors; and studies using the same patient data as other included studies.	Study procedures were conducted in accordance with the Meta-analysis of Observational Studies in Epidemiology guidelines. Using Seed-based d Mapping software, meta-analyses were performed using random-effect nonparametric statistics with group whole brain T-maps from individual studies as input. Analyses were performed across all addictions and for substance and gambling addictions separately.	Group differences (individuals with addiction vs control individuals) in reward-related brain activation during reward anticipation and outcome using fMRI (planned before data collection).	Twenty-five studies were included in the meta-analysis, representing 643 individuals with addictive behaviors and 609 healthy control individuals. During reward anticipation, individuals with substance and gambling addictions showed decreased striatal activation compared with healthy control individuals. During reward outcome, individuals with substance addiction showed increased activation in the ventral striatum, whereas individuals with gambling addiction showed decreased activation in the dorsal striatum compared with healthy control individuals.	Striatal hypoactivation in individuals with addiction during reward anticipation and in individuals with gambling addiction during reward outcome is in line with the reward-deficiency theory of addiction. However, the combination of hypoactivation during reward anticipation and hyperactivation during reward outcome in the striatum of individuals with substance addiction may be explained using learning-deficit theory.	
28145402	Impaired motivation is present in a variety of neurological disorders, suggesting that decreased motivation is caused by broad dysfunction of the nervous system across a variety of circuits. Based on evidence that impaired motivation is a major symptom in the early stages of Huntington's disease, when dopamine receptor type 2-expressing striatal medium spiny neurons (D2-MSNs) are particularly affected, we hypothesize that degeneration of these neurons would be a key node regulating motivational status. Using a progressive, time-controllable, diphtheria toxin-mediated cell ablation/dysfunction technique, we find that loss-of-function of D2-MSNs within ventrolateral striatum (VLS) is sufficient to reduce goal-directed behaviours without impairing reward preference or spontaneous behaviour. Moreover, optogenetic inhibition and ablation of VLS D2-MSNs causes, respectively, transient and chronic reductions of goal-directed behaviours. Our data demonstrate that the circuitry containing VLS D2-MSNs control motivated behaviours and that VLS D2-MSN loss-of-function is a possible cause of motivation deficits in neurodegenerative diseases.
28143961	Motor behaviors are shaped not only by current sensory signals but also by the history of recent experiences. For instance, repeated movements toward a particular target bias the subsequent movements toward that target direction. This process, called use-dependent plasticity (UDP), is considered a basic and goal-independent way of forming motor memories. Most studies consider movement history as the critical component that leads to UDP (Classen et al., 1998; Verstynen and Sabes, 2011). However, the effects of learning (i.e., improved performance) on UDP during movement repetition have not been investigated. Here, we used transcranial magnetic stimulation in two experiments to assess plasticity changes occurring in the primary motor cortex after individuals repeated reinforced and nonreinforced actions. The first experiment assessed whether learning a skill task modulates UDP. We found that a group that successfully learned the skill task showed greater UDP than a group that did not accumulate learning, but made comparable repeated actions. The second experiment aimed to understand the role of reinforcement learning in UDP while controlling for reward magnitude and action kinematics. We found that providing subjects with a binary reward without visual feedback of the cursor led to increased UDP effects. Subjects in the group that received comparable reward not associated with their actions maintained the previously induced UDP. Our findings illustrate how reinforcing consistent actions strengthens use-dependent memories and provide insight into operant mechanisms that modulate plastic changes in the motor cortex.SIGNIFICANCE STATEMENT Performing consistent motor actions induces use-dependent plastic changes in the motor cortex. This plasticity reflects one of the basic forms of human motor learning. Past studies assumed that this form of learning is exclusively affected by repetition of actions. However, here we showed that success-based reinforcement signals could affect the human use-dependent plasticity (UDP) process. Our results indicate that learning augments and interacts with UDP. This effect is important to the understanding of the interplay between the different forms of motor learning and suggests that reinforcement is not only important to learning new behaviors, but can shape our subsequent behavior via its interaction with UDP.
28143767	Dopamine (DA) is required for reinforcement learning. Hence, disruptions in DA signaling may contribute to the learning deficits associated with psychiatric disorders. The DA D1 receptor (D1R) has been linked to learning and is a target for cognitive/motivational enhancement in patients with schizophrenia. Separating the striatal D1R contribution to learning vs. motivation, however, has been challenging. We suppressed striatal D1R expression in mice using a D1R-targeting short hairpin RNA (shRNA), delivered locally to the striatum via an adeno-associated virus (AAV). We then assessed reward- and punishment-associative learning using a probabilistic learning task and motivation using a progressive-ratio breakpoint procedure. We confirmed suppression of striatal D1Rs immunohistochemically and by testing locomotor activity after the administration of (+)-doxanthrine, a full D1R agonist, in control mice and those treated with the D1RshRNA. D1RshRNA-treated mice exhibited impaired reward-associative learning, while punishment-associative learning was spared. This deficit was unrelated to general learning impairments or amotivation, because the D1shRNA-treated mice exhibited normal Barnes maze learning and normal motivation in the progressive-ratio breakpoint procedure. Suppression of striatal D1Rs selectively impaired reward-associative learning whereas punishment-associative learning, aversion-motivated learning, and appetitive motivation were spared. Because patients with schizophrenia exhibit similar reward-associative learning deficits, D1R-targeted treatments should be investigated to improve reward learning in these patients.

28140400	A recent genome-wide association study (GWAS) identified a significant single-nucleotide polymorphism (SNP) for trait-positive emotion at rs322931 on chromosome 1, which was also associated with brain activation in the reward system of healthy individuals when observing positive stimuli in a functional magnetic resonance imaging (fMRI) study. In the current study, we aimed to further validate the role of variation at rs322931 in reward processing. Using a similar fMRI approach, we use two paradigms that elicit a strong ventral striatum (VS) blood oxygen-level dependency (BOLD) response in a sample of young, healthy individuals (N=82). In the first study we use a similar picture-viewing task to the discovery sample (positive>neutral stimuli) to replicate an effect of the variant on emotion processing. In the second study we use a probabilistic reversal learning procedure to identify reward processing during decision-making under uncertainly (reward>punishment). In a region of interest (ROI) analysis of the bilateral VS, we show that the rs322931 genotype was associated with BOLD in the left VS during the positive>neutral contrast (PROI-CORRECTED=0.045) and during the reward>punishment contrast (PROI-CORRECTED=0.018), although the effect of passive picture viewing was in the opposite direction from that reported in the discovery sample. These findings suggest that the recently identified GWAS hit may influence positive emotion via individual differences in activity in the key hubs of the brain's reward system. Furthermore, these effects may not be limited to the passive viewing of positive emotional scenes, but may also be observed during dynamic decision-making. This study suggests that future studies of this GWAS locus may yield further insight into the biological mechanisms of psychopathologies characterised by deficits in reward processing and positive emotion.
28137970	Operant responding in rats provides an analog to voluntary behavior in humans and is used to study maladaptive behaviors, such as overeating, drug taking, or relapse. In renewal paradigms, extinguished behavior recovers when tested outside the context where extinction was learned. Inactivation of the prelimbic (PL) region of the medial prefrontal cortex by baclofen/muscimol (B/M) during testing attenuates renewal when tested in the original acquisition context after extinction in another context (ABA renewal). Two experiments tested the hypothesis that the PL is important in context-dependent responding learned during conditioning. In the first, rats learned to lever-press for a sucrose-pellet reward. Following acquisition, animals were infused with either B/M or vehicle in the PL and tested in the acquisition context (A) and in a different context (B). All rats showed a decrement in responding when switched from Context A to Context B, but PL inactivation decreased responding only in Context A. Experiment 2a examined the effects of PL inactivation on ABC renewal in the same rats. Here, following reacquisition of the response, responding was extinguished in a new context (C). Following infusions of B/M or vehicle in the PL, responding was tested in Context C and another new context (D). The rats exhibited ACD renewal regardless of PL inactivation. Experiment 2b demonstrated that PL inactivation attenuated the ABA renewal effect in the same animals, replicating earlier results and demonstrating that cannulae were still functional. The results suggest that, rather than attenuating renewal generally, PL inactivation specifically affects ABA renewal by reducing responding in the conditioning context.SIGNIFICANCE STATEMENT Extinguished operant behavior can recover ("renew") when tested outside the extinction context. This suggests that behaviors, such as overeating or drug taking, might be especially prone to relapse following treatment. In rats, inactivation of the prelimbic cortex (PL) attenuates renewal. However, we report that PL inactivation after training attenuates responding in the context in which responding was acquired, but not in another one. A similar inactivation has no impact on renewal when testing occurs in a new, rather than the original, context following extinction. The PL thus has a more specific role in controlling contextually dependent operant behavior than has been previously reported.
28135843	The authors examined whether a contingency management intervention using the ethyl glucuronide (EtG) alcohol biomarker resulted in increased alcohol abstinence in outpatients with co-occurring serious mental illnesses. Secondary objectives were to determine whether contingency management was associated with changes in heavy drinking, treatment attendance, drug use, cigarette smoking, psychiatric symptoms, and HIV-risk behavior.Seventy-nine (37% female, 44% nonwhite) outpatients with serious mental illness and alcohol dependence receiving treatment as usual completed a 4-week observation period and were randomly assigned to 12 weeks of contingency management for EtG-negative urine samples and addiction treatment attendance, or reinforcement only for study participation. Contingency management included the variable magnitude of reinforcement "prize draw" procedure contingent on EtG-negative samples (<150 ng/mL) three times a week and weekly gift cards for outpatient treatment attendance. Urine EtG, drug test, and self-report outcomes were assessed during the 12-week intervention and 3-month follow-up periods.	Contingency management participants were 3.1 times (95% CI=2.2-4.5) more likely to submit an EtG-negative urine test during the 12-week intervention period, attaining nearly 1.5 weeks of additional alcohol abstinence compared with controls. Contingency management participants had significantly lower mean EtG levels, reported less drinking and fewer heavy drinking episodes, and were more likely to submit stimulant-negative urine and smoking-negative breath samples, compared with controls. Differences in self-reported alcohol use were maintained at the 3-month follow-up.	This is the first randomized trial utilizing an accurate and validated biomarker (EtG) to demonstrate the efficacy of contingency management for alcohol dependence in outpatients with serious mental illness.	
28135272	Social interaction starts with perception of the world around you. This study investigated two fundamental issues regarding the development of discrimination of higher spatial frequencies, which are important building blocks of perception. Firstly, it mapped the typical developmental trajectory of higher spatial frequency discrimination. Secondly, it developed and validated a novel design that could be applied to improve atypically developed vision. Specifically, this study examined the effect of age and reward on task performance, practice effects, and motivation (i.e., number of trials completed) in a higher spatial frequency (reference frequency: 6 cycles per degree) discrimination task. We measured discrimination thresholds in children aged between 7 to 12 years and adults (N = 135). Reward was manipulated by presenting either positive reinforcement or punishment. Results showed a decrease in discrimination thresholds with age, thus revealing that higher spatial frequency discrimination continues to develop after 12 years of age. This development continues longer than previously shown for discrimination of lower spatial frequencies. Moreover, thresholds decreased during the run, indicating that discrimination abilities improved. Reward did not affect performance or improvement. However, in an additional group of 5-6 year-olds (N = 28) punishments resulted in the completion of fewer trials compared to reinforcements. In both reward conditions children aged 5-6 years completed only a fourth or half of the run (64 to 128 out of 254 trials) and were not motivated to continue. The design thus needs further adaptation before it can be applied to this age group. Children aged 7-12 years and adults completed the run, suggesting that the design is successful and motivating for children aged 7-12 years. This study thus presents developmental differences in higher spatial frequency discrimination thresholds. Furthermore, it presents a design that can be used in future developmental studies that require multiple stimulus presentations such as visual perceptual learning.
28132915	Social stress modifies the activity of brain areas involved in the rewarding effects of psychostimulants, inducing neuroadaptations in the dopaminergic mesolimbic system and modifying the sensitivity of dopamine receptors. In the present study we evaluated the effect of the dopamine D1- and D2-like receptor antagonists (SCH23390 and raclopride, respectively) on the short-time effects of acute social defeat (ASD). Male OF1 mice were socially defeated before each conditioning session of the conditioned place preference (CPP) induced by 1mg/kg or 25mg/kg of cocaine plus the corresponding dopamine antagonist. A final experiment was designed to evaluate the effect of the dopamine antagonists on the CPP induced by 3mg/kg of cocaine with or without a stress experience. Mice exposed to ASD showed an increase in reinstatement of the conditioned reinforcing effects of cocaine that was blocked by all of the dopamine receptor antagonists. Blockade of dopamine D2-like receptors with raclopride specifically prevented the effects of stress without affecting the rewarding properties of cocaine. However, SCH23390 inhibited cocaine-induced preference in the control groups and even induced aversion in defeated mice conditioned with the lower dose of cocaine. Moreover, the lowest dose of SCH23390 blocked the rewarding effects of 3mg/kg of cocaine-induced CPP. Our results confirm that the dopamine D2 receptor is involved in the short-term effects of ASD on the rewarding effects of cocaine. The dopamine D1 receptor is clearly involved in the rewarding effects of cocaine, but its role in the effects of ASD remains to be demonstrated.
28130606	Behavioural flexibility allows animals to adjust their behaviours according to changing environmental demands. Such flexibility is frequently assessed by the discrimination-reversal learning task. We examined grey squirrels' behavioural flexibility, using a simultaneous colour discrimination-reversal learning task on a touch screen. Squirrels were trained to select their non-preferred colour in the discrimination phase, and their preferred colour was rewarded in a subsequent reversal phase. We used error rates to divide learning in each phase into three stages (perseveration, chance level and 'learned') and examined response inhibition and head-switching during each stage. We found consistent behavioural patterns were associated with each learning stage: in the perseveration stage, at the beginning of each training phase, squirrels showed comparable response latencies to correct and incorrect stimuli, along with a low level of head-switching. They quickly overcame perseveration, typically in one to three training blocks. In the chance-level stage, response latencies to both stimuli were low, but during initial discrimination squirrels showed more head-switches than in the previous stage. This suggests that squirrels were learning the current reward contingency by responding rapidly to a stimulus, but with increased attention to both stimuli. In the learned stage, response latencies to the correct stimulus and the number of head-switches were at their highest, whereas incorrect response latencies were at their lowest, and differed significantly from correct response latencies. These results suggest increased response inhibition and attention allowed the squirrels to minimise errors. They also suggest that errors in the 'learned' stage were related to impulsive emission of the pre-potent or previously learned responses.
28129057	Research on adolescence has largely focused on the particular biological and neural changes that place teens at risk for negative outcomes linked to increases in sensation-seeking and risky behavior. However, there is a growing interest in the adaptive function of adolescence, with work highlighting the dual nature of adolescence as a period of potential risk and opportunity. We examined how behavioral and neural sensitivity to risk and reward varies as a function of age using the Balloon Analog Risk Task. Seventy-seven children and adolescents (ages 8-17 years) completed the Balloon Analog Risk Task during an fMRI session. Results indicate that adolescents show greater learning throughout the task. Furthermore, older participants showed increased neural responses to reward in the OFC and ventral striatum, increased activation to risk in the mid-cingulate cortex, as well as increased functional OFC-medial PFC coupling in both risk and reward contexts. Age-related changes in regional activity and interregional connectivity explain the link between age and increases in flexible learning. These results support the idea that adolescents' sensitivity to risk and reward supports adaptive learning and behavioral approaches for reward acquisition.
28129053	Learning the contingencies between stimulus, action, and outcomes is disrupted in disorders associated with altered dopamine (DA) function in the BG, such as Parkinson disease (PD). Although the role of DA in learning to act has been extensively investigated in PD, the role of DA in "learning to withhold" (or inhibit) action to influence outcomes is not as well understood. The current study investigated the role of DA in learning to act or to withhold action to receive rewarding, or avoid punishing outcomes, in patients with PD tested "off" and "on" dopaminergic medication (n = 19) versus healthy controls (n = 30). Participants performed a reward-based learning task that orthogonalized action and outcome valence (action-reward, inaction-reward, action-punishment, inaction-punishment). We tested whether DA would bias learning toward action, toward reward, or to particular action-outcome interactions. All participants demonstrated inherent learning biases preferring action with reward and inaction to avoid punishment, and this was unaffected by medication. Instead, DA produced a complex modulation of learning less natural action-outcome associations. "Off" DA medication, patients demonstrated impairments in learning to withhold action to gain reward, suggesting a difficulty to overcome a bias toward associating inaction with punishment avoidance. On DA medication, these patterns changed, and patients showed a reduced ability to learn to act to avoid punishment, indicating a bias toward action and reward. The current findings suggest that DA in PD has a complex influence on the formation of action-outcome associations, particularly those involving less natural linkages between action and outcome valence.
28129052	Hundreds of ERP studies have reported a midfrontal negative-going amplitude shift following negative compared with positive action outcomes. This feedback-related negativity (FRN) effect is typically thought to reflect an early and binary mechanism of action evaluation in the posterior midcingulate cortex. However, in prior research on the FRN effect, the instantaneous value and the long-term value of action outcomes have been perfectly confounded. That is, instantaneously positive outcomes were generally consistent with task goals, whereas instantaneously negative outcomes were inconsistent with task goals. In this study, we disentangled these two outcome aspects in two experiments. Our results reveal an interaction of instantaneous and long-term outcome values. More precisely, our findings strongly suggest that the FRN effect is mainly driven by a reward positivity, which is evoked only by outcomes that possess an instantaneously positive value and also help the organism to reach its long-term goals. These findings add to a recent literature according to which the posterior midcingulate cortex acts as a hierarchical reinforcement learning system and suggest that this system integrates instant and long-term action-outcome values. This, in turn, might be crucial for learning optimal behavioral strategies in a given setting.
28126429	Individuals have a tendency to be more risky in their choices after having experienced a monetary loss, than after a reward. Here, we examined whether prior outcomes influence differently the patterns of neural activity of individuals who are used to taking monetary risk, namely poker players. High-frequency poker players and non-gamblers were scanned while performing a controlled task that allowed measuring the effect of prior outcomes on subsequent decisions. Both non-gamblers and poker players took more risks after losing a gamble than after winning one. Neuroimaging data revealed that non-gamblers exhibited higher brain activation than poker players when pondering a decision after losing, as compared to after winning. The opposite was found in poker players. This differential pattern of activation was observed in brain regions involved in high-order motor processes (the dorsal premotor cortex). These results suggest that gambling habits introduce significant changes in action preparation during decision-making following wins and losses.
28123082	Orbitofrontal cortex (OFC), medial frontal cortex (MFC), and amygdala mediate stimulus-reward learning, but the mechanisms through which they interact are unclear. Here, we investigated how neurons in macaque OFC and MFC signaled rewards and the stimuli that predicted them during learning with and without amygdala input. Macaques performed a task that required them to evaluate two stimuli and then choose one to receive the reward associated with that option. Four main findings emerged. First, amygdala lesions slowed the acquisition and use of stimulus-reward associations. Further analyses indicated that this impairment was due, at least in part, to ineffective use of negative feedback to guide subsequent decisions. Second, the activity of neurons in OFC and MFC rapidly evolved to encode the amount of reward associated with each stimulus. Third, amygdalectomy reduced encoding of stimulus-reward associations during the evaluation of different stimuli. Reward encoding of anticipated and received reward after choices were made was not altered. Fourth, amygdala lesions led to an increase in the proportion of neurons in MFC, but not OFC, that encoded the instrumental response that monkeys made on each trial. These correlated changes in behavior and neural activity after amygdala lesions strongly suggest that the amygdala contributes to the ability to learn stimulus-reward associations rapidly by shaping encoding within OFC and MFC.SIGNIFICANCE STATEMENT Altered functional interactions among orbital frontal cortex (OFC), medial frontal cortex (MFC), and amygdala are thought to underlie several psychiatric conditions, many related to reward learning. Here, we investigated the causal contribution of the amygdala to the development of neuronal activity in macaque OFC and MFC related to rewards and the stimuli that predict them during learning. Without amygdala inputs, neurons in both OFC and MFC showed decreased encoding of stimulus-reward associations. MFC also showed increased encoding of the instrumental responses that monkeys made on each trial. Behaviorally, changes in neural activity were accompanied by slower stimulus-reward learning. The findings suggest that interactions among amygdala, OFC, and MFC contribute to learning about stimuli that predict rewards.
28123030	Addictive drugs usurp neural plasticity mechanisms that normally serve reward-related learning and memory, primarily by evoking changes in glutamatergic synaptic strength in the mesocorticolimbic dopamine circuitry. Here, we show that repeated cocaine exposure in vivo does not alter synaptic strength in the mouse prefrontal cortex during an early period of withdrawal, but instead modifies a Hebbian quantitative synaptic learning rule by broadening the temporal window and lowers the induction threshold for spike-timing-dependent LTP (t-LTP). After repeated, but not single, daily cocaine injections, t-LTP in layer V pyramidal neurons is induced at +30 ms, a normally ineffective timing interval for t-LTP induction in saline-exposed mice. This cocaine-induced, extended-timing t-LTP lasts for ∼1 week after terminating cocaine and is accompanied by an increased susceptibility to potentiation by fewer pre-post spike pairs, indicating a reduced t-LTP induction threshold. Basal synaptic strength and the maximal attainable t-LTP magnitude remain unchanged after cocaine exposure. We further show that the cocaine facilitation of t-LTP induction is caused by sensitized D1-cAMP/protein kinase A dopamine signaling in pyramidal neurons, which then pathologically recruits voltage-gated l-type Ca2+ channels that synergize with GluN2A-containing NMDA receptors to drive t-LTP at extended timing. Our results illustrate a mechanism by which cocaine, acting on a key neuromodulation pathway, modifies the coincidence detection window during Hebbian plasticity to facilitate associative synaptic potentiation in prefrontal excitatory circuits. By modifying rules that govern activity-dependent synaptic plasticity, addictive drugs can derail the experience-driven neural circuit remodeling process important for executive control of reward and addiction.It is believed that addictive drugs often render an addict's brain reward system hypersensitive, leaving the individual more susceptible to relapse. We found that repeated cocaine exposure alters a Hebbian associative synaptic learning rule that governs activity-dependent synaptic plasticity in the mouse prefrontal cortex, characterized by a broader temporal window and a lower threshold for spike-timing-dependent LTP (t-LTP), a cellular form of learning and memory. This rule change is caused by cocaine-exacerbated D1-cAMP/protein kinase A dopamine signaling in pyramidal neurons that in turn pathologically recruits l-type Ca2+ channels to facilitate coincidence detection during t-LTP induction. Our study provides novel insights on how cocaine, even with only brief exposure, may prime neural circuits for subsequent experience-dependent remodeling that may underlie certain addictive behavior.	
28123021	Telling time is fundamental to many forms of learning and behavior, including the anticipation of rewarding events. Although the neural mechanisms underlying timing remain unknown, computational models have proposed that the brain represents time in the dynamics of neural networks. Consistent with this hypothesis, changing patterns of neural activity dynamically in a number of brain areas-including the striatum and cortex-has been shown to encode elapsed time. To date, however, no studies have explicitly quantified and contrasted how well different areas encode time by recording large numbers of units simultaneously from more than one area. Here, we performed large-scale extracellular recordings in the striatum and orbitofrontal cortex of mice that learned the temporal relationship between a stimulus and a reward and reported their response with anticipatory licking. We used a machine-learning algorithm to quantify how well populations of neurons encoded elapsed time from stimulus onset. Both the striatal and cortical networks encoded time, but the striatal network outperformed the orbitofrontal cortex, a finding replicated both in simultaneously and nonsimultaneously recorded corticostriatal datasets. The striatal network was also more reliable in predicting when the animals would lick up to ∼1 s before the actual lick occurred. Our results are consistent with the hypothesis that temporal information is encoded in a widely distributed manner throughout multiple brain areas, but that the striatum may have a privileged role in timing because it has a more accurate "clock" as it integrates information across multiple cortical areas.The neural representation of time is thought to be distributed across multiple functionally specialized brain structures, including the striatum and cortex. However, until now, the neural code for time has not been compared quantitatively between these areas. Here, we performed large-scale recordings in the striatum and orbitofrontal cortex of mice trained on a stimulus-reward association task involving a delay period and used a machine-learning algorithm to quantify how well populations of simultaneously recorded neurons encoded elapsed time from stimulus onset. We found that, although both areas encoded time, the striatum consistently outperformed the orbitofrontal cortex. These results suggest that the striatum may refine the code for time by integrating information from multiple inputs.	
28122241	Cholinergic neurotransmission throughout the neocortex and hippocampus regulates arousal, learning, and attention. However, owing to the poorly characterized timing and location of acetylcholine release, its detailed behavioral functions remain unclear. Using electrochemical biosensors chronically implanted in mice, we made continuous measurements of the spatiotemporal dynamics of acetylcholine release across multiple behavioral states. We found that tonic levels of acetylcholine release were coordinated between the prefrontal cortex and hippocampus and maximal during training on a rewarded working memory task. Tonic release also increased during REM sleep but was contingent on subsequent wakefulness. In contrast, coordinated phasic acetylcholine release occurred only during the memory task and was strongly localized to reward delivery areas without being contingent on trial outcome. These results show that coordinated acetylcholine release between the prefrontal cortex and hippocampus is associated with reward and arousal on distinct timescales, providing dual mechanisms to support learned behavior acquisition during cognitive task performance.
28121026	Individuals track probabilities, such as associations between events in their environments, but less is known about the degree to which experience-within a learning session and over development-influences people's use of incoming probabilistic information to guide behavior in real time. In two experiments, children (4-11 years) and adults searched for rewards hidden in locations with predetermined probabilities. In Experiment 1, children (n = 42) and adults (n = 32) changed strategies to maximize reward receipt over time. However, adults demonstrated greater strategy change efficiency. Making the predetermined probabilities more difficult to learn (Experiment 2) delayed effective strategy change for children (n = 39) and adults (n = 33). Taken together, these data characterize how children and adults alike react flexibly and change behavior according to incoming information.
28116477	Phosphorylation of the methyl DNA-binding protein MeCP2 at Ser421 (pMeCP2-S421) is induced in corticolimbic brain regions during exposure to drugs of abuse and modulates reward-driven behaviors. However, whether pMeCP2-S421 is also involved in behavioral adaptations to aversive drugs is unknown.Our goal was to establish the role and regulation of pMeCP2-S421 in corticolimbic brain regions of mice upon acute treatment with the kappa opioid receptor agonist U50488 and during the expression of U50488-induced conditioned place aversion (CPA).	pMeCP2-S421 levels were measured in the nucleus accumbens (NAc), prelimbic cortex, infralimbic cortex (ILC), and basolateral amygdala (BLA) of male mice after intraperitoneal administration of U50488 and upon the expression of U50488-induced CPA. Fos was measured as marker of neural activity in the same brain regions. U50488-induced CPA and Fos levels were compared between knockin (KI) mice that lack pMeCP2-S421 and their wild-type (WT) littermates.	U50488 administration acutely induced pMeCP2-S421 and Fos selectively in the NAc but did not alter MeCP2 levels in any brain region. U50488-induced CPA was associated with decreased pMeCP2-S421 in the ILC and BLA and induced Fos in the BLA. MeCP2 KI mice showed CPA indistinguishable from their WT littermates, but they also showed less BLA Fos induction upon CPA.	These data are the first to show that pMeCP2-S421 is induced in the brain acutely after U50488 administration but not upon U50488-induced CPA. Although pMeCP2-S421 is not required for U50488-induced CPA, this phosphorylation event may contribute to molecular plasticities in brain regions that govern aversive behaviors.	
28115481	Memory can inform goal-directed behavior by linking current opportunities to past outcomes. The orbitofrontal cortex (OFC) may guide value-based responses by integrating the history of stimulus-reward associations into expected outcomes, representations of predicted hedonic value and quality. Alternatively, the OFC may rapidly compute flexible "online" reward predictions by associating stimuli with the latest outcome. OFC neurons develop predictive codes when rats learn to associate arbitrary stimuli with outcomes, but the extent to which predictive coding depends on most recent events and the integrated history of rewards is unclear. To investigate how reward history modulates OFC activity, we recorded OFC ensembles as rats performed spatial discriminations that differed only in the number of rewarded trials between goal reversals. The firing rate of single OFC neurons distinguished identical behaviors guided by different goals. When >20 rewarded trials separated goal switches, OFC ensembles developed stable and anticorrelated population vectors that predicted overall choice accuracy and the goal selected in single trials. When <10 rewarded trials separated goal switches, OFC population vectors decorrelated rapidly after each switch, but did not develop anticorrelated firing patterns or predict choice accuracy. The results show that, whereas OFC signals respond rapidly to contingency changes, they predict choices only when reward history is relatively stable, suggesting that consecutive rewarded episodes are needed for OFC computations that integrate reward history into expected outcomes.SIGNIFICANCE STATEMENT Adapting to changing contingencies and making decisions engages the orbitofrontal cortex (OFC). Previous work shows that OFC function can either improve or impair learning depending on reward stability, suggesting that OFC guides behavior optimally when contingencies apply consistently. The mechanisms that link reward history to OFC computations remain obscure. Here, we examined OFC unit activity as rodents performed tasks controlled by contingencies that varied reward history. When contingencies were stable, OFC neurons signaled past, present, and pending events; when contingencies were unstable, past and present coding persisted, but predictive coding diminished. The results suggest that OFC mechanisms require stable contingencies across consecutive episodes to integrate reward history, represent predicted outcomes, and inform goal-directed choices.
28112207	According to the placebo-reward hypothesis, placebo is a reward-anticipation process that increases midbrain dopamine (DA) levels. Reward-based learning processes, such as reinforcement learning, involves a large part of the DA-ergic network that is also activated by the placebo intervention. Given the neurochemical overlap between placebo and reward learning, we investigated whether verbal instructions in conjunction with a placebo intervention are capable of enhancing reward learning in healthy individuals by using a monetary reward-based reinforcement-learning task. Placebo intervention was performed with non-invasive brain stimulation techniques. In a randomized, triple-blind, cross-over study we investigated this cognitive placebo effect in healthy individuals by manipulating the participants' perceived uncertainty about the intervention's efficacy. Volunteers in the purportedly low- and high-uncertainty conditions earned more money, responded more quickly and had a higher learning rate from monetary rewards relative to baseline. Participants in the purportedly high-uncertainty conditions showed enhanced reward learning, and a model-free computational analysis revealed a higher learning rate from monetary rewards compared to the purportedly low-uncertainty and baseline conditions. Our results indicate that the placebo response is able to enhance reward learning in healthy individuals, opening up exciting avenues for future research in placebo effects on other cognitive functions.
28111829	Alcohol dependence is a mental disorder that has been associated with an imbalance in behavioral control favoring model-free habitual over model-based goal-directed strategies. It is as yet unknown, however, whether such an imbalance reflects a predisposing vulnerability or results as a consequence of repeated and/or excessive alcohol exposure. We, therefore, examined the association of alcohol consumption with model-based goal-directed and model-free habitual control in 188 18-year-old social drinkers in a two-step sequential decision-making task while undergoing functional magnetic resonance imaging before prolonged alcohol misuse could have led to severe neurobiological adaptations. Behaviorally, participants showed a mixture of model-free and model-based decision-making as observed previously. Measures of impulsivity were positively related to alcohol consumption. In contrast, neither model-free nor model-based decision weights nor the trade-off between them were associated with alcohol consumption. There were also no significant associations between alcohol consumption and neural correlates of model-free or model-based decision quantities in either ventral striatum or ventromedial prefrontal cortex. Exploratory whole-brain functional magnetic resonance imaging analyses with a lenient threshold revealed early onset of drinking to be associated with an enhanced representation of model-free reward prediction errors in the posterior putamen. These results suggest that an imbalance between model-based goal-directed and model-free habitual control might rather not be a trait marker of alcohol intake per se.
28111339	Behavioral inflexibility is a common symptom of neuropsychiatric disorders which can have a major detrimental impact on quality of life. While the orbitofrontal cortex (OFC) has been strongly implicated in behavioral flexibility in rodents across paradigms, our understanding of how the OFC mediates these behaviors is rapidly adapting. Here we examined neuronal activity during reversal learning by coupling in vivo electrophysiological recording with a mouse touch-screen learning paradigm to further elucidate the role of the OFC in updating reward value. Single unit and oscillatory activity was recorded during well-learned discrimination and 3 distinct phases of reversal (early, chance and well-learned). During touch-screen performance, OFC neuronal firing tracked rewarded responses following a previous rewarded choice when behavior was well learned, but shifted to primarily track repeated errors following a previous error in early reversal. Spike activity tracked rewarded choices independent of previous trial outcome during chance reversal, and returned to the initial pattern of reward response at criterion. Analysis of spike coupling to oscillatory local field potentials showed that less frequently occurring behaviors had significantly fewer neurons locked to any oscillatory frequency. Together, these data support the role of the OFC in tracking the value of individual choices to inform future responses and suggests that oscillatory signaling may be involved in propagating responses to increase or decrease the likelihood that action is taken in the future. They further support the use of touch-screen paradigms in preclinical studies to more closely model clinical approaches to measuring behavioral flexibility.
28108321	Computerized tasks based on conditioned place preference (CPP) methodology offer the opportunity to study learning mechanisms involved in conditioned reward in humans. In this study, we examined acquisition and extinction of a CPP for virtual environments associated with monetary reward ($). Healthy men and women (N=57) completed a computerized CPP task in which they controlled an avatar within a virtual environment. On day 1, subjects completed 6 conditioning trials in which one room was paired with high $ and another with low $. Acquisition of place conditioning was assessed by measuring the time spent in each room during an exploration test of the virtual environments and using self-reported ratings of room liking and preference. Twenty-four hours later, retention and extinction of CPP were assessed during 4 successive exploration tests of the virtual environments. Participants exhibited a place preference for (spent significantly more time in) the virtual room paired with high $ over the one paired with low $ (p=0.015). They also reported that they preferred the high $ room (p<0.001) and liked it significantly more than the low $ room (p<0.001). However, these preferences were short-lived: 24h later subjects did not exhibit a behavioral or subjective preference for the high $ room. These findings show that individuals exhibit transient behavioral and subjective preferences for a virtual environment paired with monetary reward. Variations on this task may be useful to study mechanisms and brain substrates involved in conditioned reward and to examine the influence of drugs upon appetitive conditioning.
28108010	Potential threat can prime defensive responding and avoidance behavior, which may result in the loss of rewards. When aversive consequences do not occur, avoidance should, thus, be quickly overcome in healthy individuals. This study examined the impact of threat anticipation on reward-based decisions. Sixty-five participants completed a decision-making task in which they had to choose between high- and low-reward options. To model an approach-avoidance conflict, the high-reward option was contingent with a threat-of-shock cue; the low-reward option was contingent with a safety cue. In control trials, decisions were made without threat/safety instructions. Overall, behavioral data documented a typical preference for the profitable option. Importantly, under threat-of-shock, participants initially avoided the profitable option (i.e., safe, but less profitable choices). However, when they experienced that shocks did actually not occur, participants overcame initial avoidance in favor of larger gains. Furthermore, autonomic arousal (skin conductance and heart rate responses) was elevated during threat cues compared to safety and non-threatening control cues. Taken together, threat-of-shock was associated with behavioral consequences: initially, participants avoided threat-related options but made more profitable decisions as they experienced no aversive consequences. Although socially acquired threat contingencies are typically stable, incentives for approach can help to overcome threat-related avoidance.
28106849	Over the last few decades, a number of reinforcement learning techniques have emerged, and different reinforcement learning-based applications have proliferated. However, such techniques tend to specialize in a particular field. This is an obstacle to their generalization and extrapolation to other areas. Besides, neither the reward-punishment (r-p) learning process nor the convergence of results is fast and efficient enough. To address these obstacles, this research proposes a general reinforcement learning model. This model is independent of input and output types and based on general bioinspired principles that help to speed up the learning process. The model is composed of a perception module based on sensors whose specific perceptions are mapped as perception patterns. In this manner, similar perceptions (even if perceived at different positions in the environment) are accounted for by the same perception pattern. Additionally, the model includes a procedure that statistically associates perception-action pattern pairs depending on the positive or negative results output by executing the respective action in response to a particular perception during the learning process. To do this, the model is fitted with a mechanism that reacts positively or negatively to particular sensory stimuli in order to rate results. The model is supplemented by an action module that can be configured depending on the maneuverability of each specific agent. The model has been applied in the air navigation domain, a field with strong safety restrictions, which led us to implement a simulated system equipped with the proposed model. Accordingly, the perception sensors were based on Automatic Dependent Surveillance-Broadcast (ADS-B) technology, which is described in this paper. The results were quite satisfactory, and it outperformed traditional methods existing in the literature with respect to learning reliability and efficiency.
28103715	Although irritability is among the most common reasons that children and adolescents are brought for psychiatric care, there are few effective treatments. Developmentally sensitive pathophysiological models are needed to guide treatment development. In this review, the authors present a mechanistic model of irritability that integrates clinical and translational neuroscience research. Two complementary conceptualizations of pathological irritability are proposed: 1) aberrant emotional and behavioral responding to frustrative nonreward, mediated by reward-system dysfunction; and 2) aberrant approach responding to threat, mediated by threat-system dysfunction. The authors review the pathophysiological literature, including animal studies, as well as experimental psychology and clinical studies. Data suggest that, relative to healthy children, irritable children have deficient reward learning and elevated sensitivity to reward receipt and omission. These deficits are associated with dysfunction in the prefrontal cortex, striatum, and amygdala. Youths with irritability also show maladaptive orienting to, interpreting, and labeling of potential threats, associated with prefrontal cortical and amygdalar dysfunction. Abnormalities in reward and threat processing potentiate one another. Future work should test pathophysiological hypotheses and novel interventions targeting reward- and threat-related dysfunction to improve treatment for severe irritability in youths.
28103483	Little is known about the relationship between attention and learning during decision making. Using eye tracking and multivariate pattern analysis of fMRI data, we measured participants' dimensional attention as they performed a trial-and-error learning task in which only one of three stimulus dimensions was relevant for reward at any given time. Analysis of participants' choices revealed that attention biased both value computation during choice and value update during learning. Value signals in the ventromedial prefrontal cortex and prediction errors in the striatum were similarly biased by attention. In turn, participants' focus of attention was dynamically modulated by ongoing learning. Attentional switches across dimensions correlated with activity in a frontoparietal attention network, which showed enhanced connectivity with the ventromedial prefrontal cortex between switches. Our results suggest a bidirectional interaction between attention and learning: attention constrains learning to relevant dimensions of the environment, while we learn what to attend to via trial and error.
28100748	Expectation of reward can be shaped by the observation of actions and expressions of other people in one's environment. A person's apparent confidence in the likely reward of an action, for instance, makes qualities of their evidence, not observed directly, socially accessible. This strategy is computationally distinguished from associative learning methods that rely on direct observation, by its use of inference from indirect evidence. In twenty-three healthy human subjects, we isolated effects of first-hand experience, other people's choices, and the mediating effect of their confidence, on decision-making and neural correlates of value within ventromedial prefrontal cortex (vmPFC). Value derived from first-hand experience and other people's choices (regardless of confidence) were indiscriminately represented across vmPFC. However, value computed from agent choices weighted by their associated confidence was represented with specificity for ventromedial area 10. This pattern corresponds to shifts of connectivity and overlapping cognitive processes along a posterior-anterior vmPFC axis. Task behavior and self-reported self-reliance for decision-making in other social contexts correlated. The tendency to conform in other social contexts corresponded to increased activation in cortical regions previously shown to respond to social conflict in proportion to subsequent conformity (Campbell-Meiklejohn et al., 2010). The tendency to self-monitor predicted a selectively enhanced response to accordance with others in the right temporoparietal junction (rTPJ). The findings anatomically decompose vmPFC value representations according to computational requirements and provide biological insight into the social transmission of preference and reassurance gained from the confidence of others.Decades of research have provided evidence that the ventromedial prefrontal cortex (vmPFC) signals the satisfaction we expect from imminent actions. However, we have a surprisingly modest understanding of the organization of value across this substantial and varied region. This study finds that using cues of the reliability of other peoples' knowledge to enhance expectation of personal success generates value correlates that are anatomically distinct from those concurrently computed from direct, personal experience. This suggests that representation of decision values in vmPFC is suborganized according to the underlying computation, consistent with what we know about the anatomical heterogeneity of the region. These results also provide insight into the observational learning process by which someone else's confidence can sway and reassure our choices.	
28100737	Reward motivation has been demonstrated to enhance declarative memory by facilitating systems-level consolidation. Although high-reward information is often intermixed with lower reward information during an experience, memory for high value information is prioritized. How is this selectivity achieved? One possibility is that postencoding consolidation processes bias memory strengthening to those representations associated with higher reward. To test this hypothesis, we investigated the influence of differential reward motivation on the selectivity of postencoding markers of systems-level memory consolidation. Human participants encoded intermixed, trial-unique memoranda that were associated with either high or low-value during fMRI acquisition. Encoding was interleaved with periods of rest, allowing us to investigate experience-dependent changes in connectivity as they related to later memory. Behaviorally, we found that reward motivation enhanced 24 h associative memory. Analysis of patterns of postencoding connectivity showed that, even though learning trials were intermixed, there was significantly greater connectivity with regions of high-level, category-selective visual cortex associated with high-reward trials. Specifically, increased connectivity of category-selective visual cortex with both the VTA and the anterior hippocampus predicted associative memory for high- but not low-reward memories. Critically, these results were independent of encoding-related connectivity and univariate activity measures. Thus, these findings support a model by which the selective stabilization of memories for salient events is supported by postencoding interactions with sensory cortex associated with reward.Reward motivation is thought to promote memory by supporting memory consolidation. Yet, little is known as to how brain selects relevant information for subsequent consolidation based on reward. We show that experience-dependent changes in connectivity of both the anterior hippocampus and the VTA with high-level visual cortex selectively predicts memory for high-reward memoranda at a 24 h delay. These findings provide evidence for a novel mechanism guiding the consolidation of memories for valuable events, namely, postencoding interactions between neural systems supporting mesolimbic dopamine activation, episodic memory, and perception.	
28098430	Bipolar disorder is characterized by behavioral changes such as risk-taking and increasing goal-directed activities, which may result from altered reward processing. Patients with bipolar disorder show impaired reward learning in situations that require the integration of reinforced feedback over time. In this study, we examined the behavioral and electrophysiological characteristics of reward learning in manic and euthymic patients with bipolar disorder using a probabilistic reward task.Twenty-four manic and 20 euthymic patients with bipolar I disorder and 24 healthy control subjects performed the probabilistic reward task. We assessed response bias (RB) as a preference for the stimulus paired with the more frequent reward and feedback-related negativity (FRN) to correct identification of the rich stimulus.	Both manic and euthymic patients showed significantly lower RB scores in the early learning stage (block 1) in comparison with the late learning stage (block 2 or block 3) of the task, as well as significantly lower RB scores in the early stage compared to healthy subjects. Relatively more negative FRN amplitude is elicited by no presentation of an expected reward, compared to that elicited by presentation of expected feedback. The FRN became significantly more negative from the early (block 1) to the later stages (blocks 2 and 3) in both manic and euthymic patients, but not in healthy subjects. Changes in RB scores and FRN amplitudes between blocks 2 and 3 and block 1 correlated positively in healthy controls, but correlated negatively in manic and euthymic patients. The severity of manic symptoms correlated positively with reward learning scores and negatively with the FRN.	These findings suggest that patients with bipolar disorder during euthymic or manic states have behavioral and electrophysiological alterations in reward learning compared to healthy subjects. This dysfunctional reward processing may be related to the abnormal decision-making or altered goal-directed activities frequently seen in patients with bipolar disorder.	
28095006	Recent studies show that motor variability is actively regulated as an exploration tool to promote learning in reward-based tasks. However, its role in learning processes during error-based tasks, when a reduction of the motor variability is required to achieve good performance, is still unclear. In this study, we hypothesized that error-based learning not only depends on exploration but also on the individuals' ability to measure and predict the motor error. Previous studies identified a less auto-correlated motor variability as a higher ability to perform motion adjustments. Two experiments investigated the relationship between motor learning and variability, analyzing the long-range autocorrelation of the center of pressure fluctuations through the α score of a Detrended Fluctuation Analysis in balance tasks. In Experiment 1, we assessed the relationship between variability and learning rate using a standing balance task. Based on the results of this experiment, and to maximize learning, we performed a second experiment with a more difficult sitting balance task and increased practice. The learning rate of the 2 groups with similar balance performances but different α scores was compared. Individuals with a lower α score showed a higher learning rate. Because the α scores reveal how the motor output changes over time, instead of the magnitude of those changes, the higher learning rate is mainly linked to the higher error sensitivity rather than the exploration strategies. The results of this study highlight the relevance of the structure of output motor variability as a predictor of learning rate in error-based tasks. (PsycINFO Database Record
28095003	Drug addiction implicates both reward learning and homeostatic regulation mechanisms of the brain. This has stimulated 2 partially successful theoretical perspectives on addiction. Many important aspects of addiction, however, remain to be explained within a single, unified framework that integrates the 2 mechanisms. Building upon a recently developed homeostatic reinforcement learning theory, the authors focus on a key transition stage of addiction that is well modeled in animals, escalation of drug use, and propose a computational theory of cocaine addiction where cocaine reinforces behavior due to its rapid homeostatic corrective effect, whereas its chronic use induces slow and long-lasting changes in homeostatic setpoint. Simulations show that our new theory accounts for key behavioral and neurobiological features of addiction, most notably, escalation of cocaine use, drug-primed craving and relapse, individual differences underlying dose-response curves, and dopamine D2-receptor downregulation in addicts. The theory also generates unique predictions about cocaine self-administration behavior in rats that are confirmed by new experimental results. Viewing addiction as a homeostatic reinforcement learning disorder coherently explains many behavioral and neurobiological aspects of the transition to cocaine addiction, and suggests a new perspective toward understanding addiction. (PsycINFO Database Record
28094034	Humans and other primates have evolved the ability to represent their status in the group's social hierarchy, which is essential for avoiding harm and accessing resources. Yet it remains unclear how the human brain learns dominance status and adjusts behavior accordingly during dynamic social interactions. Here we address this issue with a combination of fMRI and transcranial direct current stimulation (tDCS). In a first fMRI experiment, participants learned an implicit dominance hierarchy while playing a competitive game against three opponents of different skills. Neural activity in the rostromedial PFC (rmPFC) dynamically tracked and updated the dominance status of the opponents, whereas the ventromedial PFC and ventral striatum reacted specifically to competitive victories and defeats. In a second experiment, we applied anodal tDCS over the rmPFC to enhance neural excitability while subjects performed a similar competitive task. The stimulation enhanced the relative weight of victories over defeats in learning social dominance relationships and exacerbated the influence of one's own dominance over competitive strategies. Importantly, these tDCS effects were specific to trials in which subjects learned about dominance relationships, as they were not present for control choices associated with monetary incentives but no competitive feedback. Taken together, our findings elucidate the role of rmPFC computations in dominance learning and unravel a fundamental mechanism that governs the emergence and maintenance of social dominance relationships in humans.
28093474	The firing rate of the mitral/tufted cells in the olfactory bulb is known to undergo significant trial-to-trial variability and is affected by anesthesia. Here we ask whether odorant-elicited changes in firing rate depend on the rate before application of the stimulus in the awake and anesthetized mouse. We find that prestimulus firing rate varies widely on a trial-to-trial basis and that the stimulus-induced change in firing rate decreases with increasing prestimulus firing rate. Interestingly, this prestimulus firing rate dependence was different when the behavioral task did not involve detecting the valence of the stimulus. Finally, when the animal was learning to associate the odor with reward, the prestimulus firing rate was smaller for false alarms compared with correct rejections, suggesting that intrinsic activity reflects the anticipatory status of the animal. Thus, in this sensory modality, changes in behavioral status alter the intrinsic prestimulus activity, leading to a change in the responsiveness of the second-order neurons. We speculate that this trial-to-trial variability in odorant responses reflects sampling of the massive parallel input by subsets of mitral cells.SIGNIFICANCE STATEMENT The olfactory bulb must deal with processing massive parallel input from ∼1200 distinct olfactory receptors. In contrast, the visual system receives input from a small number of photoreceptors and achieves recognition of complex stimuli by allocating processing for distinct spatial locations to different brain areas. Here we find that the change in firing rate elicited by the odorant in second-order mitral cells depends on the intrinsic activity leading to a change of magnitude in the responsiveness of these neurons relative to this prestimulus activity. Further, we find that prestimulus firing rate is influenced by behavioral status. This suggests that there is top-down modulation allowing downstream brain processing areas to perform dynamic readout of olfactory information.
28092323	The processing of reward and reinforcement learning seems to be important determinants of pain chronicity. However, reward processing is already altered early in life and if this is related to the development of pain symptoms later on is not known. The aim of this study was first to examine whether behavioural and brain-related indicators of reward processing at the age of 14 to 15 years are significant predictors of pain complaints 2 years later, at 16 to 17 years. Second, we investigated the contribution of genetic variations in the opioidergic system, which is linked to the processing of both, reward and pain, to this prediction. We used the monetary incentive delay task to assess reward processing, the Children's Somatization Inventory as measure of pain complaints and tested the effects of 2 single nucleotide polymorphisms (rs1799971/rs563649) of the human μ-opioid receptor gene. We found a significant prediction of pain complaints by responses in the dorsal striatum during reward feedback, independent of genetic predisposition. The relationship of pain complaints and activation in the periaqueductal gray and ventral striatum depended on the T-allele of rs563649. Carriers of this allele also showed more pain complaints than CC-allele carriers. Therefore, brain responses to reward outcomes and higher sensitivity to pain might be related already early in life and may thus set the course for pain complaints later in life, partly depending on a specific opioidergic genetic predisposition.

28092193	Background and aims Precommitment refers to the ability to prospectively restrict the access to temptations. This study examined whether risk-taking during gambling is decreased when an individual has the opportunity to precommit to his forthcoming bet. Methods Sixty individuals participated in a gambling task that consisted of direct choice (simply chose one monetary option among four available ones, ranging from low-risk to high-risk options) or precommitment trials (before choosing an amount, participants had the opportunity to make a binding choice that made high-risk options unavailable). Results We found that participants utilized the precommitment option, such that risk-taking was decreased on precommitment trials compared to direct choices. Within the precommitment trials, there was no significant difference in risk-taking following decisions to restrict versus non-restrict. Discussion These findings suggest that the opportunity to precommit may be sufficient to reduce the attractiveness of risk. Conclusions Present results might be exploited to create interventions aiming at enhancing one's ability to anticipate self-control failures while gambling.
28084991	Trained neural network models, which exhibit features of neural activity recorded from behaving animals, may provide insights into the circuit mechanisms of cognitive functions through systematic analysis of network activity and connectivity. However, in contrast to the graded error signals commonly used to train networks through supervised learning, animals learn from reward feedback on definite actions through reinforcement learning. Reward maximization is particularly relevant when optimal behavior depends on an animal's internal judgment of confidence or subjective preferences. Here, we implement reward-based training of recurrent neural networks in which a value network guides learning by using the activity of the decision network to predict future reward. We show that such models capture behavioral and electrophysiological findings from well-known experimental paradigms. Our work provides a unified framework for investigating diverse cognitive and value-based computations, and predicts a role for value representation that is essential for learning, but not executing, a task.
28077716	Classical economic theory contends that the utility of a choice option should be independent of other options. This view is challenged by the attraction effect, in which the relative preference between two options is altered by the addition of a third, asymmetrically dominated option. Here, we leveraged the attraction effect in the context of intertemporal choices to test whether both decisions and reward prediction errors (RPE) in the absence of choice violate the independence of irrelevant alternatives principle. We first demonstrate that intertemporal decision making is prone to the attraction effect in humans. In an independent group of participants, we then investigated how this affects the neural and behavioral valuation of outcomes using a novel intertemporal lottery task and fMRI. Participants' behavioral responses (i.e., satisfaction ratings) were modulated systematically by the attraction effect and this modulation was correlated across participants with the respective change of the RPE signal in the nucleus accumbens. Furthermore, we show that, because exponential and hyperbolic discounting models are unable to account for the attraction effect, recently proposed sequential sampling models might be more appropriate to describe intertemporal choices. Our findings demonstrate for the first time that the attraction effect modulates subjective valuation even in the absence of choice. The findings also challenge the prospect of using neuroscientific methods to measure utility in a context-free manner and have important implications for theories of reinforcement learning and delay discounting.Many theories of value-based decision making assume that people first assess the attractiveness of each option independently of each other and then pick the option with the highest subjective value. The attraction effect, however, shows that adding a new option to a choice set can change the relative value of the existing options, which is a violation of the independence principle. Using an intertemporal choice framework, we tested whether such violations also occur when the brain encodes the difference between expected and received rewards (i.e., the reward prediction error). Our results suggest that neither intertemporal choice nor valuation without choice adhere to the independence principle.	
28072417	Although both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent. We demonstrate an oestrous cycle-dependent mechanism controlling increased cocaine reward in females. During oestrus, ventral tegmental area (VTA) dopamine neuron activity is enhanced and drives post translational modifications at the dopamine transporter (DAT) to increase the ability of cocaine to inhibit its function, an effect mediated by estradiol. Female mice conditioned to associate cocaine with contextual cues during oestrus have enhanced mesolimbic responses to these cues in the absence of drug. Using chemogenetic approaches, we increase VTA activity to mechanistically link oestrous cycle-dependent enhancement of VTA firing to enhanced cocaine affinity at DAT and subsequent reward processing. These data have implications for sexual dimorphism in addiction vulnerability and define a mechanism by which cellular activity results in protein alterations that contribute to dysfunctional learning and reward processing.
28071747	Negative symptoms in schizophrenia have been linked to selective reinforcement learning deficits in the context of gains combined with intact loss-avoidance learning. Fundamental mechanisms of reinforcement learning and choice are prediction error signaling and the precise representation of reward value for future decisions. It is unclear which of these mechanisms contribute to the impairments in learning from positive outcomes observed in schizophrenia. A recent study suggested that patients with severe apathy symptoms show deficits in the representation of expected value. Considering the fundamental relevance for the understanding of these symptoms, we aimed to assess the stability of these findings across studies. Sixty-four patients with schizophrenia and 19 healthy control participants performed a probabilistic reward learning task. They had to associate stimuli with gain or loss-avoidance. In a transfer phase participants indicated valuation of the previously learned stimuli by choosing among them. Patients demonstrated an overall impairment in learning compared to healthy controls. No effects of apathy symptoms on task indices were observed. However, patients with schizophrenia learned better in the context of loss-avoidance than in the context of gain. Earlier findings were thus partially replicated. Further studies are needed to clarify the mechanistic link between negative symptoms and reinforcement learning.
28068111	Elevated alcohol reward value (RV) has been linked to higher levels of drinking and alcohol-related consequences, and there is evidence that specific drinking motives may mediate the relationship between demand and problematic alcohol use in college students, making these variables potentially important indicators of risk for high RV and alcohol problems. The present study evaluated these relationships in a high-risk sample of military veterans. Heavy-drinking (N = 68) veterans of Operations Enduring Freedom or Iraqi Freedom (OEF/OIF) completed the alcohol purchase task (APT) measure of alcohol demand (RV), and standard assessments of alcohol consumption, alcohol-related problems, and drinking motives. RV was associated with overall alcohol consequences, interpersonal alcohol consequences, social responsibility consequences and impulse control consequences. Mediation analyses indicated significant mediation of the relationships between RV and a number of problem subscales by social motives, coping-anxiety motives, coping-depression motives and enhancement motives. This suggests that individuals who have a high valuation of alcohol may have increased motivation to drink in social, mood-enhancement, and coping situations, resulting in increased alcohol-related consequences. Demand and drinking motives should be examined as potential indicators of need for intervention services and as treatment targets in veterans. (PsycINFO Database Record
28065844	Chronic mild or unpredictability stress produces a persistent depressive-like state. The main symptoms of depression include weight loss, despair, anhedonia, diminished motivation and mild cognition impairment, which could influence the ability of reward-related learning. In the present study, we aimed to evaluate the effects of chronic restraint stress on the performance of reward-related learning of rats. We used the exposure of repeated restraint stress (6h/day, for 28days) to induce depression-like behavior in rats. Then designed tasks including Pavlovian conditioning (magazine head entries), acquisition and maintenance of instrumental conditioning (lever pressing) and goal directed learning (higher fixed ratio schedule of reinforcement) to study the effects of chronic restraint stress. The results indicated that chronic restraint stress influenced rats in those aspects including the acquisition of a Pavlovian stimulus-outcome (S-O) association, the formation and maintenance of action-outcome (A-O) causal relation and the ability of learning in higher fixed ratio schedule. In conclusion, depression could influence the performances in reward-related learning obviously and the series of instrumental learning tasks may have potential as a method to evaluate cognitive changes in depression.
28065182	Obsessive-compulsive disorder (OCD) has been linked to functional abnormalities in fronto-striatal networks as well as impairments in decision making and learning. Little is known about the neurocognitive mechanisms causing these decision-making and learning deficits in OCD, and how they relate to dysfunction in fronto-striatal networks.We investigated neural mechanisms of decision making in OCD patients, including early and late onset of disorder, in terms of reward prediction errors (RPEs) using functional magnetic resonance imaging. RPEs index a mismatch between expected and received outcomes, encoded by the dopaminergic system, and are known to drive learning and decision making in humans and animals. We used reinforcement learning models and RPE signals to infer the learning mechanisms and to compare behavioural parameters and neural RPE responses of the OCD patients with those of healthy matched controls.	Patients with OCD showed significantly increased RPE responses in the anterior cingulate cortex (ACC) and the putamen compared with controls. OCD patients also had a significantly lower perseveration parameter than controls.	Enhanced RPE signals in the ACC and putamen extend previous findings of fronto-striatal deficits in OCD. These abnormally strong RPEs suggest a hyper-responsive learning network in patients with OCD, which might explain their indecisiveness and intolerance of uncertainty.	
28062254	Tetrahydroprotoberberines (THPB) have a high affinity for dopamine (DA) D1 and D2 receptors and may provide a novel treatment for drug addiction. We assessed the effects of the THPB d-govadine on the acquisition, expression, extinction and reinstatement of d-amphetamine-(1.5mg/kg, i.p.) induced conditioned place preference (CPP). Furthermore, the effects of d-govadine on conditioned association between contextual stimuli and a natural reward were examined using food-induced CPP. In separate experiments, rats received d-govadine (0, 0.5 or 1.0mg/kg, i.p.) before a) each d-amphetamine injection during conditioning, b) expression of amphetamine-induced CPP, c) each extinction session, d) amphetamine-induced reinstatement of CPP, or e) placement into a compartment containing food during conditioning. Although d-govadine had no effect on acquisition of amphetamine CPP, treatment with d-govadine during acquisition dose-dependently extinguished a preference for the amphetamine-associated context more quickly than vehicle treatment. Moreover, d-govadine treatment facilitated the extinction of amphetamine CPP when given repeatedly throughout the extinction phase. Although the expression of amphetamine CPP was not affected by d-govadine administered prior to the expression test, amphetamine-induced reinstatement of CPP following an extinction period was blocked by d-govadine (1.0mg/kg). The intermediate dose of d-govadine blocked the acquisition of food CPP, whereas the high dose facilitated extinction of this preference as compared to vehicle-treated animals. Therefore, d-govadine attenuates the maintenance of conditioned associations between contextual stimuli and amphetamine or food reward, as well as amphetamine-induced reinstatement of drug seeking behaviour. As such, d-govadine may be a candidate for further development as a pharmacological treatment of psychostimulant drug dependence.
28060525	A range of evidence suggests that human reward functioning is partly driven by the endogenous circadian system, generating 24-hour rhythms in behavioural measures of reward activation. Reward functioning is multifaceted but literature to date is largely limited to measures of self-reported positive mood states. The aim of this study was to advance the field by testing for hypothesised diurnal variation in previously unexplored components of psychological reward: 'wanting', liking, and learning using subjective and behavioural measures. Risky decision making (automatic Balloon Analogue Risk Task), affective responsivity to positive images (International Affective Pictures System), uncued self-reported discrete emotions, and learning-contingent reward (Iowa Gambling Task) were measured at 10.00 hours, 14.00 hours, and 19.00 hours in a counterbalanced repeated measures design with 50 healthy male participants (aged 18-30). As hypothesised, risky decision making (unconscious 'wanting') and ratings of arousal towards positive images (conscious wanting) exhibited a diurnal waveform with indices highest at 14.00 hours. No diurnal rhythm was observed for liking (pleasure ratings to positive images, discrete uncued positive emotions) or in a learning-contingent reward task. Findings reaffirm that diurnal variation in human reward functioning is most pronounced in the motivational 'wanting' components of reward.
28057490	The behavioral effects of methamphetamine (METH) are mediated by the striatum, which is divided into the patch compartment, which mediates limbic and reward functions, and the matrix compartment, which mediates sensorimotor tasks. METH treatment results in repetitive behavior that is related to enhanced relative activation of the patch versus the matrix compartment. The patch, but not the matrix compartment contains a high density of μ opioid receptors, and localized blockade of patch-based μ opioid receptors attenuates METH-induced patch-enhanced activity and repetitive behaviors. Numerous studies have examined patch-enhanced activity and the contribution of patch-associated μ opioid receptors to METH-induced repetitive behavior, but it is not known whether patch-enhanced activity occurs during METH-mediated reward, nor is it known if patch-based μ opioid receptors contribute to METH reward. The goals of this study were to determine if blockade of patch-based μ opioid receptors alters METH-induced conditioned place preference (CPP), as well activation of the patch and matrix compartments following METH-mediated CPP. A biased conditioning paradigm was used to assess CPP, and conditioning occurred over an 8-d period. Animals were bilaterally infused in the striatum with the μ-specific antagonist CTAP or vehicle prior to conditioning. Animals were tested for preference 24h after the last day of conditioning, sacrificed and the brains processed for immunohistochemistry. Blockade of patch-based μ opioid receptors reduced METH-induced CPP, and reduced patch-enhanced c-Fos expression in the striatum following METH-mediated CPP. These data indicate that patch-enhanced activity is associated with METH-mediated reward and patch-based μ opioid receptors contribute to this phenomenon.
28056655	Age affects the human taste system at peripheral and central levels. Metabolic syndrome is a constellation of risk factors (e.g., abdominal obesity and hypertension) that co-occur, increase with age, and heighten risk for cardiovascular disease, diabetes, and cognitive decline. Little is known about how age, metabolic syndrome, and hunger state interact to influence how the brain processes information about taste. We investigated brain activation during the hedonic evaluation of a pleasant, nutritive stimulus (sucrose) within regions critical for taste, homeostatic energy regulation, and reward, as a function of the interactions among age, metabolic syndrome, and hunger condition. We scanned young and elderly adults, half with risk factors associated with metabolic syndrome twice: Once fasted overnight and once after a preload. Functional magnetic resonance imaging data indicated significant effects of age as well as interactive effects with metabolic syndrome and hunger condition. Age-related differences in activation were dependent on the hunger state in regions critical for homoeostatic energy regulation and basic as well as higher order sensory processing and integration. The effects of age and metabolic syndrome on activation in the insula, orbital frontal cortex, caudate, and the hypothalamus may have particularly important implications for taste processing, energy regulation, and dietary choices.
28055824	Dorsal anterior cingulate cortex (dACC) mediates updating and maintenance of cognitive models of the world used to drive adaptive reward-guided behavior. We investigated the neurochemical underpinnings of this process. We used magnetic resonance spectroscopy in humans, to measure levels of glutamate and GABA in dACC. We examined their relationship to neural signals in dACC, measured with fMRI, and cognitive task performance. Both inhibitory and excitatory neurotransmitters in dACC were predictive of the strength of neural signals in dACC and behavioral adaptation. Glutamate levels were correlated, first, with stronger neural activity representing information to be learnt about the tasks' costs and benefits and, second, greater use of this information in the guidance of behavior. GABA levels were negatively correlated with the same neural signals and the same indices of behavioral influence. Our results suggest that glutamate and GABA in dACC affect the encoding and use of past experiences to guide behavior.
28054919	Dopamine neurons are thought to encode novelty in addition to reward prediction error (the discrepancy between actual and predicted values). In this study, we compared dopamine activity across the striatum using fiber fluorometry in mice. During classical conditioning, we observed opposite dynamics in dopamine axon signals in the ventral striatum ('VS dopamine') and the posterior tail of the striatum ('TS dopamine'). TS dopamine showed strong excitation to novel cues, whereas VS dopamine showed no responses to novel cues until they had been paired with a reward. TS dopamine cue responses decreased over time, depending on what the cue predicted. Additionally, TS dopamine showed excitation to several types of stimuli including rewarding, aversive, and neutral stimuli whereas VS dopamine showed excitation only to reward or reward-predicting cues. Together, these results demonstrate that dopamine novelty signals are localized in TS along with general salience signals, while VS dopamine reliably encodes reward prediction error.
28053327	Dopamine-releasing neurons of the ventral tegmental area (VTA) have central roles in reward-related and goal-directed behaviours. VTA dopamine-releasing neurons are heterogeneous in their afferent and efferent connectivity and, in some cases, release GABA or glutamate in addition to dopamine. Recent findings show that motivational signals arising from the VTA can also be carried by non-dopamine-releasing projection neurons, which have their own specific connectivity. Both dopamine-releasing and non-dopamine-releasing VTA neurons integrate afferent signals with local inhibitory or excitatory inputs to generate particular output firing patterns. Various individual inputs, outputs and local connections have been shown to be sufficient to generate reward- or aversion-related behaviour, indicative of the impressive contribution of this small population of neurons to behaviour.
28053043	Neurons in the lateral habenula (LHb) are transiently activated by aversive events and have been implicated in associative learning. Functional changes associated with tonic and phasic activation of the LHb are often attributed to a corresponding inhibition of midbrain dopamine (DA) neurons. Activation of GABAergic neurons in the rostromedial tegmental nucleus (RMTg), a region that receives dense projections from the LHb and projects strongly to midbrain monoaminergic nuclei, is believed to underlie the transient inhibition of DA neurons attributed to activation of the LHb. To test this premise, the effects of axon-sparing lesions of the RMTg were assessed on LHb-induced inhibition of midbrain DA cell firing in anesthetized rats. Quinolinic acid lesions decreased the number of NeuN-positive neurons in the RMTg significantly while largely sparing cells in neighboring regions. Lesions of the RMTg reduced both the number of DA neurons inhibited by, and the duration of inhibition resulting from, LHb stimulation. Although the firing rate was not altered, the regularity of DA cell firing was increased in RMTg-lesioned rats. Locomotor activity in an open field was also elevated. These results are the first to show that RMTg neurons contribute directly to LHb-induced inhibition of DA cell activity and support the widely held proposition that GABAergic neurons in the mesopontine tegmentum are an important component of a pathway that enables midbrain DA neurons to encode the negative valence associated with failed expectations and aversive stimuli.Phasic changes in the activity of midbrain dopamine cells motivate and guide future behavior. Activation of the lateral habenula by aversive events inhibits dopamine neurons transiently, providing a neurobiological representation of learning models that incorporate negative reward prediction errors. Anatomical evidence suggests that this inhibition occurs via the rostromedial tegmental nucleus, but this hypothesis has yet to be tested directly. Here, we show that axon-sparing lesions of the rostromedial tegmentum attenuate habenula-induced inhibition of dopamine neurons significantly. These data support a substantial role for the rostromedial tegmentum in habenula-induced feedforward inhibition of dopamine neurons.	
28052091	Problem-solving can be facilitated with instructions or hints, which provide information about given problems. The proper amount of instruction that should be provided for learners is controversial. Research shows that tasks with intermediate difficulty induce the largest sense of accomplishment (SA), leading to an intrinsic motivation for learning. To investigate the effect of instructions, we prepared three instruction levels (No hint, Indirect hint, and Direct hint) for the same insight-problem types. We hypothesized that indirect instructions impose intermediate difficulty for each individual, thereby inducing the greatest SA per person. Based on previous neuroimaging studies that showed involvement of the bilateral caudate in learning and motivation, we expected SA to be processed in this reward system. We recruited twenty-one participants, and investigated neural activations during problem solving by functional magnetic resonance imaging (fMRI). We confirmed that the Indirect hint, which imposed intermediate difficulty, induced the largest SA among the three instruction types. Using fMRI, we showed that activations in the bilateral caudate and anterior cingulate cortex (ACC) were significantly modulated by SA. In the bilateral caudate, the indirect hint induced the largest activation, while the ACC seemed to reflect the difference between correct and incorrect trials. Importantly, such activation pattern was independent of notations (number or letter). Our results indicate that SA is represented in the reward system, and that the Indirect instruction effectively induces such sensation.
28050805	In this study, we investigated the interplay of habitual (model-free) and goal-directed (model-based) decision processes by using a two-stage Markov decision task in combination with event-related potentials (ERPs) and computational modeling. To manipulate the demands on model-based decision making, we applied two experimental conditions with different probabilities of transitioning from the first to the second stage of the task. As we expected, when the stage transitions were more predictable, participants showed greater model-based (planning) behavior. Consistent with this result, we found that stimulus-evoked parietal (P300) activity at the second stage of the task increased with the predictability of the state transitions. However, the parietal activity also reflected model-free information about the expected values of the stimuli, indicating that at this stage of the task both types of information are integrated to guide decision making. Outcome-related ERP components only reflected reward-related processes: Specifically, a medial prefrontal ERP component (the feedback-related negativity) was sensitive to negative outcomes, whereas a component that is elicited by reward (the feedback-related positivity) increased as a function of positive prediction errors. Taken together, our data indicate that stimulus-locked parietal activity reflects the integration of model-based and model-free information during decision making, whereas feedback-related medial prefrontal signals primarily reflect reward-related decision processes.


28044144	A wide range of stressful experiences can influence human decision making in complex ways beyond the simple predictions of a fight-or-flight model. Recent advances may provide insight into this complicated interaction, potentially in directions that could result in translational applications. Early research suggests that stress exposure influences basic neural circuits involved in reward processing and learning, while also biasing decisions towards habit and modulating our propensity to engage in risk-taking. That said, a substantial array of theoretical and methodological considerations in research on the topic challenge strong cross study comparisons necessary for the field to move forward. In this review we examine the multifaceted stress construct in the context of human decision making, emphasizing stress' effect on valuation, learning, and risk-taking.
28043969	Nuclear factor kappa light chain enhancer of activated B cells (NFkB) is a ubiquitous transcription factor well known for its role in the innate immune response. As such, NFkB is a transcriptional activator of inflammatory mediators such as cytokines. It has recently been demonstrated that alcohol and other drugs of abuse can induce NFkB activity and cytokine expression in the brain. A number of reviews have been published highlighting this effect of alcohol, and have linked increased NFkB function to neuroimmune-stimulated toxicity. However, in this review we focus on the potentially non-immune functions of NFkB as possible links between NFkB and addiction.An extensive review of the literature via Pubmed searches was used to assess the current state of the field.	NFkB can induce the expression of a diverse set of gene targets besides inflammatory mediators, some of which are involved in addictive processes, such as opioid receptors and neuropeptides. NFkB mediates complex behaviors including learning and memory, stress responses, anhedonia and drug reward, processes that may lie outside the role of NFkB in the classic neuroimmune response.	Future studies should focus on these non-immune functions of NFkB signaling and their association with addiction-related processes.	
28040454	Callous-unemotional traits - the insensitivity to other's welfare and well-being - are characterized by a lack of empathy. They are characteristic of psychopathy and can be found in other anti-social disorders, such as conduct disorder. Because of the increasing prevalence of anti-social disorders and the rising societal costs of violence and aggression, it is of great importance to elucidate the psychological and physiological mechanisms underlying callousness in the search for pharmacological treatments. One promising avenue is to create a relevant animal model to explore the neural bases of callousness. Here, we review recent advances in rodent models of pro-social choice that could be applied to probe the absence of pro-sociality as a proxy of callous behavior, and provide future directions for the exploration of the neural substrates of callousness.
28039794	We sometimes fail to notice unexpected objects or events when our attention is directed elsewhere, a phenomenon called inattentional blindness. We explored whether unexpected objects that shared the color of consequential objects would be noticed more often. In three pre-registered experiments, participants played a custom video game in which they avoided both low- and high-cost missiles (Experiment 1 and 2) or tried to hit rewarding missiles while avoiding costly ones (Experiment 3). After participants had played the game for about 8min, an unexpected object moved across the screen. Although participants selectively avoided more costly missiles when playing, they were no more likely to notice an unexpected object when its color was associated with greater costs. Apparently, people are no more likely to notice unexpected objects that are associated with negative consequences. Future research should examine whether objects that are themselves consequential are noticed more frequently.
28035528	Delta opioid receptor (DOR) displays a unique, highly conserved, structure and an original pattern of distribution in the central nervous system, pointing to a distinct and specific functional role among opioid peptide receptors. Over the last 15 years, in vivo pharmacology and genetic models have allowed significant advances in the understanding of this role. In this review, we will focus on the involvement of DOR in modulating different types of hippocampal- and striatal-dependent learning processes as well as motor function, motivation, and reward. Remarkably, DOR seems to play a key role in balancing hippocampal and striatal functions, with major implications for the control of cognitive performance and motor function under healthy and pathological conditions.
28031069	The main objective of this prospective longitudinal study was to investigate bidirectional associations between adolescent cannabis use (CU) and neurocognitive performance in a community sample of 294 young men from ages 13 to 20 years. The results showed that in early adolescence, and prior to initiation to CU, poor short-term and working memory, but high verbal IQ, were associated with earlier age of onset of CU. In turn, age of CU onset and CU frequency across adolescence were associated with (a) specific neurocognitive decline in verbal IQ and executive function tasks tapping trial and error learning and reward processing by early adulthood and (b) lower rates of high-school graduation. The association between CU onset and change in neurocognitive function, however, was found to be accounted for by CU frequency. Whereas the link between CU frequency across adolescence and change in verbal IQ was explained (mediated) by high school graduation, the link between CU frequency and tasks tapping trial and error learning were independent from high school graduation, concurrent cannabis and other substance use, adolescent alcohol use, and externalizing behaviors. Findings support prevention efforts aimed at delaying onset and reducing frequency of CU.
28030999	Neuromodulation technologies such as vagus nerve stimulation and deep brain stimulation, have shown some efficacy in controlling seizures in medically intractable patients. However, inherent patient-to-patient variability of seizure disorders leads to a wide range of therapeutic efficacy. A patient specific approach to determining stimulation parameters may lead to increased therapeutic efficacy while minimizing stimulation energy and side effects. This paper presents a reinforcement learning algorithm that optimizes stimulation frequency for controlling seizures with minimum stimulation energy. We apply our method to a computational model called the epileptor. The epileptor model simulates inter-ictal and ictal local field potential data. In order to apply reinforcement learning to the Epileptor, we introduce a specialized reward function and state-space discretization. With the reward function and discretization fixed, we test the effectiveness of the temporal difference reinforcement learning algorithm (TD(0)). For periodic pulsatile stimulation, we derive a relation that describes, for any stimulation frequency, the minimal pulse amplitude required to suppress seizures. The TD(0) algorithm is able to identify parameters that control seizures quickly. Additionally, our results show that the TD(0) algorithm refines the stimulation frequency to minimize stimulation energy thereby converging to optimal parameters reliably. An advantage of the TD(0) algorithm is that it is adaptive so that the parameters necessary to control the seizures can change over time. We show that the algorithm can converge on the optimal solution in simulation with slow and fast inter-seizure intervals.
28028168	Amitraz, an acaricide used to treat Varroa destructor Anderson & Trueman, is one of the most commonly detected pesticides in honey bee (Apis mellifera L.) hives. Acaricides sometimes negatively impact honey bee cognition, but potential effects of amitraz on honey bee learning have been rarely studied. We topically exposed foragers to 95th percentile field-relevant levels of amitraz and, 24 h later, tested the ability of bees to associate a sucrose reward with a conditioned odor (learning response) using the proboscis extension response (PER). We then tested the ability of the bees to retain this memory 1 h and 2 h post-conditioning. Because amitraz is thought to affect octopamine metabolism in honey bees, and because octopamine is directly related to honey bee learning and memory, we also examined effects of exposure to amitraz on octopamine levels in honey bee hemolymph. We found that acute exposure to 95th percentile doses of amitraz had no impact on honey bee learning or short-term memory as measured by PER. Concentrations of octopamine in hemolymph from our low amitraz treatment were 1.4-fold higher than control levels, but other treatments had no effect. Our results from worst-case acute exposure experiments with worker bees in the laboratory suggest that typical field-relevant (within hive) exposures to amitraz probably have little effect on honey bee learning and memory.
28018206	The ability to maximize reward and avoid punishment is essential for animal survival. Reinforcement learning (RL) refers to the algorithms used by biological or artificial systems to learn how to maximize reward or avoid negative outcomes based on past experiences. While RL is also important in machine learning, the types of mechanistic constraints encountered by biological machinery might be different than those for artificial systems. Two major problems encountered by RL are how to relate a stimulus with a reinforcing signal that is delayed in time (temporal credit assignment), and how to stop learning once the target behaviors are attained (stopping rule). To address the first problem synaptic eligibility traces were introduced, bridging the temporal gap between a stimulus and its reward. Although, these were mere theoretical constructs, recent experiments have provided evidence of their existence. These experiments also reveal that the presence of specific neuromodulators converts the traces into changes in synaptic efficacy. A mechanistic implementation of the stopping rule usually assumes the inhibition of the reward nucleus; however, recent experimental results have shown that learning terminates at the appropriate network state even in setups where the reward nucleus cannot be inhibited. In an effort to describe a learning rule that solves the temporal credit assignment problem and implements a biologically plausible stopping rule, we proposed a model based on two separate synaptic eligibility traces, one for long-term potentiation (LTP) and one for long-term depression (LTD), each obeying different dynamics and having different effective magnitudes. The model has been shown to successfully generate stable learning in recurrent networks. Although, the model assumes the presence of a single neuromodulator, evidence indicates that there are different neuromodulators for expressing the different traces. What could be the role of different neuromodulators for expressing the LTP and LTD traces? Here we expand on our previous model to include several neuromodulators, and illustrate through various examples how different these contribute to learning reward-timing within a wide set of training paradigms and propose further roles that multiple neuromodulators can play in encoding additional information of the rewarding signal.
28009292	Neural circuits involving midbrain dopaminergic (DA) neurons regulate reward and goal-directed behaviors. Although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here, we show that DA neurons use autocrine transforming growth factor β (TGF-β) signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-β type II receptor in DA neurons also disrupts the balance in TGF-β1 expression in DA neurons and neighboring GABAergic neurons, which increases inhibitory input, reduces excitatory synaptic input, and alters phasic firing patterns in DA neurons. Mice lacking TGF-β signaling in DA neurons are hyperactive and exhibit inflexibility in relinquishing learned behaviors and re-establishing new stimulus-reward associations. These results support a role for TGF-β in regulating the delicate balance of excitatory/inhibitory synaptic input in local microcircuits involving DA and GABAergic neurons and its potential contributions to neuropsychiatric disorders.
28005174	Non-consumptive effects (NCEs) of predators occur as prey alters their habitat use and foraging decisions to avoid predation. Although NCEs are recognized as being important across disparate ecosystems, the factors influencing their strength and importance remain poorly understood. Ecological context, such as time of day, predator identity, and prey condition, may modify how prey species perceive and respond to risk, thereby altering NCEs. To investigate how predator identity affects foraging of herbivorous coral reef fishes, we simulated predation risk using fiberglass models of two predator species (grouper Mycteroperca bonaci and barracuda Sphyraena barracuda) with different hunting modes. We quantified how predation risk alters herbivory rates across space (distance from predator) and time (dawn, mid-day, and dusk) to examine how prey reconciles the conflicting demands of avoiding predation vs. foraging. When we averaged the effect of both predators across space and time, they suppressed herbivory similarly. Yet, they altered feeding differently depending on time of day and distance from the model. Although feeding increased strongly with increasing distance from the predators particularly during dawn, we found that the barracuda model suppressed herbivory more strongly than the grouper model during mid-day. We suggest that prey hunger level and differences in predator hunting modes could influence these patterns. Understanding how context mediates NCEs provides insight into the emergent effects of predator-prey interactions on food webs. These insights have broad implications for understanding how anthropogenic alterations to predator abundances can affect the spatial and temporal dynamics of important ecosystem processes.
28004955	It has recently been recognized that orbitofrontal cortex has 2 subdivisions that are anatomically and functionally distinct. Most rodent research has focused on the lateral subdivision, leaving the medial subdivision (mOFC) relatively unexplored. We recently showed that inhibiting mOFC neurons eliminated the differential impact of reward probability cues on discrimination accuracy in a sustained attention task. In the present study, we tested whether increasing mOFC neuronal activity in rats would accelerate acquisition of reward contingencies. mOFC neuronal activity was increased using the DREADD (Designer Receptors Exclusively Activated by Designer Drugs) method, in which clozapine-N-oxide administration leads to neuronal modulation by acting on synthetic receptors not normally expressed in the rat brain. We predicted that rats with neuronal activation in mOFC would require fewer sessions than controls for acquisition of a task in which visual cues signal the probability of reward for correct discrimination performance. Contrary to this prediction, mOFC neuronal activation impaired task acquisition, suggesting mOFC may play a role in learning relationships between environmental cues and reward probability or for using that information in adaptive decision-making. In addition, disrupted mOFC activity may contribute to psychiatric conditions in which learning associations between environmental cues and reward probability is impaired. (PsycINFO Database Record
28003406	It has been long known that neural activity, recorded with electrophysiological methods, contains rich information about a subject's motor intentions, sensory experiences, allocation of attention, action planning, and even abstract thoughts. All these functions have been the subject of neurophysiological investigations, with the goal of understanding how neuronal activity represents behavioral parameters, sensory inputs, and cognitive functions. The field of brain-machine interfaces (BMIs) strives for a somewhat different goal: it endeavors to extract information from neural modulations to create a communication link between the brain and external devices. Although many remarkable successes have been already achieved in the BMI field, questions remain regarding the possibility of decoding high-order neural representations, such as decision making. Could BMIs be employed to decode the neural representations of decisions underlying goal-directed actions? In this review we lay out a framework that describes the computations underlying goal-directed actions as a multistep process performed by multiple cortical and subcortical areas. We then discuss how BMIs could connect to different decision-making steps and decode the neural processing ongoing before movements are initiated. Such decision-making BMIs could operate as a system with prediction that offers many advantages, such as shorter reaction time, better error processing, and improved unsupervised learning. To present the current state of the art, we review several recent BMIs incorporating decision-making components.
28002987	The mechanisms of decision-making and action selection are generally thought to be under the control of parallel cortico-subcortical loops connecting back to distinct areas of cortex through the basal ganglia and processing motor, cognitive and limbic modalities of decision-making. We have used these properties to develop and extend a connectionist model at a spiking neuron level based on a previous rate model approach. This model is demonstrated on decision-making tasks that have been studied in primates and the electrophysiology interpreted to show that the decision is made in two steps. To model this, we have used two parallel loops, each of which performs decision-making based on interactions between positive and negative feedback pathways. This model is able to perform two-level decision-making as in primates. We show here that, before learning, synaptic noise is sufficient to drive the decision-making process and that, after learning, the decision is based on the choice that has proven most likely to be rewarded. The model is then submitted to lesion tests, reversal learning and extinction protocols. We show that, under these conditions, it behaves in a consistent manner and provides predictions in accordance with observed experimental data.
28000031	Alcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol use with the goal to self-medicate and ameliorate the behavioral symptoms of a genetically induced innate depression. An induced over-expression of acid sphingomyelinase (ASM), as was observed in depressed patients, enhanced the consumption of alcohol in a mouse model of depression. ASM hyperactivity facilitates the establishment of the conditioned behavioral effects of alcohol, and thus drug memories. Opposite effects on drinking and alcohol reward learning were observed in animals with reduced ASM function. Importantly, free-choice alcohol drinking-but not forced alcohol exposure-reduces depression-like behavior selectively in depressed animals through the normalization of brain ASM activity. No such effects were observed in normal mice. ASM hyperactivity caused sphingolipid and subsequent monoamine transmitter hypo-activity in the brain. Free-choice alcohol drinking restores nucleus accumbens sphingolipid- and monoamine homeostasis selectively in depressed mice. A gene expression analysis suggested strong control of ASM on the expression of genes related to the regulation of pH, ion transmembrane transport, behavioral fear response, neuroprotection and neuropeptide signaling pathways. These findings suggest that the paradoxical antidepressant effects of alcohol in depressed organisms are mediated by ASM and its control of sphingolipid homeostasis. Both emerge as a new treatment target specifically for depression-induced alcoholism.
27999955	Social learning is predicted to evolve in socially living animals provided the learning process is not random but biased by certain socio-ecological factors. One bias of particular interest for the emergence of (cumulative) culture is the tendency to forgo personal behaviour in favour of relatively better variants observed in others, also known as the "copy-if-better" strategy. We investigated whether chimpanzees employ copy-if-better in a simple token-exchange paradigm controlling for individual and random social learning. After being trained on one token-type, subjects were confronted with a conspecific demonstrator who either received the same food reward as the subject (control condition) or a higher value food reward than the subject (test condition) for exchanging another token-type. In general, the chimpanzees persisted in exchanging the token-type they were trained on individually, indicating a form of conservatism consistent with previous studies. However, the chimpanzees were more inclined to copy the demonstrator in the test compared to the control condition, indicating a tendency to employ a copy-if-better strategy. We discuss the validity of our results by considering alternative explanations and relate our findings to the emergence of cumulative culture.
27998058	The neural circuit of the dorsal hippocampus (dHip) and nucleus accumbens (NAc) contributes to cue-induced learning and addictive behaviors, as demonstrated by the escalation of ethanol-seeking behaviors observed following deletion of the adenosine equilibrative nucleoside transporter 1 (ENT1-/-) in mice. Here we perform quantitative LC-MS/MS neuroproteomics in the dHip and NAc of ENT1-/- mice. Using Ingenuity Pathway Analysis, we identified proteins associated with increased long-term potentiation, ARP2/3-mediated actin cytoskeleton signaling and protein expression patterns suggesting deficits in glutamate degradation, GABAergic signaling, as well as significant changes in bioenergetics and energy homeostasis (oxidative phosphorylation, TCA cycle, and glycolysis). These pathways are consistent with previously reported behavioral and biochemical phenotypes that typify mice lacking ENT1. Moreover, we validated decreased expression of the SNARE complex protein VAMP1 (synaptobrevin-1) in the dHip as well as decreased expression of pro-dynorphin (PDYN), neuroendocrine convertase (PCSK1), and Leu-Enkephalin (dynorphin-A) in the NAc. Taken together, our proteomic approach provides novel pathways indicating that ENT1-regulated signaling is essential for neurotransmitter release and neuropeptide processing, both of which underlie learning and reward-seeking behaviors.
27997541	Massive activation of dopamine neurons is critical for natural reward and drug abuse. In contrast, the significance of their spontaneous activity remains elusive. In Drosophila melanogaster, depolarization of the protocerebral anterior medial (PAM) cluster dopamine neurons en masse signals reward to the mushroom body (MB) and drives appetitive memory. Focusing on the functional heterogeneity of PAM cluster neurons, we identified that a single class of PAM neurons, PAM-γ3, mediates sugar reward by suppressing their own activity. PAM-γ3 is selectively required for appetitive olfactory learning, while activation of these neurons in turn induces aversive memory. Ongoing activity of PAM-γ3 gets suppressed upon sugar ingestion. Strikingly, transient inactivation of basal PAM-γ3 activity can substitute for reward and induces appetitive memory. Furthermore, we identified the satiety-signaling neuropeptide Allatostatin A (AstA) as a key mediator that conveys inhibitory input onto PAM-γ3. Our results suggest the significance of basal dopamine release in reward signaling and reveal a circuit mechanism for negative regulation.
27995105	The medial prefrontal cortex (mPFC) is a part of brain reward system involved in cognitive functions such as learning and memory. Previous studies showed that electrical stimulation of prelymbic produced different effects on morphine-induced condition place preference. In this study, we investigated the electrical stimulation with different current intensities on spatial memory in rats.In this study, male Wister rats weighing approximately 200-300 g were used. The effect of prelymbic electrical stimulation with 25 and 150 μA currents intensities in healthy and addicted rats on spatial memory was studied. Spatial memory was investigated using the Morris water maze test in addicted rats after 9 days of electrical stimulation.	Our findings have shown that morphine reduces the memory and learning, whereas the present results indicated that electrical stimulation of prelymbic area with current intensity of the 25 μA shortened the time and distance to reach to platform that indicated improvement in spatial memory on addicted rats. Whereas the electrical stimulation of prelymbic area with the current intensity of 150 μA has special weakening effects on spatial memory and prolongs the time and distance to reach the platform.	The electrical stimulations of prelymbic with 25 μA current intensity improved the spatial memory in addicted rats while with 150 μA current intensity weakened spatial memory in rats. It is possible that increase in the release of some neurotransmitters reverses the effect of morphine on spatial memory.	
27993649	Recent research has shown that reinforcement can facilitate visual perceptual learning (VPL), but no study has examined the relations between individual differences in reinforcement sensitivity and VPL. This study tested the hypothesis that when monetary incentive was involved, the personality traits of harm avoidance and reward dependence (HA and RD, two measures of reinforcement sensitivity) would be linked to VPL performance. We trained two groups of subjects with a visual motion direction discrimination task for six days. The experimental group received monetary incentive feedback, whereas the control group received non-monetary feedback. As expected, the score of HA was negatively correlated with VPL for the experimental group, but not for the control group. RD was not a significant predictor. These results were discussed in terms of the role of non-perceptual factors such as reinforcement, personality, higher cognition, and motivation in VPL.
27993374	The amygdaloid body (AMY) plays an important role in memory, learning and reward-related processes. RFRP-1 immunoreactive fibers and NPFF receptors were identified in the AMY, and previously we verified that RFRP-1 infused into the central nucleus of AMY (CeA) induced place preference. The aim of the present study was to examine the possible effects of RFRP-1 in the CeA on passive avoidance learning. Male Wistar rats were examined in two-compartment passive avoidance paradigm. Animals were shocked with 0.5mA current and subsequently were microinjected bilaterally with 50ng or 100ng RFRP-1 in volume of 0.4μl, or 20ng NPFF receptor antagonist RF9 (ANT) alone, or antagonist 15min before 50ng RFRP-1 treatments into the CeA. Fifty nanogram dose of RFRP-1 significantly increased the step-through latency time, the 100ng RFRP-1 and the ANT alone were ineffective. The effect of 50ng RFRP-1 was eliminated by the ANT pretreatment. Our results suggest that intraamygdaloid RFRP-1 enhances learning processes and memory in aversive situations and this effect can specifically be prevented by ANT pretreatment.
27989778	Effort discounting theory suggests that the value of a reward should be lower if it was effortful to obtain, whereas contrast theory suggests that the contrast between the costly effort and the reward makes the reward seem more valuable. To test these alternative hypotheses, we used functional magnetic resonance imaging (fMRI) as participants engaged in feedback-based learning that required low or high cognitive effort to obtain positive feedback, while the objective amount of information provided by feedback remained constant. In the low effort condition, a single image was presented with four response options. In the high effort condition, two images were presented, each with two response options, and correct feedback was presented only when participants responded correctly to both of the images. Accuracy was significantly lower for the high effort condition, and all participants reported that the high effort condition was more difficult. A region of the ventral striatum selected for sensitivity to feedback value also showed increased activation to feedback presentation associated with the high effort condition relative to the low effort condition, when controlling for activation from corresponding control conditions where feedback was random. These results suggest that increased cognitive effort produces corresponding increases in positive feedback-related ventral striatum activity, in line with the predictions made by contrast theory. The accomplishment of obtaining a hard-earned intrinsic reward, such as positive feedback, may be particularly likely to promote reward-related brain activity.
27986430	Schizophrenia is a heterogeneous spectrum disorder often associated with detrimental negative symptoms. In recent years, computational approaches to psychiatry have attracted growing attention. Negative symptoms have shown some overlap with general cognitive impairments and were also linked to impaired motivational processing in brain circuits implementing reward prediction. In this review, we outline how computational approaches may help to provide a better understanding of negative symptoms in terms of the potentially underlying behavioural and biological mechanisms. First, we describe the idea that negative symptoms could arise from a failure to represent reward expectations to enable flexible behavioural adaptation. It has been proposed that these impairments arise from a failure to use prediction errors to update expectations. Important previous studies focused on processing of so-called model-free prediction errors where learning is determined by past rewards only. However, learning and decision-making arise from multiple cognitive mechanisms functioning simultaneously, and dissecting them via well-designed tasks in conjunction with computational modelling is a promising avenue. Second, we move on to a proof-of-concept example on how generative models of functional imaging data from a cognitive task enable the identification of subgroups of patients mapping on different levels of negative symptoms. Combining the latter approach with behavioural studies regarding learning and decision-making may allow the identification of key behavioural and biological parameters distinctive for different dimensions of negative symptoms versus a general cognitive impairment. We conclude with an outlook on how this computational framework could, at some point, enrich future clinical studies.
27984481	The implementation of computer games in physical therapy is motivated by characteristics such as attractiveness, motivation, and engagement, but these do not guarantee the intended therapeutic effect of the interventions. Yet, these characteristics are important variables in physical therapy interventions because they involve reward-related dopaminergic systems in the brain that are known to facilitate learning through long-term potentiation of neural connections. In this perspective we propose a way to apply game design approaches to therapy development by "designing" therapy sessions in such a way as to trigger physical and cognitive behavioral patterns required for treatment and neurological recovery. We also advocate that improving game knowledge among therapists and improving communication between therapists and game designers may lead to a novel avenue in designing applied games with specific therapeutic input, thereby making gamification in therapy a realistic and promising future that may optimize clinical practice.
27980891	Anhedonia, traditionally defined as a diminished capacity to experience pleasure, has long been considered a core symptom of schizophrenia. However, recent research calls into question whether individuals with schizophrenia are truly anhedonic, suggesting intact subjective and neurophysiological response to rewarding stimuli in-the-moment. Despite a presumably intact capacity to experience pleasure, people with schizophrenia still engage in fewer reward-seeking behaviors. This discrepancy has been explained as a dissociation between "liking" and "wanting", with dopaminergic and prefrontal influences on incentive salience leading hedonic responses to not effectively translate into motivated behavior. In the current review, the literature on a key aspect of the wanting deficit is reviewed, anticipatory pleasure.Results provide consistent evidence for impairment in some aspects of anticipatory pleasure (e.g., prospection, associative learning between reward predictive cues and outcomes), and inconsistent evidence for others (e.g., anticipatory affect and affective forecasting).	Mechanisms underlying anticipatory pleasure abnormalities in schizophrenia are discussed and a new model of anticipatory pleasure deficits is proposed. Findings suggest that anticipatory pleasure may be a critical component of impairments in wanting that impact motivated behavior in schizophrenia.	
27980074	Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic plasticity to facilitate extinction of appetitive behaviors and to reduce relapse. Rats self-administered cocaine and were given VNS during extinction. Relapse to drug-seeking was assessed in a cued reinstatement session. We used immunohistochemistry to measure changes in the expression of the phosphorylated transcription factor cAMP response-element binding protein (pCREB) in the PFC and the basolateral amygdala (BLA), which regulate cue learning and extinction. In vivo recordings of evoked field potentials measured drug- and VNS-induced changes in metaplasticity in the pathway from the PFC to the BLA. VNS-treated rats showed improved rates of extinction and reduced reinstatement. Following reinstatement, pCREB levels were reduced in the IL and BLA of VNS-treated rats. Evoked responses in the BLA were greatly reduced in VNS-treated rats, and these rats were also resistant to the induction of LTD. Taken together, these results show that VNS facilitates extinction and reduces reinstatement. Changes in the pathway between the PFC and the amygdala may contribute to these beneficial effects.
27977239	Rewards are both "liked" and "wanted," and those 2 words seem almost interchangeable. However, the brain circuitry that mediates the psychological process of "wanting" a particular reward is dissociable from circuitry that mediates the degree to which it is "liked." Incentive salience or "wanting," a form of motivation, is generated by large and robust neural systems that include mesolimbic dopamine. By comparison, "liking," or the actual pleasurable impact of reward consumption, is mediated by smaller and fragile neural systems, and is not dependent on dopamine. The incentive-sensitization theory posits the essence of drug addiction to be excessive amplification specifically of psychological "wanting," especially triggered by cues, without necessarily an amplification of "liking." This is because of long-lasting changes in dopamine-related motivation systems of susceptible individuals, called "neural sensitization." A quarter-century after its proposal, evidence has continued to grow in support the incentive-sensitization theory. Further, its scope is now expanding to include diverse behavioral addictions and other psychopathologies. (PsycINFO Database Record
27974615	Goal-directed and instrumental learning are both important controllers of human behavior. Learning about which stimulus event occurs in the environment and the reward associated with them allows humans to seek out the most valuable stimulus and move through the environment in a goal-directed manner. Stimulus-response associations are characteristic of instrumental learning, whereas response-outcome associations are the hallmark of goal-directed learning. Here we provide behavioral, computational, and neuroimaging results from a novel task in which stimulus-response and response-outcome associations are learned simultaneously but dominate behavior at different stages of the experiment. We found that prediction error representations in the ventral striatum depend on which type of learning dominates. Furthermore, the amygdala tracks the time-dependent weighting of stimulus-response versus response-outcome learning. Our findings suggest that the goal-directed and instrumental controllers dynamically engage the ventral striatum in representing prediction errors whenever one of them is dominating choice behavior.Converging evidence in human neuroimaging studies has shown that the reward prediction errors are correlated with activity in the ventral striatum. Our results demonstrate that this region is simultaneously correlated with a stimulus prediction error. Furthermore, the learning system that is currently dominating behavioral choice dynamically engages the ventral striatum for computing its prediction errors. This demonstrates that the prediction error representations are highly dynamic and influenced by various experimental context. This finding points to a general role of the ventral striatum in detecting expectancy violations and encoding error signals regardless of the specific nature of the reinforcer itself.	
27939856	Metacognition is the ability to monitor and control one's cognition. Monitoring may involve either public cues or introspection of private cognitive states. We tested rhesus monkeys (Macaca mulatta) in a series of generalization tests to determine which type of cues control metacognition. In Experiment 1, monkeys learned a perceptual discrimination in which a "decline-test" response allowed them to avoid tests and receive a guaranteed small reward. Monkeys declined more difficult than easy tests. In Experiments 2-4, we evaluated whether monkeys generalized this metacognitive responding to new perceptual tests. Monkeys showed a trend toward generalization in Experiments 2 & 3, and reliable generalization in Experiment 4. In Experiments 5 & 6, we presented the decline-test response in a delayed matching-to-sample task. Memory tests differed from perceptual tests in that the appearance of the test display could not control metacognitive responding. In Experiment 6, monkeys made prospective metamemory judgments before seeing the tests. Generalization across perceptual tests with different visual properties and mixed generalization from perceptual to memory tests provide provisional evidence that domain-general, private cues controlled metacognition in some monkeys. We observed individual differences in generalization, suggesting that monkeys differ in use of public and private metacognitive cues.
27936242	The ability to reason about causality underlies key aspects of human cognition, but the extent to which non-humans understand causality is still largely unknown. The Aesop's Fable paradigm, where objects are inserted into water-filled tubes to obtain out-of-reach rewards, has been used to test casual reasoning in birds and children. However, success on these tasks may be influenced by other factors, specifically, object preferences present prior to testing or arising during pre-test stone-dropping training. Here, we assessed this 'object-bias' hypothesis by giving New Caledonian crows and 5-10 year old children two object-choice Aesop's Fable experiments: sinking vs. floating objects, and solid vs. hollow objects. Before each test, we assessed subjects' object preferences and/or trained them to prefer the alternative object. Both crows and children showed pre-test object preferences, suggesting that birds in previous Aesop's Fable studies may also have had initial preferences for objects that proved to be functional on test. After training to prefer the non-functional object, crows, but not children, performed more poorly on these two object-choice Aesop's Fable tasks than subjects in previous studies. Crows dropped the non-functional objects into the tube on their first trials, indicating that, unlike many children, they do not appear to have an a priori understanding of water displacement. Alternatively, issues with inhibition could explain their performance. The crows did, however, learn to solve the tasks over time. We tested crows further to determine whether their eventual success was based on learning about the functional properties of the objects, or associating dropping the functional object with reward. Crows inserted significantly more rewarded, non-functional objects than non-rewarded, functional objects. These findings suggest that the ability of New Caledonian crows to produce performances rivaling those of young children on object-choice Aesop's Fable tasks is partly due to pre-existing object preferences.
27931744	Psychiatric disorders such as addiction and mania are marked by persistent reward seeking despite highly negative or aversive outcomes, but the neural mechanisms underlying this aberrant decision making are unknown. The recently identified rostromedial tegmental nucleus (RMTg) encodes a wide variety of aversive stimuli and sends robust inhibitory projections to midbrain dopamine neurons, leading to the hypothesis that the RMTg provides a brake to reward signaling in response to aversive costs.To test the role of the RMTg in punished reward seeking, adult male Sprague Dawley rats were tested in several cost-benefit decision tasks after excitotoxic lesions of the RMTg or temporally specific optogenetic inhibition of RMTg efferents in the ventral tegmental area.	RMTg lesions drastically impaired the ability of foot shock to suppress operant responding for food. Optogenetic inhibition showed that this resistance to punishment was due in part to RMTg activity at the precise moment of shock delivery and was mediated by projections to the ventral tegmental area, which is consistent with an aversive "teaching signal" role for the RMTg during encoding of the aversive event. We observed a similar resistance to punishment when the RMTg was selectively inhibited immediately prior to the operant lever press, which is consistent with a second distinct role for the RMTg during action selection. These effects were not attributable to RMTg effects on learning rate, locomotion, shock sensitivity, or perseveration.	The RMTg has two strong and dissociable roles during both encoding and recall of aversive consequences of behavior.	
27929349	This study evaluated the hypothesis that a paclitaxel treatment regimen sufficient to produce mechanical allodynia would alter sensitivities of male and female mice to the conditioned rewarding and reinforcing effects of morphine. Saline or paclitaxel were administered on Days 1, 3, 5, and 7 in male and female C57Bl/6 mice to induce morphine-reversible mechanical allodynia as measured by the Von Frey filament test. Paclitaxel treatment did not change sensitivity to morphine conditioned place preference (CPP) relative to saline treatment in either male or female mice. Morphine produced peak self-administration under a fixed ratio-1 (FR1) schedule of reinforcement for 0.03 mg/kg morphine per infusion in female mice and 0.1 mg/kg morphine per infusion in male mice. During the progressive ratio experiments, saline treatment in male mice decreased the number of morphine infusions for 12 days whereas the paclitaxel-treated male mice maintained responding for morphine similar to baseline levels during the same time period. However, paclitaxel did not have an overall effect on the reinforcing efficacy of morphine assessed over a limited dose range during the course of the repeated self-administration. These results suggest that the reward-related behavioral effects of morphine are overall not robustly altered by the presence of paclitaxel treatment under the current dosing regimen, with the exception of maintaining a small yet significant higher baseline than saline treatment during the development of allodynia in male mice. (PsycINFO Database Record
27929344	Smoking cue exposure sensitizes smokers to cigarettes (i.e., increases cravings). Research examining the overlap between perception and mental imagery suggests that mentally simulating smoking a cigarette in a manner analogous to actually smoking should lead to habituation or a decrease in a smoker's motivation to smoke. The authors sought to determine whether repetitive mental simulation of smoking can engender habituation thereby reducing smoking cue-induced craving and shifts in mood, latency to smoke, and the hedonic response to smoking. These hypotheses were tested in nontreatment seeking smokers (n = 61; 24 women/37 men) ages 18-55 years old, who were not incentivized to quit. The authors used a 2 (in vivo cue: smoking, neutral) × 2 (imagery: repetitive, limited) within-subjects design. Results revealed that repetitive imagery altered the effect of cue type for negative mood and subjective cigarette reward as evidenced by significant Imagery × Cue interactions. Repetitive imagery after a smoking cue reduced negative mood more than limited imagery (β = -1.19, p = .004). Repetitive imagery also reduced the reward derived from smoking a cigarette more than limited imagery (β = -.41, p < .0001). Only main effects of cue type on craving (β = 3.39, p = .01) and positive mood (β = -1.18, p = .03) were found. Greater imagery strength predicted a longer latency to smoke (β = .76, p = .001). Cognitive strategies that directly engage cue-induced craving through repetitive smoking imagery may reduce smoking cue-induced increases in negative mood and reward from a cigarette lapse potentially preventing smoking relapse. (PsycINFO Database Record
27926446	Motivational stimuli such as rewards elicit adaptive responses and influence various cognitive functions. Notably, increasing evidence suggests that stimuli with particular motivational values can strongly shape perception and attention. These effects resemble both selective top-down and stimulus-driven attentional orienting, as they depend on internal states but arise without conscious will, yet they seem to reflect attentional systems that are functionally and anatomically distinct from those classically associated with frontoparietal cortical networks in the brain. Recent research in human and nonhuman primates has begun to reveal how reward can bias attentional selection, and where within the cognitive system the signals providing attentional priority are generated. This review aims at describing the different mechanisms sustaining motivational attention, their impact on different behavioral tasks, and current knowledge concerning the neural networks governing the integration of motivational influences on attentional behavior.
27926445	Knowledge of performance can activate the striatum, a key region of the reward system and highly relevant for motivated behavior. Using functional magnetic resonance imaging, striatal activity linked to knowledge of performance was measured during the training of a repetitive arc-tracking task. Knowledge of performance was given after a random selection of trials or after good performance. The third group received knowledge of performance after good performance plus a monetary reward. Skill learning was measured from pre- to post- (acquisition) and from post- to 24h posttraining (consolidation). Our results demonstrate an influence of feedback on motor skill learning. Adding a monetary reward after good performance leads to better consolidation and higher ventral striatal activation than knowledge of performance alone. In turn, rewarding strategies that increase ventral striatal response during training of a motor skill may be utilized to improve skill consolidation.
27924501	Many eating behaviors form in childhood, and some unhealthy behaviors may persist into adulthood and have potential impacts on people's health. This study evaluated the effectiveness of behavioral intervention in reducing consumption of Western fast food, sweetened beverages, fried food in preschool children, and changing parents' rewarding behaviors that encourage the consumption of the unhealthy foods. The research was a cluster randomized trial of seven kindergartens, involving 1138 children aged 3-6 years and their parents in Beijing, China. Parents and children allocated to the intervention group received two lectures and printed resources, including behavior cards, educational sheets. Children's behavior cards, applied with behavior-changing techniques, were used to intervene, and monitor behavior changes over time. Children in the control group just followed their usual health education curriculum in kindergartens. Intervention effects on food consumption behaviors were assessed by examining pre- and post-questionnaires. Of the 1138 children screened at baseline, 880 (77.3%) were measured at the end of the intervention period. The intervention lasted from March to June in 2010. The results showed that consumption of Western fast food, sweetened beverages, and fried food was decreased among the intervention group (P<0.001). Proportions of parents using Western fast food as rewards for their children were decreased (P=0.002). From March to June 2010, the frequency of each target behavior in children tended to decrease over the intervention period (P<0.001). Most parents favored regularly-delivered behavior cards or materials for behavioral intervention. In conclusion, the behavioral intervention encourages the healthier eating behaviors of children and reduces the parents' practice of using unhealthy foods as reward.
27923717	The rodent tasks with food rewards are useful methods to evaluate memory functions, including hole-board and corridor tests. The AMBITUS system (a square corridor with several food rewards), as a combination of these tests, was developed for the investigation of a variety of parameters associated with exploration and cognitive performance in rodents. Experiments were performed to characterize these behaviors in healthy rats and a new "schizophrenia-like" rat substrain with impaired learning ability to reveal the reliability in tests related to these functions. A square corridor was constructed with equally spaced sites along each wall (4 inside and 4 outside) resulting in 16 side-boxes for food rewards. Photocells at each box recorded the visits into the side-boxes (as exploratory activity), while the eating parameters were obtained from video records. The animals were exposed to two types of tasks repeatedly in two series: all (16) or only the inside (8) boxes (Task 1 or Task 2, respectively) were baited. Most of the rats acquired Task 1, and their performance improved by repetition, but the new substrain showed decreased exploration and learning capacity. The introduction of Task 2 caused prompt preference of the baited inner side-boxes, and gradually improved working and reference memory during the trials. The manual and automated scoring of the visits into the side-boxes showed significant (r=0.97) correlation. The results proved that healthy animals could perform the simple tasks in the square corridor after a few repetitions. The semi-automated AMBITUS system might be appropriate to detect cognitive flexibility after different manipulations, and it provides immediate, online assessment of exploratory behavior of a large number of animals within a short period of time, and it reduces the possibility of experimenter bias.
27920957	Corvids (birds in the crow family) are hypothesised to have a general cognitive tool-kit because they show a wide range of transferrable skills across social, physical and temporal tasks, despite differences in socioecology. However, it is unknown whether relatively asocial corvids differ from social corvids in their use of social information in the context of copying the choices of others, because only one such test has been conducted in a relatively asocial corvid. We investigated whether relatively asocial Eurasian jays (Garrulus glandarius) use social information (i.e., information made available by others). Previous studies have indicated that jays attend to social context in their caching and mate provisioning behaviour; however, it is unknown whether jays copy the choices of others. We tested the jays in two different tasks varying in difficulty, where social corvid species have demonstrated social information use in both tasks. Firstly, an object-dropping task was conducted requiring objects to be dropped down a tube to release a food reward from a collapsible platform, which corvids can learn through explicit training. Only one rook and one New Caledonian crow have learned the task using social information from a demonstrator. Secondly, we tested the birds on a simple colour discrimination task, which should be easy to solve, because it has been shown that corvids can make colour discriminations. Using the same colour discrimination task in a previous study, all common ravens and carrion crows copied the demonstrator. After observing a conspecific demonstrator, none of the jays solved the object-dropping task, though all jays were subsequently able to learn to solve the task in a non-social situation through explicit training, and jays chose the demonstrated colour at chance levels. Our results suggest that social and relatively asocial corvids differ in social information use, indicating that relatively asocial species may have secondarily lost this ability due to lack of selection pressure from an asocial environment.
27920146	Reward motivation has been demonstrated to enhance declarative memory by facilitating systems level consolidation. While high reward information is often intermixed with lower reward information during an experience, memory for those experiences prioritizes high value information. How is this selectivity achieved? One possibility is that post-encoding consolidation processes bias memory strengthening to those representations associated with higher reward. To test this hypothesis, we investigated the influence of differential reward motivation on the selectivity of post-encoding markers of systems-level memory consolidation. Human participants encoded intermixed, trial-unique memoranda that were associated with either high or low value during fMRI acquisition. Encoding was interleaved with periods of rest, allowing us to investigate experience-dependent changes in connectivity as they related to later memory. Behaviorally, we found that reward motivation enhanced 24-hour associative memory. Analysis of patterns of post-encoding connectivity showed that even though learning trials were intermixed, there was significantly greater connectivity with regions of high-level, category-selective visual cortex associated with high reward trials. Specifically, increased connectivity of category-selective visual cortex with both the ventral tegmental area and the anterior hippocampus predicted associative memory for high- but not low-reward memories. Critically, these results were independent of encoding-related connectivity and univariate activity measures. Thus, these findings support a model by which the selective stabilization of memories for salient events is supported by post-encoding interactions with sensory cortex associated with reward.Reward motivation is thought to promote memory by supporting memory consolidation. Yet, little is known as to how brain selects relevant information for subsequent consolidation based on reward. We show that experience-dependent changes in connectivity of both the anterior hippocampus and the ventral tegmental area with high-level visual cortex selectively predicts memory for high-reward memoranda at a 24-hour delay. These findings provide evidence for a novel mechanism guiding the consolidation of memories for valuable events, namely post-encoding interactions between neural systems supporting mesolimbic dopamine activation, episodic memory, and perception.	
27919829	Recent evidence suggests that astrocytes convert glucose to lactate, which is released from the astrocytes and supports learning and memory. This report takes a multiple memory perspective to test the role of astrocytes in cognition using real-time lactate measurements during learning and memory. Extracellular lactate levels in the hippocampus or striatum were determined with lactate biosensors while rats were learning place (hippocampus-sensitive) or response (striatum-sensitive) versions of T-mazes. In the first experiment, rats were trained on the place and response tasks to locate a food reward. Extracellular lactate levels in the hippocampus increased beyond those of feeding controls during place training but not during response training. However, striatal lactate levels did not increase beyond those of controls when rats were trained on either the place or the response version of the maze. Because food ingestion itself increased blood glucose and brain lactate levels, the contribution of feeding may have confounded the brain lactate measures. Therefore, we conducted a second similar experiment using water as the reward. A very different pattern of lactate responses to training emerged when water was used as the task reward. First, provision of water itself did not result in large increases in either brain or blood lactate levels. Moreover, extracellular lactate levels increased in the striatum during response but not place learning, whereas extracellular lactate levels in the hippocampus did not differ across tasks. The findings from the two experiments suggest that the relative engagement of the hippocampus and striatum dissociates not only by task but also by reward type. The divergent lactate responses of the hippocampus and striatum in place and response tasks under different reward conditions may reflect ethological constraints tied to foraging for food and water.
27918282	Pavlovian conditioned approach behavior can be directed as much toward discrete cues as it is toward the environmental contexts in which those cues are encountered. The current experiments characterized a tendency of rats to approach object cues whose prior exposure had been paired with reward (conditioned object preference, COP). To demonstrate the phenomenon, rats were conditioned to associate cocaine or saline with two different objects. Rats acquired a preference, assessed using investigation times directed toward each object, for the cocaine-paired object following conditioning. Furthermore, high levels of object investigation during cocaine conditioning predicted stronger preferences for the cocaine-paired object in the test phase. Conditioned approach diminished across extinction but was reinstated through a priming injection of cocaine. To determine whether preferences are affected by reward value, rats were conditioned using three objects paired with 0, 5, or 20 mg/kg of cocaine. This produced object preferences in the post-test that scaled with cocaine dose used for conditioning. Finally, we explored whether contextual cues modulate expression of COP by testing rats for renewal of cocaine seeking. When conditioning was conducted in one context and extinction training in a second context, COP was renewed when the rats were retested in the original context. Thus, conditioned object preferences are readily acquired, easily measured, and amenable to a number of standard Pavlovian conditioning manipulations. This task promises to become a valuable addition to the panoply of behavioral tools available to test mechanisms underlying adaptive and maladaptive reward processing.
27918270	Animals learn through experience and consolidate the memories into long-time storage. Conditioning parameters to induce protein synthesis-dependent long-term memory (LTM) have been the subject of extensive studies in many animals. Here we found a case in which a conditioning trial inhibits or facilitates LTM formation depending on the intervals from preceding trials. We studied the effects of conditioning parameters on LTM formation in olfactory conditioning of maxillary-palpi extension response with sucrose reward in the cockroach Periplaneta americana We found, at first, that translation- and transcription-dependent LTM forms 1 h after training, the fastest so far reported in insects. Second, we observed that multiple-trial training with an intertrial interval (ITI) of 20 or 30 sec, often called massed training, is more effective than spaced training for LTM formation, an observation that differs from the results of most studies in other animals. Third, we found that a conditioning trial inhibits LTM formation when the intervals from preceding trials were in the range of 10-16 min. This inhibitory effect is pairing-specific and is not due to decreased motivation for learning (overtraining effect). To our knowledge, no similar inhibition of LTM formation by a conditioning trial has been reported in any animals. We propose a model to account for the effects of trial number and ITIs on LTM formation. Olfactory conditioning in cockroaches should provide pertinent materials in which to study neuronal and molecular mechanisms underlying the inhibitory and facilitatory processes for LTM formation.
27914943	To achieve long-term goals, organisms evaluate outcomes and expected consequences of their behaviors. Unfavorable decisions maintain many symptoms of borderline personality disorder (BPD); therefore, a better understanding of the mechanisms underlying decision-making in BPD is needed. In this review, the current literature comparing decision-making in patients with BPD versus healthy controls is analyzed. Twenty-eight empirical studies were identified through a structured literature search. The effect sizes from studies applying comparable experimental tasks were analyzed. It was found that (1) BPD patients discounted delayed rewards more strongly; (2) reversal learning was not significantly altered in BPD; and (3) BPD patients achieved lower net gains in the Iowa Gambling Task (IGT). Current psychotropic medication, sex and differences in age between the patient and control group moderated the IGT outcome. Altered decision-making in a variety of other tasks was supported by a qualitative review. In summary, current evidence supports the altered valuation of outcomes in BPD. A multifaceted influence on decision-making and adaptive learning is reflected in this literature.
27911750	Signals of energy homeostasis interact closely with neural circuits of motivation to control food intake. An emerging hypothesis is that the transition to maladaptive feeding behavior seen in eating disorders or obesity may arise from dysregulation of these interactions. Focusing on key brain regions involved in the control of food intake (ventral tegmental area, striatum, hypothalamus, and thalamus), we describe how activity of specific cell types embedded within these regions can influence distinct components of motivated feeding behavior. We review how signals of energy homeostasis interact with these regions to influence motivated behavioral output and present evidence that experience-dependent neural adaptations in key feeding circuits may represent cellular correlates of impaired food intake control. Future research into mechanisms that restore the balance of control between signals of homeostasis and motivated feeding behavior may inspire new treatment options for eating disorders and obesity.
27911621	To evaluate the effectiveness and sustainable impact of a multifaceted community-based weight intervention program for children, including exergaming curriculum.Eighty overweight or obese children, aged 8-12 years, were randomly assigned in a 2:1 ratio to an Exergaming for Health intervention group, comprising both exergaming and classroom curriculum, or to a control group with classroom curriculum alone. Outcome measures included body mass index (BMI), z-score change, and shuttle runs to assess cardiorespiratory endurance.	Fifty-nine participants took part in the intervention and 21 in the control group, with 35 and 13 completing 6-month follow-up, respectively. Twenty-eight intervention children were followed-up at 1 year. At the end of the 6-month intervention, the intervention group reduced its BMI z-score by -0.06 (±0.12) compared to 0 (±0.09) change for the control group; additionally, intervention subjects were two shuttle runs higher than control. However, these differences were not statistically significant (P = 0.07 and P = 0.09, respectively). Over the 6-month period after the program, the intervention group did not have an increase in weight status (BMI z-score change -0.01 [95% confidence interval -0.08 to +0.06], P = 0.76).	Use of exergaming in community pediatric weight management did not improve weight status at the end of programming, and study implementation was limited by small sample and missing data. However, there were clinically promising trends in fitness, screen time, and caloric intake. Weight status of intervention participants did not rebound 6 months after programming. Larger, longer term studies are needed to establish the impact of videogaming interventions.	
27909646	Meditation has been shown to have physical, cognitive, and psychological health benefits that can be used to promote healthy aging. However, the common and specific mechanisms of response remain elusive due to the diverse nature of mind-body practices.In this review, we aim to compare the neural circuits implicated in focused-attention meditative practices that focus on present-moment awareness to those involved in active-type meditative practices (e.g., yoga) that combine movement, including chanting, with breath practices and meditation.	Recent meta-analyses and individual studies demonstrated common brain effects for attention-based meditative practices and active-based meditations in areas involved in reward processing and learning, attention and memory, awareness and sensory integration, and self-referential processing and emotional control, while deactivation was seen in the amygdala, an area implicated in emotion processing. Unique effects for mindfulness practices were found in brain regions involved in body awareness, attention, and the integration of emotion and sensory processing. Effects specific to active-based meditations appeared in brain areas involved in self-control, social cognition, language, speech, tactile stimulation, sensorimotor integration, and motor function.	This review suggests that mind-body practices can target different brain systems that are involved in the regulation of attention, emotional control, mood, and executive cognition that can be used to treat or prevent mood and cognitive disorders of aging, such as depression and caregiver stress, or serve as "brain fitness" exercise. Benefits may include improving brain functional connectivity in brain systems that generally degenerate with Alzheimer's disease, Parkinson's disease, and other aging-related diseases.	
27909395	Biologically plausible modeling of behavioral reinforcement learning tasks has seen great improvements over the past decades. Less work has been dedicated to tasks involving contingency reversals, i.e., tasks in which the original behavioral goal is reversed one or multiple times. The ability to adjust to such reversals is a key element of behavioral flexibility. Here, we investigate the neural mechanisms underlying contingency-reversal tasks. We first conduct experiments with humans and gerbils to demonstrate memory effects, including multiple reversals in which subjects (humans and animals) show a faster learning rate when a previously learned contingency re-appears. Motivated by recurrent mechanisms of learning and memory for object categories, we propose a network architecture which involves reinforcement learning to steer an orienting system that monitors the success in reward acquisition. We suggest that a model sensory system provides feature representations which are further processed by category-related subnetworks which constitute a neural analog of expert networks. Categories are selected dynamically in a competitive field and predict the expected reward. Learning occurs in sequentialized phases to selectively focus the weight adaptation to synapses in the hierarchical network and modulate their weight changes by a global modulator signal. The orienting subsystem itself learns to bias the competition in the presence of continuous monotonic reward accumulation. In case of sudden changes in the discrepancy of predicted and acquired reward the activated motor category can be switched. We suggest that this subsystem is composed of a hierarchically organized network of dis-inhibitory mechanisms, dubbed a dynamic control network (DCN), which resembles components of the basal ganglia. The DCN selectively activates an expert network, corresponding to the current behavioral strategy. The trace of the accumulated reward is monitored such that large sudden deviations from the monotonicity of its evolution trigger a reset after which another expert subnetwork can be activated-if it has already been established before-or new categories can be recruited and associated with novel behavioral patterns.
27909007	Humans are sensitive to statistical regularities in their visual environment, but the nature of the underlying neural statistical learning signals still remains to be clarified. As in human behavioral and neuroimaging studies of statistical learning, we exposed rhesus monkeys to a continuous stream of images, presented without interstimulus interval or reward association. The stimulus set consisted of 3 groups of 5 images each (quintets). The stimulus order within each quintet was fixed, but the quintets were presented repeatedly in a random order without interruption. Thus, only transitional probabilities defined quintets of images. Postexposure recordings in inferior temporal (IT) cortex showed an enhanced response to stimuli that violated the exposed sequence. This enhancement was found only for stimuli that were not predicted by the just preceding stimulus, reflecting a temporally adjacent stimulus relationship, and was sensitive to stimulus order. By comparing IT responses with sequences with and without statistical regularities, we observed a short latency, transient response suppression for stimuli of the sequence with regularities, in addition to a later sustained response enhancement to stimuli that violated the sequence with regularities. These findings constrain models of mechanisms underlying neural responses in predictable temporal sequences, such as predictive coding.
27905069	Recent evidence shows that distractors that signal high compared to low reward availability elicit stronger attentional capture, even when this is detrimental for task-performance. This suggests that simply correlating stimuli with reward administration, rather than their instrumental relationship with obtaining reward, produces value-driven attentional capture. However, in previous studies, reward delivery was never response independent, as only correct responses were rewarded, nor was it completely task-irrelevant, as the distractor signaled the magnitude of reward that could be earned on that trial. In two experiments, we ensured that associative reward learning was completely response independent by letting participants perform a task at fixation, while high and low rewards were automatically administered following the presentation of task-irrelevant colored stimuli in the periphery (Experiment 1) or at fixation (Experiment 2). In a following non-reward test phase, using the additional singleton paradigm, the previously reward signaling stimuli were presented as distractors to assess truly task-irrelevant value driven attentional capture. The results showed that high compared to low reward-value associated distractors impaired performance, and thus captured attention more strongly. This suggests that genuine Pavlovian conditioning of stimulus-reward contingencies is sufficient to obtain value-driven attentional capture. Furthermore, value-driven attentional capture can occur following associative reward learning of temporally and spatially task-irrelevant distractors that signal the magnitude of available reward (Experiment 1), and is independent of training spatial shifts of attention towards the reward signaling stimuli (Experiment 2). This confirms and strengthens the idea that Pavlovian reward learning underlies value driven attentional capture.
27903935	To assess the decision-making impairment in patients with multiple sclerosis (MS) and how they relate to other cognitive domains.We performed a cross-sectional analysis in 84 patients with MS, and 21 matched healthy controls using four tasks taken from behavioral economics: (1) risk preferences, (2) choice consistency, (3) delay of gratification, and (4) rate of learning. All tasks were conducted using real-world reward outcomes (food or money) in different real-life conditions. Participants underwent cognitive examination using the Brief Repeatable Battery-Neuropsychology.	Patients showed higher risk aversion (general propensity to choose the lottery was 0.51 vs 0.64, p = 0.009), a trend to choose more immediate rewards over larger but delayed rewards ( p = 0.108), and had longer reactions times ( p = 0.033). Choice consistency and learning rates were not different between groups. Progressive patients chose slower than relapsing patients. In relation to general cognitive impairments, we found correlations between impaired decision-making and impaired verbal memory ( r = 0.29, p = 0.009), visual memory ( r = -0.37, p = 0.001), and reduced processing speed ( r = -0.32, p = 0.001). Normalized gray matter volume correlated with deliberation time ( r = -0.32, p = 0.005).	Patients with MS suffer significant decision-making impairments, even at the early stages of the disease, and may affect patients' quality and social life.	
27903731	Over the course of systems consolidation, there is a switch from a reliance on detailed episodic memories to generalized schematic memories. This switch is sometimes referred to as "memory transformation." Here we demonstrate a previously unappreciated benefit of memory transformation, namely, its ability to enhance reinforcement learning in a dynamic environment. We developed a neural network that is trained to find rewards in a foraging task where reward locations are continuously changing. The network can use memories for specific locations (episodic memories) and statistical patterns of locations (schematic memories) to guide its search. We find that switching from an episodic to a schematic strategy over time leads to enhanced performance due to the tendency for the reward location to be highly correlated with itself in the short-term, but regress to a stable distribution in the long-term. We also show that the statistics of the environment determine the optimal utilization of both types of memory. Our work recasts the theoretical question of why memory transformation occurs, shifting the focus from the avoidance of memory interference toward the enhancement of reinforcement learning across multiple timescales.As time passes, memories transform from a highly detailed state to a more gist-like state, in a process called "memory transformation." Theories of memory transformation speak to its advantages in terms of reducing memory interference, increasing memory robustness, and building models of the environment. However, the role of memory transformation from the perspective of an agent that continuously acts and receives reward in its environment is not well explored. In this work, we demonstrate a view of memory transformation that defines it as a way of optimizing behavior across multiple timescales.	
27899725	In this article, I address the paradox that university grade point averages have increased for decades, whereas the time students invest in their studies has decreased. I argue that one major contributor to this paradox is grading leniency, encouraged by the practice of university administrators to base important personnel decisions on student evaluations of teaching. Grading leniency creates strong incentives for instructors to teach in ways that would result in good student evaluations. Because many instructors believe that the average student prefers courses that are entertaining, require little work, and result in high grades, they feel under pressure to conform to those expectations. Evidence is presented that the positive association between student grades and their evaluation of teaching reflects a bias rather than teaching effectiveness. If good teaching evaluations reflected improved student learning due to effective teaching, they should be positively related to the grades received in subsequent courses that build on knowledge gained in the previous course. Findings that teaching evaluations of concurrent courses, though positively correlated with concurrent grades, are negatively related to student performance in subsequent courses are more consistent with the assumption that concurrent evaluations are the result of lenient grading rather than effective teaching. Policy implications are discussed.
27899333	Increased Body-Mass-Index (BMI) has been associated with brain atrophy in both gray and white matter structures. However, little is known concerning the integrity of white matter tracts in obesity. The purpose of the study was to evaluate the pattern of changes in white matter microstructure in human adiposity.The study included 268 participants (52 obese, 96 overweight and 120 normal-weight) that were retrospectively evaluated by Diffusion Tensor Imaging. The fractional anisotropy, axial, radial and mean diffusivity values were compared between the above groups using Tract Based Spatial Statistics.	The analysis revealed that the increased BMI was related with decreased fractional anisotropy in several white matter regions including the anterior and posterior thalamic radiation, the inferior fronto-occipital fasciculus, the inferior and superior longitudinal fasciculus, the corpus callosum (callosal body and forceps minor), the uncinate fasciculus, the internal capsule, the corticospinal tract and the cingulum (cingulate gyrus and hippocampus).	Anisotropic diffusion of anatomic regions governing important brain circuits such as reward seeking inhibition, motivation/drive and learning/conditioning decreases with increasing BMI.	
27896312	The propensity of animals to shift choices immediately after unexpectedly poor reinforcement outcomes is a pervasive strategy across species and tasks. We report here that the memory supporting such lose-shift responding in rats rapidly decays during the intertrial interval and persists throughout training and testing on a binary choice task, despite being a suboptimal strategy. Lose-shift responding is not positively correlated with the prevalence and temporal dependence of win-stay responding, and it is inconsistent with predictions of reinforcement learning on the task. These data provide further evidence that win-stay and lose-shift are mediated by dissociated neural mechanisms and indicate that lose-shift responding presents a potential confound for the study of choice in the many operant choice tasks with short intertrial intervals. We propose that this immediate lose-shift responding is an intrinsic feature of the brain's choice mechanisms that is engaged as a choice reflex and works in parallel with reinforcement learning and other control mechanisms to guide action selection.
27894877	Relief learning is the association of a stimulus with the offset of an aversive event. Later, the now conditioned relief stimulus induces appetitive-like behavioral changes. We previously demonstrated that the NMDA receptors within the nucleus accumbens (NAC) are involved in relief learning. The NAC is also important for reward learning and it has been shown that reward learning is mediated by an interaction of accumbal dopamine and NMDA glutamate receptors. Since conditioned relief has reward-like properties, we hypothesized that (a) acquisition of relief learning requires the activation of dopamine D1 receptors in the NAC, and (b) if D1 receptors are involved in this process as expected, a concurrent dopamine D1 and NMDA receptor activation may mediate this learning. The present study tested these hypotheses. Therefore, rats received intra-NAC injections of the dopamine D1 receptor antagonist SCH23390 and the NMDA antagonist AP5, either separately or together, at different time points of a relief conditioning procedure. First, we showed that SCH23390 dose-dependently blocked acquisition and the expression of conditioned relief. Next, we demonstrated that co-injections of SCH23390 and AP5 into the NAC, at doses that were ineffective when applied separately, blocked acquisition but not consolidation or expression of relief learning. Notably, neither of the injections affected the locomotor response of the animals to the aversive stimuli suggesting that their perception is not changed. This data indicates that a co-activation of dopamine D1 and NMDA receptors in the NAC is required for acquisition of relief learning.
27893846	The role of the cerebellum in motivation and addictive behaviors is less understood than that in control and coordination of movements. High running can be a self-rewarding behavior exhibiting addictive properties. Changes in the cerebellum transcriptional networks of mice from a line selectively bred for High voluntary running (H) were profiled relative to an unselected Control (C) line. The environmental modulation of these changes was assessed both in activity environments corresponding to 7 days of Free (F) access to running wheel and to Blocked (B) access on day 7. Overall, 457 genes exhibited a significant (FDR-adjusted P-value < 0.05) genotype-by-environment interaction effect, indicating that activity genotype differences in gene expression depend on environmental access to running. Among these genes, network analysis highlighted 6 genes (Nrgn, Drd2, Rxrg, Gda, Adora2a, and Rab40b) connected by their products that displayed opposite expression patterns in the activity genotype contrast within the B and F environments. The comparison of network expression topologies suggests that selection for high voluntary running is linked to a predominant dysregulation of hub genes in the F environment that enables running whereas a dysregulation of ancillary genes is favored in the B environment that blocks running. Genes associated with locomotor regulation, signaling pathways, reward-processing, goal-focused, and reward-dependent behaviors exhibited significant genotype-by-environment interaction (e.g. Pak6, Adora2a, Drd2, and Arhgap8). Neuropeptide genes including Adcyap1, Cck, Sst, Vgf, Npy, Nts, Penk, and Tac2 and related receptor genes also exhibited significant genotype-by-environment interaction. The majority of the 183 differentially expressed genes between activity genotypes (e.g. Drd1) were under-expressed in C relative to H genotypes and were also under-expressed in B relative to F environments. Our findings indicate that the high voluntary running mouse line studied is a helpful model for understanding the molecular mechanisms in the cerebellum that influence locomotor control and reward-dependent behaviors.
27893230	Negative symptoms are a core clinical feature of schizophrenia, but conceptual and methodological problems with current instruments can make their assessment challenging. One hypothesis is that current symptom assessments may be influenced by impairments in memory and may not be fully reflective of actual functioning outside of the laboratory. The present study sought to investigate the validity of assessing negative symptoms using ecological momentary assessment (EMA). Participants with schizophrenia (N = 31) completed electronic questionnaires on smartphones 4 times a day for 1 week. Participants also completed effort-based decision making and reinforcement learning (RL) tasks to assess the relationship between EMA and laboratory measures, which tap into negative symptom relevant domains. Hierarchical linear modeling analyses revealed that clinician-rated and self-report measures of negative symptoms were significantly related to negative symptoms assessed via EMA. However, working memory moderated the relationship between EMA and retrospective measures of negative symptoms, such that there was a stronger relationship between EMA and retrospective negative symptom measures among individuals with better working memory. The authors also found that negative symptoms assessed via EMA were related to poor performance on the effort task, whereas clinician-rated symptoms and self-reports were not. Further, they found that negative symptoms were related to poorer performance on learning reward contingencies. The findings suggest that negative symptoms can be assessed through EMA and that working memory impairments frequently seen in schizophrenia may affect recall of symptoms. Moreover, these findings suggest the importance of examining the relationship between laboratory tasks and symptoms assessed during daily life. (PsycINFO Database Record
27891082	The pedunculopontine tegmental nucleus (PPTg) in the brainstem plays a role in controlling reinforcement learning and executing conditioned behavior. We previously examined the activity of PPTg neurons in monkeys during a reward-conditioned, visually guided saccade task, and reported that a population of these neurons exhibited tonic responses throughout the task period. These tonic responses might depend on prediction of the upcoming reward, successful execution of the task, or both. Here, we sought to further distinguish these factors and to investigate how each contributes to the tonic neuronal activity of the PPTg. In our normal visually guided saccade task, the monkey initially fixated on the central fixation target (FT), then made saccades to the peripheral saccade target and received a juice reward after the saccade target disappeared. Most of the tonic activity terminated shortly after the reward delivery, when the monkey broke fixation. To distinguish between reward and behavioral epochs, we then changed the task sequence for a block of trials, such that the saccade target remained visible after the reward delivery. Under these visible conditions, the monkeys tended to continue fixating on the saccade target even after the reward delivery. Therefore, the prediction of the upcoming reward and the end of an individual trial were separated in time. Regardless of the task conditions, half of the tonically active PPTg neurons terminated their activity around the time of the reward delivery, consistent with the view that PPTg neurons might send reward prediction signals until the time of reward delivery, which is essential for computing reward prediction error in reinforcement learning. On the other hand, the other half of the tonically active PPTg neurons changed their activity dependent on the task condition. In the normal condition, the tonic responses terminated around the time of the reward delivery, while in the visible condition, the activity continued until the disappearance of the saccade target (ST) after reward delivery. Thus, for these neurons, the tonic activity might be related to maintaining attention to complete fixation behavior. These results suggest that, in addition to the reward value information, some PPTg neurons might contribute to the execution of conditioned task behavior.
27888020	Conduct problems (CP) comprise abnormal behaviors associated with aberrant aspects of affective empathy as well as learning. However, behavioral measures for affective empathy are challenging, and previous results concerning learning in patients with CP are inconsistent.Nineteen boys with CP and 24 typically developing (TD) boys aged 11-17 years (M=14.34, SD=1.93) participated in the study. An ultimatum-game was applied in order to elicit the feeling of like or dislike towards the opponent for a subsequent gambling task, which was played by the opponents (OTHER-condition) and by the participants themselves (SELF-condition). Functional MRI data were recorded throughout the experiment.	In accordance with the model of insensitivity to punishment, hypo-activation of the left amygdala, left anterior insula, ventral medial prefrontal cortex (MPFC), and bilateral temporo-parietal junction (TPJ) was observed as a response to losing in participants with CP during the SELF-condition. Callous-unemotional (CU)-traits correlated negatively with activation of amygdala and right TPJ. During the OTHER-condition, TD participants showed activation in brain areas associated with theory of mind (right TPJ, left IFG), and affect regulation (right DLPFC) rather than areas associated with affective empathy. This pattern was not found in adolescents with CP. Moreover, and independently of individual characteristics of their opponents, adolescents with CP demonstrated reward-associated activation (ventral striatum) observing others win, which was positively correlated with CU-traits. This may be interpreted in line with the theory of reward dominance.	The current study provides support for the theory of abnormal learning processing in adolescents with CP which yields implications for further research as well as clinical practice. The gambling task did not activate affective empathy networks, but was specific for cognitive empathy, inhibition, and affect regulation.	
27884551	Drug addiction is a major health problem worldwide. Recent neuroimaging studies have shed light into the underlying mechanisms of drug addiction as well as its consequences to the human brain. The most vulnerable, to heroin addiction, brain regions have been reported to be specific prefrontal, parietal, occipital, and temporal regions, as well as, some subcortical regions. The brain regions involved are usually linked with reward, motivation/drive, memory/learning, inhibition as well as emotional control and seem to form circuits that interact with each other. So, along with neuroimaging studies, recent advances in resting-state dynamics might allow further assessments upon the multilayer complexity of addiction. In the current manuscript, we comprehensively review and discuss existing resting-state neuroimaging findings classified into three overlapping and interconnected groups: functional connectivity alterations, structural deficits and abnormal topological properties. Moreover, behavioral traits of heroin-addicted individuals as well as the limitations of the currently available studies are also reviewed. Finally, in need of a contemporary therapy a multimodal therapeutic approach is suggested using classical treatment practices along with current neurotechonologies, such as neurofeedback and goal-oriented video-games.
27881782	The prelimbic prefrontal cortex (PL) has consistently been found to be necessary for the acquisition of goal-directed actions in rodents. Nevertheless, the specific cellular processes underlying this learning remain unknown. We assessed changes in learning-related expression of mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK1/2) phosphorylation (pERK) in layers 2-3 and 5-6 of the anterior and posterior PL and in the population of neurons projecting to posterior dorsomedial striatum (pDMS), also implicated in goal-directed learning. Rats were given either a single session of training to press a lever for a pellet reward or yoked reward deliveries without instrumental training and assessed 5 or 60 min after training for pERK expression. Relative to yoked training, instrumental training produced an increase in pERK expression in all regions of the PL both at 5 and 60 min, and this was accompanied by an increase in nuclear pERK expression in the posterior PL in rats given instrumental training. pDMS-projecting neurons showed a transient increase in pERK expression in posterior layer 5-6 projection neurons after 5 min, and a delayed increase in anterior layer 2-3 neurons after 60 min, suggesting that ERK expression in the PL is necessary for the consolidation of goal-directed learning. Consistent with this claim, we found that rats trained on two lever press actions for distinct outcomes and then infused with the MEK inhibitor PD98059 into the PL immediately after training failed to acquire specific action-outcome associations, suggesting that persistent pERK signaling in the PL is necessary for goal-directed learning.The prelimbic cortex is implicated in goal-directed learning in rodents; however, it is unclear whether it is involved in the consolidation of this learning, and what cellular processes are involved. We used pERK as a marker of activity-related synaptic plasticity to assess learning-induced changes in distinct layers and neuronal populations of the prelimbic prefrontal cortex (PL). Training produced long-lasting upregulation of pERK throughout the PL and specifically within neurons that project to the pDMS, another region critical for goal-directed learning. Next, we demonstrated that pERK signaling in the PL was necessary for the consolidation of goal-directed learning. Together, these results indicate that instrumental training induces ERK signaling in distinct layers and populations in the PL and this signaling underlies the consolidation of goal-directed learning.	
27877100	To ensure survival, animals must update the internal representations of their environment in a trial-and-error fashion. Psychological studies of associative learning and neurophysiological analyses of dopaminergic neurons have suggested that this updating process involves the temporal-difference (TD) method in the basal ganglia network. However, the way in which the component variables of the TD method are implemented at the neuronal level is unclear. To investigate the underlying neural mechanisms, we trained domestic chicks to associate color cues with food rewards. We recorded neuronal activities from the medial striatum or tegmentum in a freely behaving condition and examined how reward omission changed neuronal firing. To compare neuronal activities with the signals assumed in the TD method, we simulated the behavioral task in the form of a finite sequence composed of discrete steps of time. The three signals assumed in the simulated task were the prediction signal, the target signal for updating, and the TD-error signal. In both the medial striatum and tegmentum, the majority of recorded neurons were categorized into three types according to their fitness for three models, though these neurons tended to form a continuum spectrum without distinct differences in the firing rate. Specifically, two types of striatal neurons successfully mimicked the target signal and the prediction signal. A linear summation of these two types of striatum neurons was a good fit for the activity of one type of tegmental neurons mimicking the TD-error signal. The present study thus demonstrates that the striatum and tegmentum can convey the signals critically required for the TD method. Based on the theoretical and neurophysiological studies, together with tract-tracing data, we propose a novel model to explain how the convergence of signals represented in the striatum could lead to the computation of TD error in tegmental dopaminergic neurons.
27876641	Personality can influence how animals perceive and learn cues. The behaviour and physiological responses animals show during stressful events is indicative of their personality. Acute induced stress prior to a cognitive test are known to affect the judgement of a stimulus, but personality of an individual could also affect learning of a specific cognitive paradigm. Here, we assessed if adult laying hens' behaviour and physiological responses, as indicators of their personality, were related to their cognitive performance. We assessed their behavioural responses to a tonic immobility test, an open field test, and a manual restraint test, and measured plasma corticosterone levels after manual restraint. After that, hens (n=20) were trained in a pre-set training schedule to associate a colour-cue with a reward. In a two-choice go-go test, hens needed to choose between a baited or non-baited food container displayed randomly on the left or right side of an arena. Success in learning was related to personality, with better performance of hens which showed a reactive personality type by a long latency to walk, struggle or vocalize during the tests. Only eight out of 20 hens reached the training criteria. The non-learners showed a strong side preference during all training days. Side preferences were strong in hens with high levels of plasma corticosterone and with a long duration of tonic immobility, indicating that fearful, stress-sensitive hens are more prone to develop side biases. Our results show that learning can be hindered by side biases, and fearful animals with a more proactive personality type are more sensitive to develop such biases.
27875379	Suicide attempts are usually regretted by people who survive them. Furthermore, addiction and gambling are over-represented among people who attempt or die by suicide, raising the question whether their decision-making is impaired. Advances in decision neuroscience have enabled us to investigate decision processes in suicidal people and to elucidate putative neural substrates of disadvantageous decision-making.Early studies have linked attempted suicide to poor performance on gambling tasks. More recently, functional MRI augmented with a reinforcement learning computational model revealed that impaired decision-making in suicide attempters is paralleled by disrupted expected value (expected reward) signals in the ventromedial prefrontal cortex. Behavioral studies have linked increased delay discounting to low-lethality/poorly planned attempts, multiple attempts, and the co-occurrence of attempted suicide and addiction. This behavioral tendency may be related to altered integrity of the basal ganglia. By contrast, well-planned, serious suicide attempts were associated with intact/diminished delay discounting. One study has linked high-lethality suicide attempts and impaired social decision-making.	This emerging literature supports the notion that various impairments in decision-making - often broadly related to impulsivity - may mark different pathways to suicide. We propose that aggressive and self-destructive responses to social stressors in people prone to suicide result from a predominance of automatic, Pavlovian processes over goal-directed computations.	
27874153	To examine the relationship between students' collaborative performance in a problem-based learning (PBL) environment and their personality traits. Methods:This retrospective, cross-sectional study was conducted using student data of a PBL program between 2013 and 2014 at Sungkyunkwan University School of Medicine, Seoul, South Korea. Eighty students were included in the study. Student data from the Temperament and Character Inventory were used as a measure of their personality traits. Peer evaluation scores during PBL were used as a measure of students' collaborative performance. Results: Simple regression analyses indicated that participation was negatively related to harm avoidance and positively related to persistence, whereas preparedness for the group work was negatively related to reward dependence. On multiple regression analyses, low reward dependence remained a significant predictor of preparedness. Grade-point average (GPA)  was negatively associated with novelty seeking and cooperativeness and was positively associated with persistence.  Conclusion: Medical students who are less dependent on social reward are more likely to complete assigned independent work to prepare for the PBL tutorials. The findings of this study can help educators better understand and support medical students who are at risk of struggling in collaborative learning environments.
27872762	Our hypothesis is that allosteric receptor-receptor interactions in homo- and heteroreceptor complexes may form the molecular basis of learning and memory. This principle is illustrated by showing how cocaine abuse can alter the adenosine A2AR-dopamine D2R heterocomplexes and their receptor-receptor interactions and hereby induce neural plasticity in the basal ganglia. Studies with A2AR ligands using cocaine self-administration procedures indicate that antagonistic allosteric A2AR-D2R heterocomplexes of the ventral striatopallidal GABA antireward pathway play a significant role in reducing cocaine induced reward, motivation, and cocaine seeking. Anticocaine actions of A2AR agonists can also be produced at A2AR homocomplexes in these antireward neurons, actions in which are independent of D2R signaling. At the A2AR-D2R heterocomplex, they are dependent on the strength of the antagonistic allosteric A2AR-D2R interaction and the number of A2AR-D2R and A2AR-D2R-sigma1R heterocomplexes present in the ventral striatopallidal GABA neurons. It involves a differential cocaine-induced increase in sigma1Rs in the ventral versus the dorsal striatum. In contrast, the allosteric brake on the D2R protomer signaling in the A2AR-D2R heterocomplex of the dorsal striatopallidal GABA neurons is lost upon cocaine self-administration. This is potentially due to differences in composition and allosteric plasticity of these complexes versus those in the ventral striatopallidal neurons.
27872638	Associative learning, including classical conditioning and operant conditioning, is regarded as the most fundamental type of learning for animals and human beings. Many models have been proposed surrounding classical conditioning or operant conditioning. However, a unified and integrated model to explain the two types of conditioning is much less studied. Here, a model based on neuromodulated synaptic plasticity is presented. The model is bioinspired including multistored memory module and simulated VTA dopaminergic neurons to produce reward signal. The synaptic weights are modified according to the reward signal, which simulates the change of associative strengths in associative learning. The experiment results in real robots prove the suitability and validity of the proposed model.
27870614	This article describes a process theory based on active inference and belief propagation. Starting from the premise that all neuronal processing (and action selection) can be explained by maximizing Bayesian model evidence-or minimizing variational free energy-we ask whether neuronal responses can be described as a gradient descent on variational free energy. Using a standard (Markov decision process) generative model, we derive the neuronal dynamics implicit in this description and reproduce a remarkable range of well-characterized neuronal phenomena. These include repetition suppression, mismatch negativity, violation responses, place-cell activity, phase precession, theta sequences, theta-gamma coupling, evidence accumulation, race-to-bound dynamics, and transfer of dopamine responses. Furthermore, the (approximately Bayes' optimal) behavior prescribed by these dynamics has a degree of face validity, providing a formal explanation for reward seeking, context learning, and epistemic foraging. Technically, the fact that a gradient descent appears to be a valid description of neuronal activity means that variational free energy is a Lyapunov function for neuronal dynamics, which therefore conform to Hamilton's principle of least action.
27870426	The use of tobacco products represents a major public health concern, especially among women. Epidemiological data have consistently demonstrated that women have less success quitting tobacco use and a higher risk for developing tobacco-related diseases. The deleterious effects of nicotine are not restricted to adulthood, as nicotinic acetylcholine receptors regulate critical aspects of neural development. However, the exact mechanisms underlying the particular sensitivity of women to develop tobacco dependence have not been well elucidated. In this mini-review, we show that gonadal hormone-mediated sexual differentiation of the brain may be an important determinant of sex differences in the effects of nicotine. We highlight direct interactions between sex steroid hormones and ligand-gated ion channels critical for brain maturation, and discuss the extended and profound sexual differentiation of the brain. We emphasize that nicotine exposure during the perinatal and adolescent periods interferes with normal sexual differentiation and can induce long-lasting, sex-dependent alterations in neuronal structure, cognitive and executive function, learning and memory, and reward processing. We stress important age and sex differences in nicotine's effects and emphasize the importance of including these factors in preclinical research that models tobacco dependence. © 2016 Wiley Periodicals, Inc.
27869181	Proper performance of acquired abilities can be disturbed by the unexpected occurrence of external changes. Rats trained with an operant conditioning task (to press a lever in order to obtain a food pellet) using a fixed-ratio (1:1) schedule were subsequently placed in a Skinner box in which the lever could be removed randomly. Field postsynaptic potentials (fPSPs) were chronically evoked in perforant pathway-hippocampal CA1 (PP-CA1), CA1-subiculum (CA1-SUB), CA1-medial prefrontal cortex (CA1-mPFC), mPFC-nucleus accumbens (mPFC-NAc), and mPFC-basolateral amygdala (mPFC-BLA) synapses during lever IN and lever OUT situations. While lever presses were accompanied by a significant increase in fPSP slopes at the five synapses, the unpredictable absence of the lever were accompanied by decreased fPSP slopes in all, except PP-CA1 synapses. Spectral analysis of local field potentials (LFPs) recorded when the animal approached the corresponding area in the lever OUT situation presented lower spectral powers than during lever IN occasions for all recording sites, apart from CA1. Thus, the unpredictable availability of a reward-related cue modified the activity of cortical and subcortical areas related with the acquisition of operant learning tasks, suggesting an immediate functional reorganization of these neural circuits to address the changed situation and to modify ongoing behaviors accordingly.
27867937	The corticostriatothalamic circuit regulates learning behaviors via dopamine neurotransmission. D2 long (D2L) receptors are an isoform of dopamine D2 receptors (D2Rs) and may act mainly at postsynaptic sites. It is well known that D2Rs influence high brain functions, but the roles of individual D2R isoforms are still unclear. To assess the influence of D2L receptors in visual discrimination learning, we performed visual discrimination and reversal tasks with D2L knockout mice using a touchscreen operant system. There were no significant differences in an operant conditioning task between genotypes. However, D2L knockout mice were impaired in both visual discrimination and reversal learning tasks. D2L knockout mice were also significantly slower than wild-type mice in collecting the reward in the visual discrimination task. These results indicate that D2L receptors play an important role in visual discrimination and reversal learning.
27867436	We investigated fMRI responses to visual search targets appearing at locations that were predicted by the search context. Based on previous work in visual category learning we expected an intrinsic reward prediction error signal in the putamen whenever the target appeared at a location that was predicted with some degree of uncertainty. Comparing target appearance at locations predicted with 50% probability to either locations predicted with 100% probability or unpredicted locations, increased activation was observed in left posterior putamen and adjacent left posterior insula. Thus, our hypothesis of an intrinsic prediction error-like signal was confirmed. This extends the observation of intrinsic prediction error-like signals, driven by intrinsic rather than extrinsic reward, to memory-driven visual search.
27866999	The 5-HT1A/1B-receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward. How eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether eltoprazine affects different forms of impulsivity and brain reward mechanisms. Therefore, in the present study, we investigate the effects of eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task. The microdialysis studies clearly showed that eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distinct neural circuits, because 5-HT1A/1B-receptor activation decreases impulsive choice, but increases impulsive action.
27862593	The orbitofrontal cortex seems to play a crucial role in reward-guided learning and decision making, especially for impulsive choice procedures including delayed reward discounting. The central serotonergic system is closely involved in the regulation of impulsivity, but how the serotonergic firing rate and release, best investigated by the loudness dependence of auditory evoked potentials (LDAEP), interact with orbitofrontal activity is still unknown.Twenty healthy volunteers (11 males, 9 females, 31.3 ± 10.6 years old) were studied in a 3T MRI scanner (Philips, Hamburg, Germany) during a delay discounting task, after their LDAEP was recorded using a 32 electrodes EEG machine (Brain Products, Munich, Germany).	Significant positive correlations were only found between the LDAEP and the medial orbitofrontal part of the superior frontal gyrus (SFG/MO) [Δ immediate reward - delayed reward] for the right (r = 0.519; P = 0.019) and left side (r = 0.478; P = 0.033). This relationship was stronger for females compared with males. Orbitofrontal activity was also related to the Barratt Impulsivity Scale.	This study revealed that low serotonergic activity as measured by a strong LDAEP was related to a high fMRI signal intensity of SFG/MO during immediate reward behavior which is related to impulsivity. Since this relationship was only found for the infralimbic medial and not for the middle or lateral part of the orbitofrontal cortex, an exclusive projection tract of the serotonergic system to this cortical region can be assumed to regulate impulsive reward-orientated decision making. Hum Brain Mapp 38:1507-1517, 2017. © 2016 Wiley Periodicals, Inc.	
27859899	Trust in reciprocity (TR) is defined as the risky decision to invest valued resources in another party with the hope of mutual benefit. Several fMRI studies have investigated the neural correlates of TR in one-shot and multiround versions of the investment game (IG). However, an overall characterization of the underlying neural networks remains elusive. Here, a coordinate-based meta-analysis was employed (activation likelihood estimation method, 30 articles) to investigate consistent brain activations in each of the IG stages (i.e., the trust, reciprocity and feedback stage). Results showed consistent activations in the anterior insula (AI) during trust decisions in the one-shot IG and decisions to reciprocate in the multiround IG, likely related to representations of aversive feelings. Moreover, decisions to reciprocate also consistently engaged the intraparietal sulcus, probably involved in evaluations of the reciprocity options. On the contrary, trust decisions in the multiround IG consistently activated the ventral striatum, likely associated with reward prediction error signals. Finally, the dorsal striatum was found consistently recruited during the feedback stage of the multiround IG, likely related to reinforcement learning. In conclusion, our results indicate different neural networks underlying trust, reciprocity, and feedback learning. These findings suggest that although decisions to trust and reciprocate may elicit aversive feelings likely evoked by the uncertainty about the decision outcomes and the pressing requirements of social standards, multiple interactions allow people to build interpersonal trust for cooperation via a learning mechanism by which they arguably learn to distinguish trustworthy from untrustworthy partners. Hum Brain Mapp 38:1233-1248, 2017. © 2016 Wiley Periodicals, Inc.
27857686	Proactive control allows us to maneuver a changing environment and individuals are distinct in how they anticipate and approach such changes. Here, we examined how individual differences in personality traits influence cerebral responses to conflict anticipation, a critical process of proactive control. We explored this issue in an fMRI study of the stop signal task, in which the probability of stop signal - p(Stop) - was computed trial by trial with a Bayesian model. Higher p(Stop) is associated with prolonged go trial reaction time, indicating conflict anticipation and proactive control of motor response. Regional brain activations to conflict anticipation were correlated to novelty seeking (NS), harm avoidance (HA), reward dependence, as assessed by the Tridimensional Personality Questionnaire, with age and gender as covariates, in a whole-brain linear regression. Results showed that increased anticipation of the stop signal is associated with activations in the bilateral inferior parietal lobules (IPL), right lateral orbitofrontal cortex (lOFC), middle frontal gyrus (MFG), anterior pre-supplementary motor area (pre-SMA), and bilateral thalamus, with men showing greater activation in the IPL than women. NS correlated negatively to activity in the anterior pre-SMA, right IPL, and MFG/lOFC, and HA correlated negatively to activity in the thalamus during conflict anticipation. In addition, the negative association between NS and MFG/lOFC activity was significant in men but not in women. Thus, NS and HA traits are associated with reduced mobilization of cognitive control circuits when enhanced behavioral control is necessary. The findings from this exploratory study characterize the influence of NS and HA on proactive control and provide preliminary evidence for gender differences in these associations.
27856545	Undergraduate science, technology, engineering, and mathematics (STEM) education reform continues to be a national priority. We studied a reform process in undergraduate biology at a research-intensive university to explore what leadership issues arose in implementation of the initiative when characterized with a descriptive case study method. The data were drawn from transcripts of meetings that occurred over the first 2 years of the reform process. Two literature-based models of change were used as lenses through which to view the data. We find that easing the burden of an undergraduate education reform initiative on faculty through articulating clear outcomes, developing shared vision across stakeholders on how to achieve those outcomes, providing appropriate reward systems, and ensuring faculty have ample opportunity to influence the initiative all appear to increase the success of reform. The two literature-based models were assessed, and an extended model of change is presented that moves from change in STEM instructional strategies to STEM organizational change strategies. These lessons may be transferable to other institutions engaging in education reform.
27854448	We recently showed that ventral striatal (VS) lesions abolished reward prediction errors that reflect changes in reward timing while leaving relatively unaffected errors that reflect changes in reward number. Here we extended those results by examining whether normal learning-related changes in firing to the reward-predictive cues in the same dopamine neurons were also disrupted by VS lesions. This analysis revealed that dopamine neurons recorded in VS-lesioned rats failed to show value-related changes in firing to the cues in timing but showed normal changes in number blocks. This effect suggests that the loss of reward-evoked error signals in the timing blocks impaired encoding of the cue value in downstream areas, which then supply these predictions to dopamine neurons at the time of cue presentation. (PsycINFO Database Record

27853441	Humans are capable of detecting and exploiting a variety of environmental regularities, including stimulus-stimulus contingencies (e.g., visual statistical learning) and stimulus-reward contingencies. However, the relationship between these two types of learning is poorly understood. In two experiments, we sought evidence that the occurrence of rewarding events enhances or impairs visual statistical learning. Across all of our attempts to find such evidence, we employed a training stage during which we grouped shapes into triplets and presented triplets one shape at a time in an undifferentiated stream. Participants subsequently performed a surprise recognition task in which they were tested on their knowledge of the underlying structure of the triplets. Unbeknownst to participants, triplets were also assigned no-, low-, or high-reward status. In Experiments 1A and 1B, participants viewed shape streams while low and high rewards were "randomly" given, presented as low- and high-pitched tones played through headphones. Rewards were always given on the third shape of a triplet (Experiment 1A) or the first shape of a triplet (Experiment 1B), and high- and low-reward sounds were always consistently paired with the same triplets. Experiment 2 was similar to Experiment 1, except that participants were required to learn value associations of a subset of shapes before viewing the shape stream. Across all experiments, we observed significant visual statistical learning effects, but the strength of learning did not differ amongst no-, low-, or high-reward conditions for any of the experiments. Thus, our experiments failed to find any influence of rewards on statistical learning, implying that visual statistical learning may be unaffected by the occurrence of reward. The system that detects basic stimulus-stimulus regularities may operate independently of the system that detects reward contingencies.
27852776	As one learns to dance or play tennis, the desired somatosensory state is typically unknown. Trial and error is important as motor behavior is shaped by successful and unsuccessful movements. As an experimental model, we designed a task in which human participants make reaching movements to a hidden target and receive positive reinforcement when successful. We identified somatic and reinforcement-based sources of plasticity on the basis of changes in functional connectivity using resting-state fMRI before and after learning. The neuroimaging data revealed reinforcement-related changes in both motor and somatosensory brain areas in which a strengthening of connectivity was related to the amount of positive reinforcement during learning. Areas of prefrontal cortex were similarly altered in relation to reinforcement, with connectivity between sensorimotor areas of putamen and the reward-related ventromedial prefrontal cortex strengthened in relation to the amount of successful feedback received. In other analyses, we assessed connectivity related to changes in movement direction between trials, a type of variability that presumably reflects exploratory strategies during learning. We found that connectivity in a network linking motor and somatosensory cortices increased with trial-to-trial changes in direction. Connectivity varied as well with the change in movement direction following incorrect movements. Here the changes were observed in a somatic memory and decision making network involving ventrolateral prefrontal cortex and second somatosensory cortex. Our results point to the idea that the initial stages of motor learning are not wholly motor but rather involve plasticity in somatic and prefrontal networks related both to reward and exploration.In the initial stages of motor learning, the placement of the limbs is learned primarily through trial and error. In an experimental analog, participants make reaching movements to a hidden target and receive positive feedback when successful. We identified sources of plasticity based on changes in functional connectivity using resting-state fMRI. The main finding is that there is a strengthening of connectivity between reward-related prefrontal areas and sensorimotor areas in the basal ganglia and frontal cortex. There is also a strengthening of connectivity related to movement exploration in sensorimotor circuits involved in somatic memory and decision making. The results indicate that initial stages of motor learning depend on plasticity in somatic and prefrontal networks related to reward and exploration.	
27852471	Behaviourally spontaneous confabulation denotes a distinct syndrome consisting of confabulations that patients act upon, disorientation, and amnesia. It corresponds to the stable form of the original Korsakoff syndrome. While the syndrome may also occur in confusional states and degenerative dementia, this article is about the syndrome as it occurs after acute and focal brain damage. The patients act according to ideas and obligations that can mostly be traced back to real experiences in their past, but which are not currently valid guides of thinking and behaviour. This inability to abandon behavioural guides (anticipations) that are currently not valid corresponds to a failure of behavioural extinction and to the inability to abandon a previously rewarded choice in reversal learning when the expected reward (outcome) fails to occur, that is, following extinction trials. This article describes evidence from human and animal experiments showing that the posterior medial orbitofrontal cortex (OFC), which is typically damaged in these patients, and connected structures of the reward system contain the neural apparatus to signal the non-occurrence of anticipated outcomes, thereby presumably synchronizing thought and behaviour with current reality. Failure of this function, which we call orbitofrontal reality filtering, is associated with behaviourally spontaneous confabulation and disorientation after acute and focal brain damage, but not with other forms of confabulation, and not with reality confusion in degenerative dementia. Potential links with psychosis and decision making will be discussed.
27852020	Patients with the damage to the orbital region of the prefrontal cortex and monkeys with lesions in this area show impairment in emotional and motivational behavior. They also have difficulty in the extinction of learned behavior and in the reversal learning. This brain area is concerned with not only the value estimation of reward and aversive stimuli but also the expectation of these stimuli. The lateral prefrontal cortex plays an important role in the integration of emotion/motivation and cognition. The medial prefrontal cortex is concerned with action selection based on the previous reward history. The ventrolateral prefrontal cortex that comprises the anterior parts of the orbital and inferior medial prefrontal cortex plays an important role in emotion-based decision-making.
27852018	Motor areas in the frontal cortex are classified into medial and lateral functional groups. The dorsal premotor areas in the lateral groups are involved in motor guidance based on behavioral rules. The ventral premotor cortex contributes to motor guidance relying on spatial aspects of sensory information. The supplementary motor complex in the medial groups is related to the bimanual and temporal organization of multiple motor acts. The cingulate motor area is involved in motor control based on reward-prediction errors. The supplementary eye field is involved in monitoring performance and the adjustment of sequential visual search. The motor areas are coordinated in a context-dependent manner, influenced by top-down signals from the prefrontal cortex and by bottom-up signals from the parietal cortex, which are also organized into the lateral and medial functional groups. Evidence suggests that the medial and lateral functional groups are balanced by the insula cortex and anterior cingulate cortex which serve as salience detectors for changes in bodily states.
27852017	To behave appropriately in a complex and uncertain world, the brain makes use of several distinct learning systems. One such system is called the "model-free process", via which conditioning allows the association between a stimulus or response and a given reward to be learned. Another system is called the "model-based process". Via this process, the state transition between a stimulus and a response is learned so that the brain is able to plan actions prior to their execution. Several studies have tried to relate the difference between model-based and model-free processes to the difference in functions of the lateral prefrontal cortex (LPFC) and the striatum. Here, we describe a series of studies that demonstrate the ability of LPFC neurons to categorize visual stimuli by their associated behavioral responses and to generate abstract information. If LPFC neurons utilize abstract code to associate a stimulus with a reward, they should be able to infer similar relationships between other stimuli of the same category and their rewards without direct experience of these stimulus-reward contingencies. We propose that this ability of LPFC neurons to utilize abstract information can contribute to the model-based learning process.
27851807	Learning how to gain rewards (approach learning) and avoid punishments (avoidance learning) is fundamental for everyday life. While individual differences in approach and avoidance learning styles have been related to genetics and aging, the contribution of personality factors, such as traits, remains undetermined. Moreover, little is known about the computational mechanisms mediating differences in learning styles. Here, we used a probabilistic selection task with positive and negative feedbacks, in combination with computational modelling, to show that individuals displaying better approach (vs. avoidance) learning scored higher on measures of approach (vs. avoidance) trait motivation, but, paradoxically, also displayed reduced learning speed following positive (vs. negative) outcomes. These data suggest that learning different types of information depend on associated reward values and internal motivational drives, possibly determined by personality traits.
27849004	Monitoring our performance is fundamental to motor control while monitoring other's performance is fundamental to social coordination. The striatum is hypothesized to play a role in action selection, action initiation, and action parsing, but we know little of its role in performance monitoring. Furthermore, the striatum contains neurons that respond to own and other's actions. Therefore, we asked if striatal neurons signal own and conspecific's performance errors. Two macaque monkeys sitting across a touch-sensitive table in plain view of each other took turns performing a simple motor task to obtain juice rewards while we recorded single striatal neurons from one monkey at a time. Both monkeys made more errors after individually making an error but made fewer errors after a conspecific error. Thus, monkeys' behavior was influenced by their own and their conspecific's past behavior. A population of striatal neurons responded to own and conspecific's performance errors independently of a negative reward prediction error signal. Overall, these data suggest that monkeys are influenced by social errors and that striatal neurons signal performance errors. These signals might be important for social coordination, observational learning and adjusting to an ever-changing social landscape.
27848033	To document specific learning mechanisms in patients with Parkinson's disease (PD) with and without impulse control disorder (ICD). Thirty-two PD patients receiving dopamine replacement therapy (DRT) were investigated. Sixteen were diagnosed with ICD (ICD + ) and 16 PD patients matched for levodopa equivalence dosage, and DRT duration and severity of disease did not show impulsive behavior (non-ICD). Short-term learning of inhibitory control was assessed by an experimental procedure which was intended to mimic everyday life. Correct inhibition especially, had to be learned without reward (passive avoidance), and the failure to inhibit a response was punished (punishment learning). Results were compared to 16 healthy controls (HC) matched for age and sex. In ICD+ patients within-session learning of non-rewarded inhibition was at chance levels. Whereas healthy controls rapidly developed behavioral inhibition, non-ICD patients were also significantly impaired compared to HC, but gradually developed some degree of control. Both patient groups showed significantly decreased learning if the failure to withhold a response was punished. PD patients receiving DRT show impaired ability to acquire both punishment learning and passive avoidance learning, irrespective of whether or not ICD was developed. In ICD + PD patients, behavioral inhibition is nearly absent. Results demonstrate that by means of subtle learning paradigms it is possible to identify PD-DRT patients who show subtle alterations of punishment learning. This may be a behavioral measure for the identification of PD patients who are prone to develop ICD if DRT is continued.
27847490	Experiencing insight when solving problems can improve memory formation for both the problem and its solution. The underlying neural processes involved in this kind of learning are, however, thus far insufficiently understood. Here, we conceptualized insight as the sudden understanding of a novel relationship between known stimuli that fits into existing knowledge and is accompanied by a positive emotional response. Hence, insight is thought to comprise associative novelty, schema congruency, and intrinsic reward, all of which are separately known to enhance memory performance. We examined the neural correlates of learning from induced insight with functional magnetic resonance imaging (fMRI) using our own version of the compound-remote-associates-task (CRAT) in which each item consists of three clue words and a solution word. (Pseudo-)Solution words were presented after a brief period of problem-solving attempts to induce either sudden comprehension (CRA items) or continued incomprehension (control items) at a specific time point. By comparing processing of the solution words of CRA with control items, we found induced insight to elicit activation of the rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC) and left hippocampus. This pattern of results lends support to the role of schema congruency (rACC/mPFC) and associative novelty (hippocampus) in the processing of induced insight. We propose that (1) the mPFC not only responds to schema-congruent information, but also to the detection of novel schemata, and (2) that the hippocampus responds to a form of associative novelty that is not just a novel constellation of familiar items, but rather comprises a novel meaningful relationship between the items-which was the only difference between our insight and no insight conditions. To investigate episodic long-term memory encoding, we compared CRA items whose solution word was recognized 24 h after encoding to those with forgotten solutions. We found activation in the left striatum and parts of the left amygdala, pointing to a potential role of brain reward circuitry in the encoding of the solution words. We propose that learning from induced insight mainly relies on the amygdala evaluating the internal value (as an affective evaluation) of the suddenly comprehended information, and striatum-dependent reward-based learning.
27847474	Dopamine (DA) modulatory activity critically supports motivated behavior. This modulation operates at multiple timescales, but the functional roles of these distinct dynamics on cognition are still being characterized. Reward processing has been robustly linked to DA activity; thus, examining behavioral effects of reward anticipation at different timing intervals, corresponding to different putative dopaminergic dynamics, may help in characterizing the functional role of these dynamics. Towards this end, we present two research studies investigating reward motivation effects on cognitive control and episodic memory, converging in their manipulation of rapid vs. multi-second reward anticipation (consistent with timing profiles of phasic vs. ramping DA, respectively) on performance. Under prolonged reward anticipation, both control and memory performances were enhanced, specifically when combined with other experimental factors: task-informative cues (control task) and reward uncertainty (memory task). Given observations of ramping DA under uncertainty (Fiorillo et al., 2003) and arguments that uncertainty may act as a control signal increasing environmental monitoring (Mushtaq et al., 2011), we suggest that task information and reward uncertainty can both serve as "need for control" signals that facilitate learning via enhanced monitoring, and that this activity may be supported by a ramping profile of dopaminergic activity. Observations of rapid (i.e., phasic) reward on control and memory performance can be interpreted in line with prior evidence, but review indicates that contributions of different dopaminergic timescales in these processes are not well-understood. Future experimental work to clarify these dynamics and characterize a cross-domain role for reward motivation and DA in goal-directed behavior is suggested.
27847470	The eye's pupil undergoes dynamic changes in diameter associated with cognitive effort, motor activity and emotional state, and can be used to index brain state across mammalian species. Recent studies in head-fixed mice have linked arousal-related pupil dynamics with global neural activity as well as the activity of specific neuronal populations. However, it has remained unclear how pupil dynamics in mice report trial-by-trial performance of behavioral tasks, and change on a longer time scale with learning. We measured pupil dynamics longitudinally as mice learned to perform a Go/NoGo tactile decision-making task. Mice learned to discriminate between two textures presented to the whiskers by licking in response to the Go texture (Hit trial) or withholding licking in response to the NoGo texture (Correct Reject trial, CR). Characteristic pupil dynamics were associated with behavioral choices: large-amplitude pupil dilation prior to and during licking accompanied Hit and False Alarm (FA) responses, while smaller amplitude dilation followed by constriction accompanied CR responses. With learning, the choice-dependent pupil dynamics became more pronounced, including larger amplitude dilations in both Hit and FA trials and earlier onset dilations in Hit and CR trials. A more pronounced constriction was also present in CR trials. Furthermore, pupil dynamics predicted behavioral choice increasingly with learning to greater than 80% accuracy. Our results indicate that pupil dynamics reflect behavioral choice and learning in head-fixed mice, and have implications for understanding decision- and learning-related neuronal activity in pupil-linked neural circuits.
27845292	In the present study we evaluated effects of selective cholinergic or GABAergic lesions of the nucleus basalis magnocellularis (NBM) using immunotxins 192 IgG-saporin and GAT1-SAP on place and response learning in plus-shaped maze. In current behavioral paradigm rats learned food-rewarded mazes that were efficiently learned using either place or turning strategies. A histological evaluation indicated that 192 IgG-saporin lesions specifically depleted cholinergic neurons but did not result in noticeable damage to the GABAergic cells within NBM. GAT1-SAP lesions resulted extensive damage of GABAergic and a mild reduction of cholinergic NBM neurons. The results of present behavioral experiments showed, that selective lesions of cholinergic or GABAergic neurons in the NBM impair, but do not abolish, the animal's ability to learn location of rewarded arm of maze (place learning) or a skilled motor behavior (response learning). Our findings suggest the role of NBM cholinergic and GABAergic cortical projection neurons in processing of cognitive information. We suggested that lesions of NBM projections to the cortex modulate learning-mediated plasticity and impair both place and response learning.
27841363	Auditory attention theories suggest that humans are able to decompose the complex acoustic input into separate auditory streams, which then compete for attentional resources. How this attentional competition is influenced by motivational salience of sounds is, however, not well-understood. Here, we investigated whether a positive motivational value associated with sounds could bias the attentional selection in an auditory detection task. Participants went through a reward-learning period, where correct attentional selection of one stimulus (CS+) lead to higher rewards compared to another stimulus (CS-). We assessed the impact of reward-learning by comparing perceptual sensitivity before and after the learning period, when CS+ and CS- were presented as distractors for a different target. Performance decreased after reward-learning when CS+ was a distractor, while it increased when CS- was a distractor. Thus, the findings show that sounds that were associated with high rewards captures attention involuntarily. Additionally, when successful inhibition of a particular sound (CS-) was associated with high rewards then it became easier to ignore it. The current findings have important implications for the understanding of the organizing principles of auditory perception and provide, for the first time, clear behavioral evidence for reward-dependent attentional learning in the auditory domain in humans.
27836736	Cognitive biases, which are defined as distortions in cognitive processes that are influenced by a background emotional state, can provide information about an individual's affective state. For instance, negative cognitive biases, where individuals assess ambiguous situations as unrewarding, are commonly found in humans suffering from anxiety disorders. Cognitive biases are also increasingly used as indicators of affective state in animals. As it is not clear whether female and male animals differ in performance on cognitive bias tasks, we used a spatial location task to examine cognitive bias in female and male adult Norway rats (Rattus norvegicus). We trained the rats to distinguish between reward and unrewarded locations, and then provided food pots at ambiguous, intermediate positions. We found that, during testing, females were slowest to approach the unrewarded location, while they approached ambiguous and rewarded locations similarly quickly. In contrast, the males approached all locations quickly. This sex difference is consistent with previous evidence that male rats are quicker than females to extinguish previously learned associations. Cognitive bias tasks could therefore be used to examine sex differences in learning strategies, as well as providing opportunities to test predictions about sex differences in welfare requirements.
27836553	Ketamine is approved to start and maintain anaesthesia or analgesia. Ketamine is also known to be neurotoxic and an old drug of abuse. Numerous studies have proven a rapid and strong antidepressant response (AR) following parenteral sub-anaesthetic ketamine doses when applied the first time to patients with treatment resistant unipolar or bipolar major depression. This rapid and robust AR is encouraging, though short-lived (usually up to seven days). There is growing evidence that repeated und escalating ketamine administrations exert longer-lasting AR than single infusions. Yet, the clinical studies and follow-ups are still too short-lasting to get useful information about ketamine's liability to be addictive and neurotoxic after repeated or even prolonged administrations to severely depressed patients. In this vein, it could be worth to have a look at a couple of pharmacological features that ketamine shares with alcohol being presented here. In essence, there are striking similarities between ketamine and alcohol particularly in terms of modulating glutamatergic and dopaminergic signaling in cortico-limbic brain areas involved in learning, reward and mood regulation, thereby, probably mediating both, AR as well as the development of addiction. Moreover, moderate amounts of both drugs have comparable immunoinhibitory effects hypothesized to be involved in AR, too.
27833939	Anhedonia (a reduced experience of pleasure) and avolition (a reduction in goal-directed activity) are common features of schizophrenia that have substantial effects on functional outcome, but are poorly understood and treated. Here, we examined whether alterations in reinforcement learning may contribute to these symptoms in schizophrenia by impairing the translation of reward information into goal-directed action.38 stable outpatients with schizophrenia or schizoaffective disorder and 37 healthy controls underwent fMRI during a probabilistic stimulus selection reinforcement learning task with dissociated choice- and feedback-related activation, followed by a behavioral transfer task allowing separate assessment of learning from positive versus negative outcomes. A Q-learning algorithm was used to examine functional activation relating to prediction error at the time of feedback and to expected value at the time of choice.	Behavioral results suggested a reduction in learning from positive feedback in patients; however, this reduction was unrelated to anhedonia/avolition severity. On fMRI analysis, prediction error-related activation at the time of feedback was highly similar between patients and controls. During early learning, patients activated regions in the cognitive control network to a lesser extent than controls. Correlation analyses revealed reduced responses to positive feedback in dorsolateral prefrontal cortex and caudate among those patients higher in anhedonia/avolition.	Together, these results suggest that anhedonia/avolition are as strongly related to cortical learning or higher-level processes involved in goal-directed behavior such as effort computation and planning as to striatally mediated learning mechanisms.	
27833790	We examined whether striatal dopamine moderates the impact of externalizing proneness (disinhibition) on reward-based decision-making. Participants completed disinhibition and substance abuse subscales of the brief form Externalizing Spectrum Inventory, and then performed a delay discounting task to assess preference for immediate rewards along with a dynamic decision-making task that assessed long-term reward learning (i.e., inclination to choose larger delayed versus smaller immediate rewards). Striatal tonic dopamine levels were operationalized using spontaneous eyeblink rate. Regression analyses revealed that high disinhibition predicted greater delay discounting among participants with lower levels of striatal dopamine only, while substance abuse was associated with poorer long-term learning among individuals with lower levels of striatal dopamine, but better long-term learning in those with higher levels of striatal dopamine. These results suggest that disinhibition is more strongly associated with the wanting component of reward-based decision-making, whereas substance abuse behavior is associated more with learning of long-term action-reward contingencies.
27826998	Background and aims Gray's Reinforcement Sensitivity Theory has been widely applied to different clinical populations, but few studies have reported empirical evidence based on this theory for treatment outcomes in patients with gambling disorder (GD) and compulsive buying (CB). The aims of this study were to explore the association between clinical variables and personality traits with reward and punishment sensitivity (RPS) levels in women (n = 88) who met diagnostic criteria for GD (n = 61) and CB (n = 27), and to determine the predictive capacity of RPS for primary short-term outcomes in a cognitive-behavioral therapy (CBT) intervention. Methods The CBT intervention consisted of 12 weekly sessions. Data on patients' personality traits, RPS levels, psychopathology, sociodemographic factors, GD, and CB behavior were used in our analysis. Results High RPS levels were associated with higher psychopathology in both CB and GD, and were a risk factor for dropout in the CB group. In the GD group, higher reward sensitivity scores increased the risk of dropout. Discussion and conclusions Our findings suggest that both sensitivity to reward and sensitivity to punishment independently condition patients' response to treatment for behavioral addictions. The authors uphold that CBT interventions for such addictions could potentially be enhanced by taking RPS into consideration.
27824221	School-based sexual and reproductive health programmes are widely accepted as an approach to reducing high-risk sexual behaviour among adolescents. Many studies and systematic reviews have concentrated on measuring effects on knowledge or self-reported behaviour rather than biological outcomes, such as pregnancy or prevalence of sexually transmitted infections (STIs).To evaluate the effects of school-based sexual and reproductive health programmes on sexually transmitted infections (such as HIV, herpes simplex virus, and syphilis), and pregnancy among adolescents.	We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) for published peer-reviewed journal articles; and ClinicalTrials.gov and the World Health Organization's (WHO) International Clinical Trials Registry Platform for prospective trials; AIDS Educaton and Global Information System (AEGIS) and National Library of Medicine (NLM) gateway for conference presentations; and the Centers for Disease Control and Prevention (CDC), UNAIDS, the WHO and the National Health Service (NHS) centre for Reviews and Dissemination (CRD) websites from 1990 to 7 April 2016. We handsearched the reference lists of all relevant papers.	We included randomized controlled trials (RCTs), both individually randomized and cluster-randomized, that evaluated school-based programmes aimed at improving the sexual and reproductive health of adolescents.	Two review authors independently assessed trials for inclusion, evaluated risk of bias, and extracted data. When appropriate, we obtained summary measures of treatment effect through a random-effects meta-analysis and we reported them using risk ratios (RR) with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach.	We included eight cluster-RCTs that enrolled 55,157 participants. Five trials were conducted in sub-Saharan Africa (Malawi, South Africa, Tanzania, Zimbabwe, and Kenya), one in Latin America (Chile), and two in Europe (England and Scotland). Sexual and reproductive health educational programmesSix trials evaluated school-based educational interventions.In these trials, the educational programmes evaluated had no demonstrable effect on the prevalence of HIV (RR 1.03, 95% CI 0.80 to 1.32, three trials; 14,163 participants; low certainty evidence), or other STIs (herpes simplex virus prevalence: RR 1.04, 95% CI 0.94 to 1.15; three trials, 17,445 participants; moderate certainty evidence; syphilis prevalence: RR 0.81, 95% CI 0.47 to 1.39; one trial, 6977 participants; low certainty evidence). There was also no apparent effect on the number of young women who were pregnant at the end of the trial (RR 0.99, 95% CI 0.84 to 1.16; three trials, 8280 participants; moderate certainty evidence). Material or monetary incentive-based programmes to promote school attendanceTwo trials evaluated incentive-based programmes to promote school attendance.In these two trials, the incentives used had no demonstrable effect on HIV prevalence (RR 1.23, 95% CI 0.51 to 2.96; two trials, 3805 participants; low certainty evidence). Compared to controls, the prevalence of herpes simplex virus infection was lower in young women receiving a monthly cash incentive to stay in school (RR 0.30, 95% CI 0.11 to 0.85), but not in young people given free school uniforms (Data not pooled, two trials, 7229 participants; very low certainty evidence). One trial evaluated the effects on syphilis and the prevalence was too low to detect or exclude effects confidently (RR 0.41, 95% CI 0.05 to 3.27; one trial, 1291 participants; very low certainty evidence). However, the number of young women who were pregnant at the end of the trial was lower among those who received incentives (RR 0.76, 95% CI 0.58 to 0.99; two trials, 4200 participants; low certainty evidence). Combined educational and incentive-based programmesThe single trial that evaluated free school uniforms also included a trial arm in which participants received both uniforms and a programme of sexual and reproductive education. In this trial arm herpes simplex virus infection was reduced (RR 0.82, 95% CI 0.68 to 0.99; one trial, 5899 participants; low certainty evidence), predominantly in young women, but no effect was detected for HIV or pregnancy (low certainty evidence).	There is a continued need to provide health services to adolescents that include contraceptive choices and condoms and that involve them in the design of services. Schools may be a good place in which to provide these services. There is little evidence that educational curriculum-based programmes alone are effective in improving sexual and reproductive health outcomes for adolescents. Incentive-based interventions that focus on keeping young people in secondary school may reduce adolescent pregnancy but further trials are needed to confirm this.	
27822182	Dopamine systems mediate key aspects of reward learning. Parkinson's disease (PD) represents a valuable model to study reward mechanisms because both the disease process and the anti-Parkinson medications influence dopamine neurotransmission. The aim of this pilot study was to investigate whether the level of levodopa differently modulates learning from positive and negative feedback and its electrophysiological correlate, the error related negativity (ERN), in PD. Ten PD patients and ten healthy participants performed a two-stage reinforcement learning task. In the Learning Phase, they had to learn the correct stimulus within a stimulus pair on the basis of a probabilistic positive or negative feedback. Three sets of stimulus pairs were used. In the Testing Phase, the participants were tested with novel combinations of the stimuli previously experienced to evaluate whether they learned more from positive or negative feedback. PD patients performed the task both ON- and OFF-levodopa in two separate sessions while they remained on stable therapy with dopamine agonists. The electroencephalogram (EEG) was recorded during the task. PD patients were less accurate in negative than positive learning both OFF- and ON-levodopa. In the OFF-levodopa state they were less accurate than controls in negative learning. PD patients had a smaller ERN amplitude OFF- than ON-levodopa only in negative learning. In the OFF-levodopa state they had a smaller ERN amplitude than controls in negative learning. We hypothesize that high tonic dopaminergic stimulation due to the dopamine agonist medication, combined to the low level of phasic dopamine due to the OFF-levodopa state, could prevent phasic "dopamine dips" indicated by the ERN needed for learning from negative feedback.

27793769	Social behavior is regulated by conserved neural networks across vertebrates. Variation in the organization of neuropeptide systems across these networks is thought to contribute to individual and species diversity in network function during social contexts. For example, oxytocin (OT) is an ancient neuropeptide that binds to OT receptors (OTRs) in the brain and modulates social and reproductive behavior across vertebrate species, including humans. Central OTRs exhibit extraordinarily diverse expression patterns that are associated with individual and species differences in social behavior. In voles, OTR density in the nucleus accumbens (NAc)-a region important for social and reward learning-is associated with individual and species variation in social attachment behavior. Here we test whether OTRs in the NAc modulate a social salience network (SSN)-a network of interconnected brain nuclei thought to encode valence and incentive salience of sociosensory cues-during a social context in the socially monogamous male prairie vole. Using a selective OTR antagonist, we test whether activation of OTRs in the NAc during sociosexual interaction and mating modulates expression of the immediate early gene product Fos across nuclei of the SSN. We show that blockade of endogenous OTR signaling in the NAc during sociosexual interaction and mating does not strongly modulate levels of Fos expression in individual nodes of the network, but strongly modulates patterns of correlated Fos expression between the NAc and other SSN nuclei.
27732870	Bipolar disorder (BD) mania patients exhibit poor cognition and reward-seeking/hypermotivation, negatively impacting a patient's quality of life. Current treatments (e.g., lithium), do not treat such deficits. Treatment development has been limited due to a poor understanding of the neural mechanisms underlying these behaviors. Here, we investigated putative mechanisms underlying cognition and reward-seeking/motivational changes relevant to BD mania patients using two validated mouse models and neurochemical analyses.The effects of reducing dopamine transporter (DAT) functioning via genetic (knockdown vs. wild-type littermates), or pharmacological (GBR12909- vs. vehicle-treated C57BL/6J mice) means were assessed in the probabilistic reversal learning task (PRLT), and progressive ratio breakpoint (PRB) test, during either water or chronic lithium treatment. These tasks quantify reward learning and effortful motivation, respectively. Neurochemistry was performed on brain samples of DAT mutants ± chronic lithium using high performance liquid chromatography.	Reduced DAT functioning increased reversals in the PRLT, an effect partially attenuated by chronic lithium. Chronic lithium alone slowed PRLT acquisition. Reduced DAT functioning increased motivation (PRB), an effect attenuated by lithium in GBR12909-treated mice. Neurochemical analyses revealed that DAT knockdown mice exhibited elevated homovanillic acid levels, but that lithium had no effect on these elevated levels.	Reducing DAT functioning recreates many aspects of BD mania including hypermotivation and improved reversal learning (switching), as well as elevated homovanillic acid levels. Chronic lithium only exerted main effects, impairing learning and elevating norepinephrine and serotonin levels of mice, not specifically treating the underlying mechanisms identified in these models.	
27663194	Previous research has indicated a role for the dorsolateral striatum (DLS) in acquisition and retrieval of habit memory. However, the neurobiological mechanisms guiding extinction of habit memory have not been extensively investigated. The present study examined whether the dorsolateral striatum (DLS) is involved in extinction of habit memory in a food-rewarded response learning version of the plus-maze in adult male Long-Evans rats (experiment 1). In addition, to determine whether the role of this brain region in extinction is selective to habit memory, we also examined whether the DLS is required for extinction of hippocampus-dependent spatial memory in a place learning version of the plus-maze (experiment 2). Following acquisition in either task, rats received two days of extinction training, in which the food reward was removed from the maze. The number of perseverative trials (a trial in which the rat made the same previously reinforced body-turn) and latency to reach the previously correct food well were used as measures of extinction. Animals were given immediate post-training intra-DLS administration of the sodium channel blocker bupivacaine or vehicle to determine the effect of DLS inactivation on consolidation of extinction memory in each task. In the response learning task, post-training DLS inactivation impaired consolidation of extinction memory. Injections of bupivacaine delayed 2 h post-training did not affect extinction, indicating a time-dependent effect of neural inactivation on consolidation of extinction memory in this task. In contrast, post-training DLS inactivation did not impair, but instead slightly enhanced, extinction memory in the place learning task. The present findings indicate a critical role for the DLS in extinction of habit memory in the response learning task, and may be relevant to understanding the neural mechanisms through which maladaptive habits in human psychopathologies (e.g. drug addiction) may be suppressed.

27806864	To assess the functioning of mesolimbic and fronto-striatal areas involved in reward-based spatial learning in teenaged girls with bulimia nervosa (BN) that might be involved in the development and maintenance of maladaptive behaviors characteristic of the disorder.We compared functional magnetic resonance imaging blood oxygen level-dependent response in 27 adolescent girls with BN to that of 27 healthy, age-matched control participants during a reward-based learning task that required learning to use extra-maze cues to navigate a virtual 8-arm radial maze to find hidden rewards. We compared groups in their patterns of brain activation associated with reward-based spatial learning versus a control condition in which rewards were unexpected because they were allotted pseudo-randomly to experimentally prevent learning.	Both groups learned to navigate the maze to find hidden rewards, but group differences in brain activity associated with maze navigation and reward processing were detected in the fronto-striatal regions and right anterior hippocampus. Unlike healthy adolescents, those with BN did not engage the right inferior frontal gyrus during maze navigation, activated the right anterior hippocampus during the receipt of unexpected rewards (control condition), and deactivated the left superior frontal gyrus and right anterior hippocampus during expected reward receipt (learning condition). These patterns of hippocampal activation in the control condition were significantly associated with the frequency of binge-eating episodes.	
27803652	Devaluation is the key experimental paradigm used to demonstrate the presence of instrumental behaviors guided by goals in mammals. We propose a neural system-level computational model to address the question of which brain mechanisms allow the current value of rewards to control instrumental actions. The model pivots on and shows the computational soundness of the hypothesis for which the internal representation of instrumental manipulanda (e.g., levers) activate the representation of rewards (or "action-outcomes", e.g., foods) while attributing to them a value which depends on the current internal state of the animal (e.g., satiation for some but not all foods). The model also proposes an initial hypothesis of the integrated system of key brain components supporting this process and allowing the recalled outcomes to bias action selection: (a) the sub-system formed by the basolateral amygdala and insular cortex acquiring the manipulanda-outcomes associations and attributing the current value to the outcomes; (b) three basal ganglia-cortical loops selecting respectively goals, associative sensory representations, and actions; (c) the cortico-cortical and striato-nigro-striatal neural pathways supporting the selection, and selection learning, of actions based on habits and goals. The model reproduces and explains the results of several devaluation experiments carried out with control rats and rats with pre- and post-training lesions of the basolateral amygdala, the nucleus accumbens core, the prelimbic cortex, and the dorso-medial striatum. The results support the soundness of the hypotheses of the model and show its capacity to integrate, at the system-level, the operations of the key brain structures underlying devaluation. Based on its hypotheses and predictions, the model also represents an operational framework to support the design and analysis of new experiments on the motivational aspects of goal-directed behavior.
27803289	Appetitive extinction receives attention as an important model for the treatment of psychiatric disorders. However, in humans, its underlying neural correlates remain unknown. To close this gap, we investigated appetitive acquisition and extinction with fMRI in a 2-day monetary incentive delay paradigm. During appetitive conditioning, one stimulus (CS+) was paired with monetary reward, while another stimulus (CS-) was never rewarded. Twenty-four hours later, subjects underwent extinction, in which neither CS was reinforced. Appetitive conditioning elicited stronger skin conductance responses to the CS+ as compared with the CS-. Regarding subjective ratings, the CS+ was rated more pleasant and arousing than the CS- after conditioning. Furthermore, fMRI-results (CS+ - CS-) showed activation of the reward circuitry including amygdala, midbrain and striatal areas. During extinction, conditioned responses were successfully extinguished. In the early phase of extinction, we found a significant activation of the caudate, the hippocampus, the dorsal and ventral anterior cingulate cortex (dACC and vACC). In the late phase, we found significant activation of the nucleus accumbens (NAcc) and the amygdala. Correlational analyses with subjective ratings linked extinction success to the vACC and the NAcc, while associating the dACC with reduced extinction. The results reveal neural correlates of appetitive extinction in humans and extend assumptions from models for human extinction learning.
27799080	The effect of orgasm on the development and shaping of partner preferences may involve a catalysis of the neurochemical mechanisms of bonding. Therefore, understanding such process is relevant for neuroscience and psychology.A systematic review was carried out using the terms Orgasm, Sexual Reward, Partner Preference, Pair Bonding, Brain, Learning, Sex, Copulation.	In humans, concentrations of arousing neurotransmitters and potential bonding neurotransmitters increase during orgasm in the cerebrospinal fluid and the bloodstream. Similarly, studies in animals indicate that those neurotransmitters (noradrenaline, oxytocin, prolactin) and others (e.g. dopamine, opioids, serotonin) modulate the appetitive and consummatory phases of sexual behavior and reward. This suggests a link between the experience of orgasm/sexual reward and the neurochemical mechanisms of pair bonding. Orgasm/reward functions as an unconditioned stimulus (UCS). Some areas in the nervous system function as UCS-detection centers, which become activated during orgasm. Partner-related cues function as conditioned stimuli (CS) and are processed in CS-detector centers.	Throughout the article, we discuss how UCS- and CS-detection centers must interact to facilitate memory consolidation and produce recognition and motivation during future social encounters.	
27603752	There is growing interest in the use of oxytocin (OT) as a potential treatment for alcohol and other substance-use disorders. OT is a neuropeptide that modulates adaptive processes associated with addiction including reward, tolerance, associative learning, memory, and stress responses. OT exerts its effects through interactions with the hypothalamic-pituitary-adrenal axis and multiple neurotransmitter systems including the dopamine mesolimbic reward and corticotrophin-releasing factor stress systems. The effects of OT on stress systems are of high interest, given the strong link between stress, drug use and relapse, and known dysregulation of hypothalamic-pituitary-adrenal-axis activity associated with substance-use disorders. At the same time, the OT system is itself altered by acute or chronic drug exposure. This review summarizes the preclinical and clinical literature on the OT system and its relevance to drug and alcohol addiction. In addition, findings from recent clinical trials conducted in participants with cocaine, cannabis, or alcohol use disorder are included and evidence that OT may help to normalize blunted stress responses, and attenuate withdrawal-associated hypercortisolism, negative mood, and withdrawal symptoms is summarized.
27797550	The combination of reward and potential threat is termed approach/avoidance conflict and elicits specific behaviors, including passive avoidance and behavioral inhibition (BI). Anxiety-relieving drugs reduce these behaviors, and a rich psychological literature has addressed how personality traits dominated by BI predispose for anxiety disorders. Yet, a formal understanding of the cognitive inference and planning processes underlying anxiety-like BI is lacking. Here, we present and empirically test such formalization in the terminology of reinforcement learning. We capitalize on a human computer game in which participants collect sequentially appearing monetary tokens while under threat of virtual "predation." First, we demonstrate that humans modulate BI according to experienced consequences. This suggests an instrumental implementation of BI generation rather than a Pavlovian mechanism that is agnostic about action outcomes. Second, an internal model that would make BI adaptive is expressed in an independent task that involves no threat. The existence of such internal model is a necessary condition to conclude that BI is under model-based control. These findings relate a plethora of human and nonhuman observations on BI to reinforcement learning theory, and crucially constrain the quest for its neural implementation. (PsycINFO Database Record
27677944	Through associative reward learning, arbitrary cues acquire the ability to automatically capture visual attention. Previous studies have examined the neural correlates of value-driven attentional orienting, revealing elevated activity within a network of brain regions encompassing the visual corticostriatal loop [caudate tail, lateral occipital complex (LOC) and early visual cortex] and intraparietal sulcus (IPS). Such attentional priority signals raise a broader question concerning how visual signals are combined with reward signals during learning to create a representation that is sensitive to the confluence of the two. This study examines reward signals during the cued reward training phase commonly used to generate value-driven attentional biases. High, compared with low, reward feedback preferentially activated the value-driven attention network, in addition to regions typically implicated in reward processing. Further examination of these reward signals within the visual system revealed information about the identity of the preceding cue in the caudate tail and LOC, and information about the location of the preceding cue in IPS, while early visual cortex represented both location and identity. The results reveal teaching signals within the value-driven attention network during associative reward learning, and further suggest functional specialization within different regions of this network during the acquisition of an integrated representation of stimulus value.
27652894	The basal ganglia, a group of subcortical nuclei, play a crucial role in decision-making by selecting actions and evaluating their outcomes. While much is known about the function of the basal ganglia circuitry in selection, how these nuclei contribute to outcome evaluation is less clear. Here we show that neurons in the habenula-projecting globus pallidus (GPh) in mice are essential for evaluating action outcomes and are regulated by a specific set of inputs from the basal ganglia. We find in a classical conditioning task that individual mouse GPh neurons bidirectionally encode whether an outcome is better or worse than expected. Mimicking these evaluation signals with optogenetic inhibition or excitation is sufficient to reinforce or discourage actions in a decision-making task. Moreover, cell-type-specific synaptic manipulations reveal that the inhibitory and excitatory inputs to the GPh are necessary for mice to appropriately evaluate positive and negative feedback, respectively. Finally, using rabies-virus-assisted monosynaptic tracing, we show that the GPh is embedded in a basal ganglia circuit wherein it receives inhibitory input from both striosomal and matrix compartments of the striatum, and excitatory input from the 'limbic' regions of the subthalamic nucleus. Our results provide evidence that information about the selection and evaluation of actions is channelled through distinct sets of basal ganglia circuits, with the GPh representing a key locus in which information of opposing valence is integrated to determine whether action outcomes are better or worse than expected.
27614768	The onset of adolescence is associated with an increased tendency to engage in risky behaviors and a developmental shift toward peers that contributes to increased prioritization for learning about and achieving social status. There is relatively little understanding about the specific links between these adolescent-typical phenomena, particularly regarding their neural underpinnings. Based on existing models that suggest the role of puberty in promoting adolescent status-seeking and risk-taking tendencies, we investigated the relation of pubertal hormones with behavioral and neural responses to status-relevant social information in the context of risk taking. We used a probabilistic decision task in which 11- to 13-year-old girls chose to take a risk, or not, while receiving either social rank or monetary performance feedback. While feedback type did not differentially influence risk-taking behavior, whole-brain imaging results showed that activation in the anterior insula was increased for risk taking in the social rank feedback condition compared to the monetary feedback condition. This heightened activation was more pronounced in girls with higher estradiol levels. These findings suggest that brain processes involved in adolescent risky decisions may be influenced by the desire for social-status enhancement and provide preliminary evidence for the role of pubertal hormones in enhancing this adolescent-typical social sensitivity.
27793098	Reinforcement learning is a fundamental form of learning that may be formalized using the Bellman equation. Accordingly an agent determines the state value as the sum of immediate reward and of the discounted value of future states. Thus the value of state is determined by agent related attributes (action set, policy, discount factor) and the agent's knowledge of the environment embodied by the reward function and hidden environmental factors given by the transition probability. The central objective of reinforcement learning is to solve these two functions outside the agent's control either using, or not using a model.In the present paper, using the proactive model of reinforcement learning we offer insight on how the brain creates simplified representations of the environment, and how these representations are organized to support the identification of relevant stimuli and action. Furthermore, we identify neurobiological correlates of our model by suggesting that the reward and policy functions, attributes of the Bellman equitation, are built by the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC), respectively.	Based on this we propose that the OFC assesses cue-context congruence to activate the most context frame. Furthermore given the bidirectional neuroanatomical link between the OFC and model-free structures, we suggest that model-based input is incorporated into the reward prediction error (RPE) signal, and conversely RPE signal may be used to update the reward-related information of context frames and the policy underlying action selection in the OFC and ACC, respectively. Furthermore clinical implications for cognitive behavioral interventions are discussed.	
27792731	Although animals rarely use only one sense to communicate, few studies have investigated the use of combinations of different signals between animals and humans. This study assessed for the first time the spontaneous reactions of piglets to human pointing gestures and voice in an object-choice task with a reward. Piglets (Sus scrofa domestica) mainly use auditory signals-individually or in combination with other signals-to communicate with their conspecifics. Their wide hearing range (42 Hz to 40.5 kHz) fits the range of human vocalisations (40 Hz to 1.5 kHz), which may induce sensitivity to the human voice. However, only their ability to use visual signals from humans, especially pointing gestures, has been assessed to date. The current study investigated the effects of signal type (visual, auditory and combined visual and auditory) and piglet experience on the piglets' ability to locate a hidden food reward over successive tests. Piglets did not find the hidden reward at first presentation, regardless of the signal type given. However, they subsequently learned to use a combination of auditory and visual signals (human voice and static or dynamic pointing gestures) to successfully locate the reward in later tests. This learning process may result either from repeated presentations of the combination of static gestures and auditory signals over successive tests, or from transitioning from static to dynamic pointing gestures, again over successive tests. Furthermore, piglets increased their chance of locating the reward either if they did not go straight to a bowl after entering the test area or if they stared at the experimenter before visiting it. Piglets were not able to use the voice direction alone, indicating that a combination of signals (pointing and voice direction) is necessary. Improving our communication with animals requires adapting to their individual sensitivity to human-given signals.
27791160	Dopamine (DA) promotes wakefulness, and DA transporter inhibitors such as dextroamphetamine and methylphenidate are effective for increasing arousal and inducing reanimation, or active emergence from general anesthesia. DA neurons in the ventral tegmental area (VTA) are involved in reward processing, motivation, emotion, reinforcement, and cognition, but their role in regulating wakefulness is less clear. The current study was performed to test the hypothesis that selective optogenetic activation of VTA DA neurons is sufficient to induce arousal from an unconscious, anesthetized state. Floxed-inverse (FLEX)-Channelrhodopsin2 (ChR2) expression was targeted to VTA DA neurons in DA transporter (DAT)-cre mice (ChR2+ group; n = 6). Optical VTA stimulation in ChR2+ mice during continuous, steady-state general anesthesia (CSSGA) with isoflurane produced behavioral and EEG evidence of arousal and restored the righting reflex in 6/6 mice. Pretreatment with the D1 receptor antagonist SCH-23390 before optical VTA stimulation inhibited the arousal responses and restoration of righting in 6/6 ChR2+ mice. In control DAT-cre mice, the VTA was targeted with a viral vector lacking the ChR2 gene (ChR2- group; n = 5). VTA optical stimulation in ChR2- mice did not restore righting or produce EEG changes during isoflurane CSSGA in 5/5 mice. These results provide compelling evidence that selective stimulation of VTA DA neurons is sufficient to induce the transition from an anesthetized, unconscious state to an awake state, suggesting critical involvement in behavioral arousal.
27790098	Adolescence poses as both a transitional period in neurodevelopment and lifestyle practices. In particular, the developmental trajectory of the prefrontal cortex (PFC), a critical region for behavioral control and self-regulation, is enduring, not reaching functional maturity until the early 20 s in humans. Furthermore, the neurotransmitter dopamine is particularly abundant during adolescence, tuning the brain to rapidly learn about rewards and regulating aspects of neuroplasticity. Thus, adolescence is proposed to represent a period of vulnerability towards reward-driven behaviors such as the consumption of palatable high fat and high sugar diets. This is reflected in the increasing prevalence of obesity in children and adolescents as they are the greatest consumers of "junk foods". Excessive consumption of diets laden in saturated fat and refined sugars not only leads to weight gain and the development of obesity, but experimental studies with rodents indicate they evoke cognitive deficits in learning and memory process by disrupting neuroplasticity and altering reward processing neurocircuitry. Consumption of these high fat and high sugar diets have been reported to have a particularly pronounced impact on cognition when consumed during adolescence, demonstrating a susceptibility of the adolescent brain to enduring cognitive deficits. The adolescent brain, with heightened reward sensitivity and diminished behavioral control compared to the mature adult brain, appears to be a risk for aberrant eating behaviors that may underpin the development of obesity. This review explores the neurodevelopmental changes in the PFC and mesocortical dopamine signaling that occur during adolescence, and how these potentially underpin the overconsumption of palatable food and development of obesogenic diet-induced cognitive deficits.
27650534	National early childhood obesity prevention policies recommend that child-care providers avoid controlling feeding practices (CFP) (eg, pressure-to-eat, food as reward, and praising children for cleaning their plates) with children to prevent unhealthy child eating behaviors and childhood obesity. However, evidence suggests that providers frequently use CFP during mealtimes.Using the Academy of Nutrition and Dietetics (2011) benchmarks for nutrition in child care as a framework, researchers assessed child-care providers' perspectives regarding their use of mealtime CFP with young children (aged 2 to 5 years).	Using a qualitative design, individual, face-to-face, semi-structured interviews were conducted with providers until saturation was reached.	Providers were selected using maximum variation purposive sampling from varying child-care contexts (Head Start, Child and Adult Care Food Program [CACFP]-funded centers, non-CACFP programs). All providers were employed full-time in Head Start or state-licensed center-based child-care programs, cared for children (aged 2 to 5 years), and were directly responsible for serving meals and snacks.	Child-care providers' perspectives regarding CFP.	Thematic analysis using NVivo (version 9, 2010, QSR International Pty Ltd) to derive themes.	Providers' perspectives showed barriers, motivators, and facilitators regarding their use of mealtime CFP. Providers reported barriers to avoiding CFP such as CFP were effective for encouraging desired behaviors, misconceptions that providers were encouraging but not controlling children's eating, and fear of parents' negative reaction if their child did not eat. Providers who did not practice CFP were motivated to avoid CFP because they were unnecessary for encouraging children to eat, and they resulted in negative child outcomes and obesity. Facilitators as an alternative to CFP included practicing healthful feeding practices such as role modeling, peer modeling, and sensory exploration of foods.	Training providers about negative child outcomes associated with CFP, children's ability to self-regulate energy intake, and differentiating between controlling and healthful feeding strategies may help providers to avoid CFP.	
27568835	Previous studies have demonstrated that the histamine H3 receptor inverse agonist thioperamide potentiates the stimulant and rewarding effects of cocaine. However, these potentiating effects of thioperamide do not necessarily result from H3 receptor blockade since thioperamide is an imidazole-based compound capable of enhancing plasma cocaine concentrations by blocking cytochrome P450 activity. In contrast, Pitolisant is a non-imidazole H3 receptor inverse agonist that has already been tested in clinical trials but it remains to be determined whether this compound also potentiates the behavioral effects of cocaine. The present study tested the effects of Pitolisant on locomotion, on cocaine-induced hyperactivity and on the development of conditioned place preference induced by cocaine (2 and 8mg/kg, i.p.) in male C57BL/6J mice. Pitolisant was injected 30min before each cocaine-pairing session. Locomotion recorded on the first cocaine-pairing session was used to test the effects of Pitolisant on the locomotor effects of cocaine. Our results show that doses of Pitolisant higher than 10mg/kg depressed locomotion. When injected alone at doses that did not affect locomotion, Pitolisant (2.5-10mg/kg, i.p.) had no rewarding properties in the place conditioning technique. Additionally, Pitolisant did not significantly alter cocaine-induced hyperactivity and cocaine-induced conditioned place preference. Taken together, our study indicates that Pitolisant has no addictive properties alone. Moreover, this compound does not significantly affect the stimulant and rewarding effects of cocaine. These results add further evidence to support the hypothesis that a pharmacokinetic interaction is involved in the ability of thioperamide to potentiate cocaine's psychomotor effects.
27565516	The aetiology of eating disorders (EDs) is unclear, but many hypotheses implicate alterations in behavioural control. Specifically and because of its relevance to symptomatology, there has been much interest in inhibitory control, i.e., the ability to inhibit inappropriate/unwanted behaviours. This has been studied in relation to reactive motor inhibition (withholding a response in reaction to a signal), reward-based inhibition (e.g., temporal discounting paradigms) and to reversal learning (e.g., set shifting tasks assessing cognitive flexibility and compulsivity). However, there has been less explicit exploration of proactive inhibitory control, i.e., a preparatory form of inhibitory control where responses are pre-emptively suppressed to improve performance either in terms of a dynamic strategy (e.g., post-error slowing) or as a more general suppression in the context of uncertainty (e.g., when the appropriateness of a response is less certain). This review considers proactive inhibition within the context of broader conceptual considerations of inhibitory control in EDs, discusses the existing behavioural and neural evidence, and concludes that this is a construct worthy of further exploration.
27535821	Behaviour change has become a hot topic. We describe a new approach, Behaviour Centred Design (BCD), which encompasses a theory of change, a suite of behavioural determinants and a programme design process. The theory of change is generic, assuming that successful interventions must create a cascade of effects via environments, through brains, to behaviour and hence to the desired impact, such as improved health. Changes in behaviour are viewed as the consequence of a reinforcement learning process involving the targeting of evolved motives and changes to behaviour settings, and are produced by three types of behavioural control mechanism (automatic, motivated and executive). The implications are that interventions must create surprise, revalue behaviour and disrupt performance in target behaviour settings. We then describe a sequence of five steps required to design an intervention to change specific behaviours: Assess, Build, Create, Deliver and Evaluate. The BCD approach has been shown to change hygiene, nutrition and exercise-related behaviours and has the advantages of being applicable to product, service or institutional design, as well as being able to incorporate future developments in behaviour science. We therefore argue that BCD can become the foundation for an applied science of behaviour change.
27330183	Much of human learning happens in the social world. A person's social identity-the groups to which they belong, the people with whom they identify-is a powerful cue that can affect our goal-directed behaviors, often implicitly. In the present experiment, we explored the underlying neural mechanisms driving these processes, testing hypotheses derived from social identity theory. In a within-subjects design, participants underwent a minimal group manipulation where they were randomly assigned to an arbitrary ingroup. In two blocks of the experiment, participants were asked to complete a task for money while being observed by an ingroup member and outgroup member separately. Results revealed that being observed by an ingroup or outgroup member led to divergent patterns of neural activity associated with feedback monitoring, namely the feedback-related negativity (FRN). Receiving feedback in the presence of an ingroup member produced a typical FRN signal, but the FRN was dampened while receiving feedback in the presence of an outgroup member. Further, this differentiated neural pattern was exaggerated in people who reported greater intergroup bias. Together, the mere presence of a person can alter how the brain adaptively monitors feedback, impairing the reinforcement learning signal when the person observing is an outgroup member.
26893259	To use functional magnetic resonance imaging (fMRI) to investigate the neural circuitry behind effort-related valuation and motivation in a population of alcohol-dependent participants and healthy controls.Seventeen alcohol-dependent participants and a comparison group of 17 healthy control participants completed an effort-based motivation paradigm during an fMRI scan, in which they were required to exert effort at varying levels in order to earn a monetary reward.	We found that alcohol-dependent participants were less motivated during trials requiring high levels of effort. The whole-brain fMRI analysis revealed that alcohol-dependent participants displayed an increased blood-oxygen-level dependent (BOLD) signal during low and unknown effort cues in the dorsal and ventral striatum compared with healthy controls.	These findings provide the first evidence that alcohol-dependent participants and healthy controls differ in their effort-based valuation and motivation processing. Alcohol-dependent participants displayed a hyperactive mesolimbic reward circuitry recruited by non-drug rewards, potentially reflecting a sensitization to reward in this patient population.	
27787196	Economic theories posit reward probability as one of the factors defining reward value. Individuals learn the value of cues that predict probabilistic rewards from experienced reward frequencies. Building on the notion that responses of dopamine neurons increase with reward probability and expected value, we asked how dopamine neurons in monkeys acquire this value signal that may represent an economic decision variable. We found in a Pavlovian learning task that reward probability-dependent value signals arose from experienced reward frequencies. We then assessed neuronal response acquisition during choices among probabilistic rewards. Here, dopamine responses became sensitive to the value of both chosen and unchosen options. Both experiments showed also the novelty responses of dopamine neurones that decreased as learning advanced. These results show that dopamine neurons acquire predictive value signals from the frequency of experienced rewards. This flexible and fast signal reflects a specific decision variable and could update neuronal decision mechanisms.
27786302	Reward and punishment motivate behavior, but it is unclear exactly how they impact skill performance and whether the effect varies across skills. The present study investigated the effect of reward and punishment in both a sequencing skill and a motor skill context. Participants trained on either a sequencing skill (serial reaction time task) or a motor skill (force-tracking task). Skill knowledge was tested immediately after training, and again 1 hour, 24-48 hours, and 30 days after training. We found a dissociation of the effects of reward and punishment on the tasks, primarily reflecting the impact of punishment. While punishment improved serial reaction time task performance, it impaired force-tracking task performance. In contrast to prior literature, neither reward nor punishment benefitted memory retention, arguing against the common assumption that reward ubiquitously benefits skill retention. Collectively, these results suggest that punishment impacts skilled behavior more than reward in a complex, task dependent fashion.
27785126	Intertemporal choice involves the processes of valuation and choice. Choice is often the result of subjective valuation, in which reward is integrated with time delay. Here, using event-related potential (ERP) signals as temporal hallmarks, we aim to investigate temporal dynamics of how reward interacts with time delay during a delayed discounting task. We found that participants preferred immediate rewards when delayed rewards were small or over long-term delays. Our ERP results suggested that the P200 component reflected an initial valuation of reward and time delay, while the frontal N2 component correlated with individual choices of immediate option of rewards. The LPP component was modulated by the N2 component. These findings demonstrate that the N2 component is the key component in temporal dynamics of the interaction between reward and time valuation.
27736142	Gambling warning messages have been shown to lead to prevention and modification of risk-taking behaviors. Laboratory studies have shown messages can increase a player's knowledge about gambling specific risks, modify their gambling-related cognitive distortions, and even change play. In the present laboratory study, participants were randomly assigned to a winning or losing slot machine gambling experience where they either viewed periodic warning messages or not. It was hypothesized that those in the message conditions would place smaller bets, spend more time considering bets, and spend less time gambling than those in the control conditions. We also hypothesized participants would play differently across the contexts of winning or losing. The results showed those who received warning messages while winning made the fewest number of spins and did not speed up their bet rate over the course of play as much as those in other conditions. Players who received warning messages while losing decreased the size of their bets over the course of play compared to those who received messages while winning. Despite receiving warning messages, losing players did not decrease their number of spins or rate of betting. Winning or losing during slot machine play appears to have significant consequences on the impact of a warning message. Whereas a message to change gambling behavior may encourage a winning gambler to stop play, the same message for a losing player may lead to a small minimization in harm by helping them to decrease bet size, though not their rate of betting. (PsycINFO Database Record
27664298	The aim of this study was to investigate the intracellular responses associated with the acquisition and expression of cocaine-context associations. ERK (extracellular regulated kinase), CREB (cAMP responsive element binding protein), FosB and ΔFosB proteins were of particular interest due to their involvement in cocaine reward and in synaptic plasticity underlying learning and memory. We used the conditioned place preference (CPP) paradigm, which employs a Pavlovian conditioning procedure to establish an association between a drug-paired environment and the drug's rewarding effects, to study the role of these signaling pathways in cocaine-context associations. N-methyl-D-aspartate receptor (NMDAR) antagonism prior to cocaine administration during conditioning blocked the acquisition of cocaine CPP and reduced Nucleus Accumbens (NAc) phosphorylated-ERK (pERK) and phosphorylated CREB (pCREB) levels following the CPP test (drug-free). We also show that cocaine-induced increases in Caudate Putamen (CPu) FosB and ΔFosB levels are decreased after MK-801 pre-treatment during conditioning. In addition, our results provide evidence for the involvement of striatal SIRT (Silent Information Regulator of Transcription) proteins in cocaine-CPP. These results will aid in the advancement of general knowledge about the molecular formation and retrieval of cocaine-associated memories that can be used in the future when designing treatments for cocaine addiction that target both prevention and relapse.
27641323	This study adapts a widely-used acquired equivalence paradigm to investigate how opioid-addicted individuals learn from positive and negative feedback, and how they generalize this learning. The opioid-addicted group consisted of 33 participants with a history of heroin dependency currently in a methadone maintenance program; the control group consisted of 32 healthy participants without a history of drug addiction. All participants performed a novel variant of the acquired equivalence task, where they learned to map some stimuli to correct outcomes in order to obtain reward, and to map other stimuli to correct outcomes in order to avoid punishment; some stimuli were implicitly "equivalent" in the sense of being paired with the same outcome. On the initial training phase, both groups performed similarly on learning to obtain reward, but as memory load grew, the control group outperformed the addicted group on learning to avoid punishment. On a subsequent testing phase, the addicted and control groups performed similarly on retention trials involving previously-trained stimulus-outcome pairs, as well as on generalization trials to assess acquired equivalence. Since prior work with acquired equivalence tasks has associated stimulus-outcome learning with the nigrostriatal dopamine system, and generalization with the hippocampal region, the current results are consistent with basal ganglia dysfunction in the opioid-addicted patients. Further, a selective deficit in learning from punishment could contribute to processes by which addicted individuals continue to pursue drug use even at the cost of negative consequences such as loss of income and the opportunity to engage in other life activities.
27003390	The main behavioral characteristic of subthreshold depression that is observed in adolescents is the low frequency of exposure to environmental rewards. Therefore, it was considered that a simple intervention conducted in short sessions, focusing on increasing access to positively reinforcing activities, would be efficacious in increasing the availability of rewards. We conduct a randomized controlled trial to examine the efficacy of such a behavioral activation program that was conducted weekly for 5 weeks in 60-min sessions. Late adolescent university students aged 18-19 years with subthreshold depression were randomly allocated to a treatment (n = 62) or a control group (n = 56). The primary outcome of the study was the Beck Depression Inventory-II score. Results indicated that late adolescent students in the treatment group showed significant improvements in their depressive symptoms (effect size -0.90, 95 % CI -1.28 to -0.51) compared to the control group. Students in the treatment group also showed significant improvements in self-reported rating of quality of life and in behavioral characteristics. It is concluded that this intervention had a large and significant effect despite being short and simple and that this low-intensity cognitive behavioral therapy program could be conducted in many different types of institutions. It is suggested that the long-term effects of the treatment program should be targeted for investigation in future studies.
27783327	Clinical and animal studies have indicated that propofol has potential for abuse, but the specific neurobiological mechanism underlying propofol reward is not fully understood. The purpose of this study was to investigate the role of extracellular signal-regulated kinase (ERK) signal transduction pathways in the nucleus accumbens (NAc) in propofol self-administration. We tested the expression of p-ERK in the NAc following the maintenance of propofol self-administration in rats. We also assessed the effect of administration of SCH23390, an antagonist of the D1 dopamine receptor, on the expression of p-ERK in the NAc in propofol self-administering rats, and examined the effects of intra-NAc injection of U0126, an MEK inhibitor, on propofol reinforcement in rats. The results showed that the expression of p-ERK in the NAc increased significantly in rats maintained on propofol, and pre-treatment with SCH23390 inhibited the propofol self-administration and diminished the expression of p-ERK in the NAc. Moreover, intra-NAc injection of U0126 (4 µg/side) attenuated the propofol self-administration. The data suggest that ERK signal transduction pathways coupled with D1 dopamine receptors in the NAc may be involved in the maintenance of propofol self-administration and its rewarding effects.
27781362	Major depressive disorder (MDD) creates debilitating effects on a wide range of cognitive functions, including reinforcement learning (RL). In this study, we sought to assess whether reward processing as such, or alternatively the complex interplay between motivation and reward might potentially account for the abnormal reward-based learning in MDD.A total of 35 treatment resistant MDD patients and 44 age matched healthy controls (HCs) performed a standard probabilistic learning task. RL was titrated using behavioral, computational modeling and event-related brain potentials (ERPs) data.	MDD patients showed comparable learning rate compared to HCs. However, they showed decreased lose-shift responses as well as blunted subjective evaluations of the reinforcers used during the task, relative to HCs. Moreover, MDD patients showed normal internal (at the level of error-related negativity, ERN) but abnormal external (at the level of feedback-related negativity, FRN) reward prediction error (RPE) signals during RL, selectively when additional efforts had to be made to establish learning.	Collectively, these results lend support to the assumption that MDD does not impair reward processing per se during RL. Instead, it seems to alter the processing of the emotional value of (external) reinforcers during RL, when additional intrinsic motivational processes have to be engaged.	
27781281	Adolescent risk taking is strongly influenced by peer presence. The aim of the present study was to investigate the effect of peer presence on the ERP after negative and positive feedback in the time range of the feedback-related negativity (FRN). Eighteen male adolescents completed a version of the Balloon Analogue Risk Task (BART) under two conditions: playing alone and while observed by a peer. We recorded the ERPs after success or failure feedback and analyzed risk-taking behavior under both conditions. Behavioral results show that the participants were more cautious when being watched by a peer, especially after success. ERPs show that participants under peer presence exhibit more negative FRN after failure feedback than in the single condition, but no greater positivities after success feedback in the observed condition compared to the single condition. Results are in line with reinforcement learning theory and psychological aspects of loss prevention. The results suggest that the effect of peer presence on risk-taking behavior depends on the specific situational context.
27604567	Dopamine signals have repeatedly been linked to associative learning and motivational processes. However, there is considerably less agreement on a role for dopamine in reward processing, and therefore whether neuroplastic changes in dopamine function following chronic exposure to drugs of abuse such as cocaine may impair appropriate valuation of rewarding stimuli. To quantify this, we voltammetrically measured real-time dopamine release in the nucleus accumbens (NAc) core or shell while rats received unsignaled deliveries of either a small (1 pellet) or large (2 pellets) reward. In drug-naive controls, core dopamine signals did not discriminate between reward size at any point, while in the shell dopamine encoded magnitude differences only in a slower postpeak period. Despite this lack of discrimination between rewards by the peak DA response, controls easily discriminated between reward options in a subsequent choice task. In contrast, phasic dopamine reward signals were strongly altered by cocaine experience; core dopamine decreased peak response but increased discrimination between reward magnitudes while shell lost phasic responses to reward receipt altogether. Notably, animals with cocaine-associated alterations in dopamine signals for reward magnitude failed to subsequently discriminate between reward options. These findings suggest that cocaine self-administration alters the ability for dopamine signals to appropriately assign value to rewards and thus may in part contribute to later deficits in behaviors that depend on appropriate outcome valuation.
27779509	The move toward competency-based education will require medical schools and postgraduate training programs to restructure learning environments to motivate trainees to take personal ownership for learning. This qualitative study explores how medical students select and implement study strategies while enrolled in a unique, nontraditional program that emphasizes reflection on performance and competence rather than relying on high-stakes examinations or grades to motivate students to learn and excel.Fourteen first-year medical students volunteered to participate in three, 45-minute interviews (42 overall) scheduled three months apart during 2013-2014. Two medical educators used structured interview guides to solicit students' previous assessment experiences, preferred learning strategies, and performance monitoring processes. Interviews were digitally recorded and transcribed verbatim. Participants confirmed accuracy of transcripts. Researchers independently read transcripts and met regularly to discuss transcripts and judge when themes achieved saturation.	Medical students can adopt an assessment for learning mind-set with faculty guidance and implement appropriate study strategies for mastery-learning demands. Though students developed new strategies at different rates during the year, they all eventually identified study and performance monitoring strategies to meet learning needs. Students who had diverse learning experiences in college embraced mastery-based study strategies sooner than peers after recognizing that the learning environment did not reward performance-based strategies.	Medical students can take ownership for their learning and implement specific strategies to regulate behavior when learning environments contain building blocks emphasized in self-determination theory. Findings should generalize to educational programs seeking strategies to design learning environments that promote self-regulated learning.	
27777560	Previous work has demonstrated that goal-directed control of alcohol-seeking and other drug-related behaviors is reduced following extended self-administration and drug exposure. Here, we examined how the magnitude of stimulus influences on responding changes across similar training and drug exposure. Rats self-administered alcohol or sucrose for 2 or 8 weeks. Previous work has shown that 8 weeks, but not 2 weeks of self-administration produces habitual alcohol seeking. Next, all animals received equivalent Pavlovian conditioning sessions where a discrete stimulus predicted the delivery of alcohol or sucrose. Finally, the impact of the stimuli on ongoing instrumental responding was examined in a Pavlovian-instrumental transfer (PIT) test. While a significant PIT effect was observed following 2 weeks of either alcohol or sucrose self-administration, the magnitude of this effect was greater following 8 weeks of training. The specificity of the PIT effect appeared unchanged by extended training. While it is well established that evaluation of the outcome of responding contributes less to behavioral control following extended training and/or drug exposure, our data indicate that reward-predictive stimuli have a stronger contribution to responding after extended training. Together, these findings provide insight into the factors that control behavior after extended drug use, which will be important for developing effective methods for controlling and ideally reducing these behaviors.
27693139	Contemporary models of behavioral regulation maintain that balanced activity between cognitive control areas (prefrontal cortex, PFC) and subcortical reward-related regions (nucleus accumbens, NAC) mediates the selection of appropriate behavioral responses, whereas imbalanced activity (PFC < NAC) results in maladaptive behavior [1-6]. Imbalance can arise from reduced engagement of PFC (via fatigue or stress [7]) or from excessive activity in NAC [8]. Additionally, a concept far less researched is that an imbalance can result from simultaneously low PFC activity and high NAC activity. This occurs during adolescence, when the maturation of PFC lags behind that of NAC and NAC is more functionally active compared to adulthood or pre-adolescence [2, 5, 9, 10]. Accordingly, activity is disproportionately higher in NAC than in PFC, which may contribute to impulsivity and risk-taking exhibited by adolescents [5, 6, 10-12]. Despite having explanatory value, support for this notion has been solely correlational. Here, we causally tested this using chemogenetics to simultaneously decrease neural activity in the orbitofrontal cortex (OFC) and increase activity in NAC in adult rats, mimicking the imbalance during adolescence. We tested the effects on negative occasion setting, an important yet understudied form of inhibitory learning that may be particularly relevant during adolescence. Rats with combined manipulation of OFC and NAC were impaired in learning to use environmental cues to withhold a response, an effect that was greater than that of either manipulation alone. These findings provide direct evidence that simultaneous underactivity in OFC and overactivity in NAC can negatively impact behavioral control and provide insight into the neural systems that underlie inhibitory learning.
27616302	The current study aimed to determine, using a swine model of intrauterine growth restriction (IUGR), whether short- and long-term neurological deficiencies and interactive dysfunctions of Low Birth-Weight (LBW) offspring might be related to altered pattern of neurotransmitters. Hence, we compared the quantities of different neurotransmitters (catecholamines and indoleamines), which were determined by HPLC, at brain structures related to the limbic system (hippocampus and amygdala) in 14 LBW and 10 Normal Body-Weight (NBW) newborn piglets. The results showed, firstly, significant effects of sex on the NBW newborns, with females having higher dopamine (DA) concentrations than males. The IUGR processes affected DA metabolism, with LBW piglets having lower concentrations of noradrenaline at the hippocampus and higher concentrations of the DA metabolites, homovanillic acid (HVA), at both the hippocampus and the amygdala than NBW neonates. The effects of IUGR were modulated by sex; there were no significant differences between LBW and NBW females, but LBW males had higher HVA concentration at the amygdala and higher concentration of 5-hydroxyindoleacetic acid, the serotonin metabolite, at the hippocampus than NBW males. In conclusion, the present study shows that IUGR is mainly related to changes, modulated by sex, in the concentrations of catecholamine neurotransmitters, which are related to adaptation to physical activity and to essential cognitive functions such as learning, memory, reward-motivated behavior and stress.
26096355	Contexts associated with opioid reward trigger craving and relapse in opioid addiction. Effects of reward-context associative learning on nucleus accumbens (NAc) dendritic morphology were studied using morphine conditioned place preference (CPP). Morphine-conditioned mice received saline and morphine 10 mg/kg subcutaneous (s.c.) on alternate days. Saline-conditioned mice received saline s.c. each day. Morphine-conditioned and saline-conditioned groups received injections immediately before each of eight daily conditioning sessions. Morphine homecage controls had no CPP training, but received saline and morphine in the homecage concomitantly with the morphine-conditioned group. Morphine conditioning produced greater place preference than saline conditioning. Mice were sacrificed 1 day after CPP expression. Dendritic changes were studied using Golgi-Cox staining and digital tracing of NAc core and shell neurons. In the NAc core, morphine homecage administration increased spine density, while morphine conditioning increased dendritic complexity, as defined by increased dendritic count, length and intersections. Place preference positively correlated with dendritic length and intersections in the NAc core. The core may mediate reward consolidation and determine how context-related signals from the shell lead to motor behavior. The combination of drug and conditioning in the morphine-conditioned group produced unique morphological effects different from the effects of drug or conditioning procedures by themselves. An additional study found no differences in neuron morphology between saline-conditioned mice, trained as described earlier, and mice that were not conditioned, but received saline in the homecage. The unique effect of morphine reward learning on NAc core dendrites reflects a brain substrate that could be targeted for therapeutic intervention in addiction.
27771973	Major depressive disorder is characterized by reduced reward-related striatal activation and dysfunctional reward learning, putatively reflecting decreased dopaminergic signaling. The goal of this study was to test whether a pharmacological challenge designed to facilitate dopaminergic transmission can enhance striatal responses to reward and improve reward learning in depressed individuals.In a double-blind placebo-controlled design, 46 unmedicated depressed participants and 43 healthy control participants were randomly assigned to receive either placebo or a single low dose (50 mg) of the D2/D3 receptor antagonist amisulpride, which is believed to increase dopamine signaling through presynaptic autoreceptor blockade. To investigate the effects of increased dopaminergic transmission on reward-related striatal function and behavior, a monetary incentive delay task (in conjunction with functional MRI) and a probabilistic reward learning task were administered at absorption peaks of amisulpride.	Depressed participants selected previously rewarded stimuli less frequently than did control participants, indicating reduced reward learning, but this effect was not modulated by amisulpride. Relative to depressed participants receiving placebo (and control participants receiving amisulpride), depressed participants receiving amisulpride exhibited increased striatal activation and potentiated corticostriatal functional connectivity between the nucleus accumbens and the midcingulate cortex in response to monetary rewards. Stronger corticostriatal connectivity in response to rewards predicted better reward learning among depressed individuals receiving amisulpride as well as among control participants receiving placebo.	Acute enhancement of dopaminergic transmission potentiated reward-related striatal activation and corticostriatal functional connectivity in depressed individuals but had no behavioral effects. Taken together, the results suggest that targeted pharmacological treatments may normalize neural correlates of reward processing in depression; despite such acute effects on neural function, behavioral modification may require more chronic exposure. This is consistent with previous reports that antidepressant effects of amisulpride in depression emerged after sustained administration.	
27771284	The orexin/hypocretin (ORX) system regulates motivation for natural rewards and drugs of abuse such as alcohol. ORX receptor antagonists, most commonly OX1R antagonists including SB-334867 (SB), decrease alcohol drinking, self-administration and reinstatement in both genetically-bred alcohol-preferring and outbred strains of rats. Importantly, levels of alcohol seeking and drinking in outbred rats are variable, as they are in humans. We have shown that OX1R antagonism selectively decreases homecage alcohol drinking in high-, but not low-alcohol-preferring rats. It is unknown, however, whether this effect is selective to homecage drinking or whether it also applies to alcohol seeking paradigms such as self-administration and reinstatement following extinction, in which motivation is high in the absence of alcohol. Here we trained Sprague Dawley rats to self-administer 20% ethanol paired with a light-tone cue on an FR3 regimen. Rats were then extinguished and subjected to cue-induced reinstatement. Rats were segregated into high- and low-ethanol-responding groups (HR and LR) based on self-administration levels. During self-administration and cue-induced reinstatement, rats were given SB or vehicle prior to ethanol seeking. In both conditions, OX1R antagonism decreased responding selectively in HR, but not LR rats. There were no non-specific effects of SB treatment on arousal or general behavior. These data indicate that ORX signaling at the OX1R receptor specifically regulates high levels of motivation for alcohol, even in the absence of direct alcohol reinforcement. This implicates the ORX system in the pathological motivation underlying alcohol abuse and alcoholism and demonstrates that the OX1R may be an important target for treating alcohol abuse.
27770820	Around 35-45 % of people in contact with services for a first episode of psychosis are using cannabis. Cannabis use is associated with delays in remission, poorer clinical outcomes, significant increases in the risk of relapse, and lower engagement in work or education. While there is a clear need for effective interventions, so far only very limited benefits have been achieved from psychological interventions. Contingency management (CM) is a behavioural intervention in which specified desired behavioural change is reinforced through financial rewards. CM is now recognised to have a substantial evidence base in some contexts and its adoption in the UK is advocated by the National Institute for Health and Care Excellence (NICE) guidance as a treatment for substance or alcohol misuse. However, there is currently little published data testing its effectiveness for reducing cannabis use in early psychosis.CIRCLE is a two-arm, rater-blinded randomised controlled trial (RCT) investigating the clinical and cost-effectiveness of a CM intervention for reducing cannabis use among young people receiving treatment from UK Early Intervention in Psychosis (EIP) services. EIP service users (n = 544) with a recent history of cannabis use will be recruited. The experimental group will receive 12 once-weekly CM sessions, and a voucher reward if urinalysis shows that they have not used cannabis in the previous week. Both the experimental and the control groups will be offered an Optimised Treatment as Usual (OTAU) psychoeducational package targeting cannabis use. Assessment interviews will be performed at consent, at 3 months, and at 18 months. The primary outcome is time to relapse, defined as admission to an acute mental health service. Secondary outcomes include proportion of cannabis-free urine samples during the intervention period, severity of positive psychotic symptoms, quality-adjusted life years, and engagement in work or education.	CIRCLE is a RCT of CM for cannabis use in young people with a recent history of psychosis (EIP service users) and recent cannabis use. It is designed to investigate whether the intervention is a clinically and cost-effective treatment for cannabis use. It is intended to inform future treatment delivery, particularly in EIP settings.	ISRCTN33576045 : doi 10.1186/ISRCTN33576045 , registered on 28 November 2011.	
27737779	Mounting evidence indicates that adolescents exhibit heightened sensitivity to rewards and reward-related cues compared to adults, and that adolescents are often unable to exert behavioral control in the face of such cues. Moreover, differences in reward processing during adolescence have been linked to heightened risk taking and impulsivity. However, little is known about the processes by which adolescents learn about the appetitive properties of environmental stimuli that signal reward. To address this, Pavlovian conditioning procedures were used to test for differences in excitatory conditioning between adult and adolescent rats using various schedules of reinforcement. Specifically, separate cohorts of adult and adolescent rats were trained under conditions of consistent (continuous) or intermittent (partial) reinforcement. We found that the acquisition of anticipatory responding to a continuously-reinforced cue proceeded similarly in adolescents and adults. In contrast, responding increased at a greater rate in adolescents compared to adults during presentations of a partially-reinforced cue. We subsequently compared the ability of adolescent and adult rats to dynamically adjust the representation of a reward-predictive cue during extinction trials, in which a secondary inhibitory representation is acquired for the previously-reinforced stimulus. We observed significant age differences in the ability to flexibly update cue representations during extinction, in that the appetitive properties of cues with a history of either continuous or partial reinforcement persisted to a greater extent in adolescents relative to adults.
27640134	Iron deficiency (ID) is the most prevalent single-nutrient deficiency worldwide. There is evidence that ID early in development (preweaning in rat) causes irreversible neurologic, behavioral, and motor development deficits. Many of these effects have been attributed to damage to dopamine systems, including ID-induced changes in transporter and receptor numbers in the striatum and nucleus accumbens. These mesolimbic dopaminergic neurons are, in part, responsible for mediating reward and thus play a key role in addiction. However, there has been relatively little investigation into the behavioral effects of ID on drug addiction. In 2002, we found that rats made ID from weaning (postnatal day 21) and throughout the experiment acquired cocaine self-administration significantly more slowly than controls and failed to increase responding when the dose of the drug was decreased. In the present study, we assessed addiction for self-administered cocaine in rats with a history of preweaning ID only during postnatal days 4 through 21, and iron replete thereafter. The results showed that while ID did not affect the number of cocaine infusions or the overall addiction-like behavior score, ID rats scored higher on a measure of continued responding for drug than did iron replete controls. This increase in responding, however, was less goal-directed as ID rats also responded more quickly to the non-rewarded manipulandum than did control rats. Thus, while ID early in infancy did not significantly increase addiction-like behaviors for cocaine in this small study, the pattern of data suggests a possible underlying learning or performance impairment. Future studies will be needed to elucidate the exact neuro-behavioral deficits that lead to the increase in indiscriminate responding for drug in rats with a history of perinatal ID.
27639551	The brain has evolved different approaches to solve problems, but the mechanisms that determine which approach to take remain unclear. One possibility is that control progresses from simpler processes, such as associative learning, to more complex ones, such as relational reasoning, when the simpler ones prove inadequate. Alternatively, control could be based on competition between the processes. To test between these possibilities, we posed the support problem to rhesus monkeys using a tool-use paradigm, in which subjects could pull an object (the tool) toward themselves to obtain an otherwise out-of-reach goal item. We initially provided one problem exemplar as a choice: for the correct option, a food item placed on the support tool; for the incorrect option, the food item placed off the tool. Perceptual cues were also correlated with outcome: e.g., red, triangular tool correct, blue, rectangular tool incorrect. Although the monkeys simply needed to touch the tool to register a response, they immediately pulled it, reflecting a relational reasoning process between themselves and another object (Rself-other), rather than an associative one between the arbitrary touch response and reward (Aresp-reward). Probe testing then showed that all four monkeys used a conjunction of perceptual features to select the correct option, reflecting an associative process between stimuli and reward (Astim-reward). We then added a second problem exemplar and subsequent testing revealed that the monkeys switched to using the on/off relationship, reflecting a relational reasoning process between two objects (Rother-other). Because behavior appeared to reflect Rself-other rather than Aresp-reward, and Astim-reward prior to Rother-other, our results suggest that cognitive processes are selected via competitive control dynamics.
27633458	Withdrawal and avoidance behavior are common symptoms of depression and can appear as a consequence of absence of reward, i.e. extinction-induced depression (EID). This is particularly relevant for the aged organism subjected to pronounced loss of former rewards. Avoidance of the former site of reward and increased withdrawal into a distant compartment accompany extinction of food-rewarded behavior in rodent models. During extinction, behavioral markers for re-learning dissociate from indicators of extinction-induced depression. Here we examined the effect of a chronic treatment with corticosterone (CORT), a well-known inducer of depression-related behavior, on EID in adult and aged rats. Adult (3-4months) and aged (18months) male rats were treated with CORT via drinking water for 3weeks prior to extinction of a cued food-reward task. CORT treatment increased the distance from the site of reward and decreased goal tracking behavior during extinction, especially in the aged rats. Plasma hormone levels measured before and after restraint stress showed a decline in basal ACTH- and CORT-levels after chronic CORT treatment in aged animals. The treatment significantly impaired the HPA-axis activation after acute stress in both, adult and aged animals, alike. Altogether, these findings show an enhancement of EID after chronic CORT treatment in the aged organism, which may be mediated by an impaired HPA-axis sensitivity. These findings may have special relevance for the investigation of human geriatric depression.
27012890	N-methyl-d-aspartate receptors (NMDARs) are profound regulators of glutamate neurotransmission and behavior. To coordinate components of the limbic system, the dorsal and ventral striatum integrate cognitive and emotional information towards the execution of complex behaviors. Striatal outflow is conveyed by medium spiny neurons (MSNs), which can be dichotomized by expression of dopamine receptor subtype 1 (D1) or adenosine receptor subtype 2A (A2A). To examine how striatal NMDAR function modulates reward-related behaviors, we generated D1- and A2A-specific genetic deletions of the obligatory GluN1 subunit. Interestingly, we observed no differences in any GluN1-/- genotype in reward learning as assessed by acquisition or extinction of cocaine conditioned place preference (CPP). Control and A2A-GluN-/- mice exhibited robust cocaine-primed reinstatement, however this behavior was markedly absent in D1-GluN-/- mice. Interestingly, dual D1-/A2A-GluN-/- mice displayed an intermediate reinstatement phenotype. Next, we examined models of exploration, anxiety, and despair, states often associated with relapse to addiction-related behavior, to determine NMDAR contribution in D1 and A2A cell types to these behaviors. D1-GluN1-/- mice displayed aberrant exploratory locomotion in a novel environment, but the phenotype was absent in dual D1/A2A-GluN1-/- mice. In contrast A2A-GluN1-/- mice displayed a despair-resistant phenotype, and this phenotype persisted in dual D1/A2A-GluN-/- mice. These data support the hypothesis that cell type-specific NMDAR signaling regulates separable behavioral outcomes related to locomotion, despair, and relapse. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.
26234951	We tested 8- and 10-month-old infants' visual working memory (VWM) for object-location bindings - what is where - with a novel paradigm, Delayed Match Retrieval, that measured infants' anticipatory gaze responses (using a Tobii T120 eye tracker). In an inversion of Delayed-Match-to-Sample tasks and with inspiration from the game Memory, in test trials, three face-down virtual 'cards' were presented. Two flipped over sequentially (revealing, e.g. a swirl pattern and then a star), and then flipped back face-down. Next, the third card was flipped to reveal a match (e.g. a star) to one of the previously seen, now face-down cards. If infants looked to the location where the (now face-down) matching card had been shown, this was coded as a correct response. To encourage anticipatory looks, infants subsequently received a reward (a brief, engaging animation) presented at that location. Ten-month-old infants performed significantly above chance, showing that their VWM could hold object-location information for the two cards. Overall, 8-month-olds' performance was at chance, but they showed a robust learning trend. These results corroborate previous findings (Kaldy & Leslie, 2005; Oakes, Ross-Sheehy & Luck, 2006) and point to rapid development of VWM for object-location bindings. However, compared to previous paradigms that measure passive gaze responses to novelty, this paradigm presents a more challenging, ecologically relevant test of VWM, as it measures the ability to make online predictions and actively localize objects based on VWM. In addition, this paradigm can be readily scaled up to test toddlers or older children without significant modification.
27580969	The developmental period of adolescence is characterized by increasing incidence of health risk behaviors, including experimenting with drugs and alcohol. We examined how inhibitory control interacts with reward and punishment sensitivity to predict substance use severity and age of onset among early adolescents. The sample was comprised of 157 early adolescents (13-14 years of age, 52% male). Composite scores for behavioral activation system (BAS), behavioral inhibition system (BIS), and substance use severity and onset were computed using adolescents' questionnaire data, and inhibitory control was assessed based on adolescents' behavioral performance and brain imaging during the Multiple Source Interference Task (MSIT). Structural equation modeling analyses indicated that for both behavioral performance and neural activity indicators of inhibitory control, high levels of BAS predicted earlier onset of substance use among adolescents with low inhibitory control-but not among adolescents with high inhibitory control. BIS was not related to substance use severity and onset among adolescents. The results support the theoretically hypothesized moderating role of inhibitory control and its associated frontal cortex functioning, and offer new insights into the identification of adolescents with neurobehavioral vulnerabilities to developing maladaptive substance use behaviors.
27526666	Nostalgia is an emotion that is most commonly associated with personally and socially relevant memories. It is primarily positive in valence and is readily evoked by music. It is also an idiosyncratic experience that varies between individuals based on affective traits. We identified frontal, limbic, paralimbic, and midbrain brain regions in which the strength of the relationship between ratings of nostalgia evoked by music and blood-oxygen-level-dependent (BOLD) signal was predicted by affective personality measures (nostalgia proneness and the sadness scale of the Affective Neuroscience Personality Scales) that are known to modulate the strength of nostalgic experiences. We also identified brain areas including the inferior frontal gyrus, substantia nigra, cerebellum, and insula in which time-varying BOLD activity correlated more strongly with the time-varying tonal structure of nostalgia-evoking music than with music that evoked no or little nostalgia. These findings illustrate one way in which the reward and emotion regulation networks of the brain are recruited during the experiencing of complex emotional experiences triggered by music. These findings also highlight the importance of considering individual differences when examining the neural responses to strong and idiosyncratic emotional experiences. Finally, these findings provide a further demonstration of the use of time-varying stimulus-specific information in the investigation of music-evoked experiences.
27477630	While almost everyone discounts the value of future rewards over immediate rewards, people differ in their so-called delay-discounting. One of the several factors that may explain individual differences in delay-discounting is reward-processing. To study individual-differences in reward-processing, however, one needs to consider the heterogeneity of neural-activity at each reward-processing stage. Here using EEG, we separated reward-related neural activity into distinct reward-anticipation and reward-outcome stages using time-frequency characteristics. Thirty-seven individuals first completed a behavioral delay-discounting task. Then reward-processing EEG activity was assessed using a separate reward-learning task, called a reward time-estimation task. During this EEG task, participants were instructed to estimate time duration and were provided performance feedback on a trial-by-trial basis. Participants received monetary-reward for accurate-performance on Reward trials, but not on No-Reward trials. Reward trials, relative to No-Reward trials, enhanced EEG activity during both reward-anticipation (including, cued-locked delta power during cue-evaluation and pre-feedback alpha suppression during feedback-anticipation) and reward-outcome (including, feedback-locked delta, theta and beta power) stages. Moreover, all of these EEG indices correlated with behavioral performance in the time-estimation task, suggesting their essential roles in learning and adjusting performance to maximize winnings in a reward-learning situation. Importantly, enhanced EEG power during Reward trials, as reflected by stronger 1) pre-feedback alpha suppression, 2) feedback-locked theta and 3) feedback-locked beta, was associated with a greater preference for larger-but-delayed rewards in a separate, behavioral delay-discounting task. Results highlight the association between a stronger preference toward larger-but-delayed rewards and enhanced reward-processing. Moreover, our reward-processing EEG indices detail the specific stages of reward-processing where these associations occur.
27766090	To investigate brain activity during the reinforcement learning process in social contexts is a topic of increasing research interest. Previous studies have mainly focused on using electroencephalograms (EEGs) for feedback evaluation in reinforcement learning tasks by measuring event-related potentials. Few studies have investigated the time-frequency (TF) profiles of a cue that manifested whether a following feedback is available or not after decision-making. Moreover, it remains unclear whether the TF profiles of the cue interact with different agents to whom the feedback related. In this study we used the TF approach to test EEG oscillations of the cue stimuli in three agents ('Self', 'Other', and 'Computer') conditions separately. The results showed that the increased central-posterior delta power was elicited by the feedback unavailable cues more so than with the feedback available cue within 200-350 ms after the onset of the cue, but only in the self-condition. Moreover, a frontal-central theta oscillation had enhanced power when following the feedback unavailable cue as opposed to the feedback available cue across three agencies. These findings demonstrated that the cue for knowing an outcome produced reward prediction error-like signals, which were mirrored by the delta and theta oscillations during decision-making. More importantly, the present study demonstrated that the theta and delta oscillations reflected separable components of the advanced cue processing before the feedback in decision-making.
27353570	Adolescence is characterized by pronounced changes in motivated behavior, during which emphasis on potential rewards may result in an increased tendency to approach things that are novel and bring potential for positive reinforcement. While this may result in risky and health-endangering behavior, it may also lead to positive consequences, such as behavioral flexibility and greater learning. In this review we will discuss both the maladaptive and adaptive properties of heightened reward-sensitivity in adolescents by reviewing recent cognitive neuroscience findings in relation to behavioral outcomes. First, we identify brain regions involved in processing rewards in adults and adolescents. Second, we discuss how functional changes in reward-related brain activity during adolescence are related to two behavioral domains: risk taking and cognitive control. Finally, we conclude that progress lies in new levels of explanation by further integration of neural results with behavioral theories and computational models. In addition, we highlight that longitudinal measures, and a better conceptualization of adolescence and environmental determinants, are of crucial importance for understanding positive and negative developmental trajectories.
27339692	Adolescence is a time of critical brain changes that pave the way for adult learning processes. However, the extent to which learning in adolescence is best characterized as a transitional linear progression from childhood to adulthood, or represents a period that differs from earlier and later developmental stages, remains unclear. Here we examine behavioral literature on associative fear conditioning and complex choice behavior with rodent models. Many aspects of fear conditioning are intact by adolescence and do not differ from adult patterns. Sufficient evidence, however, suggests that adolescent learning cannot be characterized simply as an immature precursor to adulthood. Across different paradigms assessing choice behavior, literature suggests that adolescent animals typically display more impulsive patterns of responding compared to adults. The extent to which the development of basic conditioning processes serves as a scaffold for later adult decision making is an additional research area that is important for theory, but also has widespread applications for numerous psychological conditions.
27764214	In anorexia nervosa (AN), motivational salience is attributed to illness-compatible cues (e.g., underweight and active female bodies) and this is hypothesised to involve dopaminergic reward circuitry. We investigated the effects of reducing dopamine (DA) transmission on the motivational processing of AN-compatible cues in women recovered from AN (AN REC, n = 17) and healthy controls (HC, n = 15). This involved the acute phenylalanine and tyrosine depletion (APTD) procedure and a startle eye-blink modulation (SEM) task. In a balanced amino acid state, AN REC showed an increased appetitive response (decreased startle potentiation) to illness-compatible cues (underweight and active female body pictures (relative to neutral and non-active cues, respectively)). The HC had an aversive response (increased startle potentiation) to the same illness-compatible stimuli (relative to neutral cues). Importantly, these effects, which may be taken to resemble symptoms observed in the acute stage of illness and healthy behaviour respectively, were not present when DA was depleted. Thus, AN REC implicitly appraised underweight and exercise cues as more rewarding than did HC and the process may, in part, be DA-dependent. It is proposed that the positive motivational salience attributed to cues of emaciation and physical activity is, in part, mediated by dopaminergic reward processes and this contributes to illness pathology. These observations are consistent with the proposal that, in AN, aberrant reward-based learning contributes to the development of habituation of AN-compatible behaviours.
27764142	Reduced sensitivity to physical pain (hypoalgesia) has been reported after events involving reward devaluation. Reward devaluation was implemented in a consummatory successive negative contrast (cSNC) task. Food-deprived Wistar rats had access to 32% sucrose during 16 sessions followed by access to 4% sucrose during 3 additional sessions. An unshifted control group had access to 4% sucrose throughout the 19 sessions. Pain sensitivity was measured using von Frey filaments (Experiment 1) and Hargreaves thermal stimuli (Experiment 2) in pretraining baseline, 5 min, and 300 min after either the first (session 17) or second (session 18) devaluation session in the cSNC situation. Sucrose consumption was lower in downshifted groups relative to unshifted groups during postshift sessions-the cSNC effect. Hypoalgesia was observed in downshifted groups relative to unshifted controls when pain sensitivity was assessed 5 min after either the first or second devaluation session, regardless of the pain sensitivity test used. Both pain sensitivity tests yielded evidence of hypoalgesia 300 min after the second downshift session, but not 300 min after the first devaluation session. Whereas hypoalgesia was previously shown only after the second devaluation session, here we report evidence of hypoalgesia after both the first and second devaluation sessions using mechanical and thermal nociceptive stimuli. Moreover, the hypoalgesia observed 300 min after the second devaluation session in both experiments provides unique evidence of the effects of reward loss on sensitivity to physical pain 5 hours after the loss episode. The underlying neurobehavioral mechanisms remain to be identified.
27762477	Ginsenoside Rg1 is one of the major active ingredients of Panax ginseng and has showed notable improving learning and memory effects in several behavioral tasks, such as water maze, shuttle-box, and step-through, based on avoidance. However, there was no report about the role of Rg1 on the performance of reward-directed instrumental conditioning, which could reflect the adaptive capacity to ever-changing environments. Thus, in this study, the reward devaluation test and conditional visual discrimination task were conducted to study the ameliorating effects of Rg1 on cognitive deficits, especially the loss of adaptation capacity in chronic restraint stress (CRS) rat model. Our results showed that rat subjected to CRS became insensitive to the changes in outcome value, and it significantly harmed the rat's performance in conditional visual discrimination task. Moreover, the levels of BDNF, TrkB, and Erk phosphorylation were decreased in the prefrontal cortex of CRS rats. However, these changes were effectively reversed by Rg1 (5 and 10 mg/kg, i.p.). Therefore, it demonstrated that Rg1 has a good ability to improve learning and memory and also ameliorate impaired adaptive capacity induced by CRS. This amelioration effect of Rg1 might be mediated partially by BDNF/TrkB/Erk pathway in prefrontal cortex. Copyright © 2016 John Wiley & Sons, Ltd.
27761125	Adolescence is a period of increased sensitivity to social contexts. To evaluate how social context sensitivity changes over development-and influences reward learning-we investigated how children and adolescents perceive and integrate rewards for oneself and others during a dynamic risky decision-making task. Children and adolescents (N = 75, 8-16 years) performed the Social Gambling Task (SGT, Kwak et al., 2014) and completed a set of questionnaires measuring other-regarding behavior. In the SGT, participants choose amongst four card decks that have different payout structures for oneself and for a charity. We examined patterns of choices, overall decision strategies, and how reward outcomes led to trial-by-trial adjustments in behavior, as estimated using a reinforcement-learning model. Performance of children and adolescents was compared to data from a previously collected sample of adults (N = 102) performing the identical task. We found that that children/adolescents were not only more sensitive to rewards directed to the charity than self but also showed greater prosocial tendencies on independent measures of other-regarding behavior. Children and adolescents also showed less use of a strategy that prioritizes rewards for self at the expense of rewards for others. These results support the conclusion that, compared to adults, children and adolescents show greater sensitivity to outcomes for others when making decisions and learning about potential rewards.
27760002	Dopamine is thought to regulate learning from appetitive and aversive events. Here we examined how optogenetically-identified dopamine neurons in the lateral ventral tegmental area of mice respond to aversive events in different conditions. In low reward contexts, most dopamine neurons were exclusively inhibited by aversive events, and expectation reduced dopamine neurons' responses to reward and punishment. When a single odor predicted both reward and punishment, dopamine neurons' responses to that odor reflected the integrated value of both outcomes. Thus, in low reward contexts, dopamine neurons signal value prediction errors (VPEs) integrating information about both reward and aversion in a common currency. In contrast, in high reward contexts, dopamine neurons acquired a short-latency excitation to aversive events that masked their VPE signaling. Our results demonstrate the importance of considering the contexts to examine the representation in dopamine neurons and uncover different modes of dopamine signaling, each of which may be adaptive for different environments.
26403462	Although cognitive control is commonly identified as the basis of self-controlled behavior, correlations found between trait self-control and laboratory measures of cognitive control such as Stroop interference are typically low. Based on the notion that self-control requires the ability to refrain from rewarded behaviors, and inspired by the recent finding that Stroop interference is modulated by reward associations, we propose the idea that the modulation of interference by reward associations (MIRA) is a cognitive marker of trait self-control. Two independent samples of participants completed (1) a modified Stroop task designed to assess MIRA and (2) two common measures of trait self-control: the Brief Self-Control Scale (BSCS) and the Barratt Impulsiveness Scale (BIS-11). MIRA was strongly correlated with the BSCS and moderately correlated with two of the three subscales of the BIS-11. MIRA thus appears to reflect a cognitive endophenotype of individual differences in self-control, and perhaps of related mental disorders.
26280758	It has been proposed that sudden insight into the solutions of problems can enhance long-term memory for those solutions. However, the nature of insight has been operationalized differently across studies. Here, we examined two main aspects of insight problem-solving-the generation of a solution and the subjective "aha!" experience-and experimentally evaluated their respective relationships to long-term memory formation (encoding). Our results suggest that generation (generated solution vs. presented solution) and the "aha!" experience ("aha!" vs. no "aha!") are independently related to learning from insight, as well as to the emotional response towards understanding the solution during encoding. Moreover, we analyzed the relationship between generation and the "aha!" experience and two different kinds of later memory tests, direct (intentional) and indirect (incidental). Here, we found that the generation effect was larger for indirect testing, reflecting more automatic retrieval processes, while the relationship with the occurrence of an "aha!" experience was somewhat larger for direct testing. Our results suggest that both the generation of a solution and the subjective experience of "aha!" indicate processes that benefit long-term memory formation, though differently. This beneficial effect is possibly due to the intrinsic reward associated with sudden comprehension and the detection of schema-consistency, i.e., that novel information can be easily integrated into existing knowledge.
27755551	Cooperativeness is an essential behavioral trait evolved to facilitate group living. Social and cognitive mechanisms involved in cooperation (e.g., motivation, reward encoding, action evaluation, and executive functions) are sub-served by the striatal-projected circuits, whose physical existence has been confirmed by animal studies, human postmortem studies, and in vivo human brain studies. The current study investigated the associations between Cooperativeness and fiber connectivities from the striatum to nine subcortical and cortical regions, including the amygdala, hippocampus, medial orbitofrontal cortex, lateral orbitofrontal cortex, ventrolateral prefrontal cortex, dorsolateral prefrontal cortex, posterior cingulate cortex/retrosplenial cortex, dorsal cingulate cortex, and rostral cingulate cortex. Results showed that Cooperativeness was negatively correlated with fiber connectivity for the cognitive control system (from the dorsal caudate to the rostral cingulate cortex and ventrolateral prefrontal cortex), but not with fiber connectivity for the social cognitive system (e.g., connectivity with the medial prefrontal cortex and amygdala). These results partially supported Declerck et al.'s (2013) cognitive neural model of the role of cognitive control and social cognition in cooperation.
27754410	Picture-object correspondence provides an alternate method of investigating delayed matching by providing a cue (picture) which may be spontaneously perceived as similar but different from a corresponding target. Memory for, and corresponding choice of, a target corresponding to a cue could be facilitated by the use of a picture. Bumblebees have been found to both easily differentiate images from corresponding objects but also spontaneously perceive a similarity between the two. Herein, an approach was designed to test the possible use of picture cues to signal reward in a delayed matching task. Target choice preference corresponding to picture cues was tested among three bumblebee (Bombus impatiens) colonies using photograph cues (presented prior to target stimuli) corresponding to one of four target stimuli. Photograph cues were the only predictor of corresponding target reward, presented in stable locations. Rewarded and unrewarded tests show a choice preference significantly higher than chance for targets matching the cue. Results suggest that bumblebees can learn to use picture cues in a delayed matching task. Furthermore, experience, conditions of reward inconsistency and location, are discussed as possible contributing factors to learning in a delayed matching task.
27751826	Kai Xin San (KXS), a traditional formula of Chinese medicine, has been used to treat dementia.The present study aimed to investigate its ameliorating effects on Aβ1-40-induced cognitive impairment in rats using a series of novel reward-directed instrumental learning tasks, and to determine its possible mechanism of action.	Rats were pretreated with KXS aqueous extract (0.72 and 1.44g/kg, p.o.) for 10 days, and were trained to gain reward reinforcement by lever pressing at the meantime. Thereafter, rats received a bilateral microinjection of Aβ1-40 in CA1 regions of the hippocampus. Cognitive performance was evaluated with the goal directed (higher response ratio) and habit (visual signal discrimination and extinction) learning tasks, as well as on the levels of memory-related biochemical parameters and molecules.	Our findings first demonstrated that KXS can improve Aβ1-40-induced amnesia in RDIL via enhancing the comprehension of action-outcome association and the utilization of cue information to guide behavior. Then, its ameliorating effects should be attributed to the modulation of memory-related molecules in the hippocampus.	In conclusion, KXS has the potential to prevent and/or delay the deterioration of cognitive impairment in AD.	
27751532	Behavioral abnormalities associated with opiate addiction include memory and learning deficits, which are the result of some alterations in the neuromodulatory systems. Recently, orexin has shown to influence drug addiction neural circuitry, specifically in mediating reward-related perception and memory. To explore the possible interaction of orexinergic and opioidergic system on modulation of learning and memory, we have investigated the effects of intra-dorsal hippocampal (intra-CA1) administration of orexin-1 receptor agonist and the competitive orexin-1 antagonist, SB-334867, on morphine-induced memory impairment by using step-down passive avoidance task in mice. Pre-training injection of morphine (5mg/kg, i.p.) impaired memory, which was restored when 24h later the same dose of the drug was administered. Pre-test administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) had not a significant effect on the retention latency compared to the saline-treated animals, but it restored the memory impairment induced by pre-training morphine (5mg/kg, i.p.). Pre-test administration of SB-334867 (10, 20 and 40nmol, intra-CA1) by itself decreased the retention latencies of passive avoidance task. Co-administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) and morphine (1mg/kg, i.p.) on the test day induced morphine state-dependent memory. Conversely, pre-test injection of SB-334867 (10, 20 and 40nmol, intra-CA1) inhibited the orexin-1-induced potentiation of morphine state-dependent learning on the test day. It is concluded that dorsal hippocampal orexin-1 receptors may be involved, at least in part, in morphine state-dependent learning in mice.
27747818	ERP studies commonly utilize gambling-based reinforcement tasks to elicit feedback negativity (FN) responses. This study used a pattern learning task in order to limit gambling-related fallacious reasoning and possible affective responses to gambling, while investigating relationships between the FN components between high and low reward expectation conditions. Eighteen undergraduates completed measures of reinforcement sensitivity, trait and state affect, and psychophysiological recording. The pattern learning task elicited a FN component for both high and low win expectancy conditions, which was found to be independent of reward expectation and showed little relationship with task and personality variables. We also observed a P3 component, which showed sensitivity to outcome expectancy variation and relationships to measures of anxiety, appetitive motivation, and cortical asymmetry, although these varied by electrode location and expectancy condition. Findings suggest that the FN reflected a binary reward-related signal, with little relationship to reward expectation found in previous studies, in the absence of positive affective responses.
27441458	Individuals with anorexia nervosa (AN) experience insecure attachment. We investigated whether insecure attachment is associated with punishment and reward sensitivity in women with AN. Women with AN (n = 24) and comparison women (n = 26) (CW) completed The Eating Disorder Examination Questionnaire, Depression Anxiety Stress Scale, The Attachment Style Questionnaire, and Sensitivity to Punishment/Sensitivity to Reward Questionnaire. Participants with AN returned higher ratings for insecure attachment (anxious and avoidant) experiences and greater sensitivity to punishment (p = 0.001) than CW. In AN, sensitivity to punishment was positively correlated with anxious attachment and negative emotionality but not eating disorder symptoms. Regression analysis revealed that anxious attachment independently predicted punishment sensitivity in AN. Anxious attachment experiences are related to punishment sensitivity in AN, independent of negative emotionality and eating disorder symptoms. Results support ongoing investigation of the contribution of attachment experiences in treatment and recovery.
27742666	The first brain-wide voxel-level resting state functional connectivity neuroimaging analysis of depression is reported, with 421 patients with major depressive disorder and 488 control subjects. Resting state functional connectivity between different voxels reflects correlations of activity between those voxels and is a fundamental tool in helping to understand the brain regions with altered connectivity and function in depression. One major circuit with altered functional connectivity involved the medial orbitofrontal cortex Brodmann area 13, which is implicated in reward, and which had reduced functional connectivity in depression with memory systems in the parahippocampal gyrus and medial temporal lobe, especially involving the perirhinal cortex Brodmann area 36 and entorhinal cortex Brodmann area 28. The Hamilton Depression Rating Scale scores were correlated with weakened functional connectivity of the medial orbitofrontal cortex Brodmann area 13. Thus in depression there is decreased reward-related and memory system functional connectivity, and this is related to the depressed symptoms. The lateral orbitofrontal cortex Brodmann area 47/12, involved in non-reward and punishing events, did not have this reduced functional connectivity with memory systems. Second, the lateral orbitofrontal cortex Brodmann area 47/12 had increased functional connectivity with the precuneus, the angular gyrus, and the temporal visual cortex Brodmann area 21. This enhanced functional connectivity of the non-reward/punishment system (Brodmann area 47/12) with the precuneus (involved in the sense of self and agency), and the angular gyrus (involved in language) is thus related to the explicit affectively negative sense of the self, and of self-esteem, in depression. A comparison of the functional connectivity in 185 depressed patients not receiving medication and 182 patients receiving medication showed that the functional connectivity of the lateral orbitofrontal cortex Brodmann area 47/12 with these three brain areas was lower in the medicated than the unmedicated patients. This is consistent with the hypothesis that the increased functional connectivity of the lateral orbitofrontal cortex Brodmann area 47/12 is related to depression. Relating the changes in cortical connectivity to our understanding of the functions of different parts of the orbitofrontal cortex in emotion helps to provide new insight into the brain changes related to depression.
27739396	Trait impulsivity, which is often defined as a strong preference for immediate over delayed rewards and results in behaviors that are socially inappropriate, maladaptive, and short-sighted, is a predisposing vulnerability to all externalizing spectrum disorders. In contrast, anhedonia is characterized by chronically low motivation and reduced capacity to experience pleasure, and is common to depressive disorders. Although externalizing and depressive disorders have virtually nonoverlapping diagnostic criteria in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, heterotypic comorbidity between them is common. Here, we review common neural substrates of trait impulsivity, anhedonia, and irritability, which include both low tonic mesolimbic dopamine activity and low phasic mesolimbic dopamine responding to incentives during reward anticipation and associative learning. We also consider how other neural networks, including bottom-up emotion generation systems and top-down emotion regulation systems, interact with mesolimbic dysfunction to result in alternative manifestations of psychiatric illness. Finally, we present a model that emphasizes a translational, transdiagnostic approach to understanding externalizing/depression comorbidity. This model should refine ways in which internalizing and externalizing disorders are studied, classified, and treated.
27739062	Like adults, children need to allocate study time and endeavour optimally in order to enhance learning effectiveness.The aim of this study was to investigate the development of shifting from habitual to agenda-based processes on study decisions.	The participants were 309 children in the second, fourth, and sixth grades.	We adopted the research paradigm proposed by Ariel and Dunlosky (2013, Mem. Cognit., 41, 416). In Experiment 1, the students selected items to study either with or without time constraint. In Experiment 2, the students were instructed to select all three items or one item to study per trial.	The results of Experiment 1 showed that for sixth graders, the likelihood of selecting high-value items under the restricted-study-time condition was higher than that under the restricted-total-time condition; second and fourth graders failed to construct an agenda of prioritizing high-reward items for study in the restricted-study-time condition. In Experiment 2, when students were instructed to select one item to study per trial, high-value items were prioritized over items on the left of the array for sixth graders; on the contrary, second and fourth graders seemed to choose item for study arbitrary, although they tend to choose high-value items compared with their choice pattern in no-choice-limit condition.	The results indicate that children can shift towards agenda-based process when habitual responding cannot maximize reward, and there is an age-related improvement in shifting between grade 4 and grade 6.	
27736881	It has been suggested that dopamine (DA) represents reward-prediction-error (RPE) defined in reinforcement learning and therefore DA responds to unpredicted but not predicted reward. However, recent studies have found DA response sustained towards predictable reward in tasks involving self-paced behavior, and suggested that this response represents a motivational signal. We have previously shown that RPE can sustain if there is decay/forgetting of learned-values, which can be implemented as decay of synaptic strengths storing learned-values. This account, however, did not explain the suggested link between tonic/sustained DA and motivation. In the present work, we explored the motivational effects of the value-decay in self-paced approach behavior, modeled as a series of 'Go' or 'No-Go' selections towards a goal. Through simulations, we found that the value-decay can enhance motivation, specifically, facilitate fast goal-reaching, albeit counterintuitively. Mathematical analyses revealed that underlying potential mechanisms are twofold: (1) decay-induced sustained RPE creates a gradient of 'Go' values towards a goal, and (2) value-contrasts between 'Go' and 'No-Go' are generated because while chosen values are continually updated, unchosen values simply decay. Our model provides potential explanations for the key experimental findings that suggest DA's roles in motivation: (i) slowdown of behavior by post-training blockade of DA signaling, (ii) observations that DA blockade severely impairs effortful actions to obtain rewards while largely sparing seeking of easily obtainable rewards, and (iii) relationships between the reward amount, the level of motivation reflected in the speed of behavior, and the average level of DA. These results indicate that reinforcement learning with value-decay, or forgetting, provides a parsimonious mechanistic account for the DA's roles in value-learning and motivation. Our results also suggest that when biological systems for value-learning are active even though learning has apparently converged, the systems might be in a state of dynamic equilibrium, where learning and forgetting are balanced.
27733628	Modafinil (MOD) exhibits therapeutic efficacy for treating sleep and psychiatric disorders; however, its mechanism is not completely understood. Compared with other psychostimulants inhibiting dopamine (DA) uptake, MOD weakly interacts with the dopamine transporter (DAT) and modestly elevates striatal dialysate DA, suggesting additional targets besides DAT. However, the ability of MOD to induce wakefulness is abolished with DAT knockout, conversely suggesting that DAT is necessary for MOD action. Another psychostimulant target, but one not established for MOD, is activation of phasic DA signaling. This communication mode during which burst firing of DA neurons generates rapid changes in extracellular DA, the so-called DA transients, is critically implicated in reward learning. Here, we investigate MOD effects on phasic DA signaling in the striatum of urethane-anesthetized rats with fast-scan cyclic voltammetry. We found that MOD (30-300 mg/kg i.p.) robustly increases the amplitude of electrically evoked phasic-like DA signals in a time- and dose-dependent fashion, with greater effects in dorsal versus ventral striata. MOD-induced enhancement of these electrically evoked amplitudes was mediated preferentially by increased DA release compared with decreased DA uptake. Principal component regression of nonelectrically evoked recordings revealed negligible changes in basal DA with high-dose MOD (300 mg/kg i.p.). Finally, in the presence of the D2 DA antagonist, raclopride, low-dose MOD (30 mg/kg i.p.) robustly elicited DA transients in dorsal and ventral striata. Taken together, these results suggest that activation of phasic DA signaling is an important mechanism underlying the clinical efficacy of MOD.
27730429	Studies conducted in monozygotic and dizygotic twins have established a strong genetic component in eating behavior. Rare mutations and common variants of the melanocortin 4 receptor (MC4R) gene have been linked to obesity and eating behavior scores. However, few studies have assessed common variants in MC4R gene with the rewarding value of food in children. The objective of the study was to evaluate the association between the MC4R rs17782313 polymorphism with homeostatic and non-homeostatic eating behavior patterns in Chileans children. This is a cross-sectional study in 258 Chilean children (44 % female, 8-14 years old) showing a wide variation in BMI. Anthropometric measurements (weight, height, Z-score of BMI and waist circumference) were performed by standard procedures. Eating behavior was assessed using the Eating in Absence of Hunger Questionnaire (EAHQ), the Child Eating Behavior Questionnaire (CEBQ), the Three-Factor Eating Questionnaire (TFEQ), and the Food Reinforcement Value Questionnaire (FRVQ). Genotype of the rs17782313 nearby MC4R was determined by a Taqman assay. Association of the rs17782313 C allele with eating behavior was assessed using non-parametric tests. We found that children carrying the CC genotype have higher scores of food responsiveness (p value = 0.02). In obese girls, carriers of the C allele showed lower scores of satiety responsiveness (p value = 0.02) and higher scores of uncontrolled eating (p value = 0.01). Obese boys carrying the C allele showed lower rewarding value of food in relation to non-carriers. The rs17782313 C allele is associated with eating behavior traits that may predispose obese children to increased energy intake and obesity.
27729874	It is not uncommon for humans or animals to experience traumatic events in their lifetimes. However, the majority of individuals are resilient to long-term detrimental changes turning into anxiety and depression, such as post-traumatic stress disorder (PTSD). What underlying neural mechanism accounts for individual variability in stress resilience? Hyperactivity in fear circuits, such as the amygdalar system, is well-known to be the major pathophysiological basis for PTSD, much like a "stuck accelerator." Interestingly, increasing evidence demonstrates that dopamine (DA) - traditionally known for its role in motivation, reward prediction, and addiction - is also crucial in regulating fear learning and anxiety. Yet, how dopaminergic (DAergic) neurons control stress resilience is unclear, especially given that DAergic neurons have multiple subtypes with distinct temporal dynamics. Here, we propose the Rebound-Excitation Theory, which posits that DAergic neurons' rebound-excitation at the termination of fearful experiences serves as an important "brake" by providing intrinsic safety-signals to fear-processing neural circuits in a spatially and temporally controlled manner. We discuss how DAergic neuron rebound-excitation may be regulated by genetics and experiences, and how such physiological properties may be used as a brain-activity biomarker to predict and confer individual resilience to stress and anxiety.
27728914	Obesity is increasing in prevalence across all sectors of society, and with it a constellation of associated ailments including hypertension, type 2 diabetes, and eating disorders. The melanocortin system is a critical neural system underlying the control of body weight and other functions. Deficits in the melanocortin system may promote or exacerbate the comorbidities of obesity. This system has therefore generated great interest as a potential target for treatment of obesity. However, drugs targeting melanocortin receptors are plagued by problematic side effects, including undesirable increases in sympathetic nervous system activity, heart rate, and blood pressure. Circumnavigating this roadblock will require a clearer picture of the precise neural circuits that mediate the functions of melanocortins. Recent, novel experimental approaches have significantly advanced our understanding of these pathways. We here review the latest advances in our understanding of the role of melanocortins in food intake, reward pathways, blood pressure, glucose control, and energy expenditure. The evidence suggests that downstream melanocortin-responsive circuits responsible for different physiological actions do diverge. Ultimately, a more complete understanding of melanocortin pathways and their myriad roles should allow treatments tailored to the mix of metabolic disorders in the individual patient.
27721750	The striatum is an important subcortical structure with extensive connections to other regions of the brain. These connections are believed to play important roles in behaviors such as reward-related processes and impulse control, which show significant sex differences. However, little is known about sex differences in the striatum-projected fiber connectivity. The current study examined sex differences between 50 Chinese males and 79 Chinese females in their fiber connections between the striatum and nine selected cortical and subcortical regions. Despite overall similarities, males showed stronger fiber connections between the left caudate and rostral cingulate cortex, between the right putamen and the lateral orbitofrontal cortex, between the bilateral putamen and the ventro-lateral prefrontal cortex, and between the right caudate and the ventro-lateral prefrontal cortex, whereas females showed stronger fiber connections between the right putamen and the dorsolateral prefrontal cortex, between bilateral caudate and hippocampus, and between the left putamen and hippocampus. These findings help us to understand sex differences in the striatum-projected fiber connections and their implications for sex differences in behaviors.
27719874	Placebos have long been considered a nuisance in clinical research, for they have always been used as comparators for the validation of new treatments. By contrast, today they represent an active field of research, and, due to the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. There is not a single placebo effect, but many, with different mechanisms across different medical conditions and therapeutic interventions. Expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena and genetic variants. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinson's disease. In these medical conditions, several neurotransmitters have been identified, such as endogenous opioids, cholecystokinin, dopamine, as well as lipidic mediators, for example, endocannabinoids and prostaglandins. Since the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and therapeutic rituals, may change the chemistry of the patient's brain, and these effects are similar to those induced by drugs.
27716545	Individuals with substance abuse (SA) histories show impairment in the computations necessary for decision-making, including expected value (EV) and prediction error (PE). Neuroimaging findings, however, have been inconsistent. Sixteen youth with (SApositive) and 29 youth without (SAnegative) substance abuse histories completed a passive avoidance task while undergoing functional MRI. The groups did not significantly differ on age, gender composition or IQ. Behavioral results indicated that SApositive youth showed significantly less learning than SAnegative youth over the task. SApositive youth show problems representing EV information when attempting to avoid sub-optimal choices in bilateral inferior frontal gyrus and striatum. Furthermore, SApositive youth showed a significantly increased differential response to reward versus punishment feedback modulated by PE in posterior cingulate cortex relative to SAnegative youth. Disrupted decision-making is likely to exacerbate SA as a failure to represent EV during the avoidance of sub-optimal choices is likely to increase the likelihood of SA. With respect to the representation of PE, future work will be needed to clarify the impact of different substances on the neural systems underpinning PE representation. Moreover, interaction of age/development and substance abuse on PE signaling will need to be explored.
27715426	Caffeine is a plant-derived alkaloid that is generally known as a central nervous system (CNS) stimulant. In order to examine the effects of caffeine on higher CNS functions in insects, we used an appetitive olfactory learning paradigm for the cricket Gryllus bimaculatus. Crickets can form significant long-term memories (LTMs) after repetitive training sessions, during which they associate a conditioned stimulus (CS: odor) with an unconditioned stimulus (US: reward). Administration of hemolymphal injections of caffeine established LTM after only single-trial conditioning over a wide range of caffeine dosages (1.6 µµg/kg to 39 mg/kg). We investigated the physiological mechanisms underlying this enhancement of olfactory learning performance pharmacologically, focusing on three major physiological roles of caffeine: 1) inhibition of phosphodiesterase (PDE), 2) agonism of ryanodine receptors, and 3) antagonism of adenosine receptors. Application of drugs relevant to these actions resulted in significant effects on LTM formation. These results suggest that externally applied caffeine enhances LTM formation in insect olfactory learning via multiple cellular mechanisms.
27710793	Adolescents are notorious for engaging in reward-seeking behaviors, a tendency attributed to heightened activity in the brain's reward systems during adolescence. It has been suggested that reward sensitivity in adolescence might be adaptive, but evidence of an adaptive role has been scarce. Using a probabilistic reinforcement learning task combined with reinforcement learning models and fMRI, we found that adolescents showed better reinforcement learning and a stronger link between reinforcement learning and episodic memory for rewarding outcomes. This behavioral benefit was related to heightened prediction error-related BOLD activity in the hippocampus and to stronger functional connectivity between the hippocampus and the striatum at the time of reinforcement. These findings reveal an important role for the hippocampus in reinforcement learning in adolescence and suggest that reward sensitivity in adolescence is related to adaptive differences in how adolescents learn from experience.
27710782	Adolescence is a time of tumultuous behavior that may result, in part, from brain circuitry that enhances reward seeking. In this issue of Neuron, Davidow et al. (2016) present a convincing argument that adolescent brain functionality can be adaptive in certain contexts, particularly probabilistic learning environments.
27709065	Motivational signals influence a wide variety of cognitive processes and components of behavioral performance. Cognitive dysfunction in patients with childhood chronic fatigue syndrome (CCFS) may be closely associated with a low motivation to learn induced by impaired neural reward processing. However, the extent to which reward processing is impaired in CCFS patients is unclear. The aim of the present functional magnetic resonance imaging (fMRI) study was to determine whether brain activity in regions related to reward sensitivity is impaired in CCFS patients. fMRI data were collected from 13 CCFS patients (mean age, 13.6 ± 1.0 years) and 13 healthy children and adolescents (HCA) (mean age, 13.7 ± 1.3 years) performing a monetary reward task. Neural activity in high- and low-monetary-reward conditions was compared between CCFS and HCA groups. Severity of fatigue and the reward obtained from learning in daily life were evaluated by questionnaires. Activity of the putamen was lower in the CCFS group than in the HCA group in the low-reward condition, but not in the high-reward condition. Activity of the putamen in the low-reward condition in CCFS patients was negatively and positively correlated with severity of fatigue and the reward from learning in daily life, respectively. We previously revealed that motivation to learn was correlated with striatal activity, particularly the neural activity in the putamen. This suggests that in CCFS patients low putamen activity, associated with altered dopaminergic function, decreases reward sensitivity and lowers motivation to learn.
27708101	Whether invertebrates exhibit positive emotion-like states and what mechanisms underlie such states remain poorly understood. We demonstrate that bumblebees exhibit dopamine-dependent positive emotion-like states across behavioral contexts. After training with one rewarding and one unrewarding cue, bees that received pretest sucrose responded in a positive manner toward ambiguous cues. In a second experiment, pretest consumption of sucrose solution resulted in a shorter time to reinitiate foraging after a simulated predator attack. These behavioral changes were abolished with topical application of the dopamine antagonist fluphenazine. Further experiments established that pretest sucrose does not simply cause bees to become more exploratory. Our findings present a new opportunity for understanding the fundamental neural elements of emotions and may alter the view of how emotion states affect decision-making in animals.
27707960	The endocannabinoid (eCB) system has emerged as one of the most important mediators of physiological and pathological reward-related synaptic plasticity. eCBs are retrograde messengers that provide feedback inhibition, resulting in the suppression of neurotransmitter release at both excitatory and inhibitory synapses, and they serve a critical role in the spatiotemporal regulation of both short- and long-term synaptic plasticity that supports adaptive learning of reward-motivated behaviors. However, mechanisms of eCB-mediated synaptic plasticity in reward areas of the brain are impaired following exposure to drugs of abuse. Because of this, it is theorized that maladaptive eCB signaling may contribute to the development and maintenance of addiction-related behavior. Here we review various forms of eCB-mediated synaptic plasticity present in regions of the brain involved in reward and reinforcement and explore the potential physiological relevance of maladaptive eCB signaling to addiction vulnerability.
27705742	Correlates of value are routinely observed in the prefrontal cortex (PFC) during reward-guided decision making. In previous work (Hunt et al., 2015), we argued that PFC correlates of chosen value are a consequence of varying rates of a dynamical evidence accumulation process. Yet within PFC, there is substantial variability in chosen value correlates across individual neurons. Here we show that this variability is explained by neurons having different temporal receptive fields of integration, indexed by examining neuronal spike rate autocorrelation structure whilst at rest. We find that neurons with protracted resting temporal receptive fields exhibit stronger chosen value correlates during choice. Within orbitofrontal cortex, these neurons also sustain coding of chosen value from choice through the delivery of reward, providing a potential neural mechanism for maintaining predictions and updating stored values during learning. These findings reveal that within PFC, variability in temporal specialisation across neurons predicts involvement in specific decision-making computations.
27703101	Midbrain dopamine neurons are activated by reward and sensory cue that predicts reward. Their responses resemble reward prediction error that indicates the discrepancy between obtained and expected reward values, which has been thought to play an important role as a teaching signal in reinforcement learning. Indeed, pharmacological blockade of dopamine transmission interferes with reinforcement learning. Recent studies reported, however, that not all dopamine neurons transmit the reward-related signal. They found that a subset of dopamine neurons transmits signals related to non-rewarding, salient experiences such as aversive stimulations and cognitively demanding events. How these signals contribute to animal behavior is not yet well understood. This article reviews recent findings on dopamine signals related to rewarding and non-rewarding experiences, and discusses their contributions to reinforcement learning.
27701411	Social insects make elaborate use of simple mechanisms to achieve seemingly complex behavior and may thus provide a unique resource to discover the basic cognitive elements required for culture, i.e., group-specific behaviors that spread from "innovators" to others in the group via social learning. We first explored whether bumblebees can learn a nonnatural object manipulation task by using string pulling to access a reward that was presented out of reach. Only a small minority "innovated" and solved the task spontaneously, but most bees were able to learn to pull a string when trained in a stepwise manner. In addition, naïve bees learnt the task by observing a trained demonstrator from a distance. Learning the behavior relied on a combination of simple associative mechanisms and trial-and-error learning and did not require "insight": naïve bees failed a "coiled-string experiment," in which they did not receive instant visual feedback of the target moving closer when tugging on the string. In cultural diffusion experiments, the skill spread rapidly from a single knowledgeable individual to the majority of a colony's foragers. We observed that there were several sequential sets ("generations") of learners, so that previously naïve observers could first acquire the technique by interacting with skilled individuals and, subsequently, themselves become demonstrators for the next "generation" of learners, so that the longevity of the skill in the population could outlast the lives of informed foragers. This suggests that, so long as animals have a basic toolkit of associative and motor learning processes, the key ingredients for the cultural spread of unusual skills are already in place and do not require sophisticated cognition.
27699943	Anhedonia, or loss of interest or pleasure in usual activities, is characteristic of depression, some types of anxiety, as well as substance abuse and schizophrenia. Anhedonia is a predictor of poor long-term outcomes, including suicide, and poor treatment response. Because extant psychological and pharmacological treatments are relatively ineffective for anhedonia, there is an unmet therapeutic need for this high-risk symptom. Current psychological and drug treatments for anxiety and depression focus largely on reducing excesses in negative affect rather than improving deficits in positive affect. Recent advances in affective neuroscience posit that anhedonia is associated with deficits in the appetitive reward system, specifically the anticipation, consumption, and learning of reward. In this paper, we review the evidence for positive affect as a symptom cluster, and its neural underpinnings, and introduce a novel psychological treatment for anxiety and depression that targets appetitive responding. First, we review anhedonia in relation to positive and negative valence systems and current treatment approaches. Second, we discuss the evidence linking anhedonia to biological, experiential, and behavioral deficits in the reward subsystems. Third, we describe the therapeutic approach for Positive Affect Treatment (PAT), an intervention designed to specifically target deficits in reward sensitivity.
27699501	Honey bees (Apis mellifera) are prone to judge an ambiguous stimulus negatively if they had been agitated through shaking which simulates a predator attack. Such a cognitive bias has been suggested to reflect an internal emotional state analogous to humans who judge more pessimistically when they do not feel well. In order to test cognitive bias experimentally, an animal is conditioned to respond to two different stimuli, where one is punished while the other is rewarded. Subsequently a third, ambiguous stimulus is presented and it is measured whether the subject responds as if it expects a reward or a punishment. Generally, it is assumed that negative experiences lower future expectations, rendering the animals more pessimistic. Here we tested whether a most likely negatively experienced formic acid treatment against the parasitic mite Varroa destructor also affects future expectations of honey bees. We applied an olfactory learning paradigm (i.e., conditioned proboscis extension response) using two odorants and blends of these odorants as the ambiguous stimuli. Unlike agitating honey bees, exposure to formic acid did not significantly change the response to the ambiguous stimuli in comparison with untreated bees. Overall evidence suggests that the commonest treatment against one of the most harmful bee pests has no detrimental effects on cognitive bias in honey bees.
27699148	Internet gaming disorder (IGD) is characterized by high levels of craving for online gaming and related cues. Since addiction-related cues can evoke increased activation in brain areas involved in motivational and reward processing and may engender gaming behaviors or trigger relapse, ameliorating cue-induced craving may be a promising target for interventions for IGD. This study compared neural activation between 40 IGD and 19 healthy control (HC) subjects during an Internet-gaming cue-reactivity task and found that IGD subjects showed stronger activation in multiple brain areas, including the dorsal striatum, brainstem, substantia nigra, and anterior cingulate cortex, but lower activation in the posterior insula. Furthermore, twenty-three IGD subjects (CBI + group) participated in a craving behavioral intervention (CBI) group therapy, whereas the remaining 17 IGD subjects (CBI - group) did not receive any intervention, and all IGD subjects were scanned during similar time intervals. The CBI + group showed decreased IGD severity and cue-induced craving, enhanced activation in the anterior insula and decreased insular connectivity with the lingual gyrus and precuneus after receiving CBI. These findings suggest that CBI is effective in reducing craving and severity in IGD, and it may exert its effects by altering insula activation and its connectivity with regions involved in visual processing and attention bias.
27696399	Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure. Metabolomics conducted on cortical tissue established that acute exposure to toluene produces alterations in cellular metabolism indicative of a glutamatergic and GABAergic profile. Similarly, in vitro electrophysiology in Xenopus oocytes found that acute toluene exposure reduced NMDA receptor signalling. Finally, in an adolescent rodent model of chronic intermittent exposure to toluene (10 000 ppm), we found that, while toluene exposure did not affect initial learning, it induced a deficit in updating that learning when response-outcome relationships were reversed or degraded in an instrumental conditioning paradigm. There were also group differences when more effort was required to obtain the reward; toluene-exposed animals were less sensitive to progressive ratio schedules and to delayed discounting. These behavioural deficits were accompanied by changes in subunit expression of both NMDA and GABA receptors in adulthood, up to 10 weeks after the final exposure to toluene in the hippocampus, prefrontal cortex and ventromedial striatum; regions with recognized roles in behavioural flexibility and decision-making. Collectively, our data suggest that exposure to toluene is sufficient to induce adaptive changes in glutamatergic and GABAergic systems and in adaptive behaviour that may underlie the deficits observed following adolescent inhalant abuse, including susceptibility to further drug-use.
27694969	Gelotophobics have social deficits in the form of relative humorlessness and heightened sensitivity to aggressive humor; however, little is known about the neural reward mechanisms for this group. The present study attempted to identify the neural substrates of responses to hostile and non-hostile jokes in gelotophobics and non-gelotophobics. Gelotophobics showed greater activation than did non-gelotophobics in the dorsal corticostriatal system, which comprises the dorsolateral prefrontal cortex and dorsal striatum, suggesting a higher degree of voluntary top-down cognitive control of emotion. As expected, gelotophobics showed less activation in the ventral mesocorticolimbic system (MCL) in response to both hostile and non-hostile jokes, suggesting a relative deficit in the reward system. Conversely, non-gelotophobics displayed greater activation than gelotophobics did in the MCL system, particularly for non-hostile jokes, which suggests a more robust bottom-up emotional response. In response to non-hostile jokes, non-gelotophobics showed greater activation in the ventral MCL reward system, which comprises the midbrain, amygdalae, nucleus accumbens, ventral anterior cingulate cortex, and insula. Psychophysiological interaction analyses further showed that gelotophobics exhibited diminished MCL activation in response to hostile jokes. These group differences may have important implications for our understanding of the neural correlates of social motivation and humor appreciation.
27694920	Feedback information is essential for us to adapt appropriately to the environment. The feedback-related negativity (FRN), a frontocentral negative deflection after the delivery of feedback, has been found to be larger for outcomes that are worse than expected, and it reflects a reward prediction error derived from the midbrain dopaminergic projections to the anterior cingulate cortex (ACC), as stated in reinforcement learning theory. In contrast, the prediction of response-outcome (PRO) model claims that the neural activity in the mediofrontal cortex (mPFC), especially the ACC, is sensitive to the violation of expectancy, irrespective of the valence of feedback. Additionally, increasing evidence has demonstrated significant activities in the striatum, anterior insula and occipital lobe for unexpected outcomes independently of their valence. Thus, the neural mechanism of the feedback remains under dispute. Here, we investigated the feedback with monetary reward and electrical pain shock in one task via functional magnetic resonance imaging. The results revealed significant prediction-error-related activities in the bilateral fusiform gyrus, right middle frontal gyrus and left cingulate gyrus for both money and pain. This implies that some regions underlying the feedback may signal a salience prediction error rather than a reward prediction error.
27687121	Social cognition is a topic of enormous interest and much research, but we are far from having an agreed taxonomy or factor structure of relevant processes. The aim of this review is to outline briefly what is known about the structure of social cognition and to suggest how further progress can be made to delineate the in(ter)dependence of core sociocognitive processes. We focus in particular on several processes that have been discussed and tested together in typical and atypical (notably autism spectrum disorder) groups: imitation, biological motion, empathy, and theory of mind. We consider the domain specificity/generality of core processes in social learning, reward, and attention, and we highlight the potential relevance of dual-process theories that distinguish systems for fast/automatic and slow/effortful processing. We conclude with methodological and conceptual suggestions for future progress in uncovering the structure of social cognition.
27687119	In this review, we summarize findings supporting the existence of multiple behavioral strategies for controlling reward-related behavior, including a dichotomy between the goal-directed or model-based system and the habitual or model-free system in the domain of instrumental conditioning and a similar dichotomy in the realm of Pavlovian conditioning. We evaluate evidence from neuroscience supporting the existence of at least partly distinct neuronal substrates contributing to the key computations necessary for the function of these different control systems. We consider the nature of the interactions between these systems and show how these interactions can lead to either adaptive or maladaptive behavioral outcomes. We then review evidence that an additional system guides inference concerning the hidden states of other agents, such as their beliefs, preferences, and intentions, in a social context. We also describe emerging evidence for an arbitration mechanism between model-based and model-free reinforcement learning, placing such a mechanism within the broader context of the hierarchical control of behavior.
27683899	Given that the range of rewarding and punishing outcomes of actions is large but neural coding capacity is limited, efficient processing of outcomes by the brain is necessary. One mechanism to increase efficiency is to rescale neural output to the range of outcomes expected in the current context, and process only experienced deviations from this expectation. However, this mechanism comes at the cost of not being able to discriminate between unexpectedly low losses when times are bad versus unexpectedly high gains when times are good. Thus, too much adaptation would result in disregarding information about the nature and absolute magnitude of outcomes, preventing learning about the longer-term value structure of the environment. Here we investigate the degree of adaptation in outcome coding brain regions in humans, for directly experienced outcomes and observed outcomes. We scanned participants while they performed a social learning task in gain and loss blocks. Multivariate pattern analysis showed two distinct networks of brain regions adapt to the most likely outcomes within a block. Frontostriatal areas adapted to directly experienced outcomes, whereas lateral frontal and temporoparietal regions adapted to observed social outcomes. Critically, in both cases, adaptation was incomplete and information about whether the outcomes arose in a gain block or a loss block was retained. Univariate analysis confirmed incomplete adaptive coding in these regions but also detected nonadapting outcome signals. Thus, although neural areas rescale their responses to outcomes for efficient coding, they adapt incompletely and keep track of the longer-term incentives available in the environment.Optimal value-based choice requires that the brain precisely and efficiently represents positive and negative outcomes. One way to increase efficiency is to adapt responding to the most likely outcomes in a given context. However, too strong adaptation would result in loss of precise representation (e.g., when the avoidance of a loss in a loss-context is coded the same as receipt of a gain in a gain-context). We investigated an intermediate form of adaptation that is efficient while maintaining information about received gains and avoided losses. We found that frontostriatal areas adapted to directly experienced outcomes, whereas lateral frontal and temporoparietal regions adapted to observed social outcomes. Importantly, adaptation was intermediate, in line with influential models of reference dependence in behavioral economics.	
27683883	It is well documented that variability in motor performance decreases with practice, yet the neural and computational mechanisms that underlie this decline, particularly during long-term practice, are little understood. Decreasing variability is frequently examined in terms of error corrections from one trial to the next. However, the ubiquitous noise from all levels of the sensorimotor system is also a significant contributor to overt variability. While neuromotor noise is typically assumed and modeled as immune to practice, the present study challenged this notion. We investigated the long-term practice of a novel motor skill to test whether neuromotor noise can be attenuated, specifically when aided by reward. Results showed that both reward and self-guided practice over 11 days improved behavior by decreasing noise rather than effective error corrections. When the challenge for obtaining reward increased, subjects reduced noise even further. Importantly, when task demands were relaxed again, this reduced level of noise persisted for 5 days. A stochastic learning model replicated both the attenuation and persistence of noise by scaling the noise amplitude as a function of reward. More insight into variability and intrinsic noise and its malleability has implications for training and rehabilitation interventions.
27677776	Data from experimental animals and human subjects has provided convergent evidence for the key role of the striatum in the formation of stimulus-response habits. Habits can be distinguished from associative memories that support goal-directed actions based on their insensitivity to reward devaluation and contingency degradation. Behavior on many instrumental learning tasks can be supported by both declarative knowledge and habits, and these contributions shift with the amount of training. This shift appears to be accompanied by the involvement of different cortico-striatal loops in controlling behavior. Factors that encourage the shift toward and maintenance of habits include learning under conditions of stress, distraction, and interval or probabilistic schedules of reinforcement.
27676446	Core deficits in social functioning are associated with various neuropsychiatric and neurodevelopmental disorders, yet biomarker identification and the development of effective pharmacological interventions has been limited. Recent data suggest the intriguing possibility that endogenous cannabinoids, a class of lipid neuromodulators generally implicated in the regulation of neurotransmitter release, may contribute to species-typical social functioning. Systematic study of the endogenous cannabinoid signaling could, therefore, yield novel approaches to understand the neurobiological underpinnings of atypical social functioning. This article provides a critical review of the major components of the endogenous cannabinoid system (for example, primary receptors and effectors-Δ9-tetrahydrocannabinol, cannabidiol, anandamide and 2-arachidonoylglycerol) and the contributions of cannabinoid signaling to social functioning. Data are evaluated in the context of Research Domain Criteria constructs (for example, anxiety, chronic stress, reward learning, motivation, declarative and working memory, affiliation and attachment, and social communication) to enable interrogation of endogenous cannabinoid signaling in social functioning across diagnostic categories. The empirical evidence reviewed strongly supports the role for dysregulated cannabinoid signaling in the pathophysiology of social functioning deficits observed in brain disorders, such as autism spectrum disorder, schizophrenia, major depressive disorder, posttraumatic stress disorder and bipolar disorder. Moreover, these findings indicate that the endogenous cannabinoid system holds exceptional promise as a biological marker of, and potential treatment target for, neuropsychiatric and neurodevelopmental disorders characterized by impairments in social functioning.
27672359	The activity of the epigenetic writers DNA methyltransferases (Dnmts) after olfactory reward conditioning is important for both stimulus-specific long-term memory (LTM) formation and extinction. It, however, remains unknown which components of memory formation Dnmts regulate (e.g., associative vs. non-associative) and in what context (e.g., varying training conditions). Here, we address these aspects in order to clarify the role of Dnmt-mediated DNA methylation in memory formation. We used a pharmacological Dnmt inhibitor and classical appetitive conditioning in the honeybee Apis mellifera, a well characterized model for classical conditioning. We quantified the effect of DNA methylation on naïve odor and sugar responses, and on responses following olfactory reward conditioning. We show that (1) Dnmts do not influence naïve odor or sugar responses, (2) Dnmts do not affect the learning of new stimuli, but (3) Dnmts influence odor-coding, i.e., 'correct' (stimulus-specific) LTM formation. Particularly, Dnmts reduce memory specificity when experience is low (one-trial training), and increase memory specificity when experience is high (multiple-trial training), generating an ecologically more useful response to learning. (4) In reversal learning conditions, Dnmts are involved in regulating both excitatory (re-acquisition) and inhibitory (forgetting) processes. 
27671733	In humans, activation of the ventral striatum, a region associated with reward processing, is associated with the extinction of fear, a goal in the treatment of fear-related disorders. This evidence suggests that extinction of aversive memories engages reward-related circuits, but a causal relationship between activity in a reward circuit and fear extinction has not been demonstrated. Here, we identify a basolateral amygdala (BLA)-ventral striatum (NAc) pathway that is activated by extinction training. Enhanced recruitment of this circuit during extinction learning, either by pairing reward with fear extinction training or by optogenetic stimulation of this circuit during fear extinction, reduces the return of fear that normally follows extinction training. Our findings thus identify a specific BLA-NAc reward circuit that can regulate the persistence of fear extinction and point toward a potential therapeutic target for disorders in which the return of fear following extinction therapy is an obstacle to treatment.
27671661	The basal ganglia (BG) network has been divided into interacting actor and critic components, modulating the probabilities of different state-action combinations through learning. Most models of learning and decision making in the BG focus on the roles of the striatum and its dopaminergic inputs, commonly overlooking the complexities and interactions of BG downstream nuclei. In this study, we aimed to reveal the learning-related activity of the external segment of the globus pallidus (GPe), a downstream structure whose computational role has remained relatively unexplored. Recording from monkeys engaged in a deterministic three-choice reversal learning task, we found that changes in GPe discharge rates predicted subsequent behavioral shifts on a trial-by-trial basis. Furthermore, the activity following the shift encoded whether it resulted in reward or not. The frequent changes in stimulus-outcome contingencies (i.e., reversals) allowed us to examine the learning-related neural activity and show that GPe discharge rates closely matched across-trial learning dynamics. Additionally, firing rates exhibited a linear decrease in sequences of correct responses, possibly reflecting a gradual shift from goal-directed execution to automaticity. Thus, modulations in GPe spiking activity are highest for attention-demanding aspects of behavior (i.e., switching choices) and decrease as attentional demands decline (i.e., as performance becomes automatic). These findings are contrasted with results from striatal tonically active neurons, which show none of these task-related modulations. Our results demonstrate that GPe, commonly studied in motor contexts, takes part in cognitive functions, in which movement plays a marginal role.
27669988	Dorsal anterior cingulate cortex (dACC) carries a wealth of value-related information necessary for regulating behavioral flexibility and persistence. It signals error and reward events informing decisions about switching or staying with current behavior. During decision-making, it encodes the average value of exploring alternative choices (search value), even after controlling for response selection difficulty, and during learning, it encodes the degree to which internal models of the environment and current task must be updated. dACC value signals are derived in part from the history of recent reward integrated simultaneously over multiple time scales, thereby enabling comparison of experience over the recent and extended past. Such ACC signals may instigate attentionally demanding and difficult processes such as behavioral change via interactions with prefrontal cortex. However, the signal in dACC that instigates behavioral change need not itself be a conflict or difficulty signal. 
27658676	A recent study found that guppies (Poecilia reticulata) can be trained to discriminate 4 versus 5 objects, a numerical discrimination typically achieved only by some mammals and birds. In that study, guppies were required to discriminate between two patches of small objects on the bottom of the tank that they could remove to find a food reward. It is not clear whether this species possesses exceptional numerical accuracy compared with the other ectothermic vertebrates or whether its remarkable performance was due to a specific predisposition to discriminate between differences in the quality of patches while foraging. To disentangle these possibilities, we trained guppies to the same numerical discriminations with a more conventional two-choice discrimination task. Stimuli were sets of dots presented on a computer screen, and the subjects received a food reward upon approaching the set with the larger numerosity. Though the cognitive problem was identical in the two experiments, the change in the experimental setting led to a much poorer performance as most fish failed even the 2 versus 3 discrimination. In four additional experiments, we varied the duration of the decision time, the type of stimuli, the length of training, and whether correction was allowed in order to identify the factors responsible for the difference. None of these parameters succeeded in increasing the performance to the level of the previous study, although the group trained with three-dimensional stimuli learned the easiest numerical task. We suggest that the different results with the two experimental settings might be due to constraints on learning and that guppies might be prepared to accurately estimate patch quality during foraging but not to learn an abstract stimulus-reward association.
27658428	A computer-based game, named Timo's Adventure, was developed to assess specific cognitive functions (eg, attention, planning, and working memory), time perception, and reward mechanisms in young school-aged children. The game consists of 6 mini-games embedded in a story line and includes fantasy elements to enhance motivation.The aim of this study was to investigate the validity of Timo's Adventure in normally developing children and in children with attention-deficit/hyperactivity disorder (ADHD).	A total of 96 normally developing children aged 4-8 years and 40 children with ADHD were assessed using the game. Clinical validity was investigated by examining the effects of age on performances within the normally developing children, as well as performance differences between the healthy controls and the ADHD group.	Our analyses in the normally developing children showed developmental effects; that is, older children made fewer inhibition mistakes (r=-.33, P=.001), had faster (and therefore better) reaction times (r=-.49, P<.001), and were able to produce time intervals more accurately than younger children (ρ=.35, P<.001). Discriminant analysis showed that Timo's Adventure was accurate in most classifications whether a child belonged to the ADHD group or the normally developing group: 78% (76/97) of the children were correctly classified as having ADHD or as being in the normally developing group. The classification results showed that 72% (41/57) children in the control group were correctly classified, and 88% (35/40) of the children in the ADHD group were correctly classified as having ADHD. Sensitivity (0.89) and specificity (0.69) of Timo's Adventure were satisfying.	Computer-based games seem to be a valid tool to assess specific strengths and weaknesses in young children with ADHD.	
27656032	Experience with sexual behavior causes cross-sensitization of amphetamine reward, an effect dependent on a period of sexual reward abstinence. We previously showed that ΔFosB in the nucleus accumbens (NAc) is a key mediator of this cross-sensitization, potentially via dopamine receptor activation. However, the role of mesolimbic dopamine for sexual behavior or cross-sensitization between natural and drug reward is unknown. This was tested using inhibitory designer receptors exclusively activated by designer drugs in ventral tegmental area (VTA) dopamine cells. rAAV5/hSvn-DIO-hm4D-mCherry was injected into the VTA of TH::Cre adult male rats. Males received clozapine N-oxide (CNO) or vehicle injections before each of 5 consecutive days of mating or handling. Following an abstinence period of 7 d, males were tested for amphetamine conditioned place preference (CPP). Next, males were injected with CNO or vehicle before mating or handling for analysis of mating-induced cFos, sex experience-induced ΔFosB, and reduction of VTA dopamine soma size. Results showed that CNO did not affect mating behavior. Instead, CNO prevented sexual experience-induced cross-sensitization of amphetamine CPP, ΔFosB in the NAc and medial prefrontal cortex, and decreases in VTA dopamine soma size. Expression of hm4D-mCherry was specific to VTA dopamine cells and CNO blocked excitation and mating-induced cFos expression in VTA dopamine cells. These findings provide direct evidence that VTA dopamine activation is not required for initiation or performance of sexual behavior. Instead, VTA dopamine directly contributes to increased vulnerability for drug use following loss of natural reward by causing neuroplasticity in the mesolimbic pathway during the natural reward experience.Drugs of abuse act on the neural pathways that mediate natural reward learning and memory. Exposure to natural reward behaviors can alter subsequent drug-related reward. Specifically, experience with sexual behavior, followed by a period of abstinence from sexual behavior, causes increased reward for amphetamine in male rats. This study demonstrates that activation of ventral tegmental area dopamine neurons during sexual experience regulates cross-sensitization of amphetamine reward. Finally, ventral tegmental area dopamine cell activation is essential for experience-induced neural adaptations in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. These findings demonstrate a role of mesolimbic dopamine in the interaction between natural and drug rewards, and identify mesolimbic dopamine as a key mediator of changes in vulnerability for drug use after loss of natural reward.	
27656023	Real-world decisions are typically made between options that vary along multiple dimensions, requiring prioritization of the important dimensions to support optimal choice. Learning in this setting depends on attributing decision outcomes to the dimensions with predictive relevance rather than to dimensions that are irrelevant and nonpredictive. This attribution problem is computationally challenging, and likely requires an interplay between selective attention and reward learning. Both these processes have been separately linked to the prefrontal cortex, but little is known about how they combine to support learning the reward value of multidimensional stimuli. Here, we examined the necessary contributions of frontal lobe subregions in attributing feedback to relevant and irrelevant dimensions on a trial-by-trial basis in humans. Patients with focal frontal lobe damage completed a demanding reward learning task where options varied on three dimensions, only one of which predicted reward. Participants with left lateral frontal lobe damage attributed rewards to irrelevant dimensions, rather than the relevant dimension. Damage to the ventromedial frontal lobe also impaired learning about the relevant dimension, but did not increase reward attribution to irrelevant dimensions. The results argue for distinct roles for these two regions in learning the value of multidimensional decision options under dynamic conditions, with the lateral frontal lobe required for selecting the relevant dimension to associate with reward, and the ventromedial frontal lobe required to learn the reward association itself.The real world is complex and multidimensional; how do we attribute rewards to predictive features when surrounded by competing cues? Here, we tested the critical involvement of human frontal lobe subregions in a probabilistic, multidimensional learning environment, asking whether focal lesions affected trial-by-trial attribution of feedback to relevant and irrelevant dimensions. The left lateral frontal lobe was required for filtering option dimensions to allow appropriate feedback attribution, while the ventromedial frontal lobe was necessary for learning the value of features in the relevant dimension. These findings argue that selective attention and associative learning processes mediated by anatomically distinct frontal lobe subregions are both critical for adaptive choice in more complex, ecologically valid settings.	
27649777	Modafinil is becoming increasingly popular as a cognitive enhancer. Research on the effects of modafinil on cognitive function have yielded mixed results, with negative findings for simple memory and attention tasks and enhancing effects for more complex tasks. In the present study we examined whether modafinil, due to its known effect on the dopamine level in the striatum, alters feedback-related choice behaviour. We applied a task that separately tests the choice of previously rewarded behaviours (approach) and avoidance of previously punished behaviours. 18 participants received a single dose of 200 mg modafinil. Their performance was compared to a group of 22 participants who received placebo in a double-blind design. Modafinil but not placebo induced a significant bias towards approach behaviour as compared to the frequency of avoidance behaviour. General attention, overall feedback-based acquisition of choice behaviour and reaction times in high vs low conflict choices were not significantly affected by modafinil. This finding suggests that modafinil has a specific effect on dopamine-mediated choice behaviour based on the history of feedback, while a contribution of noradrenaline is also conceivable. The described change in decision making cannot be considered as cognitive enhancement, but might rather have detrimental effects on decisions in everyday life.
27644419	Humans constantly learn in the absence of explicit rewards. However, the neurobiological mechanisms supporting this type of internally-guided learning (without explicit feedback) are still unclear. Here, participants who completed a task in which no external reward/feedback was provided, exhibited enhanced fMRI-signals within the dopaminergic midbrain, hippocampus, and ventral striatum (the SN/VTA-Hippocampal loop) when successfully grasping the meaning of new-words. Importantly, new-words that were better remembered showed increased activation and enhanced functional connectivity between the midbrain, hippocampus, and ventral striatum. Moreover, enhanced emotion-related physiological measures and subjective pleasantness ratings during encoding were associated with remembered new-words after 24 hr. Furthermore, increased subjective pleasantness ratings were also related to new-words remembered after seven days. These results suggest that intrinsic-potentially reward-related-signals, triggered by self-monitoring of correct performance, can promote the storage of new information into long-term memory through the activation of the SN/VTA-Hippocampal loop, possibly via dopaminergic modulation of the midbrain. 
27639719	The goal of reinforcement learning is to learn an optimal policy which controls an agent to acquire the maximum cumulative reward. The model-based reinforcement learning approach learns a transition model of the environment from data, and then derives the optimal policy using the transition model. However, learning an accurate transition model in high-dimensional environments requires a large amount of data which is difficult to obtain. To overcome this difficulty, in this paper, we propose to combine model-based reinforcement learning with the recently developed least-squares conditional entropy (LSCE) method, which simultaneously performs transition model estimation and dimension reduction. We also further extend the proposed method to imitation learning scenarios. The experimental results show that policy search combined with LSCE performs well for high-dimensional control tasks including real humanoid robot control.
27631963	Deficits in reinforcement-based decision making have been reported in generalized anxiety disorder. However, the pathophysiology of these deficits is largely unknown; published studies have mainly examined adolescents, and the integrity of core functional processes underpinning decision making remains undetermined. In particular, it is unclear whether the representation of reinforcement prediction error (PE) (the difference between received and expected reinforcement) is disrupted in generalized anxiety disorder. This study addresses these issues in adults with the disorder.Forty-six unmedicated individuals with generalized anxiety disorder and 32 healthy comparison subjects group-matched on IQ, gender, and age performed a passive avoidance task while undergoing functional MRI. Data analyses were performed using a computational modeling approach.	Behaviorally, individuals with generalized anxiety disorder showed impaired reinforcement-based decision making. Imaging results revealed that during feedback, individuals with generalized anxiety disorder relative to healthy subjects showed a reduced correlation between PE and activity within the ventromedial prefrontal cortex, ventral striatum, and other structures implicated in decision making. In addition, individuals with generalized anxiety disorder relative to healthy participants showed a reduced correlation between punishment PEs, but not reward PEs, and activity within the left and right lentiform nucleus/putamen.	This is the first study to identify computational impairments during decision making in generalized anxiety disorder. PE signaling is significantly disrupted in individuals with the disorder and may lead to their decision-making deficits and excessive worry about everyday problems by disrupting the online updating ("reality check") of the current relationship between the expected values of current response options and the actual received rewards and punishments.	
27629367	Both positive psychotic symptoms and anhedonia are associated with striatal functioning, but few studies have linked risk for psychotic disorders to a neural measure evoked during a striatal dopamine-related reward and punishment-based learning task, such as a reversal learning task (RLT; Cools et al, 2009). The feedback-related negativity (FRN) is a neural response that in part reflects striatal dopamine functioning. We recorded EEG during the RLT in three groups: (a) people with psychotic experiences (PE; n=20) at increased risk for psychotic disorders; (b) people with extremely elevated social anhedonia (SocAnh; n=22); and (c) controls (n=20). Behaviorally, consistent with increased striatal dopamine, the PE group exhibited better behavioral learning (ie, faster responses) after unexpected reward than after unexpected punishment. Moreover, although the control and SocAnh groups showed a larger FRN to punishment than reward, the PE group showed similar FRNs to punishment and reward, with a numerically larger FRN to reward than punishment (with similar results on these trials also found for a P3a component). These results are among the first to link a neural response evoked by a reward and punishment-based learning task specifically with elevated psychosis risk.
27628967	Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity.We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test, a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory. Dopamine synthesis capacity, indexed as the influx rate constant K i cer , was measured in 10 users and six controls with 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine positron emission tomography.	There was no significant difference in aberrant salience between the groups [F 1,32 = 1.12, p = 0.30 (implicit); F 1,32 = 1.09, p = 0.30 (explicit)]. Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r = 0.61, p = 0.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F 1,15 = 5.8, p = 0.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r = -0.91, p = 0.01), whereas this relationship was non-significant within users (difference between correlations: Z = -2.05, p = 0.04).	Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use.	
27628616	Adolescence is a critical maturation period for human cognitive control and executive function. In this study, a large sample of adolescents (n = 85) performed a reversal learning task during functional magnetic resonance imaging. We analyzed behavioral data using a reinforcement learning model to provide individually fitted parameters and imaging data with regard to reward prediction errors (PE). Following a model-based approach, we formed two groups depending on whether individuals tended to update expectations predominantly for the chosen stimulus or also for the unchosen one. These groups significantly differed in their problem behavior score obtained using the child behavior checklist (CBCL) and in a measure of their developmental stage. Imaging results showed that dorsolateral striatal areas covaried with PE. Participants who relied less on learning based on task structure showed less prefrontal activation compared with participants who relied more on task structure. An exploratory analysis revealed that PE-related activity was associated with pubertal development in prefrontal areas, insula and anterior cingulate. These findings support the hypothesis that the prefrontal cortex is implicated in mediating flexible goal-directed behavioral control.

27627826	The concepts and investigations reviewed above suggest the following * Schizophrenia is a clinical syndrome that can be deconstructed into meaningful domains of psychopathology. * Individual patients vary substantially on which domains are present as well as severity. * Negative symptoms are common in persons with schizophrenia, but only primary negative symptoms are a manifestation of schizophrenia psychopathology in the "weakening of the wellsprings of volition" sense that Kraepelin described. * The failure to distinguish primary from secondary negative symptoms has profound consequences as viewed in the vast majority of clinical trials that report negative symptom efficacy without regard for causation and without controlling for pseudospecificity. * Schizophrenia is now broadly defined with positive psychotic symptoms, and a subgroup with primary negative symptoms is a candidate disease entity. * Evidence of negative symptoms as a taxon supports the separate classification of persons with primary negative symptoms. * Negative symptoms are an unmet therapeutic need. * Two factors best define the negative symptom construct and these may have different pathophysiological and treatment implications. * The avolitional component may not be based on a diminished capacity to experience pleasure, but difficulty using mental representations of affective value to guide decision-making and goal-directed behavior. Part II in this volume by Strauss et al. will address the range of laboratory-based investigations of negative symptoms, clarify current hypotheses and theories concerning negative symptom pathology, and address future directions for negative symptom research and clinical care.
27624437	Deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson's disease is known to cause a subtle but important adverse impact on behaviour, with impulsivity its most widely reported manifestation. However, precisely which computational components of the decision process are modulated is not fully understood. Here we probe a number of distinct subprocesses, including temporal discount, outcome utility, instrumental learning rate, instrumental outcome sensitivity, reward-loss trade-offs, and perseveration. We tested 22 Parkinson's Disease patients both on and off subthalamic nucleus deep brain stimulation (STN-DBS), while they performed an instrumental learning task involving financial rewards and losses, and an inter-temporal choice task for financial rewards. We found that instrumental learning performance was significantly worse following stimulation, due to modulation of instrumental outcome sensitivity. Specifically, patients became less sensitive to decision values for both rewards and losses, but without any change to the learning rate or reward-loss trade-offs. However, we found no evidence that DBS modulated different components of temporal impulsivity. In conclusion, our results implicate the subthalamic nucleus in a modulation of outcome value in experience-based learning and decision-making in Parkinson's disease, suggesting a more pervasive role of the subthalamic nucleus in the control of human decision-making than previously thought. 
27623191	The incidence of pathological gambling in Parkinson's patients is significantly greater than in the general population. A correlation has been observed between dopamine agonist medication and the development of pathological gambling. However, scientists conjecture that the affected patients have underlying risk factors. Studies analysing Parkinson's patients have detected that patients who developed pathological gambling are younger, score higher on novelty-seeking tests, are more impulsive and are more likely to have a personal or family history of alcohol addiction. In addition, some genetic variations have been associated with the susceptibility of developing pathological gambling, which include mutations of DRD3, 5-HTTLPR and GRIN2B. Studies focusing on neurofunctional discrepancies between Parkinson's patients with and without pathological gambling have found increased functional activation and dopamine release in regions associated with the mesolimbic reward system. Furthermore, there is also evidence showing increased processing of reward and decreased activation elicited by punishment, suggesting altered learning processes. Furthermore, the role of deep brain stimulation of the nucleus subthalamicus (STN DBS) is controversial. In most Parkinson's patients, pathological gambling resolved after the initiation of the STN DBS, which might be explained by discontinuation or decrease in dopamine agonist medication. However, it has been also shown that some patients are more impulsive while the STN DBS is activated. These differences may depend on the DBS localization in the more limbic or motor part of the STN and their regulative effects on impulsivity. Further research is needed to clarify susceptibility factors for the development of pathological gambling in Parkinson's patients.
27622983	Circadian time-place learning (TPL) is the ability to remember both the place and biological time of day that a significant event occurred (e.g., food availability). This ability requires that a circadian clock provide phase information (a time tag) to cognitive systems involved in linking representations of an event with spatial reference memory. To date, it is unclear which neuronal substrates are critical in this process, but one candidate structure is the hippocampus (HPC). The HPC is essential for normal performance on tasks that require allocentric spatial memory and exhibits circadian rhythms of gene expression that are sensitive to meal timing. Using a novel TPL training procedure and enriched, multidimensional environment, we trained rats to locate a food reward that varied between two locations relative to time of day. After rats acquired the task, they received either HPC or SHAM lesions and were re-tested. Rats with HPC lesions were initially impaired on the task relative to SHAM rats, but re-attained high scores with continued testing. Probe tests revealed that the rats were not using an alternation strategy or relying on light-dark transitions to locate the food reward. We hypothesize that transient disruption and recovery reflect a switch from HPC-dependent allocentric navigation (learning places) to dorsal striatum-dependent egocentric spatial navigation (learning routes to a location). Whatever the navigation strategy, these results demonstrate that the HPC is not required for rats to find food in different locations using circadian phase as a discriminative cue.
27622930	Addiction is associated with changes in synaptic plasticity mediated, in part, by alterations in the trafficking and stabilization of AMPA receptors at synapses within the nucleus accumbens. Exposure to cocaine can lead to protein kinase C-mediated phosphorylation of GluA2 AMPA subunits and this phosphorylation event leads to the internalization of GluA2-containing AMPARs, which are calcium-impermeable. However, it is not clear whether this internalization is necessary for the expression of addictive phenotypes. Utilizing a mouse with a point mutation within the GluA2 subunit c-terminus, the current study demonstrates that disrupting PKC-mediated GluA2 phosphorylation potentiates reinstatement of both cue-induced cocaine seeking and cocaine conditioned reward without affecting operant learning, food self-administration or cocaine sensitization. Electrophysiological recordings revealed increased GluA2-mediated AMPA transmission as evidenced by increased sEPSC amplitude without any changes in sEPSC frequency or rectification. In support of this increase in GluA2 activity mediating the augmented cocaine reinstatement, we found that accumbal overexpression of GluA2 recapitulated this behavioral effect in wildtype mice while not altering reinstatement behavior in the GluA2 K882A knock-in mice. In addition, disrupting GluA2 phosphorylation was associated with blunted long-term depression in the nucleus accumbens, mimicking the anaplasticity seen following cocaine self-administration. Taken together these results indicate that disrupting GluA2 phosphorylation and increasing GluA2-mediated transmission in the nucleus accumbens leads to increased vulnerability to cocaine relapse. Further, these results indicate that modulating GluA2-containing AMPAR trafficking can contribute to addictive phenotypes in the absence of alterations in GluA2-lacking receptors. These results highlight the GluA2 phosphorylation site as a novel target for the development of cocaine addiction therapeutics.
27618944	We review the psychology and neuroscience of reinforcement learning (RL), which has experienced significant progress in the past two decades, enabled by the comprehensive experimental study of simple learning and decision-making tasks. However, one challenge in the study of RL is computational: The simplicity of these tasks ignores important aspects of reinforcement learning in the real world: (a) State spaces are high-dimensional, continuous, and partially observable; this implies that (b) data are relatively sparse and, indeed, precisely the same situation may never be encountered twice; furthermore, (c) rewards depend on the long-term consequences of actions in ways that violate the classical assumptions that make RL tractable. A seemingly distinct challenge is that, cognitively, theories of RL have largely involved procedural and semantic memory, the way in which knowledge about action values or world models extracted gradually from many experiences can drive choice. This focus on semantic memory leaves out many aspects of memory, such as episodic memory, related to the traces of individual events. We suggest that these two challenges are related. The computational challenge can be dealt with, in part, by endowing RL systems with episodic memory, allowing them to (a) efficiently approximate value functions over complex state spaces, (b) learn with very little data, and (c) bridge long-term dependencies between actions and rewards. We review the computational theory underlying this proposal and the empirical evidence to support it. Our proposal suggests that the ubiquitous and diverse roles of memory in RL may function as part of an integrated learning system.
27616766	Parasitic wasps can learn cues that alter their behavioral responses and increase their fitness, such as those that improve host location efficiency. Psyttalia concolor (Szépligeti) (Hymenoptera: Braconidae) is a koinobiont endoparasitoid of 14 economically important tephritid species, including the olive fruit fly, Bactrocera oleae (Rossi) (Diptera: Tephritidae). In this research, we investigated the nature of olfactory cues mediating this tritrophic interaction. First, we identified the chemical stimuli emanating from uninfested and B. oleae-infested olive fruits via solid phase microextraction and gas chromatography-mass spectrometry analyses and identified >70 volatile organic compounds (VOCs). Two of these were increased by B. oleae infestation, (E)-β-ocimene and 2-methyl-6-methylene-1,7-octadien-3-one, and four were decreased, α-pinene, β-pine ne, limonene, and β-elemene. Innate positive chemotaxis of mated P. concolor females toward these VOCs was then tested in olfactometer assays. Females were attracted only by (E)-β-ocimene, at both tested dosages, indicating an intrinsic response to this compound as a short-range attractant. Next, we tested whether mated P. concolor females could learn to respond to innately unattractive VOCs if they were first presented with a food reward. Two nonassociative controls were conducted, i.e., "odor only" and "reward only." Following training, females showed positive chemotaxis toward these VOCs in all tested combinations, with the exception of limonene, a VOC commonly produced by flowers. Control females showed no significant preferences, indicating that positive associative learning had occurred. These results clarify how learned cues can fine-tune innate responses to B. oleae-induced VOCs in this generalist parasitoid of tephritid flies.
27610576	Optogenetic studies in mice have revealed new relationships between well-defined neurons and brain functions. However, there are currently no means to achieve the same cell-type specificity in monkeys, which possess an expanded behavioral repertoire and closer anatomical homology to humans. Here, we present a resource for cell-type-specific channelrhodopsin expression in Rhesus monkeys and apply this technique to modulate dopamine activity and monkey choice behavior. These data show that two viral vectors label dopamine neurons with greater than 95% specificity. Infected neurons were activated by light pulses, indicating functional expression. The addition of optical stimulation to reward outcomes promoted the learning of reward-predicting stimuli at the neuronal and behavioral level. Together, these results demonstrate the feasibility of effective and selective stimulation of dopamine neurons in non-human primates and a resource that could be applied to other cell types in the monkey brain.
27603181	Reward is thought to enhance episodic memory formation via dopaminergic consolidation. Bunzeck, Dayan, Dolan, and Duzel [(2010). A common mechanism for adaptive scaling of reward and novelty. Human Brain Mapping, 31, 1380-1394] provided functional magnetic resonance imaging (fMRI) and behavioural evidence that reward and episodic memory systems are sensitive to the contextual value of a reward-whether it is relatively higher or lower-as opposed to absolute value or prediction error. We carried out a direct replication of their behavioural study and did not replicate their finding that memory performance associated with reward follows this pattern of adaptive scaling. An effect of reward outcome was in the opposite direction to that in the original study, with lower reward outcomes leading to better memory than higher outcomes. There was a marginal effect of reward context, suggesting that expected value affected memory performance. We discuss the robustness of the reward memory relationship to variations in reward context, and whether other reward-related factors have a more reliable influence on episodic memory.
27601269	What is distinctive about a bringing a learning perspective to moral psychology? Part of the answer lies in the remarkable transformations that have taken place in learning theory over the past two decades, which have revealed how powerful experience-based learning can be in the acquisition of abstract causal and evaluative representations, including generative models capable of attuning perception, cognition, affect, and action to the physical and social environment. When conjoined with developments in neuroscience, these advances in learning theory permit a rethinking of fundamental questions about the acquisition of moral understanding and its role in the guidance of behavior. For example, recent research indicates that spatial learning and navigation involve the formation of non-perspectival as well as ego-centric models of the physical environment, and that spatial representations are combined with learned information about risk and reward to guide choice and potentiate further learning. Research on infants provides evidence that they form non-perspectival expected-value representations of agents and actions as well, which help them to navigate the human environment. Such representations can be formed by highly-general mental processes such as causal and empathic simulation, and thus afford a foundation for spontaneous moral learning and action that requires no innate moral faculty and can exhibit substantial autonomy with respect to community norms. If moral learning is indeed integral with the acquisition and updating of casual and evaluative models, this affords a new way of understanding well-known but seemingly puzzling patterns in intuitive moral judgment-including the notorious "trolley problems."
27599017	Reinforcement learning (RL) in complex environments relies on selective attention to uncover those aspects of the environment that are most predictive of reward. Whereas previous work has focused on age-related changes in RL, it is not known whether older adults learn differently from younger adults when selective attention is required. In 2 experiments, we examined how aging affects the interaction between RL and selective attention. Younger and older adults performed a learning task in which only 1 stimulus dimension was relevant to predicting reward, and within it, 1 "target" feature was the most rewarding. Participants had to discover this target feature through trial and error. In Experiment 1, stimuli varied on 1 or 3 dimensions and participants received hints that revealed the target feature, the relevant dimension, or gave no information. Group-related differences in accuracy and RTs differed systematically as a function of the number of dimensions and the type of hint available. In Experiment 2 we used trial-by-trial computational modeling of the learning process to test for age-related differences in learning strategies. Behavior of both young and older adults was explained well by a reinforcement-learning model that uses selective attention to constrain learning. However, the model suggested that older adults restricted their learning to fewer features, employing more focused attention than younger adults. Furthermore, this difference in strategy predicted age-related deficits in accuracy. We discuss these results suggesting that a narrower filter of attention may reflect an adaptation to the reduced capabilities of the reinforcement learning system. (PsycINFO Database Record
27598687	When learning from direct experience, neurons in the primate brain have been shown to encode a teaching signal used by algorithms in artificial intelligence: the reward prediction error (PE)-the difference between how rewarding an event is, and how rewarding it was expected to be. However, in humans and other species learning often takes place by observing other individuals. Here, we show that, when humans observe other players in a card game, neurons in their rostral anterior cingulate cortex (rACC) encode both the expected value of an observed choice, and the PE after the outcome was revealed. Notably, during the same task neurons recorded in the amygdala (AMY) and the rostromedial prefrontal cortex (rmPFC) do not exhibit this type of encoding. Our results suggest that humans learn by observing others, at least in part through the encoding of observational PEs in single neurons in the rACC. 
27598058	Extensive research has documented evidence for rule learning in sequential behavior tasks in both rats and humans. We adapted the 2-choice serial multiple choice (SMC) task developed for use with rats (Fountain & Rowan, 1995a) to study sequence behavior in pigeons. Pigeons were presented with 8 disks arranged in a circular array on a touchscreen, and pecking to an illuminated disk could lead to reward. Correct responding consisted of serial patterns involving "run" chunks of 3 elements (123 234, etc.). Some pigeons experienced a violation of the chunk rule in the final chunk. Unlike rats, pigeons made fewer errors on violation chunks than run chunks, suggesting the use of low-level cues to guide choices. Removal of low-level cues and increasing the number of simultaneously illuminated disks to an 8-choice SMC task resulted in more errors on the violation chunk. Pigeons were able to use the rule when the array of disks was contracted or expanded, and when chunk length was extended to 4 and 5 elements, but not when disks were removed from or added to the array. Pigeons were also able to abstract structure from a "trill" pattern (121 232 etc.), as shown by high error rates on a violation trial. These results suggest that pigeons, like rats and humans, can abstract sequence structure, but do so primarily in the absence of specific low-level feature-based information. (PsycINFO Database Record
27596928	In the past decades, neuroimaging of humans has gained a position of status within neuroscience, and data-driven approaches and functional connectivity analyses of functional magnetic resonance imaging (fMRI) data are increasingly favored to depict the complex architecture of human brains. However, the reliability of these findings is jeopardized by too many analysis methods and sometimes too few samples used, which leads to discord among researchers. We propose a tunable consensus clustering paradigm that aims at overcoming the clustering methods selection problem as well as reliability issues in neuroimaging by means of first applying several analysis methods (three in this study) on multiple datasets and then integrating the clustering results. To validate the method, we applied it to a complex fMRI experiment involving affective processing of hundreds of music clips. We found that brain structures related to visual, reward, and auditory processing have intrinsic spatial patterns of coherent neuroactivity during affective processing. The comparisons between the results obtained from our method and those from each individual clustering algorithm demonstrate that our paradigm has notable advantages over traditional single clustering algorithms in being able to evidence robust connectivity patterns even with complex neuroimaging data involving a variety of stimuli and affective evaluations of them. The consensus clustering method is implemented in the R package "UNCLES" available on http://cran.r-project.org/web/packages/UNCLES/index.html .
27594829	Appetitive conditioning refers to the process of learning cue-reward associations and is mediated by the mesocorticolimbic system. Appetitive conditioned responses are difficult to extinguish, especially for highly salient reward such as food and drugs. We investigate whether aversive counterconditioning can alter reward reinstatement in the ventral striatum in healthy volunteers using functional magnetic resonance imaging (fMRI). In the initial conditioning phase, two different stimuli were reinforced with a monetary reward. In the subsequent counterconditioning phase, one of these stimuli was paired with an aversive shock to the wrist. In the following extinction phase, none of the stimuli were reinforced. In the final reinstatement phase, reward was reinstated by informing the participants that the monetary gain could be doubled. Our fMRI data revealed that reward signaling in the ventral striatum and ventral tegmental area following reinstatement was smaller for the stimulus that was counterconditioned with an electrical shock, compared to the non-counterconditioned stimulus. A functional connectivity analysis showed that aversive counterconditioning strengthened striatal connectivity with the hippocampus and insula. These results suggest that reward signaling in the ventral striatum can be attenuated through aversive counterconditioning, possibly by concurrent retrieval of the aversive association through enhanced connectivity with hippocampus and insula. 
27593624	Exposure to addictive substances such as cocaine is well-known to alter brain organisation. Cocaine-induced neuroadaptations depend on several factors, including drug administration paradigm. To date, studies addressing the consequences of cocaine exposure on dopamine transmission have either not been designed to investigate the role of response contingency or focused only on short-term neuroplasticity. We demonstrate a key role of response contingency in directing long-term cocaine-induced neuroplasticity throughout projection areas of the mesocorticolimbic dopamine system. We found enhanced electrically-evoked [(3)H]dopamine release from superfused brain slices of nucleus accumbens shell and core, dorsal striatum and medial prefrontal cortex three weeks after cessation of cocaine self-administration. In yoked cocaine rats receiving the same amount of cocaine passively, sensitised dopamine terminal reactivity was only observed in the nucleus accumbens core. Control sucrose self-administration experiments demonstrated that the observed neuroadaptations were not the result of instrumental learning per se. Thus, long-term withdrawal from cocaine self-administration is associated with widespread sensitisation of dopamine terminals throughout frontostriatal circuitries. 
27589489	Learning the reliability of different sources of rewards is critical for making optimal choices. However, despite the existence of detailed theory describing how the expected reward is learned in the basal ganglia, it is not known how reward uncertainty is estimated in these circuits. This paper presents a class of models that encode both the mean reward and the spread of the rewards, the former in the difference between the synaptic weights of D1 and D2 neurons, and the latter in their sum. In the models, the tendency to seek (or avoid) options with variable reward can be controlled by increasing (or decreasing) the tonic level of dopamine. The models are consistent with the physiology of and synaptic plasticity in the basal ganglia, they explain the effects of dopaminergic manipulations on choices involving risks, and they make multiple experimental predictions. 
27585792	Anecdotally, both acute and chronic cannabis use have been associated with apathy, amotivation, and other reward processing deficits. To date, empirical support for these effects is limited, and no previous studies have assessed both acute effects of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), as well as associations with cannabis dependence.The objectives of this study were (1) to examine acute effects of cannabis with CBD (Cann + CBD) and without CBD (Cann-CBD) on effort-related decision-making and (2) to examine associations between cannabis dependence, effort-related decision-making and reward learning.	In study 1, 17 participants each received three acute vaporized treatments, namely Cann-CBD (8 mg THC), Cann + CBD (8 mg THC + 10 mg CBD) and matched placebo, followed by a 50 % dose top-up 1.5 h later, and completed the Effort Expenditure for Rewards Task (EEfRT). In study 2, 20 cannabis-dependent participants were compared with 20 non-dependent, drug-using control participants on the EEfRT and the Probabilistic Reward Task (PRT) in a non-intoxicated state.	Cann-CBD reduced the likelihood of high-effort choices relative to placebo (p = 0.042) and increased sensitivity to expected value compared to both placebo (p = 0.014) and Cann + CBD (p = 0.006). The cannabis-dependent and control groups did not differ on the EEfRT. However, the cannabis-dependent group exhibited a weaker response bias than the control group on the PRT (p = 0.007).	Cannabis acutely induced a transient amotivational state and CBD influenced the effects of THC on expected value. In contrast, cannabis dependence was associated with preserved motivation alongside impaired reward learning, although confounding factors, including depression, cannot be disregarded. This is the first well powered, fully controlled study to objectively demonstrate the acute amotivational effects of THC.	
27584878	In reward learning, the integration of NMDA-dependent calcium and dopamine by striatal projection neurons leads to potentiation of corticostriatal synapses through CaMKII/PP1 signaling. In order to elicit the CaMKII/PP1-dependent response, the calcium and dopamine inputs should arrive in temporal proximity and must follow a specific (dopamine after calcium) order. However, little is known about the cellular mechanism which enforces these temporal constraints on the signal integration. In this computational study, we propose that these temporal requirements emerge as a result of the coordinated signaling via two striatal phosphoproteins, DARPP-32 and ARPP-21. Specifically, DARPP-32-mediated signaling could implement an input-interval dependent gating function, via transient PP1 inhibition, thus enforcing the requirement for temporal proximity. Furthermore, ARPP-21 signaling could impose the additional input-order requirement of calcium and dopamine, due to its Ca2+/calmodulin sequestering property when dopamine arrives first. This highlights the possible role of phosphoproteins in the temporal aspects of striatal signal transduction. 
27583636	This study uses cellular c-fos activation to assess effects of novel ingestion of fat and sugar on brain dopamine (DA) pathways in rats. Intakes of sugars and fats are mediated by their innate attractions as well as learned preferences. Brain dopamine, especially meso-limbic and meso-cortical projections from the ventral tegmental area (VTA), has been implicated in both of these unlearned and learned responses. The concept of distributed brain networks, wherein several sites and transmitter/peptide systems interact, has been proposed to mediate palatable food intake, but there is limited evidence empirically demonstrating such actions. Thus, sugar intake elicits DA release and increases c-fos-like immunoreactivity (FLI) from individual VTA DA projection zones including the nucleus accumbens (NAC), amygdala (AMY) and medial prefrontal cortex (mPFC) as well as the dorsal striatum. Further, central administration of selective DA receptor antagonists into these sites differentially reduce acquisition and expression of conditioned flavor preferences elicited by sugars or fats. One approach by which to determine whether these sites interacted as a distributed brain network in response to sugar or fat intake would be to simultaneous evaluate whether the VTA and its major mesotelencephalic DA projection zones (prelimbic and infralimbic mPFC, core and shell of the NAc, basolateral and central-cortico-medial AMY) as well as the dorsal striatum would display coordinated and simultaneous FLI activation after oral, unconditioned intake of corn oil (3.5%), glucose (8%), fructose (8%) and saccharin (0.2%) solutions. This approach is a successful first step in identifying the feasibility of using cellular c-fos activation simultaneously across relevant brain sites to study reward-related learning in ingestion of palatable food in rodents. 
27576923	During speech processing, human listeners can separately analyze lexical and intonational cues to arrive at a unified representation of communicative content. The evolution of this capacity can be best investigated by comparative studies. Using functional magnetic resonance imaging, we explored whether and how dog brains segregate and integrate lexical and intonational information. We found a left-hemisphere bias for processing meaningful words, independently of intonation; a right auditory brain region for distinguishing intonationally marked and unmarked words; and increased activity in primary reward regions only when both lexical and intonational information were consistent with praise. Neural mechanisms to separately analyze and integrate word meaning and intonation in dogs suggest that this capacity can evolve in the absence of language.
27576865	Many chronic pain syndromes are characterized by enhanced perception of painful stimuli as well as alterations in cortical processing in sensory and motor regions. In this review article the alterations in muscle pain and neuropathic pain are described. Alterations in patients with fibromyalgia and chronic back pain are described as examples for musculoskeletal pain and also in patients with phantom limb pain after amputation and complex regional pain syndrome as examples for neuropathic pain. In addition to altered pain perception, cumulative evidence on alterations in the processing of reward and the underlying mechanisms in chronic pain has been described. A description is given of what is known on how pain and reward interact and affect each other. The relevance of such interactions for chronic pain is discussed. The implications of these findings for therapeutic approaches are delineated with respect to sensorimotor training and behavioral therapy, focusing on the effectiveness of these approaches, mechanisms and future developments. In particular, we discuss operant behavioral therapy in patients with chronic back pain and fibromyalgia as well as prosthesis training in patients with phantom limb pain and discrimination, mirror and imaginary training in patients with phantom limb pain and complex regional pain syndrome. With respect to the processing of reward, the focus of the discussion is on the role of reward and associated learning in pain therapy.
27576530	While the effects of lead pollution have been well studied in vertebrates, it is unclear to what extent lead may negatively affect insect cognition. Lead pollution in soils can elevate lead in plant tissues, suggesting it could negatively affect neural development of insect herbivores. We used the cabbage white butterfly (Pieris rapae) as a model system to study the effect of lead pollution on insect cognitive processes, which play an important role in how insects locate and handle resources. Cabbage white butterfly larvae were reared on a 4-ppm lead diet, a concentration representative of vegetation in polluted sites; we measured eye size and performance on a foraging assay in adults. Relative to controls, lead-reared butterflies did not differ in time or ability to search for a food reward associated with a less preferred color. Indeed, lead-treated butterflies were more likely to participate in the behavioral assay itself. Lead exposure did not negatively affect survival or body size, and it actually sped up development time. The effects of lead on relative eye size varied with sex: lead tended to reduce eye size in males, but increase eye size in females. These results suggest that low levels of lead pollution may have mixed effects on butterfly vision, but only minimal impacts on performance in foraging tasks, although follow-up work is needed to test whether this result is specific to cabbage whites, which are often associated with disturbed areas.
27574507	There is an increasing number of neuroimaging studies using visual sexual stimuli (VSS), especially within the emerging field of research on compulsive sexual behaviors (CSB). A central question in this field is whether behaviors such as excessive pornography consumption share common brain mechanisms with widely studied substance and behavioral addictions. Depending on how VSS are conceptualized, different predictions can be formulated within the frameworks of Reinforcement Learning or Incentive Salience Theory, where a crucial distinction is made between conditioned and unconditioned stimuli (related to reward anticipation vs. reward consumption, respectively). Surveying 40 recent human neuroimaging studies we show existing ambiguity about the conceptualization of VSS. Therefore, we feel that it is important to address the question of whether VSS should be considered as conditioned stimuli (cue) or unconditioned stimuli (reward). Here we present our own perspective, which is that in most laboratory settings VSS play a role of reward, as evidenced by: (1) experience of pleasure while watching VSS, possibly accompanied by genital reaction; (2) reward-related brain activity correlated with these pleasurable feelings in response to VSS; (3) a willingness to exert effort to view VSS similarly as for other rewarding stimuli such as money; and (4) conditioning for cues predictive of VSS. We hope that this perspective article will initiate a scientific discussion on this important and overlooked topic and increase attention for appropriate interpretations of results of human neuroimaging studies using VSS. 
27573822	Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2-expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Overall, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience. 
27573375	Cigarettes and alcohol are the most abused substances in the world and are commonly co-abused. Nicotine primarily acts in the brain on nicotinic acetylcholine receptors (nAChR), which are also a target for alcohol. The alpha6 subunit of nAChR is expressed almost exclusively in the brain reward system and may modulate the rewarding properties of alcohol and nicotine. Recently, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI) was synthesized as a selective, brain penetrant α6 subunit antagonist that reduces nicotine self-administration. The current study aimed to examine the effects of bPiDI on alcohol self-administration in inbred alcohol-preferring (iP) rats. Adult, male iP rats were trained to self-administer alcohol or sucrose. Once stable responding was achieved, rats were injected with bPiDI (1, 3 mg/kg, i.p.) and tested for self-administration under fixed and progressive ratio schedules of reinforcement. They subsequently underwent extinction, in which no rewards or cues were presented in the operant chambers. Then, they were injected with bPiDI prior to testing for cue-induced reinstatement of reward seeking. bPiDI (3 mg/kg) significantly reduced alcohol self-administration in both fixed and progressive ratios without any effects on sucrose self-administration or locomotor activity. In contrast, bPiDI (3 mg/kg) did not inhibit cue-induced reinstatement of either alcohol or sucrose seeking. The results support the involvement of α6 containing nAChR in reinforcing effects of alcohol, but not relapse to alcohol-seeking, without any impact on responding for a natural reward or general activity. bPiDI may be a potential lead molecule for a therapeutic strategy to limit nicotine and alcohol consumption.
27572627	Affective biases seemingly play a crucial role for the onset and development of depression. Acute treatment with monoamine-based antidepressants positively influences emotional processing, and an early correction of biases likely results in repeated positive experiences that ultimately lead to improved mood.Using two conventional antidepressants, sertraline and duloxetine, we aimed to forward the characterization of a newly developed affective bias test (ABT) for rats. Further, we examined the effect of vortioxetine, a recently approved antidepressant, and the α2 adrenoceptor antagonist idazoxan on affective biases.	Sprague Dawley rats were tested in an affective bias test using a fully balanced within-subject study design. Rats learned to associate two different digging substrates with a reward during six reward-pairing days. The absolute value of the rewards was identical, but the affective state at the time of learning induces a positive or negative bias towards the treatment-paired digging substrate at recall. The choice bias between the two digging substrates at recall represents the affective bias. Sertraline (1, 3 and 10 mg/kg), duloxetine (1, 3 and 10 mg/kg), vortioxetine (1, 3 and 10 mg/kg) and idazoxan (3 and 10 mg/kg) were tested in the ABT.	All four drugs, regardless of their mechanism of action, induced a positive affective bias in the ABT, although the overall effect of treatment was not statistically significant for sertraline and duloxetine. The largest effects were induced by vortioxetine and idazoxan, both of which caused significant positive biases at all tested doses.	
27568569	The ventral tegmental area (VTA) receives phenotypically distinct innervations from the pedunculopontine tegmental nucleus (PPTg). While PPTg-to-VTA inputs are thought to play a critical role in stimulus-reward learning, direct evidence linking PPTg-to-VTA phenotypically distinct inputs in the learning process remains lacking. Here, we used optogenetic approaches to investigate the functional contribution of PPTg excitatory and inhibitory inputs to the VTA in appetitive Pavlovian conditioning. We show that photoinhibition of PPTg-to-VTA cholinergic or glutamatergic inputs during cue presentation dampens the development of anticipatory approach responding to the food receptacle during the cue. Furthermore, we employed in vivo optetrode recordings to show that photoinhibition of PPTg cholinergic or glutamatergic inputs significantly decreases VTA non-dopamine (non-DA) neural activity. Consistently, photoinhibition of VTA non-DA neurons disrupts the development of cue-elicited anticipatory approach responding. Taken together, our study reveals a crucial regulatory mechanism by PPTg excitatory inputs onto VTA non-DA neurons during appetitive Pavlovian conditioning. 
27568518	Hippocampal replays are episodes of sequential place cell activity during sharp-wave ripple oscillations (SWRs). Conflicting hypotheses implicate awake replay in learning from reward and in memory retrieval for decision making. Further, awake replays can be forward, in the same order as experienced, or reverse, in the opposite order. However, while the presence or absence of reward has been reported to modulate SWR rate, the effect of reward changes on replay, and on replay direction in particular, has not been examined. Here we report divergence in the response of forward and reverse replays to changing reward. While both classes of replays were observed at reward locations, only reverse replays increased their rate at increased reward or decreased their rate at decreased reward, while forward replays were unchanged. These data demonstrate a unique relationship between reverse replay and reward processing and point to a functional distinction between different directions of replay. VIDEO ABSTRACT. 
27565454	Learning from feedback is a prerequisite for adapting to the environment. Prediction error signals coded by midbrain dopamine (DA) neurons are projected to the basal ganglia and anterior cingulate cortex (ACC). It has been suggested that neuronal activity shifts away from the DA system when feedback is delayed. The feedback-related negativity (FRN), an ERP that is generated in the ACC and has been shown to be sensitive to feedback valence and prediction error magnitude, was found to be reduced for delayed feedback. It has, however, not yet been investigated if the FRN for delayed feedback reflects a reward prediction error. In this study, effects of feedback delay (1 s vs. 7 s) on the processing of expected and unexpected positive and negative feedback were investigated in a between-subjects design in healthy human participants conducting a probabilistic feedback learning task. FRN and P300 amplitudes were decreased for subjects learning from delayed compared to immediate feedback. Importantly, the FRN, extracted from the negative-positive feedback difference wave, was significantly smaller for expected compared to unexpected feedback for both the immediate and delayed feedback conditions. Expectancy effects for the P300 were also seen, but did not interact with feedback valence. These results demonstrate an influence of feedback expectancy, and thus the prediction error, on early feedback processing even for delayed feedback, suggesting that neuronal structures underlying feedback processing are comparable for immediate and delayed feedback, at least to some extent. Modulations of the P300 by feedback delay may be linked to feedback salience.
27564993	For most animals, survival depends on rapid detection of rewarding objects, but search for an object surrounded by many others is known to be difficult and time consuming. However, there is neuronal evidence for robust and rapid differentiation of objects based on their reward history in primates (Hikosaka, Kim, Yasuda, & Yamamoto, 2014). We hypothesized that such robust coding should support efficient search for high-value objects, similar to a pop-out mechanism. To test this hypothesis, we let subjects (n = 4, macaque monkeys) view a large number of complex objects with consistently biased rewards with variable training durations (1, 5, or 30 + days). Following training, subjects searched for a high-value object (Good) among a variable number of low-value objects (Bad). Consistent with our hypothesis, we found that Good objects were accurately and quickly targeted, often by a single and direct saccade with a very short latency (<200 ms). The dependence of search times on display size reduced significantly with longer reward training, giving rise to a more efficient search (40 ms/item to 16 ms/item). This object-finding skill showed a large capacity for value-biased objects and was maintained in the long-term memory with no interference from reward learning with other objects. Such object-finding skill, and in particular its large capacity and long term retention, would be crucial for maximizing rewards and biological fitness throughout life where many objects are experienced continuously and/or intermittently. 
27564707	Rewards associated with actions are critical for motivation and learning about the consequences of one's actions on the world. The motor cortices are involved in planning and executing movements, but it is unclear whether they encode reward over and above limb kinematics and dynamics. Here, we report a categorical reward signal in dorsal premotor (PMd) and primary motor (M1) neurons that corresponds to an increase in firing rates when a trial was not rewarded regardless of whether or not a reward was expected. We show that this signal is unrelated to error magnitude, reward prediction error, or other task confounds such as reward consumption, return reach plan, or kinematic differences across rewarded and unrewarded trials. The availability of reward information in motor cortex is crucial for theories of reward-based learning and motivational influences on actions. 
27564094	Many accounts of decision making and reinforcement learning posit the existence of two distinct systems that control choice: a fast, automatic system and a slow, deliberative system. Recent research formalizes this distinction by mapping these systems to "model-free" and "model-based" strategies in reinforcement learning. Model-free strategies are computationally cheap, but sometimes inaccurate, because action values can be accessed by inspecting a look-up table constructed through trial-and-error. In contrast, model-based strategies compute action values through planning in a causal model of the environment, which is more accurate but also more cognitively demanding. It is assumed that this trade-off between accuracy and computational demand plays an important role in the arbitration between the two strategies, but we show that the hallmark task for dissociating model-free and model-based strategies, as well as several related variants, do not embody such a trade-off. We describe five factors that reduce the effectiveness of the model-based strategy on these tasks by reducing its accuracy in estimating reward outcomes and decreasing the importance of its choices. Based on these observations, we describe a version of the task that formally and empirically obtains an accuracy-demand trade-off between model-free and model-based strategies. Moreover, we show that human participants spontaneously increase their reliance on model-based control on this task, compared to the original paradigm. Our novel task and our computational analyses may prove important in subsequent empirical investigations of how humans balance accuracy and demand. 
27562760	Organisms making repeated simple decisions are faced with a tradeoff between urgent and cautious strategies. While animals can adopt a statistically optimal policy for this tradeoff, findings about human decision-makers have been mixed. Some studies have shown that people can optimize this "speed-accuracy tradeoff", while others have identified a systematic bias towards excessive caution. These issues have driven theoretical development and spurred debate about the nature of human decision-making. We investigated a potential resolution to the debate, based on two factors that routinely differ between human and animal studies of decision-making: the effects of practice, and of longer-term feedback. Our study replicated the finding that most people, by default, are overly cautious. When given both practice and detailed feedback, people moved rapidly towards the optimal policy, with many participants reaching optimality with less than 1 h of practice. Our findings have theoretical implications for cognitive and neural models of simple decision-making, as well as methodological implications.
27562376	The nociceptin (NOP) receptor is a G-protein-coupled receptor whose natural ligand is the NOP/orphanin FQ (N/OFQ) peptide. Evidence from pharmacological studies suggests that the N/OFQ system is implicated in the regulation of several addiction-related phenomena, such as drug intake, withdrawal, and relapse. Here, to further explore the role of NOP system in addiction, we used NOP (-/-) rats to study the motivation for cocaine, heroin, and alcohol self-administration in the absence of N/OFQ function. Conditioned place preference (CPP) and saccharin (0.2% w/v) self-administration were also investigated. Results showed that NOP (-/-) rats self-administer less cocaine (0.25, 0.125, or 0.5 mg/infusion) both under a fixed ratio 1 and a progressive ratio schedule of reinforcement compared with wild-type (Wt) controls. Consistently, cocaine (10 mg/kg, i.p.) was able to induce CPP in Wt but not in NOP (-/-). When NOP (-/-) rats were tested for heroin (20 μg/infusion) and ethanol (10% v/v) self-administration, they showed significantly lower drug intake compared with Wt. Conversely, saccharin self-administration was not affected by NOP deletion, excluding the possibility of nonspecific learning deficits or generalized disruption of reward mechanisms in NOP (-/-) rats. These findings were confirmed with pharmacological experiments using two selective NOP antagonists, SB-612111 and LY2817412. Both drugs attenuated alcohol self-administration in Wt rats but not in NOP (-/-) rats. In conclusion, our results demonstrate that genetic deletion of NOP receptors confers resilience to drug abuse and support a role for NOP receptor antagonism as a potential treatment option for drug addiction.
27559719	We use eye movements to gain information about our visual environment; this information can indirectly be used to affect the environment. Whereas eye movements are affected by explicit rewards such as points or money, it is not clear whether the information gained by finding a hidden target has a similar reward value. Here we tested whether finding a visual target can reinforce eye movements in visual search performed in a noise background, which conforms to natural scene statistics and contains a large number of possible target locations. First we tested whether presenting the target more often in one specific quadrant would modify eye movement search behavior. Surprisingly, participants did not learn to search for the target more often in high probability areas. Presumably, participants could not learn the reward structure of the environment. In two subsequent experiments we used a gaze-contingent display to gain full control over the reinforcement schedule. The target was presented more often after saccades into a specific quadrant or a specific direction. The proportions of saccades meeting the reinforcement criteria increased considerably, and participants matched their search behavior to the relative reinforcement rates of targets. Reinforcement learning seems to serve as the mechanism to optimize search behavior with respect to the statistics of the task. 
27555829	Recent work has found that personality factors that confer vulnerability to addiction can also affect learning and economic decision making. One personality trait which has been implicated in vulnerability to addiction is intolerance to uncertainty (IU), i.e., a preference for familiar over unknown (possibly better) options. In animals, the motivation to obtain drugs is often assessed through conditioned place preference (CPP), which compares preference for contexts where drug reward was previously received. It is an open question whether participants with high IU also show heightened preference for previously rewarded contexts. To address this question, we developed a novel computer-based CPP task for humans in which participants guide an avatar through a paradigm in which one room contains frequent reward (i.e., rich) and one contains less frequent reward (i.e., poor). Following exposure to both contexts, subjects are assessed for preference to enter the previously rich and previously poor room. Individuals with low IU showed little bias to enter the previously rich room first, and instead entered both rooms at about the same rate which may indicate a foraging behavior. By contrast, those with high IU showed a strong bias to enter the previously rich room first. This suggests an increased tendency to chase reward in the intolerant group, consistent with previously observed behavior in opioid-addicted individuals. Thus, the personality factor of high IU may produce a pre-existing cognitive bias that provides a mechanism to promote decision-making processes that increase vulnerability to addiction. 
27554505	Background and aims Addiction has been reliably associated with biased emotional reactions to risky choices. Problematic Internet use (PIU) is a relatively new concept and its classification as an addiction is debated. Implicit emotional responses were measured in individuals expressing nonproblematic and problematic Internet behaviors while they made risky/ambiguous decisions to explore whether they showed similar responses to those found in agreed-upon addictions. Methods The design of the study was cross sectional. Participants were adult Internet users (N = 72). All testing took place in the Psychophysics Laboratory at the University of Bath, UK. Participants were given the Iowa Gambling Task (IGT) which provides an index of an individual's ability to process and learn probabilities of reward and loss. Integration of emotions into current decision-making frameworks is vital for optimal performance on the IGT and thus, skin conductance responses (SCRs) to reward, punishment, and in anticipation of both were measured to assess emotional function. Results Performance on the IGT did not differ between the groups of Internet users. However, problematic Internet users expressed increased sensitivity to punishment as revealed by stronger SCRs to trials with higher punishment magnitude. Discussion and conclusions PIU seems to differ on behavioral and physiological levels with other addictions. However, our data imply that problematic Internet users were more risk-sensitive, which is a suggestion that needs to be incorporated into in any measure and, potentially, any intervention for PIU. 
27553218	This study examined reward-related decision-making in children and adolescents with ADHD in a social context, using economic games. We furthermore examined the role of individual differences in reward-related decision-making, specifically, the roles of reward sensitivity and prosocial skills. Children and adolescents (9-17 years) with ADHD-combined subtype (n = 29; 20 boys) and healthy controls (n = 38; 20 boys) completed the ultimatum game and dictator game as measures of reward-related decision-making in social contexts. Prosocial skills were measured with the Interpersonal Reactivity Index. The ADHD group had a larger discrepancy between ultimatum game and dictator game offers than controls, indicating strategic rather than fairness driven decisions. This finding was supported by self-reports showing fewer individuals with ADHD than controls who considered fairness as motive for the decisions. Perspective taking or empathic concern did not differ between groups and was not significantly associated with offers. In conclusion, the results suggest that rather than a failure to understand the perspective of others, children and adolescents with ADHD were less motivated by fairness than controls in simple social situations. Results encourage the use of economic games in ADHD research.
27549757	Ethanol has rewarding and aversive properties, and the balance of these properties influences voluntary ethanol consumption. Preclinical and clinical evidence show that the aversive properties of ethanol limit intake. The neural circuits underlying ethanol-induced aversion learning are not fully understood. We have previously shown that the lateral habenula (LHb), a region critical for aversive conditioning, plays an important role in ethanol-directed behaviors. However, the neurocircuitry through which LHb exerts its actions is unknown.In the present study, we investigate a role for the rostromedial tegmental nucleus (RMTg), a major LHb projection target, in regulating ethanol-directed behaviors.	Rats received either sham or RMTg lesions and were studied during voluntary ethanol consumption; operant ethanol self-administration, extinction, and yohimbine-induced reinstatement of ethanol-seeking; and ethanol-induced conditioned taste aversion (CTA).	RMTg lesions increased voluntary ethanol consumption and accelerated extinction of ethanol-induced CTA.	The RMTg plays an important role in regulating voluntary ethanol consumption, possibly by mediating ethanol-induced aversive conditioning.	
27548391	Accurate monitoring and control are essential for effective self-regulated learning. These metacognitive abilities may be particularly important for developing math skills, such as when children are deciding whether a math task is difficult or whether they made a mistake on a particular item. The present experiments investigate children's ability to monitor and control their math performance. Experiment 1 assessed task- and item-level monitoring while children performed a number line estimation task. Children in 1st, 2nd, and 4th grade (N = 59) estimated the location of numbers on small- and large-scale number lines and judged their confidence in each estimate. Consistent with their performance, children were more confident in their small-scale estimates than their large-scale estimates. Experiments 2 (N = 54) and 3 (N = 85) replicated this finding in new samples of 1st, 2nd, and 4th graders and assessed task- and item-level control. When asked which estimates they wanted the experimenter to evaluate for a reward, children tended to select estimates associated with lower error and higher confidence. Thus, children can accurately monitor their performance during number line estimation and use their monitoring to control their subsequent performance. (PsycINFO Database Record
27544888	Using a young driver sample, this experimental study sought to identify which combinations of threat-appraisal (TA) and coping-appraisal (CA) messages derived from protection motivation theory (PMT) participants would judge as most effective for themselves, and for other drivers.The criterion variable was reported intention to drive within a signed speed limit. All possible TA/CA combinations of 18 previously highly-rated anti-speeding messages were presented both simultaneously and sequentially. These represented PMT's three TA components: severity, vulnerability, and rewards, and three CA components: self-efficacy, response efficacy, and response costs. Eighty-eight young drivers (34 males) each rated 54 messages for perceived effectiveness for self and other drivers.	Messages derived from the TA severity component were judged the most effective. Response cost messages were most effective for females. Reverse third-person effects were found for both females and males, which suggested that combining TA and CA components may increase the perceived relevance of anti-speeding messages for males.	The findings have potential value for creating effective roadside anti-speeding messages, meriting further investigation in field studies.	
27544850	The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) affects numerous behavioral and physiological processes. Drugs that alter 5-HT signaling treat several major psychiatric disorders and may lead to widespread abuse. The dorsal raphe nucleus (DRN) in the midbrain provides a majority of 5-HT for the forebrain. The importance of 5-HT signaling propels the search for a general theoretical framework under which the diverse functions of the DRN 5-HT neurons can be interpreted and additional therapeutic solutions may be developed. However, experimental data so far support several seeming irreconcilable theories, suggesting that 5-HT neurons mediate behavioral inhibition, aversive processing, or reward signaling. Here, we review recent progresses and propose that DRN 5-HT neurons encode "beneficialness" - how beneficial the current environmental context represents for an individual. Specifically, we speculate that the activity of these neurons reflects the possible net benefit of the current context as determined by p·R-C, in which p indicates reward probability, R the reward value, and C the cost. Through the widespread projections of these neurons to the forebrain, the beneficialness signal may reconfigure neural circuits to bias perception, boost positive emotions, and switch behavioral choices. The "beneficialness" hypothesis can explain many conflicting observations, and at the same time raises new questions. We suggest additional experiments that will help elucidate the exact computational functions of the DRN 5-HT neurons.
27544424	The nucleus reuniens (RE) of the ventral midline thalamus is strongly reciprocally connected with the hippocampus (HF) and the medial prefrontal cortex (mPFC) and has been shown to mediate the transfer of information between these structures. It has become increasingly well established that RE serves a critical role in mnemonic tasks requiring the interaction of the HF and mPFC, but essentially not tasks relying solely on the HF. Very few studies have addressed the independent actions of RE on prefrontal executive functioning. The present report examined the effects of lesions of the ventral midline thalamus, including RE and the dorsally adjacent rhomboid nucleus (RH) in rats on attention and behavioral flexibility using the attentional set shifting task (AST). The task uses odor and tactile stimuli to test for attentional set formation, attentional set shifting, behavioral flexibility and reversal learning. By comparison with sham controls, lesioned rats were significantly impaired on reversal learning and intradimensional (ID) set shifting. Specifically, RE/RH lesioned rats were impaired on the first reversal stage of the task which required a change in response strategy to select a previously non-rewarded stimulus for reward. RE/RH lesioned rats also exhibited deficits in the ability to transfer or generalize rules of the task which requires making the same modality-based choices (e.g., odor vs. tactile) to different sets of stimuli in the ID stage of the task. These results demonstrate that in addition to its role in tasks dependent on HF-mPFC interactions, nucleus reuniens is also critically involved cognitive/executive functions associated with the medial prefrontal cortex. As such, the deficits in the AST task produced by RE/RH lesions suggest the ventral midline thalamus directly contributes to flexible goal directed behavior.
27542919	There is a growing body of literature demonstrating domain effects where the rate of temporal discounting depends, in part, on the commodity being evaluated. The commodity of money, for example, is typically discounted much less steeply than commodities of entertainment or food. There are several plausible explanations for domain effects: differences in conditioned reinforcer status, degree of fungibility, and differences in metabolic function. While money can be thought of as a conditioned reinforcer exchangeable for a number of different outcomes (highly fungible), comparing money to food (non-fungible) does not separate whether the difference in rates of discounting are due to food having metabolic importance, being perishable, being less fungible, or all of the above. We systematically manipulated the degree of fungibility and perishability of various outcomes and found that while food outcomes tend to be discounted most steeply, the rate of discounting for these outcomes can be moderated by reducing perishability and by increasing fungibility. Important here is that we have identified two independent means of moderating the effect of delay on the value of the outcome. 
27542906	The brain's reward system influences ingestive behavior and subsequently obesity risk. Functional magnetic resonance imaging (fMRI) is a common method for investigating brain reward function. This study sought to assess the reproducibility of fasting-state brain responses to visual food stimuli using BOLD fMRI.A priori brain regions of interest included bilateral insula, amygdala, orbitofrontal cortex, caudate, and putamen. Fasting-state fMRI and appetite assessments were completed by 28 women (n = 16) and men (n = 12) with overweight or obesity on 2 days. Reproducibility was assessed by comparing mean fasting-state brain responses and measuring test-retest reliability of these responses on the two testing days.	Mean fasting-state brain responses on day 2 were reduced compared with day 1 in the left insula and right amygdala, but mean day 1 and day 2 responses were not different in the other regions of interest. With the exception of the left orbitofrontal cortex response (fair reliability), test-retest reliabilities of brain responses were poor or unreliable.	fMRI-measured responses to visual food cues in adults with overweight or obesity show relatively good mean-level reproducibility but considerable within-subject variability. Poor test-retest reliability reduces the likelihood of observing true correlations and increases the necessary sample sizes for studies.	
27539808	Reinforcement learning requires the dynamic interplay of several specialized networks distributed across the brain. A potential mechanism to establish accurate temporal coordination among these paths is through the synchronization of neuronal activity to a common rhythm of neuronal firing. Previous EEG studies have suggested that theta oscillatory activity might be crucial in the integration of information from motivational and attentional paths that converge into the medial Prefrontal Cortex (mPFC) during reward-guided learning. However, due to the low spatial resolution of EEG, this hypothesis has not been directly tested. Here, by combining EEG and fMRI, we show that theta oscillations serve as common substrate for the engagement of separated sub-regions within the mPFC (the pre-Supplementary Motor Area and the dorsomedial Prefrontal Cortex), underlying different cognitive operations (encoding of outcome valence and unsigned prediction errors) through separate functional paths (the Salience and the Central Executive Networks).
27536223	Behavioral adaptation is required for the successful navigation of a constantly changing environment. Impairments in behavioral flexibility are commonly observed in psychiatric disorders including those of addiction. This study investigates two distinct facets of compulsivity, namely reversal learning and attentional set shifting, implicating orbitofrontal and lateral prefrontal regions respectively, across disorders of primary and secondary rewards. Obese subjects with and without binge eating disorder (BED), individuals with compulsive sexual behaviors (CSB), alcohol dependence (AD) and pathological video-gaming (VG) were tested with two computerized tasks: the probabilistic reversal task (trials to criterion and win-stay/lose-shift errors) and the intra/extra-dimensional set shift task (IED). Individuals with AD and pathological VG were slower at reversal learning irrespective of valence, with AD subjects more likely to perseverate after losses. Compared to obese subjects without BED, BED subjects were worse at reversal learning to wins but better at losses highlighting valence effects as a function of binge eating. CSB subjects demonstrated enhanced sensitivity to reward outcomes with faster acquisition and greater perseveration with higher magnitude rewards. We further show an impairment in attentional set shifting in individuals with BED and AD relative to healthy volunteers (HV). This study provides evidence for commonalities and differences in two distinct dimensions of behavioral inflexibility across disorders of compulsivity. We summarize studies on compulsivity subtypes within this same patient population. We emphasize commonalities in AD and BED with impairments across a range of compulsivity indices, perhaps supporting pathological binge eating as a form of behavioral addiction. We further emphasize commonalities in reversal learning across disorders and the crucial role of valence effects. These findings highlight the role of behavioral inflexibility and compulsivity as a relevant domain in defining dimensional psychiatry and the identification of relevant cognitive endophenotypes as targets for therapeutic modulation. 
27533282	String-pulling is one of the most popular tests in animal cognition because of its apparent complexity, and of its potential to be applied to very different taxa. In birds, the basic procedure involves a food reward, suspended from a perch by a string, which can be reached by a series of coordinated pulling actions with the beak and holding actions of the pulled lengths of string with the foot. The taxonomic distribution of species that pass the test includes several corvids, parrots and parids, but in other families, data are much spottier and the number of individuals per species that succeed is often low. To date, the association between string-pulling ability and other cognitive traits was never tested. It is generally assumed that string-pulling is a complex form of problem-solving, suggesting that performance on string-pulling and other problem-solving tasks should be correlated. Here, we show that individuals of two innovative species from Barbados, the bullfinch Loxigilla barbadensis and the Carib grackle Quiscalus lugubris fortirostris, pass the string-pulling test. Eighteen of the 42 bullfinches tested succeeded, allowing us to correlate performance on this test to that on several other behavioral measurements. Surprisingly, string-pulling in bullfinches was unrelated to shyness, neophobia, problem-solving, discrimination and reversal learning performance. Only two of 31 grackles tested succeeded, precluding correlational analyses with other measures but still, the two successful birds largely differed in their other behavioral traits. 
27532746	Concurrent use of tobacco and alcohol or psychostimulants represents a major public health concern, with use of one substance influencing consumption of the other. Co-abuse of these drugs leads to substantial negative health outcomes, reduced cessation, and high economic costs, but the underlying mechanisms are poorly understood. Epidemiological data suggest that tobacco use during adolescence plays a particularly significant role. Adolescence is a sensitive period of development marked by major neurobiological maturation of brain regions critical for reward processing, learning and memory, and executive function. Nicotine exposure during this time produces a unique and long-lasting vulnerability to subsequent substance use, likely via actions at cholinergic, dopaminergic, and serotonergic systems. In this review, we discuss recent clinical and preclinical data examining the genetic factors and mechanisms underlying co-use of nicotine and alcohol or cocaine and amphetamines. We evaluate the critical role of nicotinic acetylcholine receptors throughout, and emphasize the dearth of preclinical studies assessing concurrent drug exposure. We stress important age and sex differences in drug responses, and highlight a brief, low-dose nicotine exposure paradigm that may better model early use of tobacco products. The escalating use of e-cigarettes among youth necessitates a closer look at the consequences of early adolescent nicotine exposure on subsequent alcohol and drug abuse.
27531838	Several forms of long-term depression (LTD) of glutamatergic synaptic transmission have been identified in the dorsal striatum and in the nucleus accumbens (NAc). Such experience-dependent synaptic plasticity might play important roles in reward-related learning. The GABAA receptor agonist muscimol was recently found to trigger a long-lasting depression of glutamatergic synaptic transmission in the NAc of adolescent mice, but the mechanisms that underlie this novel form of LTD were not studied. Here we examined the effect of muscimol applied in the perfusion solution on the amplitude of field excitatory postsynaptic potentials/population spikes (fEPSP/PSs) in mouse brain slices. We found that muscimol depressed the fEPSP/PS in the NAc of adolescent mice but not adult mice, through both postsynaptic and presynaptic mechanisms. Indeed, muscimol altered the fEPSP/PS paired-pulse ratio, depolarized the membrane of projection neurons, and decreased the frequency, but not amplitude, of spontaneous excitatory postsynaptic currents in the NAc of adolescent mice. The LTD induced by muscimol likely involved endocannabinoids, metabotropic glutamate receptors (mGluRs), but not TRPV1 receptors. Muscimol-LTD was occluded by prior induction of LTD through low-frequency stimulation (LFS) of the slice, demonstrating a common pathway in the induction of LFS-LTD and muscimol-LTD. We also found that muscimol induced a form of LTD in the dorsolateral striatum of adult but not adolescent mice. This LTD was mediated by endocannabinoids but did not involve mGluRs or TRPV1 receptors. These results identify a novel form of synaptic plasticity, and its mechanisms of induction, which is age and region dependent. These findings may contribute to a better understanding of the increased susceptibility of the adolescent brain to long-term synaptic changes in regions associated with reward mechanisms. 
27531638	Extinction is a fundamental form of memory updating in which one learns to stop expecting an event that no longer occurs. This learning ensues when one experiences a change in environmental contingencies, that is, when an expected outcome fails to occur (simple extinction), or when a novel inflated expectation of a double outcome (overexpectation) is in conflict with the real outcome, and is a process that has been linked to amygdala function. Here, we show that in rats, the same neuronal population in the amygdala central nucleus updates reward expectancies and behaviour in both types of extinction, and neural changes in one paradigm are reflected in the other. This work may have implications for the management of addiction and anxiety disorders that require treatments based on the outcome omission, and disorders such as obesity that could use overexpectation, but not omission strategies. 
27531122	Prospective memory performance can be enhanced by task importance, for example by promising a reward. Typically, this comes at costs in the ongoing task. However, previous research has suggested that social importance (e.g., providing a social motive) can enhance prospective memory performance without additional monitoring costs in activity-based and time-based tasks. The aim of the present study was to investigate the influence of social importance in an event-based task. We compared four conditions: social importance, promising a reward, both social importance and promising a reward, and standard prospective memory instructions (control condition). The results showed enhanced prospective memory performance for all importance conditions compared to the control condition. Although ongoing task performance was slowed in all conditions with a prospective memory task when compared to a baseline condition with no prospective memory task, additional costs occurred only when both the social importance and reward were present simultaneously. Alone, neither social importance nor promising a reward produced an additional slowing when compared to the cost in the standard (control) condition. Thus, social importance and reward can enhance event-based prospective memory at no additional cost.
27528669	Reinforcement learning theory powerfully characterizes how we learn to benefit ourselves. In this theory, prediction errors-the difference between a predicted and actual outcome of a choice-drive learning. However, we do not operate in a social vacuum. To behave prosocially we must learn the consequences of our actions for other people. Empathy, the ability to vicariously experience and understand the affect of others, is hypothesized to be a critical facilitator of prosocial behaviors, but the link between empathy and prosocial behavior is still unclear. During functional magnetic resonance imaging (fMRI) participants chose between different stimuli that were probabilistically associated with rewards for themselves (self), another person (prosocial), or no one (control). Using computational modeling, we show that people can learn to obtain rewards for others but do so more slowly than when learning to obtain rewards for themselves. fMRI revealed that activity in a posterior portion of the subgenual anterior cingulate cortex/basal forebrain (sgACC) drives learning only when we are acting in a prosocial context and signals a prosocial prediction error conforming to classical principles of reinforcement learning theory. However, there is also substantial variability in the neural and behavioral efficiency of prosocial learning, which is predicted by trait empathy. More empathic people learn more quickly when benefitting others, and their sgACC response is the most selective for prosocial learning. We thus reveal a computational mechanism driving prosocial learning in humans. This framework could provide insights into atypical prosocial behavior in those with disorders of social cognition. 
27524106	It is well known that emergency departments (EDs) suffer from crowding and throughput challenges, which make the ED a challenging workplace. However, the interplay between the throughput of patients and how staff experience work is seldom studied. The aim of this study was to investigate whether staff experience of work (efficiency, work-related efforts and rewards, and quantity and quality of work) differs between days with low and high patient throughput rates.Throughput times were collected from electronic medical records and staff (n=252 individuals, mainly nurses) ratings in daily questionnaires over a total of six weeks. Days were grouped into low and high throughput rate days for the orthopedic, surgical and internal medicine sections, respectively, and staff ratings were compared.	On days with low throughput rates, employees rated their efficiency, effort, reward and quantity of work significantly higher than on days with high throughput rates. There was no difference in perceived quality of work.	There is a complex relationship between ED throughput rates and staff perceptions of efficiency and efforts/rewards with work, suggesting that whereas low throughput may be troublesome from a patient and organizational perspective, working conditions may still be perceived as more favorable.	
27520750	Human depression, for which chronic psychosocial stress is a major risk factor, is characterized by consistent alterations in neurocircuitry. For example, there is increased functional connectivity (FC) within and between regions comprising the default mode network (DMN) including prefrontal cortex and cingulate cortex. Alterations in network FC are associated with specific aspects of psychopathology. In mice, chronic psychosocial stress (CPS) leads to depression-relevant behavior, including increased fear learning, learned helplessness, fatigue and decreased motivation for reward. Using multimodal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS), we investigated CPS effects on function and structure in the mouse brain under light anesthesia. Mice underwent a baseline MRI/MRS session, followed by 15-day CPS (n=26) or control handling (n=27), and a post-treatment MRI/MRS session. In BOLD fMRI, relative to controls, CPS mice exhibited robust, reproducible increases in FC within 8 of 9 identified cortical networks, including the prefrontal and cingulate cortices that contribute to the "mouse DMN". CPS mice exhibited increases in between-network FC, including amygdala - prefrontal cortex and amygdala - cingulate cortex. MRS identified metabolic alterations in CPS mice as increased inositol levels in amygdala and increased glycerophosphorylcholine levels in prefrontal cortex. Diffusion-weighted MRI detected increased fractional anisotropic values in the cingulum. This study demonstrates that chronic psychosocial stress induces FC states in the mouse brain analogous to those observed in depression, as well as cerebral metabolism and white matter pathway alterations that contribute to understanding of pathological processes. It also demonstrates the importance of brain imaging to the establishment of valid animal models in translational psychiatry.
27515532	Tumor necrosis factor alpha (TNF) is increased in depression and clinical-trial evidence indicates that blocking peripheral TNF has some antidepressant efficacy. In rodents, peripheral or intracerebroventricular TNF results in sickness e.g. reduced body weight, altered emotional behavior and impaired memory. However, the underlying pathways and responsible brain regions are poorly understood. The aim of this mouse study was to increase understanding by comparing the effects of sustained increases in TNF in the circulation, in brain regions impacted by increased circulating TNF, or specific brain regions. Increased peripheral TNF achieved by repeated daily injection (IP-TNF) or osmotic pump resulted in decreased body weight, decreased saccharin (reward) consumption, and increased memory of an aversive conditioned stimulus. These effects co-occurred with increased plasma interleukin-6 and increased IP-derived TNF in brain peri-ventricular regions. An adenovirus-associated viral TNF vector (AAV-TNF) was constructed, brain injection of which resulted in dose-dependent, sustained and region-specific TNF expression, and was without effect on blood cytokine levels. Lateral ventricle AAV-TNF yielded increased TNF in the same brain regions as IP-TNF. In contrast to IP-TNF it was without effect on body weight, saccharin consumption and fear memory, although it did increase anxiety. Hippocampal AAV-TNF led to decreased body weight. It increased conditioning to but not subsequent memory of an aversive context, suggesting impaired consolidation; it also increased anxiety. Amygdala AAV-TNF was without effect on body weight and aversive stimulus learning-memory, but reduced saccharin consumption and increased anxiety. This study adds significantly to the evidence that both peripheral and brain region-specific increases in TNF lead to both sickness and depression- and anxiety disorder-relevant behavior and do so via different pathways. It thereby highlights the complexity in terms of indirect and direct pathways via which increased TNF can act and which need to be taken into account when considering it as a therapeutic target.
27514774	Variation in common personality traits, such as boldness or exploration, is often associated with risk-reward trade-offs and behavioural flexibility. To date, only a few studies have examined the effects of consistent behavioural traits on both learning and cognition. We investigated whether certain personality traits ('exploration' and 'sociability') of individuals were related to cognitive performance, learning flexibility and learning style in a social ungulate species, the goat (Capra hircus). We also investigated whether a preference for feature cues rather than impaired learning abilities can explain performance variation in a visual discrimination task. We found that personality scores were consistent across time and context. Less explorative goats performed better in a non-associative cognitive task, in which subjects had to follow the trajectory of a hidden object (i.e. testing their ability for object permanence). We also found that less sociable subjects performed better compared to more sociable goats in a visual discrimination task. Good visual learning performance was associated with a preference for feature cues, indicating personality-dependent learning strategies in goats. Our results suggest that personality traits predict the outcome in visual discrimination and non-associative cognitive tasks in goats and that impaired performance in a visual discrimination tasks does not necessarily imply impaired learning capacities, but rather can be explained by a varying preference for feature cues.
27507657	The phenotype of addiction includes prominent attentional biases for drug cues, which play a role in motivating drug-seeking behavior and contribute to relapse. In a separate line of research, arbitrary stimuli have been shown to automatically capture attention when previously associated with reward in non-clinical samples.Here, I argue that these two attentional biases reflect the same cognitive process. I outline five characteristics that exemplify attentional biases for drug cues: resistant to conflicting goals, robust to extinction, linked to dorsal striatal dopamine and to biases in approach behavior, and can distinguish between individuals with and without a history of drug dependence. I then go on to describe how attentional biases for arbitrary reward-associated stimuli share all of these features, and conclude by arguing that the attentional components of addiction reflect a normal cognitive process that promotes reward-seeking behavior.	
27504806	Recent experiments have shown that animals and humans have a remarkable ability to adapt their learning rate according to the volatility of the environment. Yet the neural mechanism responsible for such adaptive learning has remained unclear. To fill this gap, we investigated a biophysically inspired, metaplastic synaptic model within the context of a well-studied decision-making network, in which synapses can change their rate of plasticity in addition to their efficacy according to a reward-based learning rule. We found that our model, which assumes that synaptic plasticity is guided by a novel surprise detection system, captures a wide range of key experimental findings and performs as well as a Bayes optimal model, with remarkably little parameter tuning. Our results further demonstrate the computational power of synaptic plasticity, and provide insights into the circuit-level computation which underlies adaptive decision-making. 
27503819	Decision making is aided by emotions. Bodily responses, such as sweating, heartbeat, and visceral sensation, are used to monitor the emotional state during decision making. Because decision making in dairy life is complicated and cognitively demanding, these bodily signals are thought to facilitate the decision making process by assigning positive or negative values for each of the behavioral options. The sweat response in a decision making task is measured by skin conductance response (SCR). SCR in decision making is divided into two categories: anticipatory SCR is observed before making decisions, and reward/punishment SCR is observed after the outcome of the decision is perceived. Brain lesion studies in human revealed that the amygdala and ventromedial prefrontal cortex are important in decision making. Patients with lesinon in the amygdala exhibit neither the anticipatory nor reward/punishment SCRs, while patients with the ventromedial prefrontal lesions have deficits only in the anticipatory SCRs. Decision making tasks and SCR analysis have contributed to reveal the implicit aspects of decision making. Further research is necessary for clarifying the role of explicit process of decision making and its relationship with the implicit process. 
27503018	Pediatric dental fear, if left unchecked, can persist for a lifetime and adversely impact the physical and psychological health of a patient. In this study, a feasible nonmedical method for relieving pediatric dental fear was investigated.A randomized, single-blind, controlled trial model was applied. The juvenile patients experiencing dental fear, whose parents or guardian had signed an informed consent form, were randomly divided into two groups. Group A (n = 50) was the control group, while Group B (n = 50) was the reward group. Participants in Group A accepted routine treatment. Participants in Group B were told that they would obtain a gift as a rewarda for their good behavior if they were compliant during their dental treatments. The Chinese version of the Children's Fear Survey Schedule-Dental Subscale (CFSS-DS) was used to evaluate the level of dental fear of each patient both before and after each treatment. A contrast analysis and a correlation analysis of the results were used to assess the efficacy of the reward mechanism.	All participants in Group B, were obedient during the dental treatment, and they also successfully chose the present they wanted at the end of their dental treatment. Children at different ages showed different reward preferences. Significant difference in the fear scores of the participants in Group B before the treatment and after receiving the reward was found (independent samples t-test, t = 14.72, P < 0.001). In Group A, 86% children's fear score did not undergo a noticeable change.	A reward system is proved feasible to relieve pediatric dental fear, and the form of reward should meet the demand of patients.	
27497734	Although the relationship between criminal activity and ADHD has been heavily studied, this paper reviews a largely neglected area of academic discourse: how symptoms of ADHD that often contribute to offending behavior may also potentially create further problems for offenders with ADHD after they come into contact with the criminal justice system and pilot their way through the legal process. The main symptoms of ADHD that are primarily connected to criminal offending are examined and contextualized with respect to diagnosed offenders' experiences with the justice system. Symptoms of ADHD, specifically reward deficiency, behavioral inhibition, and attention deficits, may affect whether individuals will be successful in their experiences in court, with probation, and during incarceration. This is especially true for individuals whose ADHD diagnoses are unknown to the criminal justice system or have never been formally diagnosed. Actors in the criminal justice need to be aware of the symptomatic features and behavioral patterns of offenders with ADHD in order to recognize and identify these offenders, and correspondingly, to refer them to mental health services. Recognizing that at least some of an offender's behavior may be related to symptoms of ADHD will help the criminal justice system better provide recommendations regarding sentencing, probation, and treatment provisions, as well as better ensure that offenders with ADHD have a more successful and just experience in their interactions with the criminal justice system.
27497292	Anorexia Nervosa (AN) is a disorder characterised by compulsive behaviour, such as self-starvation and excessive exercise, which develop in the pursuit of weight-loss. Recent theory suggests that once established, compulsive weight-loss behaviours in AN may become habitual. In two parallel studies, we measured whether individuals with AN showed a bias toward habits using two outcome-devaluation tasks. In Study 1, 23 women with AN (restrictive and binge/purge subtypes), and 18 healthy controls (HC) completed the slips-of-action paradigm, designed to assess reward-based habits. In Study 2, 13 women with restrictive AN, 14 women recovered from restrictive AN, and 17 female HC participants completed the slips-of-action paradigm, and an avoidance paradigm, designed to assess aversive habits. AN participants showed no deficit relative to HCs in the ability to use feedback to respond correctly to stimuli. Following devaluation of outcomes, all groups in both studies were equally able to withhold inappropriate responses, suggesting no deficit in the balance between goal-directed and habitual control of behaviour in these tasks in AN. These results suggest that individuals with AN do not show a generalised tendency to rely on habits in two outcome-devaluation tasks. Future research is needed to investigate the potential role of disorder-specific habits in the maintenance of behaviour in AN. 
27496691	The obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. Combining gut/brain peptide, GLP-1, with estrogen into a conjugate may represent a novel, safe and potent, strategy to treat diabesity. Here we demonstrate that the central administration of GLP-1-estrogen conjugate reduced food reward, food intake, and body weight in rats. In order to determine the brain location of the interaction of GLP-1 with estrogen, we avail of single-photon emission computed tomography imaging of regional cerebral blood flow and pinpoint a brain site unexplored for its role in feeding and reward, the supramammillary nucleus (SUM) as a potential target of the conjugated GLP-1-estrogen. We confirm that conjugated GLP-1 and estrogen directly target the SUM with site-specific microinjections. Additional microinjections of GLP-1-estrogen into classic energy balance controlling nuclei, the lateral hypothalamus (LH) and the nucleus of the solitary tract (NTS) revealed that the metabolic benefits resulting from GLP-1-estrogen injections are mediated through the LH and to some extent by the NTS. In contrast, no additional benefit of the conjugate was noted on food reward when the compound was microinjected into the LH or the NTS, identifying the SUM as the only neural substrate identified here to underlie the reward reducing benefits of GLP-1 and estrogen conjugate. Collectively we discover a surprising neural substrate underlying food intake and reward effects of GLP-1 and estrogen and uncover a new brain area capable of regulating energy balance and reward. 
27496590	Typical adults can track reward probabilities across trials to estimate the volatility of the environment and use this information to modify their learning rate (Behrens et al., 2007). In a stable environment, it is advantageous to take account of outcomes over many trials, whereas in a volatile environment, recent experience should be more strongly weighted than distant experience. Recent predictive coding accounts of autism propose that autistic individuals will demonstrate atypical updating of their behaviour in response to the statistics of the reward environment. To rigorously test this hypothesis, we administered a developmentally appropriate version of Behrens et al.'s (2007) task to 34 cognitively able children on the autism spectrum aged between 6 and 14 years, 32 age- and ability-matched typically developing children and 19 typical adults. Participants were required to choose between a green and a blue pirate chest, each associated with a randomly determined reward value between 0 and 100 points, with a combined total of 100 points. On each trial, the reward was given for one stimulus only. In the stable condition, the ratio of the blue or green response being rewarded was fixed at 75:25. In the volatile condition, the ratio alternated between 80:20 and 20:80 every 20 trials. We estimated the learning rate for each participant by fitting a delta rule model and compared this rate across conditions and groups. All groups increased their learning rate in the volatile condition compared to the stable condition. Unexpectedly, there was no effect of group and no interaction between group and condition. Thus, autistic children used information about the statistics of the reward environment to guide their decisions to a similar extent as typically developing children and adults. These results help constrain predictive coding accounts of autism by demonstrating that autism is not characterized by uniform differences in the weighting of prediction error.
27494932	As the snacking pattern of European adolescents is of great concern, effective interventions are necessary. Till now health promotion efforts in children and adolescents have had only limited success in changing adolescents' eating patterns and anthropometrics. Therefore, the present study proposes an innovative approach to influence dietary behaviors in youth based on new insights on effective behavior change strategies and attractive intervention channels to engage adolescents. This article describes the rationale, the development, and evaluation design of the 'Snack Track School' app. The aim of the app is to improve the snacking patterns of Flemish 14- to 16-year olds.The development of the app was informed by the systematic, stepwise, iterative, and collaborative principles of the Intervention Mapping protocol. A four week mHealth intervention was developed based on the dual-system model with behavioral change strategies targeting both the reflective (i.e., active learning, advance organizers, mere exposure, goal-setting, monitoring, and feedback) and automatic processes (i.e., rewards and positive reinforcement). This intervention will be evaluated via a controlled pre-post design in Flemish schools among 1400 adolescents.	When this intervention including strategies focused on both the reflective and automatic pathway proves to be effective, it will offer a new scientifically-based vision, guidelines and practical tools for public health and health promotion (i.e., incorporation of learning theories in intervention programs).	
27494187	Chronic exposure to stress or drugs of abuse has been linked to altered gene expression throughout the body, and changes in gene expression in discrete brain regions are thought to underlie many psychiatric diseases, including major depressive disorder and drug addiction. Preclinical models of these disorders have provided evidence for mechanisms of this altered gene expression, including transcription factors, but evidence supporting a role for these factors in human patients has been slow to emerge. The transcription factor ΔFosB is induced in the prefrontal cortex (PFC) and hippocampus (HPC) of rodents in response to stress or cocaine, and its expression in these regions is thought to regulate their "top down" control of reward circuitry, including the nucleus accumbens (NAc). Here, we use biochemistry to examine the expression of the FosB family of transcription factors and their potential gene targets in PFC and HPC postmortem samples from depressed patients and cocaine addicts. We demonstrate that ΔFosB and other FosB isoforms are downregulated in the HPC but not the PFC in the brains of both depressed and addicted individuals. Further, we show that potential ΔFosB transcriptional targets, including GluA2, are also downregulated in the HPC but not PFC of cocaine addicts. Thus, we provide the first evidence of FosB gene expression in human HPC and PFC in these psychiatric disorders, and in light of recent findings demonstrating the critical role of HPC ΔFosB in rodent models of learning and memory, these data suggest that reduced ΔFosB in HPC could potentially underlie cognitive deficits accompanying chronic cocaine abuse or depression. 
27493625	The brain enables animals to behaviorally adapt in order to survive in a complex and dynamic environment, but how reward-oriented behaviors are achieved and computed by its underlying neural circuitry is an open question. To address this concern, we have developed a spiking model of the basal ganglia (BG) that learns to dis-inhibit the action leading to a reward despite ongoing changes in the reward schedule. The architecture of the network features the two pathways commonly described in BG, the direct (denoted D1) and the indirect (denoted D2) pathway, as well as a loop involving striatum and the dopaminergic system. The activity of these dopaminergic neurons conveys the reward prediction error (RPE), which determines the magnitude of synaptic plasticity within the different pathways. All plastic connections implement a versatile four-factor learning rule derived from Bayesian inference that depends upon pre- and post-synaptic activity, receptor type, and dopamine level. Synaptic weight updates occur in the D1 or D2 pathways depending on the sign of the RPE, and an efference copy informs upstream nuclei about the action selected. We demonstrate successful performance of the system in a multiple-choice learning task with a transiently changing reward schedule. We simulate lesioning of the various pathways and show that a condition without the D2 pathway fares worse than one without D1. Additionally, we simulate the degeneration observed in Parkinson's disease (PD) by decreasing the number of dopaminergic neurons during learning. The results suggest that the D1 pathway impairment in PD might have been overlooked. Furthermore, an analysis of the alterations in the synaptic weights shows that using the absolute reward value instead of the RPE leads to a larger change in D1. 
27491478	Obsessive-Compulsive Disorder (OCD) is characterized by maladaptive patterns of repetitive, inflexible cognition and behavior that suggest a lack of cognitive flexibility. Consistent with this clinical observation, many neurocognitive studies suggest behavioral and neurobiological abnormalities in cognitive flexibility in individuals with OCD. Meta-analytic reviews support a pattern of cognitive inflexibility, with effect sizes generally in the medium range. Heterogeneity in assessments and the way underlying constructs have been operationalized point to the need for better standardization across studies, as well as more refined overarching models of cognitive flexibility and executive function (EF). Neuropsychological assessments of cognitive flexibility include measures of attentional set shifting, reversal and alternation, cued task-switching paradigms, cognitive control measures such as the Trail-Making and Stroop tasks, and several measures of motor inhibition. Differences in the cognitive constructs and neural substrates associated with these measures suggest that performance within these different domains should be examined separately. Additional factors, such as the number of consistent trials prior to a shift and whether a shift is explicitly signaled or must be inferred from a change in reward contingencies, may influence performance, and thus mask or accentuate deficits. Several studies have described abnormalities in neural activation in the absence of differences in behavioral performance, suggesting that our behavioral probes may not be adequately sensitive, but also offering important insights into potential compensatory processes. The fact that deficits of moderate effect size are seen across a broad range of classic neuropsychological tests in OCD presents a conceptual challenge, as clinical symptomatology suggests greater specificity. Traditional cognitive probes may not be sufficient to delineate specific domains of deficit in this and other neuropsychiatric disorders; a new generation of behavioral tasks that test more specific underlying constructs, supplemented by neuroimaging to provide insight into the underlying processes, may be needed.
27491014	Those with borderline personality disorder (BPD) display altered evaluations regarding reward and punishment compared to others. The processing of rewards is basal for operant conditioning. However, studies addressing operant conditioning in BPD patients are rare. In the current study, an operant conditioning task combining learning acquisition and reversal was used. BPD patients and matched healthy controls (HCs) were exposed to aversive and neutral stimuli to assess the influence of emotion on learning. Picture content, dissociation, aversive tension and symptom severity were rated. Error rates were measured. Results showed no group interactions between aversive versus neutral scenes. The higher emotional arousal, dissociation and tension, the worse the acquisition, but not reversal, scores were for BPD patients. Scores from the Borderline Symptom List were associated with more errors in the reversal, but not the acquisition phase. The results are preliminary evidence for impaired acquisition learning due to increased emotional arousal, dissociation and tension in BPD patients. A failure to process punishment in the reversal phase was associated with symptom severity and may be related to neuropsychological dysfunctioning involving the ventromedial prefrontal cortex. Conclusions are limited due to the correlational study design and the small sample size. 

27487462	Playing recreational videogames is a common activity, yet little is known about its role in the lives of people who are coping with serious illness. These individuals may experience depression and isolation and may turn to games to help alleviate negative experiences and support well-being. We explored these possibilities in the context of cancer survivors. The study aimed to discover motivations underlying game play and the extent to which motivations are associated with psychological health and well-being.We conducted a cross-sectional online survey of survivors who play recreational games (N = 794). Key variables were motivations and indicators of psychological health, including self-efficacy in cancer communications, resilient coping, and beliefs that one is living a fulfilling and meaningful life (flourishing).	Participants were most likely to be motivated to play for stimulation and a sense of accomplishment (intrinsic rewards), followed by development of self, sense of community, and personal affirmation. Multiple regression analyses revealed positive associations between playing for intrinsic rewards and all three psychological health outcomes. Playing for a sense of community was also positively associated with coping and flourishing.	Playing recreational videogames, particularly to receive intrinsic rewards and to connect with others, may play a supportive role in the psychological health of survivors. Findings suggest future areas for research and implications for development of serious games.	
27483696	Obesity is a medical and social problem with a dramatically increasing prevalence. It is important to take action since childhood to prevent and treat obesity and metabolic syndrome. Infantile obesity affects all body systems starting in childhood and continuing to adulthood. Understanding the impact of stressors on weight status may be especially important for preventing obesity. The relationship between stress, eating behavior and obesity is not fully understood. However, there is evidence that stress causes disorders in hypothalamic-pituitary-adrenal (HPA) axis, system that regulates both stress and feeding responses. Also, the response is different depending on the type of stressors. Chronic stress, especially when people live in a palatable food environment, induces HPA stimulation, excess glucocorticoids, insulin resistance, which lead to inhibition of lipid mobilization, accumulation of triglyceride and retention of abdominal fat.
27483371	In order to behave adaptively, attention can be directed in space either voluntarily (i.e., endogenously) according to strategic goals, or involuntarily (i.e., exogenously) through reflexive capture by salient or novel events. The emotional or motivational value of stimuli can also strongly influence attentional orienting. However, little is known about how reward-related effects compete or interact with endogenous and exogenous attention mechanisms, particularly outside of awareness. Here we developed a visual search paradigm to study subliminal value-based attentional orienting. We systematically manipulated goal-directed or stimulus-driven attentional orienting and examined whether an irrelevant, but previously rewarded stimulus could compete with both types of spatial attention during search. Critically, reward was learned without conscious awareness in a preceding phase where one among several visual symbols was consistently paired with a subliminal monetary reinforcement cue. Our results demonstrated that symbols previously associated with a monetary reward received higher attentional priority in the subsequent visual search task, even though these stimuli and reward were no longer task-relevant, and despite reward being unconsciously acquired. Thus, motivational processes operating independent of conscious awareness may provide powerful influences on mechanisms of attentional selection, which could mitigate both stimulus-driven and goal-directed shifts of attention. 
27479484	Studies using the Iowa Gambling Task (IGT) have distinguished between good and bad decision makers and have provided an explanation for deficits in decision making. Previous studies have demonstrated a link between Wisconsin Card Sorting Test (WCST) performance and IGT performance, but the results were not consistent and failed to explain why WCST performance can predict IGT performance. The present study aimed to demonstrate that WCST performance can predict IGT performance and to identify the cognitive component of the WCST that affects IGT performance using event-related potentials (ERPs).In this study, 39 healthy subjects (5 subjects were excluded) were divided into a high group and a low group based on their global score on the WCST. A single-choice version of the IGT was used to eliminate the impact of retrieval strategies on the choice evaluation process and interference due to uncorrelated decks. Differences in the underlying neural mechanisms and explicit knowledge between the two groups during the three stages of the decision-making process were described.	Based on the information processing perspective, we divided the decision-making process into three stages: choice evaluation, response selection, and feedback processing. The behavioral results showed that the highly cognitively flexible participants performed better on the IGT and acquired more knowledge of the task. The ERP results showed that during the choice evaluation stage, the P300 recorded from central and parietal regions when a bad deck appeared was larger in the high group participants than in the low group participants. During the response selection stage, the effect of choice type was significant only in the frontal region in the high group, with a larger effect for passing. During the feedback evaluation stage, a larger FRN was evoked for a loss than for a win in the high group, whereas the FRN effect was absent in the low group.	Compared with the participants with low cognitive flexibility, the participants with high cognitive flexibility performed better on the IGT, acquired more knowledge of the task, and displayed more obvious somatic markers. The low group participants showed reduced working memory abilities during the choice evaluation stage. The appropriate somatic markers reflected by the DPN is formed only when conceptual knowledge is gained in the response selection stage. The absence of an FRN effect in the subjects who performed poorly on the WCST suggests a significant deficit in feedback learning and reward prediction.	
27478141	Dopamine's (DA) role in reward-processing is currently discussed as either providing a teaching signal to guide learning or mediating the transfer of incentive salience (i.e. motivational aspects) from unconditioned stimuli (US) to conditioned stimuli (CS). We used a Pavlovian conditioned approach (PCA) procedure to further investigate DAs contribution to these processes. Experiment 1 assessed the acquisition of PCA to a manipulable lever cue for 7days under DA-blockade with Flupenthixol (FLU; 225μg/kg) or Saline (SAL) treatment, followed by 6-days off-drug testing. FLU decreased the number of conditioned responses (CR) during the treatment phase, but cessation of treatment resulted in an immediate increase in CR to levels comparable to SAL controls; notably, CR in FLU-treated rats were restricted to goal tracking behaviour. During continued off-drug testing, rats from the FLU group developed sign tracking with a similar temporal pattern as controls. In experiment 2, acquisition of PCA to a non-manipulable auditory cue was investigated. FLU reduced the number of CR during treatment, and removing DA antagonism resulted in a similar rapid increase of CR as seen in experiment 1. These data complement other reports by demonstrating that, independently from the physical properties of the CS, DA is not required for learning predictive aspects of a CS-US relationship but for the development of behaviour (namely sign tracking) which is based on the motivational aspects of a CS-US relationship. 
27477632	In many natural environments the value of a choice gradually gets better or worse as circumstances change. Discerning such trends makes predicting future choice values possible. We show that humans track such trends by comparing estimates of recent and past reward rates, which they are able to hold simultaneously in the dorsal anterior cingulate cortex (dACC). Comparison of recent and past reward rates with positive and negative decision weights is reflected by opposing dACC signals indexing these quantities. The relative strengths of time-linked reward representations in dACC predict whether subjects persist in their current behaviour or switch to an alternative. Computationally, trend-guided choice can be modelled by using a reinforcement-learning mechanism that computes a longer-term estimate (or expectation) of prediction errors. Using such a model, we find a relative predominance of expected prediction errors in dACC, instantaneous prediction errors in the ventral striatum and choice signals in the ventromedial prefrontal cortex. 
27475876	Previous research shows that goal-directed behavior might be modulated by cues that predict (dis)similar outcomes. However, the literature investigating this modulation with pain outcomes is scarce. Therefore, this experiment investigated whether environmental cues predicting pain or reward modulate defensive pain responding. Forty-eight healthy participants completed a joystick movement task with two different movement orientations. Performing one movement was associated with a painful stimulus, whereas performance of another movement was associated with reward, i.e. lottery tickets. In a subsequent task, participants learned to associate three different cues withpain, reward, or neither of the two. Next, these cues were integrated in the movement task. This study demonstrates that in general, aversive cues enhance and appetitive cues reduce pain-related fear. Furthermore, we found that incongruence between the outcomes predicted by the movement and the cue results in more oscillatory behavior, i.e., participants were more willing to perform a painful movement when a cue predicting reward was simultaneously presented, and vice versa. Similarly, when given a choice, participants preferred to perform the reward movement, unless there was an incongruence between the outcomes predicted by the movements and cues. Taken together, these results provide experimental evidence that environmental cues are capable of modulating pain-related fear and avoidance behavior. 
27473323	The retrosplenial cortex (RSC) plays an important role in memory and spatial navigation. It shares functional similarities with the hippocampus, including the presence of place fields and lesion-induced impairments in spatial navigation, and the RSC is an important source of visual-spatial input to the hippocampus. Recently, the RSC has been the target of intense scrutiny among investigators of human memory and navigation. fMRI and lesion data suggest an RSC role in the ability to use landmarks to navigate to goal locations. However, no direct neurophysiological evidence of encoding navigational cues has been reported so the specific RSC contribution to spatial cognition has been uncertain. To examine this, we trained rats on a T-maze task in which the reward location was explicitly cued by a flashing light and we recorded RSC neurons as the rats learned. We found that RSC neurons rapidly encoded the light cue. Additionally, RSC neurons encoded the reward and its location, and they showed distinct firing patterns along the left and right trajectories to the goal. These responses may provide key information for goal-directed navigation, and the loss of these signals may underlie navigational impairments in subjects with RSC damage.
27473320	Reward and motivation have powerful effects on cognition and brain activity, yet it remains unclear how they affect sustained cognitive performance. We have recently shown that a variety of motivators improve accuracy and reduce variability during sustained attention. In the current study, we investigate how neural activity in task-positive networks supports these sustained attention improvements. Participants performed the gradual-onset continuous performance task with alternating motivated (rewarded) and unmotivated (unrewarded) blocks. During motivated blocks, we observed increased sustained neural recruitment of task-positive regions, which interacted with fluctuations in task performance. Specifically, during motivated blocks, participants recruited these regions in preparation for upcoming targets, and this activation predicted accuracy. In contrast, during unmotivated blocks, no such advanced preparation was observed. Furthermore, during motivated blocks, participants had similar activation levels during both optimal (in-the-zone) and suboptimal (out-of-the-zone) epochs of performance. In contrast, during unmotivated blocks, task-positive regions were only engaged to a similar degree as motivated blocks during suboptimal (out-of-the-zone) periods. These data support a framework in which motivated individuals act as "cognitive investors," engaging task-positive resources proactively and consistently during sustaining attention. When unmotivated, however, the same individuals act as "cognitive misers," engaging maximal task-positive resources only during periods of struggle.
27473116	Leadership is a key feature in implementation efforts, which is highlighted in most implementation frameworks. However, in studying leadership and implementation, only few studies rely on established leadership theory, which makes it difficult to draw conclusions regarding what kinds of leadership managers should perform and under what circumstances. In industrial and organizational psychology, transformational leadership and contingent reward have been identified as effective leadership styles for facilitating change processes, and these styles map well onto the behaviors identified in implementation research. However, it has been questioned whether these general leadership styles are sufficient to foster specific results; it has therefore been suggested that the leadership should be specific to the domain of interest, e.g., implementation. To this end, an intervention specifically involving leadership, which we call implementation leadership, is developed and tested in this project. The aim of the intervention is to increase healthcare managers' generic implementation leadership skills, which they can use for any implementation efforts in the future.The intervention is conducted in healthcare in Stockholm County, Sweden, where first- and second-line managers were invited to participate. Two intervention groups are included, including 52 managers. Intervention group 1 consists of individual managers, and group 2 of managers from one division. A control group of 39 managers is additionally included. The intervention consists of five half-day workshops aiming at increasing the managers' implementation leadership, which is the primary outcome of this intervention. The intervention will be evaluated through a mixed-methods approach. A pre- and post-design applying questionnaires at three time points (pre-, directly after the intervention, and 6 months post-intervention) will be used, in addition to process evaluation questionnaires related to each workshop. In addition, interviews will be conducted over time to evaluate the intervention.	The proposed intervention represents a novel contribution to the implementation literature, being the first to focus on strengthening healthcare managers' generic skills in implementation leadership.	
27472785	Motivation and reward can have differential effects on separate aspects of sustained attention. We previously demonstrated that continuous reward/punishment throughout a sustained attention task improves overall performance, but not vigilance decrements. One interpretation of these findings is that vigilance decrements are due to resource depletion, which is not overcome by increasing overall motivation. However, an alternative explanation is that as one performs a continuously rewarded task there are less potential gains/losses as the task progresses, which could decrease motivation over time, producing a vigilance decrement. This would predict that keeping future gains/losses consistent throughout the task would reduce the vigilance decrement. In the current study, we examined this possibility by comparing two versions (continuous-small loss vs. anticipate-large loss) of a 10-minute gradual onset continuous performance task (gradCPT), a challenging go/no-go sustained attention task. Participants began each task with the potential to keep $18. In the continuous-small-loss version, small monetary losses were accrued continuously throughout the task for each error. However, in the anticipate-large-loss version, participants lost all $18 if they erroneously responded to one target that always appeared toward the end of the vigil. Typical vigilance decrements were observed in the continuous-small-loss condition. In the anticipate-large-loss condition, vigilance decrements were reduced, particularly when the anticipate-large loss condition was completed second. This suggests that the looming possibility of a large loss can attenuate the vigilance decrement and that this attenuation may occur most consistently after sufficient task experience. We discuss these results in the context of current theories of sustained attention. 
27472538	The balance between action and reward during neurofeedback may influence reinforcement learning of brain self-regulation.Eleven healthy volunteers participated in three runs of motor imagery-based brain-machine interface feedback where a robot passively opened the hand contingent to β-band modulation. For each run, the β-desynchronization threshold to initiate the hand robot movement increased in difficulty (low, moderate, and demanding). In this context, the incentive to learn was estimated by the change of reward per action, operationalized as the change in reward duration per movement onset.	Variance analysis revealed a significant interaction between threshold difficulty and the relationship between reward duration and number of movement onsets (p<0.001), indicating a negative learning incentive for low difficulty, but a positive learning incentive for moderate and demanding runs. Exploration of different thresholds in the same data set indicated that the learning incentive peaked at higher thresholds than the threshold which resulted in maximum classification accuracy.	Specificity is more important than sensitivity of neurofeedback for reinforcement learning of brain self-regulation.	Learning efficiency requires adequate challenge by neurofeedback interventions.	
27471754	The Behavioural Inhibition System/Behavioural Activation System scales (BIS/BAS scales) constitute one of the most prominent questionnaires to assess individual differences in sensitivity to punishment and reward. However, some studies questioned its validity, especially that of the French and German translations. The aim of the present study was to re-evaluate the psychometric characteristics of the BIS/BAS scales in a large sample of French- and German-speaking young Swiss men (N = 5872). Results showed that factor structures previously found in the literature did not meet the standards of fit. Nine items had to be removed to achieve adequate fit statistics in confirmatory factor analysis, yielding a shortened version with four factors: one BIS factor comprising five items and three BAS factors, namely Reward Reactivity, Drive and Fun Seeking, each comprising two items. Convergent validity and group invariance analyses suggest that the shortened BIS/BAS scales constitute a valid and reliable instrument. Researchers interested in assessing individual differences in BIS and BAS reactivity in French- and German-speaking individuals should avoid using the BIS/BAS scales as originally specified. The shortened version may be a sound alternative at least in samples of young adults. Its shorter format may be particularly suited for surveys with constraints on questionnaire length.
27468271	Little is known about the specific neural mechanisms through which cognitive factors influence craving and associated brain responses, despite the initial success of cognitive therapies in treating drug addiction. In this study, we investigated how cognitive factors such as beliefs influence subjective craving and neural activities in nicotine-addicted individuals using model-based functional magnetic resonance imaging (fMRI) and neuropharmacology. Deprived smokers (N = 24) participated in a two-by-two balanced placebo design, which crossed beliefs about nicotine (told "nicotine" vs. told "no nicotine") with the nicotine content in a cigarette (nicotine vs. placebo) which participants smoked immediately before performing a fMRI task involving reward learning. Subjects' reported craving was measured both before smoking and after the fMRI session. We found that first, in the presence of nicotine, smokers demonstrated significantly reduced craving after smoking when told "nicotine in cigarette" but showed no change in craving when told "no nicotine." Second, neural activity in the insular cortex related to craving was only significant when smokers were told "nicotine" but not when told "no nicotine." Both effects were absent in the placebo condition. Third, insula activation related to computational learning signals was modulated by belief about nicotine regardless of nicotine's presence. These results suggest that belief about nicotine has a strong impact on subjective craving and insula responses related to both craving and learning in deprived smokers, providing insights into the complex nature of belief-drug interactions. 
27466806	The current study avoided the typical laboratory context to determine instead whether over-imitation-the disposition to copy even visibly, causally unnecessary actions-occurs in a real-world context in which participants are unaware of being in an experiment. We disguised a puzzle-box task as an interactive item available to the public within a science engagement zone of Edinburgh Zoo. As a member of the public approached, a confederate acting as a zoo visitor retrieved a reward from the box using a sequence of actions containing both causally relevant and irrelevant elements. Despite the absence of intentional demonstration, or social pressure to copy, a majority of both child and even adult observers included all causally irrelevant actions in their reproduction. This occurred even though causal irrelevance appeared manifest because of the transparency of the puzzle-box. That over-imitation occurred so readily in a naturalistic context, devoid of social interaction and pressure, suggests that humans are opportunistic social learners throughout the lifespan, copying the actions of other individuals even when these actions are not intentionally demonstrated, and their causal significance is not readily apparent. The disposition to copy comprehensively, even when a mere onlooker, likely provides humans, irrespective of their age, with a powerful mechanism to extract maximal information from the social environment. 
27466331	The ability to use information about the uncertainty of future outcomes is critical for adaptive behavior in an uncertain world. We show that the basal forebrain (BF) contains at least two distinct neural-coding strategies to support this capacity. The dorsal-lateral BF, including the ventral pallidum (VP), contains reward-sensitive neurons, some of which are selectively suppressed by uncertain-reward predictions (U(-)). In contrast, the medial BF (mBF) contains reward-sensitive neurons, some of which are selectively enhanced (U(+)) by uncertain-reward predictions. In a two-alternative choice-task, U(-) neurons were selectively suppressed while monkeys chose uncertain options over certain options. During the same choice-epoch, U(+) neurons signaled the subjective reward value of the choice options. Additionally, after the choice was reported, U(+) neurons signaled reward uncertainty until the choice outcome. We suggest that uncertainty-related suppression of VP may participate in the mediation of uncertainty-seeking actions, whereas uncertainty-related enhancement of the mBF may direct cognitive resources to monitor and learn from uncertain-outcomes.To survive in an uncertain world, we must approach uncertainty and learn from it. Here we provide evidence for two mostly distinct mechanisms for processing uncertainty about rewards within different subregions of the primate basal forebrain (BF). We found that uncertainty suppressed the representation of certain (or safe) reward values by some neurons in the dorsal-lateral BF, in regions occupied by the ventral pallidum. This uncertainty-related suppression was evident as monkeys made risky choices. We also found that uncertainty-enhanced the activity of many medial BF neurons, most prominently after the monkeys' choices were completed (as they awaited uncertain outcomes). Based on these findings, we propose that different subregions of the BF could support action and learning under uncertainty in distinct but complimentary manners.	
27457669	We recently developed a conditioned place preference (CPP) procedure, commonly used to study rewarding drug effects, to demonstrate that dominant sexually-experienced CD-1 male mice form CPP to contexts previously associated with defeating subordinate male C57BL/6J mice. Here we further characterized conditioned and unconditioned aggression behavior in CD-1 mice. In Exp. 1 we used CD-1 mice that displayed a variable spectrum of unconditioned aggressive behavior toward younger subordinate C57BL/6J intruder mice. We then trained the CD-1 mice in the CPP procedure where one context was intruder-paired, while a different context was not. We then tested for aggression CPP 1 day after training. In Exp. 2, we tested CD-1 mice for aggression CPP 1 day and 18 days after training. In Exp. 3-4, we trained the CD-1 mice to lever-press for palatable food and tested them for footshock punishment-induced suppression of food-reinforced responding. In Exp. 5, we characterized unconditioned aggression in hybrid CD-1 × C57BL/6J D1-Cre or D2-Cre F1 generation crosses. Persistent aggression CPP was observed in CD-1 mice that either immediately attacked C57BL/6J mice during all screening sessions or mice that gradually developed aggressive behavior during the screening phase. In contrast, CD-1 mice that did not attack the C57BL/6J mice during screening did not develop CPP to contexts previously paired with C57BL/6J mice. The aggressive phenotype did not predict resistance to punishment-induced suppression of food-reinforced responding. CD-1 × D1-Cre or D2-Cre F1 transgenic mice showed strong unconditioned aggression. Our study demonstrates that aggression experience causes persistent CPP and introduces transgenic mice for circuit studies of aggression.
27457495	The mammalian forebrain is characterized by the presence of several parallel cortico-basal ganglia circuits that shape the learning and control of actions. Among these are the associative, limbic and sensorimotor circuits. The function of all of these circuits has now been implicated in responses to drugs of abuse, as well as drug seeking and drug taking. While the limbic circuit has been most widely examined, key roles for the other two circuits in control of goal-directed and habitual instrumental actions related to drugs of abuse have been shown. In this review we describe the three circuits and effects of acute and chronic drug exposure on circuit physiology. Our main emphasis is on drug actions in dorsal striatal components of the associative and sensorimotor circuits. We then review key findings that have implicated these circuits in drug seeking and taking behaviors, as well as drug use disorders. Finally, we consider different models describing how the three cortico-basal ganglia circuits become involved in drug-related behaviors. This topic has implications for drug use disorders and addiction, as treatments that target the balance between the different circuits may be useful for reducing excessive substance use.
27452791	We propose that schizophrenia involves a combination of decreased phasic dopamine responses for relevant stimuli and increased spontaneous phasic dopamine release. Using insights from computational reinforcement-learning models and basic-science studies of the dopamine system, we show that each of these two disturbances contributes to a specific symptom domain and explains a large set of experimental findings associated with that domain. Reduced phasic responses for relevant stimuli help to explain negative symptoms and provide a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with negative symptoms: reduced learning from rewards; blunted activation of the ventral striatum, midbrain, and other limbic regions for rewards and positive prediction errors; blunted activation of the ventral striatum during reward anticipation; blunted autonomic responding for relevant stimuli; blunted neural activation for aversive outcomes and aversive prediction errors; reduced willingness to expend effort for rewards; and psychomotor slowing. Increased spontaneous phasic dopamine release helps to explain positive symptoms and provides a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with positive symptoms: aberrant learning for neutral cues (assessed with behavioral and autonomic responses), and aberrant, increased activation of the ventral striatum, midbrain, and other limbic regions for neutral cues, neutral outcomes, and neutral prediction errors. Taken together, then, these two disturbances explain many findings in schizophrenia. We review evidence supporting their co-occurrence and consider their differential implications for the treatment of positive and negative symptoms.
27450925	Single pellet reaching is an established task for studying fine motor control in which rats reach for, grasp, and eat food pellets in a stereotyped sequence. Most incarnations of this task require constant attention, limiting the number of animals that can be tested and the number of trials per session. Automated versions allow more interventions in more animals, but must be robust and reproducible.Our system automatically delivers single reward pellets for rats to grasp with their forepaw. Reaches are detected using real-time computer vision, which triggers video acquisition from multiple angles using mirrors. This allows us to record high-speed (>300 frames per second) video, and trigger interventions (e.g., optogenetics) with high temporal precision. Individual video frames are triggered by digital pulses that can be synchronized with behavior, experimental interventions, or recording devices (e.g., electrophysiology). The system is housed within a soundproof chamber with integrated lighting and ventilation, allowing multiple skilled reaching systems in one room.	We show that rats acquire the automated task similarly to manual versions, that the task is robust, and can be synchronized with optogenetic interventions.	Existing skilled reaching protocols require high levels of investigator involvement, or, if ad libitum, do not allow for integration of high-speed, synchronized data collection.	This task will facilitate the study of motor learning and control by efficiently recording large numbers of skilled movements. It can be adapted for use with modern neurophysiology, which demands high temporal precision.	
27450031	Schizophrenia is a debilitating neuropsychiatric disorder typically diagnosed from late adolescence to adulthood. Subthreshold behavioral symptoms (e.g., cognitive deficits and substance abuse) often precede the clinical diagnosis of schizophrenia. However, these prodromal symptoms have not been consistently associated with structural and functional brain biomarkers, limiting the chance of early diagnosis of schizophrenia.Using an extensively multimodal range of magnetic resonance methods (for anatomy, metabolism, and function), we screened early biomarkers in a methylazoxymethanol acetate (MAM) rat model of schizophrenia and saline-treated control (SHAM) rats, in conjunction with immunohistochemistry, myelin staining, and a novel three-choice, reversal-learning task to identify early behavioral markers corresponding the subthreshold symptoms.	MAM (vs. SHAM) rats had lower/higher structural connectivity in anterior/posterior corpus callosum. The orbitofrontal cortex of MAM rats showed lower resting-state functional magnetic resonance imaging functional connectivity in conjunction with lower neuronal density, lower glucose oxidation, and attenuated neurotransmission (hypofrontality). In contrast, these measures were all higher in visual cortex of MAM rats (posterior hyperactivity), which might parallel perceptual problems in schizophrenia. In behavioral studies, MAM (vs. SHAM) rats displayed abnormal orbitofrontal cortex-mediated decision-making processes, resulting in a novel reward-sensitive hyperflexible phenotype, which might reflect vulnerability of prodromal patients to substance abuse.	We identified two novel biomarkers of early schizophrenia in a preclinical rat model: hypofrontality associated with the hyperflexible phenotype, and posterior hyperactivity. Because each of these magnetic resonance methods is clinically translatable, these markers could contribute to early diagnosis and the development of novel therapies of schizophrenia.	
27445732	The larval brain of Drosophila melanogaster provides an excellent system for the study of the neurocircuitry mechanism of memory. Recent development of neurogenetic techniques in fruit flies enables manipulations of neuronal activities in freely behaving animals. This protocol describes detailed steps for artificial induction of olfactory associative memory in Drosophila larvae. In this protocol, the natural reward signal is substituted by thermogenetic activation of octopaminergic neurons in the brain. In parallel, the odor signal is substituted by optogenetic activation of a specific class of olfactory receptor neurons. Association of reward and odor stimuli is achieved with the concomitant application of blue light and heat that leads to activation of both sets of neurons in living transgenic larvae. Given its operational simplicity and robustness, this method could be utilized to further our knowledge on the neurocircuitry mechanism of memory in the fly brain. 
27444843	The forebrain medial septum, which is an integral part of the septo-hippocampal network, is implicated in sensorimotor integration, fear and anxiety, and spatial learning and memory. A body of evidence also suggests that the septal region affects experimental pain. Indeed, some explorations in humans have raised the possibility that the region may modulate clinical pain as well. This review explores the evidence that implicates the medial septum in nociception and suggests that non-overlapping circuits in the region facilitate acute nociceptive behaviors and defensive behaviors that reflect affect and cognitive appraisal, especially in relation to persistent nociception. In line with a role in nociception, the region modulates nociceptive responses in the neuraxis, including the hippocampus and the anterior cingulate cortex. The aforementioned forebrain regions have also been implicated in persistent/long-lasting nociception. The review also weighs the effects of the medial septum on nociception vis-à-vis the known roles of the region and emphasizes the fact that the region is a part of network of forebrain structures which have been long associated with reward, cognition and affect-motivation and are now implicated in persistent/long-lasting nociception.

27443506	The striatum controls multiple cognitive aspects including motivation, reward perception, decision-making and motor planning. In particular, the dorsolateral striatum contributes to motor learning. Here we define an approach for investigating synaptic plasticity in mouse dorsolateral cortico-striatal circuitry and interrogate the relative contributions of neurotransmitter receptors and intracellular signaling components. Consistent with previous studies, we show that long-term potentiation (LTP) in cortico-striatal circuitry is facilitated by dopamine, and requires activation of D1-dopamine receptors, as well as NMDA receptors (NMDAR) and their calcium-dependent downstream effectors, including CaMKII. Moreover, we assessed the contribution of the protein kinase Cdk5, a key neuronal signaling molecule, in cortico-striatal LTP. Pharmacological Cdk5 inhibition, brain-wide Cdk5 conditional knockout, or viral-mediated dorsolateral striatal-specific loss of Cdk5 all impaired dopamine-facilitated LTP or D1-dopamine receptor-facilitated LTP. Selective loss of Cdk5 in dorsolateral striatum increased locomotor activity and attenuated motor learning. Taken together, we report an approach for studying synaptic plasticity in mouse dorsolateral striatum and critically implicate D1-dopamine receptor, NMDAR, Cdk5, and CaMKII in cortico-striatal plasticity. Furthermore, we associate striatal plasticity deficits with effects upon behaviors mediated by this circuitry. This approach should prove useful for the study of the molecular basis of plasticity in the dorsolateral striatum. 
27440124	There is recognition that cognitive problems can contribute to renewed drug taking in former addicts. Our previous work has indicated that current smokers show reduced performance on a probabilistic reversal learning (PRL) task, relative to former smokers. To further explore PRL performance and its relevance to smoking, in addition to the role of nicotine, we developed a model of nicotine withdrawal-induced deficits in rodents. A second goal was to test varenicline, an α4β2 partial agonist, for its ability to restore any cognitive impairment. Acute effects of nicotine and varenicline on PRL performance in non-dependent animals were minimal and confined to speed of responding. When rats were made dependent on nicotine via osmotic minipumps implanted for 7 days (3.16 mg/kg/day), repeated tests at specified withdrawal time points revealed PRL disruption peaking at 12 and 24 hours following surgical removal of minipumps. Withdrawal was characterized by significant deficits in the number of reversals (P < 0.05), speed of responding (P < 0.01) and increases in omissions (P < 0.05). Nicotine (0.2 mg/kg SC) or varenicline (0.3 and 1.0 mg/kg SC) administered 10-minute prior to PRL test sessions during withdrawal, relieved the performance deficits. At 24-hour withdrawal, nicotine and varenicline (1 mg/kg) prevented decrements in reversals, in addition to ameliorating slower speed of responding. The high dose of varenicline only reduced omissions. These results confirm the role of nicotine in withdrawal-induced disruption of PRL performance and suggest that the model may be useful for investigating efficacy of potential new treatments for smoking cessation.
27436299	Stress interferes with instrumental learning. However, choice is also influenced by non-instrumental factors, most strikingly by biases arising from Pavlovian associations that facilitate action in pursuit of rewards and inaction in the face of punishment. Whether stress impacts on instrumental learning via these Pavlovian associations is unknown. Here, in a task where valence (reward or punishment) and action (go or no-go) were orthogonalised, we asked whether the impact of stress on learning was action or valence specific. We exposed 60 human participants either to stress (socially-evaluated cold pressor test) or a control condition (room temperature water). We contrasted two hypotheses: that stress would lead to a non-selective increase in the expression of Pavlovian biases; or that stress, as an aversive state, might specifically impact action production due to the Pavlovian linkage between inaction and aversive states. We found support for the second of these hypotheses. Stress specifically impaired learning to produce an action, irrespective of the valence of the outcome, an effect consistent with a Pavlovian linkage between punishment and inaction. This deficit in action-learning was also reflected in pupillary responses; stressed individuals showed attenuated pupillary responses to action, hinting at a noradrenergic contribution to impaired action-learning under stress. 
27429991	The decision to gather information should take into account both the value of information and its accrual costs in time, energy and money. Here we explore how people balance the monetary costs and benefits of gathering additional information in a perceptual-motor estimation task. Participants were rewarded for touching a hidden circular target on a touch-screen display. The target's center coincided with the mean of a circular Gaussian distribution from which participants could sample repeatedly. Each "cue" - sampled one at a time - was plotted as a dot on the display. Participants had to repeatedly decide, after sampling each cue, whether to stop sampling and attempt to touch the hidden target or continue sampling. Each additional cue increased the participants' probability of successfully touching the hidden target but reduced their potential reward. Two experimental conditions differed in the initial reward associated with touching the hidden target and the fixed cost per cue. For each condition we computed the optimal number of cues that participants should sample, before taking action, to maximize expected gain. Contrary to recent claims that people gather less information than they objectively should before taking action, we found that participants over-sampled in one experimental condition, and did not significantly under- or over-sample in the other. Additionally, while the ideal observer model ignores the current sample dispersion, we found that participants used it to decide whether to stop sampling and take action or continue sampling, a possible consequence of imperfect learning of the underlying population dispersion across trials.
27427328	The surprising omission of a reinforcer can enhance the associability of the stimuli that were present when the reward prediction error was induced, so that they more readily enter into new associations in the future. Previous research from this laboratory identified brain circuit elements critical to the enhancement of stimulus associability by the omission of an expected event and to the subsequent expression of that altered associability in more rapid learning. These elements include the amygdala, the midbrain substantia nigra, the basal forebrain substantia innominata, the dorsolateral striatum, the secondary visual cortex, and the posterior parietal cortex. Here, we found that consolidation of a surprise-enhanced associability memory in a serial prediction task depends on processing in the amygdala central nucleus (CeA) after completion of sessions that included the surprising omission of an expected event. Post-surprise infusions of anisomycin, lidocaine, or muscimol prevented subsequent display of surprise-enhanced associability. Because previous studies indicated that CeA function is unnecessary for the expression of associability enhancements that were induced previously when CeA function was intact (Holland & Gallagher, 2006), we interpreted these results as indicating that post-surprise activity of CeA ("surprise replay") is necessary for the consolidation of altered associability memories elsewhere in the brain, such as the posterior parietal cortex (Schiffino et al., 2014a). 
27423562	The influence of promised rewards on conflict resolution processes is not clearly defined in the literature, and the underlying mechanisms are poorly understood. Some studies have shown no effect of reward, while others have demonstrated a beneficial influence. In addition, although the basal ganglia are known to play a critical role in the association between motivation and cognition, the influence of promised rewards on conflict resolution processes in Parkinson's disease (PD) has received little attention. In this context, we assessed the influence of promised rewards on both impulse activation and suppression in 36 healthy participants and 36 patients with PD, using a rewarded Simon task. Analysis of performances revealed that promised rewards worsened the overall congruence effect, but only in healthy participants. Although the incentive context did not modulate the congruence effect in patients, by using the activation-suppression model, we were able to show that promised rewards did influence impulse suppression in patients-but not in healthy participants. Suppressing inappropriate response activation in an incentive context appears to be harder in medically treated Parkinson's disease. This indicates that incentive motivation can modulate at least one cognitive process involved in cognitive action control in patients with medically treated PD. The activation-suppression model provides essential additional information concerning the influence of promised rewards on conflict resolution processes in a pathological population. 
27423521	Dopamine signaling is involved in a variety of neurobiological processes that contribute to learning and memory. D1-like dopamine receptors (including D1 and D5 receptors) are thought to be involved in memory and reward processes, but pharmacological approaches have been limited in their ability to distinguish between D1 and D5 receptors. Here, we examine the effects of a specific knockout of D1 receptors in associative learning tasks involving aversive (shock) or appetitive (cocaine) unconditioned stimuli. We find that D1 knockout mice show similar levels of cued and contextual fear conditioning to WT controls following conditioning protocols involving one, two, or four shocks. D1 knockout mice show increased generalization of fear conditioning and extinction across contexts, revealed as increased freezing to a novel context following conditioning and decreased freezing to an extinguished cue during a contextual renewal test. Further, D1 knockout mice show mild enhancements in extinction following an injection of SKF81297, a D1/D5 receptor agonist, suggesting a role for D5 receptors in extinction enhancements induced by nonspecific pharmacological agonists. Finally, although D1 knockout mice show decreased locomotion induced by cocaine, they are able to form a cocaine-induced conditioned place preference. We discuss these findings in terms of the role of dopamine D1 receptors in general learning and memory processes. 
27422761	A major domain of depression is decreased motivation for reward. Translational automated tests can be applied in humans and animals to study operant reward behaviour, aetio-pathophysiology underlying deficits therein, and effects of antidepressant treatment. Three inter-related experiments were conducted to investigate depression-relevant effects of chronic psychosocial stress on operant behaviour in mice. (A) Non-manipulated mice were trained on a complex reversal learning (CRL) test with sucrose reinforcement; relative to vehicle (VEH), acute antidepressant agomelatine (AGO, 25mg/kg p.o.) increased reversals. (B) Mice underwent chronic social defeat (CSD) or control handling (CON) on days 1-15, and were administered AGO or VEH on days 10-22. In a progressive ratio schedule motivation test for sucrose on day 15, CSD mice made fewer responses; AGO tended to reverse this effect. In a CRL test on day 22, CSD mice completed fewer reversals; AGO tended to increase reversals in CSD mice associated with an adaptive increase in perseveration. (C) Mice with continuous operant access to water and saccharin solution in the home cage were exposed to CSD or CON; CSD mice made fewer responses for saccharin and water and drank less saccharin in the active period, and drank more water in the inactive period. In a separate CSD cohort, repeated AGO was without effect on these home cage operant and consummatory changes. Overall, this study demonstrates that psychosocial stress in mice leads to depression-relevant decreases in motivation and cognition in operant reward tests; partial reversal of these deficits by AGO provides evidence for predictive validity. 
27422085	We investigated the potential of deep brain stimulation (DBS) in the central nucleus of the amygdala (CeA) in rats to modulate functional reward mechanisms. The CeA is the major output of the amygdala with direct connections to the hypothalamus and gustatory brainstem, and indirect connections with the nucleus accumbens. Further, the CeA has been shown to be involved in learning, emotional integration, reward processing, and regulation of feeding. We hypothesized that DBS, which is used to treat movement disorders and other brain dysfunctions, might block reward motivation. In rats performing a lever-pressing task to obtain sugar pellet rewards, we stimulated the CeA and control structures, and compared stimulation parameters. During CeA stimulation, animals stopped working for rewards and rejected freely available rewards. Taste reactivity testing during DBS exposed aversive reactions to normally liked sucrose tastes and even more aversive taste reactions to normally disliked quinine tastes. Interestingly, given the opportunity, animals implanted in the CeA would self-stimulate with 500 ms trains of stimulation at the same frequency and current parameters as continuous stimulation that would stop reward acquisition. Neural recordings during DBS showed that CeA neurons were still active and uncovered inhibitory-excitatory patterns after each stimulus pulse indicating possible entrainment of the neural firing with DBS. In summary, DBS modulation of CeA may effectively usurp normal neural activity patterns to create an 'information lesion' that not only decreased motivational 'wanting' of food rewards, but also blocked 'liking' of rewards.
27418578	Declarative memories are our so-called daily language memories, which we are able to describe or explicitly experience through the act of remembering. This conscious recollection makes it possible for us to think about the future based on our previous experience (episodic memory) and knowledge (semantic memory). This cognitive function is substantiated by the medial temporal lobe (MTL), a hierarchically organized complex in which the perirhinal cortex and parahippocampal cortex provide item and context information to the hippocampus via the entorhinal cortex, and the hippocampus plays the main role in association and recollection. This conventional view provides an easily understood structure to the declarative memory system. However, neurophysiological studies reporting the activities of single neurons bring a more complicated view. In this article, I review single-unit studies, particularly those focused on the perirhinal cortex and hippocampus, and suggest that association processes for declarative memory are more distributed over the MTL areas. The perirhinal cortex represents both between-domain associations (e.g., item-reward, item-place and item-time) and within-domain associations (e.g., item-item) and contributes to both subcategories of declarative memory (i.e., episodic and semantic memory) in a way that is complementary with the hippocampus.
27418069	Gambling is a harmless, recreational pastime that is ubiquitous across cultures. However, for some, gambling becomes a maladaptive and compulsive, and this syndrome is conceptualized as a behavioural addiction. Laboratory models that capture the key cognitive processes involved in gambling behaviour, and that can be translated across species, have the potential to make an important contribution to both decision neuroscience and the study of addictive disorders. The Iowa gambling task has been widely used to assess human decision-making under uncertainty, and this paradigm can be successfully modelled in rodents. Similar neurobiological processes underpin choice behaviour in humans and rats, and thus, a preference for the disadvantageous "high-risk, high-reward" options may reflect meaningful vulnerability for mental health problems. However, the choice behaviour operationalized by these tasks does not necessarily approximate the vulnerability to gambling disorder (GD) per se. We consider a number of psychological challenges that apply to modelling gambling in a translational way, and evaluate the success of the existing models. Heterogeneity in the structure of gambling games, as well as in the motivations of individuals with GD, is highlighted. The potential issues with extrapolating too directly from established animal models of drug dependency are discussed, as are the inherent difficulties in validating animal models of GD in the absence of any approved treatments for GD. Further advances in modelling the cognitive biases endemic in human decision-making, which appear to be exacerbated in GD, may be a promising line of research. 
27417434	Recent evidence indicates that the attentional priority of objects and locations is altered by the controlled delivery of reward, reflecting reward-based attentional learning. Here, we take an approach hinging on intersubject variability to probe the neurobiological bases of the reward-driven plasticity of spatial priority maps. Specifically, we ask whether an individual's susceptibility to the reward-based treatment can be accounted for by specific predictors, notably personality traits that are linked to reward processing (along with more general personality traits), but also gender. Using a visual search protocol, we show that when different target locations are associated with unequal reward probability, different priorities are acquired by the more rewarded relative to the less rewarded locations. However, while males exhibit the expected pattern of results, with greater priority for locations associated with higher reward, females show an opposite trend. Critically, both the extent and the direction of reward-based adjustments are further predicted by personality traits indexing reward sensitivity, indicating that not only male and female brains are differentially sensitive to reward, but also that specific personality traits further contribute to shaping their learning-dependent attentional plasticity. These results contribute to a better understanding of the neurobiology underlying reward-dependent attentional learning and cross-subject variability in this domain.
27412662	The present study aimed to investigate whether or not the evaluative processing of action feedback can be modulated by temporal prediction. For this purpose, we examined the effects of the predictability of the timing of action feedback on an ERP effect that indexed the evaluative processing of action feedback, that is, an ERP effect that has been interpreted as a feedback-related negativity (FRN) elicited by "bad" action feedback or a reward positivity (RewP) elicited by "good" action feedback. In two types of experimental blocks, the participants performed a gambling task in which they chose one of two cards and received an action feedback that indicated monetary gain or loss. In fixed blocks, the time interval between the participant's choice and the onset of the action feedback was fixed at 0, 500, or 1,000 ms in separate blocks; thus, the timing of action feedback was predictable. In mixed blocks, the time interval was randomly chosen from the same three intervals with equal probability; thus, the timing was less predictable. The results showed that the FRN/RewP was smaller in mixed than fixed blocks for the 0-ms interval trial, whereas there was no difference between the two block types for the 500-ms and 1,000-ms interval trials. Interestingly, the smaller FRN/RewP was due to the modulation of gain ERPs rather than loss ERPs. These results suggest that temporal prediction can modulate the evaluative processing of action feedback, and particularly good feedback, such as that which indicates monetary gain. 
27408906	To many, the poster child for David Marr's famous three levels of scientific inquiry is reinforcement learning-a computational theory of reward optimization, which readily prescribes algorithmic solutions that evidence striking resemblance to signals found in the brain, suggesting a straightforward neural implementation. Here we review questions that remain open at each level of analysis, concluding that the path forward to their resolution calls for inspiration across levels, rather than a focus on mutual constraints.
27404012	Effective demand creation strategies are needed to increase uptake of medical male circumcision and reduce new HIV infections in eastern and southern Africa. Building on insights from behavioral economics, we assessed whether providing compensation for opportunity costs of time or lottery-based rewards can increase male circumcision uptake in Kenya.Uncircumcised men aged 21-39 years were randomized in 1:1:1 ratio to 2 intervention groups or a control group. One intervention group was offered compensation of US $12.50 conditional on circumcision uptake. Compensation was provided in the form of food vouchers. A second intervention group was offered the opportunity to participate in a lottery with high-value prizes on undergoing circumcision. The primary outcome was circumcision uptake within 3 months.	Among 903 participants enrolled, the group that received compensation of US $12.50 had the highest circumcision uptake (8.4%, 26/308), followed by the lottery-based rewards group (3.3%, 10/302), and the control group (1.3%, 4/299). Logistic regression analysis showed that compared with the control group, the fixed compensation group had significantly higher circumcision uptake [adjusted odds ratio 7.1; 95% CI: 2.4 to 20.8]. The lottery-based rewards group did not have significantly higher circumcision uptake than the control group (adjusted odds ratio 2.5; 95% CI: 0.8 to 8.1).	Providing compensation was effective in increasing circumcision uptake among men over a short period. The results are consistent with studies showing that such interventions can modify health behaviors by addressing economic barriers and behavioral biases in decision making. Contrary to findings from studies of other health behaviors, lottery-based rewards did not significantly increase circumcision uptake.	Registry for International Development Impact Evaluations: RIDIE-STUDY-ID-530e60df56107.	
27401960	The habituation of the acoustic startle reflex (ASR) was examined concerning individual differences in sensitivity to punishment (PUN) and sensitivity to reward (REW), within the general framework of the reinforcement sensitivity theory (RST) of personality. Two hypotheses derived from the RST were evaluated: the separable subsystems hypothesis and the joint subsystems hypothesis. In addition, we examined the direction of the relationship of PUN and REW with the habituation of the ASR. A habituation segment of electromyography recordings of the orbicularis oculi was assessed with an unconditional latent curve model. In accordance with the RST hypotheses, the relationship of PUN and REW on the habituation process was assessed with two conditional latent curve models. There was higher support for the separable subsystems hypothesis. In addition, PUN and REW related with the habituation trajectory of the ASR in the expected directions. Higher levels of PUN and lower levels of REW related with a slower habituation of the ASR, whereas lower levels of PUN and higher levels of REW related with a faster habituation of the ASR. 
27398617	Dopaminergic projection axons from the midbrain to the striatum are crucial for motor control, as their degeneration in Parkinson disease results in profound movement deficits. Paradoxically, most recording methods report rapid phasic dopamine signalling (~100-ms bursts) in response to unpredicted rewards, with little evidence for movement-related signalling. The leading model posits that phasic signalling in striatum-targeting dopamine neurons drives reward-based learning, whereas slow variations in firing (tens of seconds to minutes) in these same neurons bias animals towards or away from movement. However, current methods have provided little evidence to support or refute this model. Here, using new optical recording methods, we report the discovery of rapid phasic signalling in striatum-targeting dopaminergic axons that is associated with, and capable of triggering, locomotion in mice. Axons expressing these signals were largely distinct from those that responded to unexpected rewards. These results suggest that dopaminergic neuromodulation can differentially impact motor control and reward learning with sub-second precision, and indicate that both precise signal timing and neuronal subtype are important parameters to consider in the treatment of dopamine-related disorders.
27397517	The mammalian hippocampus is critical for spatial information processing and episodic memory. Its primary output cells, CA1 pyramidal cells (CA1 PCs), vary in genetics, morphology, connectivity, and electrophysiological properties. It is therefore possible that distinct CA1 PC subpopulations encode different features of the environment and differentially contribute to learning. To test this hypothesis, we optically monitored activity in deep and superficial CA1 PCs segregated along the radial axis of the mouse hippocampus and assessed the relationship between sublayer dynamics and learning. Superficial place maps were more stable than deep during head-fixed exploration. Deep maps, however, were preferentially stabilized during goal-oriented learning, and representation of the reward zone by deep cells predicted task performance. These findings demonstrate that superficial CA1 PCs provide a more stable map of an environment, while their counterparts in the deep sublayer provide a more flexible representation that is shaped by learning about salient features in the environment. VIDEO ABSTRACT. 
27395470	Electrophysiological studies in monkeys have shown that dopaminergic neurons respond to the reward prediction error. In addition, striatal neurons alter their responsiveness to cortical or thalamic inputs in response to dopamine signals, via dopamine-regulated synaptic plasticity. These findings have led to the hypothesis that the striatum exhibits synaptic plasticity under the influence of reward prediction error and conducts reinforcement learning throughout the basal ganglia circuits. The reinforcement learning model is useful; however, the mechanism by which such a process emerges in the basal ganglia needs to be anatomically explained. The actor-critic model has been previously proposed and extended by the existence of role sharing within the striatum, with particular focus on the striosome and matrix compartments. However, this hypothesis has been difficult to confirm morphologically, partly because of the complex structure of the striosome and matrix compartments. Here, we review recent morphological studies that elucidate the input/output organization of the striatal compartments. 
27394698	Immunisation is a powerful public health strategy for improving child survival, not only by directly combating key diseases that kill children but also by providing a platform for other health services. However, each year millions of children worldwide, mostly from low- and middle-income countries (LMICs), do not receive the full series of vaccines on their national routine immunisation schedule. This is an update of the Cochrane review published in 2011 and focuses on interventions for improving childhood immunisation coverage in LMICs.To evaluate the effectiveness of intervention strategies to boost and sustain high childhood immunisation coverage in LMICs.	We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2016, Issue 4, part of The Cochrane Library. www.cochranelibrary.com, including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register (searched 12 May 2016); MEDLINE In-Process and Other Non-Indexed Citations, MEDLINE Daily and MEDLINE 1946 to Present, OvidSP (searched 12 May 2016); CINAHL 1981 to present, EbscoHost (searched 12 May 2016); Embase 1980 to 2014 Week 34, OvidSP (searched 2 September 2014); LILACS, VHL (searched 2 September 2014); Sociological Abstracts 1952 - current, ProQuest (searched 2 September 2014). We did a citation search for all included studies in Science Citation Index and Social Sciences Citation Index, 1975 to present; Emerging Sources Citation Index 2015 to present, ISI Web of Science (searched 2 July 2016). We also searched the two Trials Registries: ICTRP and ClinicalTrials.gov (searched 5 July 2016) SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCT), non-RCTs, controlled before-after studies, and interrupted time series conducted in LMICs involving children aged from birth to four years, caregivers, and healthcare providers.	We independently screened the search output, reviewed full texts of potentially eligible articles, assessed risk of bias, and extracted data in duplicate; resolving discrepancies by consensus. We then conducted random-effects meta-analyses and used GRADE to assess the certainty of evidence.	Fourteen studies (10 cluster RCTs and four individual RCTs) met our inclusion criteria. These were conducted in Georgia (one study), Ghana (one study), Honduras (one study), India (two studies), Mali (one study), Mexico (one study), Nicaragua (one study), Nepal (one study), Pakistan (four studies), and Zimbabwe (one study). One study had an unclear risk of bias, and 13 had high risk of bias. The interventions evaluated in the studies included community-based health education (three studies), facility-based health education (three studies), household incentives (three studies), regular immunisation outreach sessions (one study), home visits (one study), supportive supervision (one study), information campaigns (one study), and integration of immunisation services with intermittent preventive treatment of malaria (one study).We found moderate-certainty evidence that health education at village meetings or at home probably improves coverage with three doses of diphtheria-tetanus-pertussis vaccines (DTP3: risk ratio (RR) 1.68, 95% confidence interval (CI) 1.09 to 2.59). We also found low-certainty evidence that facility-based health education plus redesigned vaccination reminder cards may improve DTP3 coverage (RR 1.50, 95% CI 1.21 to 1.87). Household monetary incentives may have little or no effect on full immunisation coverage (RR 1.05, 95% CI 0.90 to 1.23, low-certainty evidence). Regular immunisation outreach may improve full immunisation coverage (RR 3.09, 95% CI 1.69 to 5.67, low-certainty evidence) which may substantially improve if combined with household incentives (RR 6.66, 95% CI 3.93 to 11.28, low-certainty evidence). Home visits to identify non-vaccinated children and refer them to health clinics may improve uptake of three doses of oral polio vaccine (RR 1.22, 95% CI 1.07 to 1.39, low-certainty evidence). There was low-certainty evidence that integration of immunisation with other services may improve DTP3 coverage (RR 1.92, 95% CI 1.42 to 2.59).	Providing parents and other community members with information on immunisation, health education at facilities in combination with redesigned immunisation reminder cards, regular immunisation outreach with and without household incentives, home visits, and integration of immunisation with other services may improve childhood immunisation coverage in LMIC. Most of the evidence was of low certainty, which implies a high likelihood that the true effect of the interventions will be substantially different. There is thus a need for further well-conducted RCTs to assess the effects of interventions for improving childhood immunisation coverage in LMICs.	
27388686	Comparison of lateralization in social and non-social bees tests the hypothesis that population-level, directional asymmetry has evolved as an adjunct to social behaviour. Previous research has supported this hypothesis: directional bias of antennal use in responding to odours and learning to associate odours with a food reward is absent in species that feed individually, such as mason bees, whereas it is clearly present in eusocial honeybees and stingless bees. Here we report that, when mason bees engage in agonistic interactions, a species-typical interactive behaviour, they do exhibit a directional bias according to which antenna is available to be used. Aggression was significantly higher in dyads using only their left antennae (LL) than it was in those using only their right antennae (RR). This asymmetry was found in both males and females but it was stronger in females. LL dyads of a male and a female spent significantly more time together than did other dyadic combinations. No asymmetry was present in non-aggressive contacts, latency to first contact or body wiping. Hence, population-level lateralization is present only for social interactions common and frequent in the species' natural behaviour. This leads to a refinement of the hypothesis linking directional lateralization to social behaviour. 
27388608	Recent studies have reported that polyunsaturated fatty acids (PUFAs) are associated with mood and behaviors including depression and suicide risk. The aim of this study was to examine the relationship between PUFAs and personality traits in healthy subjects.A total of 279 subjects completed the Temperament and Character Inventory and Beck Depression Inventory. Serum levels of the PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), the x03C9;-6 fatty acid arachidonic acid (AA), and dihomo-x03B3;-linolenic acid were measured.	Pearson's correlation analysis showed a positive correlation between DHA and cooperativeness scores. In the multiple regression analysis, harm avoidance scores were positively associated with AA, and a negative association was found between the EPA/AA ratio and reward dependence scores. However, these associations were nonsignificant after a Bonferroni correction.	The results of the present study suggest that the blood levels of PUFAs are not likely to be associated with personality traits.	
27388114	In the one-trial taste-avoidance task in day-old chicks, acetylcholine receptor activation has been shown to be important for memory formation. Injection of scopolamine produces amnesia, which appears to be very similar in type to that of Alzheimer's disease, which is correlated with low levels of acetylcholine in the brain. Traditional pharmacological treatments of Alzheimer's disease, such as cholinesterase inhibitors and glutamate receptor blockers, improve memory and delay the onset of impairments in memory compared with placebo controls. These agents also ameliorate scopolamine-induced amnesia in the day-old chick trained on the one-trial taste-avoidance task. The present experiments examined the ability of two less traditional treatments for Alzheimer's disease, phosphatidylserine and curcumin, to ameliorate scopolamine-induced amnesia in day-old chicks. The results showed that 37.9 mmol/l phosphatidylserine and 2.7 mmol/l curcumin significantly improved retention in chicks administered scopolamine, whereas lower doses were not effective. Scopolamine did not produce state-dependent learning, indicating that this paradigm in day-old chicks might be a useful one to study the effects of possible Alzheimer's treatments. In addition, chicks administered curcumin or phosphatidylserine showed little avoidance of a bead associated with water reward, indicating that these drugs did not produce response inhibition. The current results extend the findings that some nontraditional memory enhancers can ameliorate memory impairment and support the hypothesis that these treatments might be of benefit in the treatment of Alzheimer's disease. 
27384542	Marijuana use may alter ventral striatal response to reward, which might heighten susceptibility to substance use disorder. Longitudinal research is needed to determine the effects of marijuana use on neural function involved in reward response.To determine whether marijuana use among young adults prospectively affects nucleus accumbens (NAcc) activation during reward anticipation.	One hundred eight young adults were recruited from the Michigan Longitudinal Study, an ongoing study of youth at high risk for substance use disorder and a contrast sample of control families. Participants underwent 3 consecutive functional magnetic resonance imaging scans at approximate ages of 20 (time 1), 22 (time 2), and 24 (time 3) years. Self-report data on marijuana and other drug use occasions were collected annually since age 11 years.	Cross-lagged models were used to test the association of marijuana use with neural response in the NAcc to reward anticipation during a monetary incentive delay task controlling for sex, age, other substance use, and family history of substance use disorder.	Of 108 participants, 39 (36.1%) were female and mean (SD) age at baseline was 20.1 (1.4) years. Greater marijuana use was associated with later blunted activation in the NAcc during reward anticipation (time 1 to time 2: β = -0.26, P = .04; time 2 to time 3: β = -0.25, P = .01). When the cross-lagged model was tested with the inclusion of previous and concurrent cigarette use, the effect of marijuana use from time 2 to time 3 remained significant (β = -0.29; P = .005) and the effect of cigarette use was nonsignificant.	The findings of this study indicate that marijuana use is associated with decreased neural response in the NAcc during the anticipation of nondrug rewards. Over time, marijuana use may alter anticipatory reward processing in the NAcc, which may increase the risk for continued drug use and later addiction.	
27384424	Psychotic disorders are characterized by attenuated activity in the brain's valuation system in key reward processing areas, such as the ventral striatum (VS), as measured with functional magnetic resonance imaging.To examine whether common risk variants for psychosis are associated with individual variation in the VS.	A cross-sectional study of a large cohort of adolescents from the IMAGEN study (a European multicenter study of reinforcement sensitivity in adolescents) was performed from March 1, 2008, through December 31, 2011. Data analysis was conducted from October 1, 2015, to January 9, 2016. Polygenic risk profile scores (RPSs) for psychosis were generated for 1841 healthy adolescents. Sample size and characteristics varied across regression analyses, depending on mutual information available (N = 1524-1836).	Reward-related brain function was assessed with blood oxygen level dependency (BOLD) in the VS using the monetary incentive delay (MID) task, distinguishing reward anticipation and receipt. Behavioral impulsivity, IQ, MID task performance, and VS BOLD were regressed against psychosis RPS at 4 progressive P thresholds (P < .01, P < .05, P < .10, and P < .50 for RPS models 1-4, respectively).	In a sample of 1841 healthy adolescents (mean age, 14.5 years; 906 boys and 935 girls), we replicated an association between increasing psychosis RPS and reduced IQ (matrix reasoning: corrected P = .003 for RPS model 2, 0.4% variance explained), supporting the validity of the psychosis RPS models. We also found a nominally significant association between increased psychosis RPS and reduced MID task performance (uncorrected P = .03 for RPS model 4, 0.2% variance explained). Our main finding was a positive association between psychosis RPS and VS BOLD during reward anticipation at all 4 psychosis RPS models and for 2 P thresholds for reward receipt (RPS models 1 and 3), correcting for the familywise error rate (0.8%-1.9% variance explained).	These findings support an association between psychosis RPS and VS BOLD in adolescents. Genetic risk for psychosis may shape an individual's response to rewarding stimuli.	

27381822	Internet gaming disorder (IGD) has become a serious mental health issue worldwide. Evaluating the benefits of interventions for IGD is of great significance. Thirty-six young adults with IGD and 19 healthy comparison (HC) subjects were recruited and underwent resting-state fMRI scanning. Twenty IGD subjects participated in a group craving behavioral intervention (CBI) and were scanned before and after the intervention. The remaining 16 IGD subjects did not receive an intervention. The results showed that IGD subjects showed decreased amplitude of low fluctuation in the orbital frontal cortex and posterior cingulate cortex, and exhibited increased resting-state functional connectivity between the posterior cingulate cortex and dorsolateral prefrontal cortex, compared with HC subjects. Compared with IGD subjects who did not receive the intervention, those receiving CBI demonstrated significantly reduced resting-state functional connectivity between the: (1) orbital frontal cortex with hippocampus/parahippocampal gyrus; and, (2) posterior cingulate cortex with supplementary motor area, precentral gyrus, and postcentral gyrus. These findings suggest that IGD is associated with abnormal resting-state neural activity in reward-related, default mode and executive control networks. Thus, the CBI may exert effects by reducing interactions between regions within a reward-related network, and across the default mode and executive control networks. 
27381786	BACKGROUND Questionnaire surveys are important for surveying the health and disease behaviour of the population, but recent years have seen a fall in participation. Our study tested whether incentives can increase participation in these surveys.MATERIAL AND METHOD We sent a questionnaire on risk factors for colorectal cancer (height, weight, smoking, self-reported diagnoses, family medical history) to non-screened participants in a randomised colonoscopy screening study for colorectal cancer: participants who were invited but did not attend for colonoscopy examination (screening-invited) and persons who were not offered colonoscopy (control group). The persons were randomised to three groups: no financial incentive, lottery scratch cards included with the form, or a prize draw for a tablet computer when they responded to the form. We followed up all the incentive groups with telephone reminder calls, and before the prize draw for the tablet computer.RESULTS Altogether 3 705 of 6 795 persons (54.5  %) responded to the questionnaire; 43.5  % of those invited for screening and 65.6  % of the control group (p < 0.001). The proportion that answered was not influenced by incentives, either among those invited for screening (42.4  % in the non-prize group, 45.5  % in the lottery scratch card group and 42.6  % in the prize draw group; p = 0.24), or in the control group (65.6  % in the non-prize group, 66.4  % in the lottery scratch card group and 64.7  % in the prize draw group; p = 0.69). Prior to reminder calls, 39.2  % responded. A further 15.3  % responded following telephone reminder calls (14.1  % of the screening-invited and 16.5  % of the control group; p < 0.001).INTERPRETATION Incentives did not increase participation in this medical questionnaire survey. Use of telephone reminder calls and telephone interviews increased participation, but whether this is more effective than other methods requires further study. 

27380621	There is growing evidence that alterations in reward rates modify timing behavior demonstrating the role of motivational factors in interval timing behavior. This study aimed to investigate the effects of manipulations of rewards and penalties on temporal bisection performance in humans. Participants were trained to classify experienced time intervals as short or long based on the reference durations. Two groups of participants were tested under three different bias conditions in which either the relative reward magnitude or penalty associated with correct or incorrect categorizations of short and long reference durations was manipulated. Participants adapted their choice behavior (i.e., psychometric functions shifted) based on these payoff manipulations in directions predicted by reward maximization. The signal detection theory-based analysis of the data revealed that payoff contingencies affected the response bias parameter (B″) without altering participants' sensitivity (A') to temporal distances. Finally, the response time (RT) analysis showed that short categorization RTs increased, whereas long categorization RTs decreased as a function of stimulus durations. However, overall RTs did not exhibit any modulation in response to payoff manipulations. Taken together, this study provides additional support for the effects of motivational variables on temporal decision-making. 
27378952	Patients with psychosis spectrum disorders exhibit deficits in social and neurocognition, as well as hallmark abnormalities in motivation and reward processing. Aspects of reward processing may overlap behaviorally and neurobiologically with some elements of cognitive functioning, and abnormalities in these processes may share partially overlapping etiologies in patients. However, whether reward processing and cognition are associated across the psychoses and linked to state and trait clinical symptomatology is unclear.The present study examined associations between cognitive functioning, reward learning, and clinical symptomatology in a cross-diagnostic sample. Patients with schizophrenia (SZ; n = 37), bipolar I disorder with psychosis (BD; n = 42), and healthy controls (n = 29) were assessed for clinical symptoms (patients only), neurocognitive functioning using the MATRICS Battery (MCCB) and reward learning using the probabilistic reward task (PRT). Groups were compared on neurocognition and PRT response bias, and associations between PRT response bias and neurocognition or clinical symptoms were examined controlling for demographic variables and PRT task difficulty (discriminability).	Patients with SZ performed worse than controls on most measures of neurocognition; patients with BD exhibited deficits in some domains between the level of patients with SZ and controls. The SZ - but not BD - group exhibited deficits in social cognition compared to controls. Patients and controls did not differ on PRT response bias, but did differ on PRT discriminability. Better response bias across the sample was associated with poorer social cognition, but not neurocognition; conversely, discriminability was associated with neurocognition but not social cognition. Symptoms of psychosis, particularly negative symptoms, were associated with poorer response bias across patient groups.	Reward learning was associated with symptoms of psychosis - in particular negative symptoms - across diagnoses, and was predictive of worse social cognition. Reward learning was not associated with neurocognitive performance, suggesting that, across patient groups, social cognition but not neurocognition may share common pathways with this aspect of reinforcement learning. Better understanding of how cognitive dysfunction and reward processing deficits relate to one another, to other key symptom dimensions (e.g., psychosis), and to diagnostic categories, may help clarify shared etiological pathways and guide efforts toward targeted treatment approaches.	
27378888	Repetitive transcranial magnetic stimulation over the left dorsolateral prefrontal cortex (DLPFC) has been documented to influence striatal and orbitofrontal dopaminergic activity implicated in reward processing. However, the exact neuropsychological mechanisms of how DLPFC stimulation may affect the reward system and how trait hedonic capacity may interact with the effects remains to be elucidated.In this sham-controlled study in healthy individuals, we investigated the effects of a single session of neuronavigated intermittent theta burst stimulation (iTBS) on reward responsiveness, as well as the influence of trait hedonic capacity.	We used a randomized crossover single session iTBS design with an interval of 1 week. We assessed reward responsiveness using a rewarded probabilistic learning task and measured individual trait hedonic capacity (the ability to experience pleasure) with the temporal experience of pleasure scale questionnaire.	As expected, the participants developed a response bias toward the most rewarded stimulus (rich stimulus). Reaction time and accuracy for the rich stimulus were respectively shorter and higher as compared to the less rewarded stimulus (lean stimulus). Active or sham stimulation did not seem to influence the outcome. However, when taking into account individual trait hedonic capacity, we found an early significant increase in the response bias only after active iTBS. The higher the individual's trait hedonic capacity, the more the response bias toward the rich stimulus increased after the active stimulation.	When taking into account trait hedonic capacity, one active iTBS session over the left DLPFC improved reward responsiveness in healthy male participants with higher hedonic capacity. This suggests that individual differences in hedonic capacity may influence the effects of iTBS on the reward system.	
27378872	The principal feature of Parkinson's disease (PD) is the impaired ability to acquire and express habitual-automatic actions due to the loss of dopamine in the dorsolateral striatum, the region of the basal ganglia associated with the control of habitual behavior. Dopamine replacement therapy (DRT) compensates for the lack of dopamine, representing the standard treatment for different motor symptoms of PD (such as rigidity, bradykinesia and resting tremor). On the other hand, rehabilitation treatments, exploiting the use of cognitive strategies, feedbacks and external cues, permit to "learn to bypass" the defective basal ganglia (using the dorsolateral area of the prefrontal cortex) allowing the patients to perform correct movements under executive-volitional control. Therefore, DRT and rehabilitation seem to be two complementary and synergistic approaches. Learning and reward are central in rehabilitation: both of these mechanisms are the basis for the success of any rehabilitative treatment. Anyway, it is known that "learning resources" and reward could be negatively influenced from dopaminergic drugs. Furthermore, DRT causes different well-known complications: among these, dyskinesias, motor fluctuations, and dopamine dysregulation syndrome (DDS) are intimately linked with the alteration in the learning and reward mechanisms and could impact seriously on the rehabilitative outcomes. These considerations highlight the need for careful titration of DRT to produce the desired improvement in motor symptoms while minimizing the associated detrimental effects. This is important in order to maximize the motor re-learning based on repetition, reward and practice during rehabilitation. In this scenario, we review the knowledge concerning the interactions between DRT, learning and reward, examine the most impactful DRT side effects and provide suggestions for optimizing rehabilitation in PD. 
27378831	It is well established that obesity decreases overall life expectancy and increases the risk of several adverse health conditions. Mounting evidence indicates that body fat is likely also associated with structural and functional brain changes, reduced cognitive function, and greater impulsivity. However, previously reported differences in brain structure and function have been variable across studies and difficult to reconcile due to sample population and methodological differences. To clarify these issues, we correlated two independent measures of body composition-i.e., body mass index (BMI) and body fat percent (BFP)-with structural and functional neuroimaging data obtained from a cohort of 32 neurologically healthy adults. Whole-brain voxel-wise analyses indicated that higher BMI and BFP were associated with widespread decreases in gray matter volume, white matter volume, and white matter microstructure (including several regions, such as the striatum and orbitofrontal cortex, which may influence value assessment, habit formation, and decision-making). Moreover, closer examination of resting state functional connectivity, white matter volume, and white matter microstructure throughout the default mode network (DMN), executive control network (ECN), and salience network (SN) revealed that higher BMI and BFP were associated with increased SN functional connectivity and decreased white matter volumes throughout all three networks (i.e., the DMN, ECN, and SN). Taken together, these findings: (1) offer a biologically plausible explanation for reduced cognitive performance, greater impulsivity, and altered reward processing among overweight individuals, and (2) suggest neurobiological mechanisms (i.e., altered functional and structural brain connectivity) that may affect overweight individuals' ability to establish and maintain healthy lifestyle choices. 
27378537	The electrophysiological response to positive and negative feedback during reinforcement learning has been well documented over the past two decades, yet, little is known about the neural response to uninformative events that often follow our actions. To address this issue, we recorded the electroencephalograph (EEG) during a time-estimation task using both informative (positive and negative) and uninformative (neutral) feedback. In the time-frequency domain, uninformative feedback elicited significantly less induced beta-gamma activity than informative feedback. This result suggests that beta-gamma activity is particularly sensitive to feedback that can guide behavioral adjustments, consistent with other work. In contrast, neither theta nor delta activity were sensitive to the difference between negative and neutral feedback, though both frequencies discriminated between positive, and non-positive (neutral or negative) feedback. Interestingly, in the time domain, we observed a linear relationship in the amplitude of the feedback-related negativity (neutral>negative>positive), a component of the event-related brain potential thought to index a specific kind of reinforcement learning signal called a reward prediction error. Taken together, these results suggest that the reinforcement learning system treats neutral feedback as a special case, providing valuable information about the electrophysiological measures used to index the cognitive function of frontal midline cortex. 
27375515	Religion can have an important influence in moral decision-making, and religious reminders may deter people from unethical behavior. Previous research indicated that religious contexts may increase prosocial behavior and reduce cheating. However, the perceptual-behavioral link between religious contexts and decision-making lacks thorough scientific understanding. This study adds to the current literature by testing the effects of purely audial religious symbols (instrumental music) on moral behavior across three different sites: Mauritius, the Czech Republic, and the USA. Participants were exposed to one of three kinds of auditory stimuli (religious, secular, or white noise), and subsequently were given a chance to dishonestly report on solved mathematical equations in order to increase their monetary reward. The results showed cross-cultural differences in the effects of religious music on moral behavior, as well as a significant interaction between condition and religiosity across all sites, suggesting that religious participants were more influenced by the auditory religious stimuli than non-religious participants. We propose that religious music can function as a subtle cue associated with moral standards via cultural socialization and ritual participation. Such associative learning can charge music with specific meanings and create sacred cues that influence normative behavior. Our findings provide preliminary support for this view, which we hope further research will investigate more closely. 
27375453	The present study is part of a series of experiments, where we analyze why and how damage of the rat's dorsal hippocampus (dHC) can enhance performance in a sequential reaction time task (SRTT). In this task, sequences of distinct visual stimulus presentations are food-rewarded in a fixed-ratio-13-schedule. Our previous study (Busse and Schwarting, 2016) had shown that rats with lesions of the dHC show substantially shorter session times and post-reinforcement pauses (PRPs) than controls, which allows for more practice when daily training is kept constant. Since sequential behavior is based on instrumental performance, a sequential benefit might be secondary to that. In order to test this hypothesis in the present study, we performed two experiments, where pseudorandom rather than sequential stimulus presentation was used in rats with excitotoxic dorsal hippocampal lesions. Again, we found enhanced performance in the lesion-group in terms of shorter session times and PRPs. During the sessions we found that the lesion-group spent less time with non-instrumental behavior (i.e., grooming, sniffing, and rearing) after prolonged instrumental training. Also, such rats showed moderate evidence for an extinction impairment under devalued food reward conditions and significant deficits in a response-outcome (R-O)-discrimination task in comparison to a control-group. These findings suggest that facilitatory effects on instrumental performance after dorsal hippocampal lesions may be primarily a result of complex behavioral changes, i.e., reductions of behavioral flexibility and/or alterations in motivation, which then result in enhanced instrumental learning. 
27375276	This paper offers an active inference account of choice behaviour and learning. It focuses on the distinction between goal-directed and habitual behaviour and how they contextualise each other. We show that habits emerge naturally (and autodidactically) from sequential policy optimisation when agents are equipped with state-action policies. In active inference, behaviour has explorative (epistemic) and exploitative (pragmatic) aspects that are sensitive to ambiguity and risk respectively, where epistemic (ambiguity-resolving) behaviour enables pragmatic (reward-seeking) behaviour and the subsequent emergence of habits. Although goal-directed and habitual policies are usually associated with model-based and model-free schemes, we find the more important distinction is between belief-free and belief-based schemes. The underlying (variational) belief updating provides a comprehensive (if metaphorical) process theory for several phenomena, including the transfer of dopamine responses, reversal learning, habit formation and devaluation. Finally, we show that active inference reduces to a classical (Bellman) scheme, in the absence of ambiguity. 
27374160	The hippocampus plays a vital role in processing contextual memories and reward related learning tasks, such as conditioned place preference (CPP). Among the neurotransmitters in the hippocampus, dopamine is deeply involved in reward-related processes. This study assessed the role of D1- and D2-like dopamine receptors within the CA1 region of the hippocampus in the acquisition and reinstatement of morphine-CPP. To investigate the role of D1 and D2 receptors in morphine acquisition, the animals received different doses of D1- and/or D2-like dopamine receptor antagonists (SCH23390 and sulpiride, respectively) into the CA1, 5min before the administration of morphine (5mg/kg, subcutaneously) during a 3-days conditioning phase. To evaluate the involvement of these receptors in morphine reinstatement, the animals received different doses of SCH23390 or sulpiride (after extinction period) 5min before the administration of a low dose of morphine (1mg/kg) in order to reinstate the extinguished morphine-CPP. Conditioning scores were recorded by Ethovision software. The results of this study showed that the administration of SCH23390 or sulpiride, significantly decreased the acquisition of morphine-CPP. Besides, the injection of these antagonists before the administration of a priming dose of morphine, following the extinction period, decreased the reinstatement of morphine-CPP in sacrificed rats. However, the effect of sulpiride on the acquisition and reinstatement of morphine-CPP was more significant than that of SCH23390. These findings suggested that D1- and D2-like dopamine receptors in the CA1 are involved in the acquisition and reinstatement of morphine-CPP, and antagonism of these receptors can reduce the rewarding properties of morphine. 
27372858	Addiction is a chronic compulsion and relapsing disorder. It involves several brain areas and circuits, which encode vary functions such as reward, motivation, and memory. Drug addiction is defined as a "pathological pattern of use of a substance", characterized by the loss of control on drug-taking-related behaviors, the pursuance of those behaviors even in the presence of negative consequences, and a strong motivated activity to assume substances. Three different theories guide experimental research on drug addiction. Each of these theories consider singles features, such as an aberrant motivation, a hedonic dysregulation, and an aberrant habit learning as the main actor to explain the entire process of the addictive behaviors. The major goal of this study is to present a new hypotheses of transitionality from a controlled use to abuse of addictive substances trough the overview of the three different theories, considering all the single features of each single theory together on the same "temporal continuum" from use to abuse of addictive substances. Recently, it has been suggested that common neural systems may be activated by natural and pharmacological stimuli, raising the hypotheses that binge-eating disorders could be considered as addictive behaviors. The second goal of this study is to present evidences in order to highlight a possible psycho-bio-physiological superimposition between drug and "food addiction". Finally, interesting questions are brought up starting from last findings about a theoretical/psycho-bio-physiological superimposition between drug and "food addiction" and their possibly same transitionality along the same "temporal continuum" from use to abuse of addictive substances in order to investigate new therapeutic strategies based on new therapeutic strategies based on the individual moments characterizing the transition from the voluntary intake of substances to the maladaptive addictive behavior. 
27371365	The subthalamic nucleus (STN) is part of the motor, associative, and limbic cortico-striatal circuits through which it can influence a range of behaviours, with preclinical and clinical evidence suggesting that the STN is involved in motivational modulation of behaviour. In the present study, we investigated if in Parkinson's disease (PD) motivational modulation of movement speed is altered by deep brain stimulation (DBS) of the STN (STN-DBS).We studied the effect of monetary incentive on speed of movement initiation and execution in a computer-based simple reaction time task in 10 operated patients with Parkinson's disease using a STN DBS ON/OFF design and also in 11 healthy participants.	Prospect of reward improved speed of movement initiation in PD patients both with STN-DBS ON and OFF. However, only with STN-DBS ON, the patients showed greater speeding of initiation time with higher reward magnitude, suggesting enhanced responsivity to higher reward value. Also, on the rewarded trials, PD patients ON stimulation made more anticipation errors than on unrewarded trials, reflecting a propensity to impulsive responses triggered by prospect of reward by subthalamic stimulation. The motivational modulation of movement speed was preserved and enhanced in PD with STN-DBS.	Motivational modulation of movement speed in PD is maintained with STN-DBS, with STN stimulation having a further energizing effect on movement initiation in response to greater incentive value. Our results suggest that STN plays a role in integrating motivational influences into motor action, which may explain some previous reports of STN-DBS induced impulsivity with increased motivational salience of stimuli.	
27371135	Stimulus-reward learning has been heavily linked to the reward-prediction error learning hypothesis and dopaminergic function. However, some evidence suggests dopaminergic function may not strictly underlie reward-prediction error learning, but may be specific to incentive salience attribution. Utilizing a Pavlovian conditioned approach procedure consisting of two stimuli that were equally reward-predictive (both undergoing reward-prediction error learning) but functionally distinct in regard to incentive salience (levers that elicited sign-tracking and tones that elicited goal-tracking), we tested the differential role of D1 and D2 dopamine receptors and nucleus accumbens dopamine in the acquisition of sign- and goal-tracking behavior and their associated conditioned reinforcing value within individuals. Overall, the results revealed that both D1 and D2 inhibition disrupted performance of sign- and goal-tracking. However, D1 inhibition specifically prevented the acquisition of sign-tracking to a lever, instead promoting goal-tracking and decreasing its conditioned reinforcing value, while neither D1 nor D2 signaling was required for goal-tracking in response to a tone. Likewise, nucleus accumbens dopaminergic lesions disrupted acquisition of sign-tracking to a lever, while leaving goal-tracking in response to a tone unaffected. Collectively, these results are the first evidence of an intraindividual dissociation of dopaminergic function in incentive salience attribution from reward-prediction error learning, indicating that incentive salience, reward-prediction error, and their associated dopaminergic signaling exist within individuals and are stimulus-specific. Thus, individual differences in incentive salience attribution may be reflective of a differential balance in dopaminergic function that may bias toward the attribution of incentive salience, relative to reward-prediction error learning only. 
27368345	Bipolar disorder is often misdiagnosed as major depressive disorder, which leads to inadequate treatment. Depressed individuals versus healthy control subjects, show increased expectation of negative outcomes. Due to increased impulsivity and risk for mania, however, depressed individuals with bipolar disorder may differ from those with major depressive disorder in neural mechanisms underlying anticipation processes. Graph theory methods for neuroimaging data analysis allow the identification of connectivity between multiple brain regions without prior model specification, and may help to identify neurobiological markers differentiating these disorders, thereby facilitating development of better therapeutic interventions. This study aimed to compare brain connectivity among regions involved in win/loss anticipation in depressed individuals with bipolar disorder (BDD) versus depressed individuals with major depressive disorder (MDD) versus healthy control subjects using graph theory methods. The study was conducted at the University of Pittsburgh Medical Center and included 31 BDD, 39 MDD, and 36 healthy control subjects. Participants were scanned while performing a number guessing reward task that included the periods of win and loss anticipation. We first identified the anticipatory network across all 106 participants by contrasting brain activation during all anticipation periods (win anticipation + loss anticipation) versus baseline, and win anticipation versus loss anticipation. Brain connectivity within the identified network was determined using the Independent Multiple sample Greedy Equivalence Search (IMaGES) and Linear non-Gaussian Orientation, Fixed Structure (LOFS) algorithms. Density of connections (the number of connections in the network), path length, and the global connectivity direction ('top-down' versus 'bottom-up') were compared across groups (BDD/MDD/healthy control subjects) and conditions (win/loss anticipation). These analyses showed that loss anticipation was characterized by denser top-down fronto-striatal and fronto-parietal connectivity in healthy control subjects, by bottom-up striatal-frontal connectivity in MDD, and by sparse connectivity lacking fronto-striatal connections in BDD. Win anticipation was characterized by dense connectivity of medial frontal with striatal and lateral frontal cortical regions in BDD, by sparser bottom-up striatum-medial frontal cortex connectivity in MDD, and by sparse connectivity in healthy control subjects. In summary, this is the first study to demonstrate that BDD and MDD with comparable levels of current depression differed from each other and healthy control subjects in density of connections, connectivity path length, and connectivity direction as a function of win or loss anticipation. These findings suggest that different neurobiological mechanisms may underlie aberrant anticipation processes in BDD and MDD, and that distinct therapeutic strategies may be required for these individuals to improve coping strategies during expectation of positive and negative outcomes. 
27367139	The Achilles Heel of stochastic optimization algorithms is getting trapped on local optima. Novelty Search mitigates this problem by encouraging exploration in all interesting directions by replacing the performance objective with a reward for novel behaviors. This reward for novel behaviors has traditionally required a human-crafted, behavioral distance function. While Novelty Search is a major conceptual breakthrough and outperforms traditional stochastic optimization on certain problems, it is not clear how to apply it to challenging, high-dimensional problems where specifying a useful behavioral distance function is difficult. For example, in the space of images, how do you encourage novelty to produce hawks and heroes instead of endless pixel static? Here we propose a new algorithm, the Innovation Engine, that builds on Novelty Search by replacing the human-crafted behavioral distance with a Deep Neural Network (DNN) that can recognize interesting differences between phenotypes. The key insight is that DNNs can recognize similarities and differences between phenotypes at an abstract level, wherein novelty means interesting novelty. For example, a DNN-based novelty search in the image space does not explore in the low-level pixel space, but instead creates a pressure to create new types of images (e.g., churches, mosques, obelisks, etc.). Here, we describe the long-term vision for the Innovation Engine algorithm, which involves many technical challenges that remain to be solved. We then implement a simplified version of the algorithm that enables us to explore some of the algorithm's key motivations. Our initial results, in the domain of images, suggest that Innovation Engines could ultimately automate the production of endless streams of interesting solutions in any domain: for example, producing intelligent software, robot controllers, optimized physical components, and art. 
27363510	A blunted neural response to rewards has recently emerged as a potential mechanistic biomarker of adolescent depression. The reward positivity, an event-related potential elicited by feedback indicating monetary gain relative to loss, has been associated with risk for depression. The authors examined whether the reward positivity prospectively predicted the development of depression 18 months later in a large community sample of adolescent girls.The sample included 444 girls 13.5-15.5 years old with no lifetime history of a depressive disorder, along with a biological parent for each girl. At baseline, the adolescents' reward positivity was measured using a monetary guessing task, their current depressive symptoms were assessed using a self-report questionnaire, and the adolescents' and parents' lifetime psychiatric histories were evaluated with diagnostic interviews. The same interview and questionnaire were administered to the adolescents again approximately 18 months later.	A blunted reward positivity at baseline predicted first-onset depressive disorder and greater depressive symptom scores 18 months later. The reward positivity was also a significant predictor independent of other prominent risk factors, including baseline depressive symptoms and adolescent and parental lifetime psychiatric history. The combination of a blunted reward positivity and greater depressive symptom scores at baseline provided the greatest positive predictive value for first-onset depressive disorder.	This study provides strong converging evidence that a blunted neural response to rewards precedes adolescent-onset depression and symptom emergence. Blunted neural response may therefore constitute an important target for screening and prevention.	
27363460	Background and aims Impulsivity has consistently been associated with over-consumption and addiction. Recent research has reconceptualized impulsivity as a two-dimensional construct ( Dawe, Gullo, & Loxton, 2004 ). This study explores the relationship of the two components of impulsivity, reward drive (RD) and rash impulsivity (RI), on a broad group of 23 hedonic consumption behaviors (e.g., gambling, substance use, eating, and media use). We tentatively grouped the behaviors into three descriptive classes: entertainment, foodstuffs, and illicit activities and substances. Results RD and RI positively predicted elevated levels of consumption in a community sample (N=5,391; 51% female), for the vast majority of the behaviors considered. However, the effect sizes for RD and RI varied significantly depending on the behavior; a pattern that appeared to be at least partially attributable to the class of consumption. Results support the view that RD is related more strongly to the consumption of products that provide social engagement or a sense of increased status; whereas RI better reflects an approach toward illicit or restricted products that are intensely rewarding with clear negative consequences. Discussion and conclusion Results support the utility of the two-factor model of impulsivity in explaining individual differences in patterns of hedonic consumption in the general population. We discuss findings in terms of strengthening current conceptualizations of RI and RD as having distinct implications with respect to health-related behaviors. 
27363005	Much past research has focused on the correlation between procrastination and personality traits (e.g., impulsivity). According to the temporal motivation theory, procrastinators are impulsive and sensitive to delays in time. However, there is still a lack of direct evidence of the tendency of procrastinators to prefer immediate over future rewards. To investigate this question, we recorded event-related potentials (ERPs) in the brain while participants performed an intertemporal choice task involving both time delay and reward processing. The participants were assigned to a high procrastination group and a low procrastination group according to their scores on self-report measures. We found that high procrastination participants preferred immediate rewards compared to future ones whereas low procrastination participants did not. High procrastinators also exhibited a larger and delayed P2 component, indicating delay time processing and abnormal reward processing. No significant effect associated with procrastination was found on the P300 component. Taken together, these findings suggest that high procrastinators are more impulsive and encode the information of delay time more slowly but with a higher level of motivation-driven attention. The current study substantiates higher impulsivity in procrastination and verifies that a difference exists in the sensitivity to time delay between high and low procrastinators. 
27362655	Abnormalities in tactile perception, such as sensory defensiveness, are common features in autism spectrum disorder (ASD). While not a diagnostic criterion for ASD, deficits in tactile perception contribute to the observed lack of social communication skills. However, the influence of tactile perception deficits on the development of social behaviors remains uncertain, as do the effects on neuronal circuits related to the emotional regulation of social interactions. In neonatal rodents, whiskers are the most important tactile apparatus, so bilateral whisker trimming is used as a model of early tactile deprivation. To address the influence of tactile deprivation on adult behavior, we performed bilateral whisker trimming in mice for 10 days after birth (BWT10 mice) and examined social behaviors, tactile discrimination, and c-Fos expression, a marker of neural activation, in adults after full whisker regrowth. Adult BWT10 mice exhibited significantly shorter crossable distances in the gap-crossing test than age-matched controls, indicating persistent deficits in whisker-dependent tactile perception. In contrast to controls, BWT10 mice exhibited no preference for the social compartment containing a conspecific in the three-chamber test. Furthermore, the development of amygdala circuitry was severely affected in BWT10 mice. Based on the c-Fos expression pattern, hyperactivity was found in BWT10 amygdala circuits for processing fear/anxiety-related responses to height stress but not in circuits for processing reward stimuli during whisker-dependent cued learning. These results demonstrate that neonatal whisker trimming and concomitant whisker-dependent tactile discrimination impairment severely disturbs the development of amygdala-dependent emotional regulation. 
27357956	Reward learning is known to influence the automatic capture of attention. This study examined how the rate of learning, after high- or low-value reward outcomes, can influence future transfers into value-driven attentional capture. Participants performed an instrumental learning task that was directly followed by an attentional capture task. A hierarchical Bayesian reinforcement model was used to infer individual differences in learning from high or low reward. Results showed a strong relationship between high-reward learning rates (or the weight that is put on learning after a high reward) and the magnitude of attentional capture with high-reward colors. Individual differences in learning from high or low rewards were further related to performance differences when high- or low-value distractors were present. These findings provide novel insight into the development of value-driven attentional capture by showing how information updating after desired or undesired outcomes can influence future deployments of automatic attention.
27357796	Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing. 
27356121	W. Horsley Gantt and Joseph V. Brady laid a rich foundation for understanding the concept of emotion, derived from 2 prominent traditions of physiology and psychology: classic conditioning and operant conditioning, respectively. This framework guided my fierce interest in motivation in general and the interaction between reward and stress, which began at John Hopkins with my thesis work under the guidance of Drs. Zoltan Annau, Solomon Synder, and Joseph Brady, among many others. Using the study of the neurobiology of addiction as a framework, I argue that drug addiction not only involves positive reinforcement associated with the rewarding effects of drugs of abuse but also involves another major source of reinforcement, specifically negative reinforcement driven by negative emotional states (termed the "dark side" of addiction). Excessive activation of the brain reward systems leads to antireward or a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of the brain stress systems, both of which may be neurobiologically linked. Understanding the neuroplasticity of the neurocircuitry that comprises the negative reinforcement associated with addiction is a key to understanding negative emotional states in general and their pathophysiology.
27354193	Classification and sequence learning are relevant capabilities used by living beings to extract complex information from the environment for behavioral control. The insect world is full of examples where the presentation time of specific stimuli shapes the behavioral response. On the basis of previously developed neural models, inspired by Drosophila melanogaster, a new architecture for classification and sequence learning is here presented under the perspective of the Neural Reuse theory. Classification of relevant input stimuli is performed through resonant neurons, activated by the complex dynamics generated in a lattice of recurrent spiking neurons modeling the insect Mushroom Bodies neuropile. The network devoted to context formation is able to reconstruct the learned sequence and also to trace the subsequences present in the provided input. A sensitivity analysis to parameter variation and noise is reported. Experiments on a roving robot are reported to show the capabilities of the architecture used as a neural controller. 
27352364	Foraging insects leave chemical footprints on flowers that subsequent foragers may use as indicators for recent flower visits and, thus, potential resource depletion. Accordingly, foragers should reject food sources presenting these chemical cues. Contrasting this assumption, experimental studies in stingless bees (Apidae, Meliponini), so far, demonstrated an attractive effect of footprints. These findings lead to doubts about the meaning of these chemical cues in natural foraging contexts. Here, we asked whether foragers of stingless bees (Melipona scutellaris) use footprints according to the previously experienced reward level of visited food sources. Bees were trained to artificial flower patches, at which the reward of a flower either decreased or, alternatively, increased after a visit by a forager. Individuals were allowed a total of nine foraging bouts to the patch, after which their preference for visited or unvisited flowers was tested. In the choice tests, bees trained under the decreasing reward context preferred unvisited flowers, whereas individuals trained under the increasing reward context preferred visited flowers. Foragers without experience chose randomly between visited and unvisited flowers. These results demonstrate that M. scutellaris learns to associate unspecific footprint cues at food sources with differential, specific reward contexts, and uses these chemical cues accordingly for their foraging decisions. 
27350195	Caloric diet, such as fat and sugar intake, has rewarding effects, and has been indicated to affect the responses to addictive substances in animal experiments. However, the possible association between sucrose reward and the motivation for addictive drugs remains to be elucidated. Thus, we carried out behavioral tests after sucrose self-administration training to determine the effects of sucrose experience on rats' motivation for cocaine, locomotor sensitivity to cocaine, basal locomotor activity, anxiety level, and associative learning ability. The sucrose-experienced (sucrose) group exhibited higher lever press, cocaine infusion and break point, as well as upshift of cocaine dose-response curve in cocaine self-administration test, as compared with the control (chow) group. Additionally, despite similar locomotor activity in open field test and comparable score in cocaine-induced conditioned place preference, the sucrose group showed higher cocaine-induced locomotor sensitivity as compared with the chow group. The anxiety level and the performance in vocal-cue induced fear memory were similar between these two groups in elevated plus maze and fear conditioning tests, respectively. Taken together, our work indicates that sucrose experience promotes the rats' motivation for cocaine. 
27346394	To identify meaningful types of rewards and the consequences of rewards as expressed by Finnish registered nurses working in primary and private healthcare.Previous studies have found significant associations between nurses' rewards and both their commitment and job satisfaction. Furthermore, appropriate rewards can have beneficial effects on factors including workforce stability and occupational satisfaction that are highly important in times of nurse shortages.	A cross-sectional, qualitative interview study.	Data were collected via individual semi-structured interviews (n = 20) with registered nurses working in Finland's primary and private healthcare, and subjected to qualitative content analysis.	Six meaningful types of rewards were identified by the registered nurses: Financial compensation and benefits, Work-Life balance, Work content, Professional development, Recognition, and Supportive leadership. Rewards encouraged respondents to perform their work correctly and reinforced occupational satisfaction, but also caused feelings of envy and stress.	It is essential to pay attention to nurses' preferences for particular rewards and to reward management. When designing effective reward systems for registered nurses, it is not sufficient to provide financial rewards alone, as various kinds of non-financial rewards are both meaningful and necessary.	When trying to improve registered nurses' commitment and job satisfaction through reward management, it is important to listen to nurses' opinions to create a reward system that integrates financial and non-financial rewards and is fair from their perspective. Healthcare organisations that offer registered nurses a holistic reward system are more likely to retain satisfied and committed nurses at a time of increasing nursing shortages.	
27345425	The zebrafish has been gaining prominence in the field of behavioural brain research as this species offers a good balance between system complexity and practical simplicity. While the number of studies examining the behaviour of zebrafish has exponentially increased over the past decade, the need is still substantial for paradigms capable of assessing cognitive and mnemonic characteristics of this species. Here we describe and utilize a novel visual discrimination task with which we evaluated acquisition of CS (colour)-US (sight of conspecifics) association in adult zebrafish. We report significant acquisition of CS-US association indicated by the increased time the fish spent in and the increased frequency of visits of the target chamber during a probe trial in the absence of reward. Given the simplicity of the apparatus and procedure, we conclude that the new task may be employed to assay learning and memory in adult zebrafish in an efficient manner. 
27344588	Patients with borderline personality disorder (BPD) show deficits in reward-guided decision making and learning. The present study examined risk-taking behavior in combination with feedback processing. Eighteen BPD patients and 18 healthy controls performed a probabilistic two-choice gambling task, while an electroencephalogram was recorded. Options differed in risk, but were identical in expected value and outcome probability. The feedback-related negativity (FRN) and the feedback-related P300 were analyzed. Healthy controls preferred low-risk over high-risk options, whereas BPD patients chose both option with equal probability. FRN amplitudes were reduced in BPD, but effects of feedback valence and risk did not differ between groups. This suggests attenuated outcome processing in the anterior cingulate cortex, but intact reward prediction error signaling. Furthermore, the modulation of the feedback-related P300 with feedback valence and risk was smaller in BPD patients, and decreased P300 amplitudes were associated with increased behavioral risk-taking behavior. These findings could relate to the reduced ability of BPD patients to learn and adequately adjust their behavior based on feedback information, possibly due to reduced significance of negative feedback. 
27343621	Domestic dogs have demonstrated striking social skills towards humans, however, there are few studies investigating impulsivity with delay-choice tasks in communicative contexts. In Study 1 we introduced a novel social delay-choice task in which subjects had to choose between one human cueing an immediate, low quality reward and another human signaling a delayed, high quality reward. In Study 2 we evaluated the tolerance to increasing delays using social and non-social cues. We also explored if more self-controlled dogs show any distinct behaviours during delays. Finally, we correlated all results with the Dog Impulsivity Assessment Scale (Wright et al., 2011). In Study 1 dogs reached an average maximum delay of 11.55s. In Study 2 that average was 52.14s with social cues and 40.2s with non-social, but differences were not significant. Tolerance to delays showed high interindividual variation. Dogs remained mostly standing and near the delayed experimenter in the social tasks although we could not to find any distinct coping strategies. No significant correlations were found between the delay reached and behaviours, neither with the scale. These results show the relevance of the parameters and methods used to investigate tolerance to delay of reinforcements. More investigations are required, especially an assessment of the same subjects performing the same tasks using different contexts. 
27343481	We investigated whether nonhuman great apes (N=23), 2.5-year-old (N=20), and 3-year-old children (N=40) infer causal relations from patterns of variation and covariation by adapting the blicket detector paradigm for apes. We presented chimpanzees (Pan troglodytes), bonobos (Pan paniscus), orangutans (Pongo abelii), gorillas (Gorilla gorilla), and children (Homo sapiens) with a novel reward dispenser, the blicket detector. The detector was activated by inserting specific (yet randomly determined) objects, the so-called blickets. Once activated a reward was released, accompanied by lights and a short tone. Participants were shown different patterns of variation and covariation between two different objects and the activation of the detector. When subsequently choosing between one of the two objects to activate the detector on their own all species, except gorillas (who failed the training), took these patterns of correlation into account. In particular, apes and 2.5-year-old children ignored objects whose effect on the detector completely depended on the presence of another object. Follow-up experiments explored whether the apes and children were also able to re-evaluate evidence retrospectively. Only children (3-year-olds in particular) were able to make such retrospective inferences about causal structures from observing the effects of the experimenter's actions. Apes succeeded here only when they observed the effects of their own interventions. Together, this study provides evidence that apes, like young children, accurately infer causal structures from patterns of (co)variation and that they use this information to inform their own interventions. 
27343054	Early colonization by Zyginidia scutellaris leafhoppers might be a key factor in the attraction and settling of generalist predators, such as Orius spp., in maize fields. In this paper, we aimed to determine whether our observations of early season increases in field populations of Orius spp. reflect a specific attraction to Z. scutellaris-induced maize volatiles, and how the responses of Orius predators to herbivore-induced volatiles (HIPVs) might be affected by previous experiences on plants infested by herbivorous prey. Therefore, we examined the innate and learned preferences of Orius majusculus toward volatiles from maize plants attacked by three potential herbivores with different feeding strategies: the leafhopper Z. scutellaris (mesophyll feeder), the lepidopteran Spodoptera littoralis (chewer), and another leafhopper Dalbulus maidis (phloem feeder). In addition, we examined the volatile profiles emitted by maize plants infested by the three herbivores. Our results show that predators exhibit a strong innate attraction to volatiles from maize plants infested with Z. scutellaris or S. littoralis. Previous predation experience in the presence of HIPVs influences the predator's odor preferences. The innate preference for plants with cell or tissue damage may be explained by these plants releasing far more volatiles than plants infested by the phloem-sucking D. maidis. However, a predation experience on D. maidis-infested plants increased the preference for D. maidis-induced maize volatiles. After O. majusculus experienced L3-L4 larvae (too large to serve as prey) on S. littoralis-infested plants, they showed reduced attraction toward these plants and an increased attraction toward D. maidis-infested plants. When offered young larvae of S. littoralis, which are more suitable prey, preference toward HIPVs was similar to that of naive individuals. The HIPVs from plants infested by herbivores with distinctly different feeding strategies showed distinguishable quantitative differences in (Z)-3-hexenal, (E)-2-hexenal, and methyl salicylate. These compounds might serve as reliable indicators of prey presence and identity for the predator. Our results support the idea that feeding by Z. scutellaris results in the emission of maize's HIPVs that initially recruit Orius spp. into maize fields. 
27342815	To examine how signals from different sensory modalities are integrated to generate an appropriate goal-oriented behavior, we trained rats in an eight-arm radial maze to visit a cue arm provided with intramaze cues from different sensory modalities, i.e. visual, tactile and auditory, in order to obtain a reward. When the same rats were then examined on test trials in which the cue arm contained one of the stimuli that the animals were trained with (i.e. light, sound or rough sheet), they showed a significant impairment with respect to the performance on the polymodal-cue task. The contribution of the dorsal hippocampus to the acquisition and retention of polymodal-cue guided task was also examined. We found that rats with dorsal hippocampal lesions before training showed a significant deficit in the acquisition of polymodal-cue oriented task that improved with overtraining. The selective lesion of the dorsal hippocampus after training disrupted memory retention, but the animals' performance improved following retraining of the polymodal task. All hippocampal lesioned rats displayed an impaired performance on the unimodal test. These findings suggest that the dorsal hippocampus contributes to the processing of multimodal sensory information for the associative memory formation and consolidation. 
27341100	Animals learn to make predictions, such as associating the sound of a bell with upcoming feeding or predicting a movement that a motor command is eliciting. How predictions are realized on the neuronal level and what plasticity rule underlies their learning is not well understood. Here we propose a biologically plausible synaptic plasticity rule to learn predictions on a single neuron level on a timescale of seconds. The learning rule allows a spiking two-compartment neuron to match its current firing rate to its own expected future discounted firing rate. For instance, if an originally neutral event is repeatedly followed by an event that elevates the firing rate of a neuron, the originally neutral event will eventually also elevate the neuron's firing rate. The plasticity rule is a form of spike timing dependent plasticity in which a presynaptic spike followed by a postsynaptic spike leads to potentiation. Even if the plasticity window has a width of 20 milliseconds, associations on the time scale of seconds can be learned. We illustrate prospective coding with three examples: learning to predict a time varying input, learning to predict the next stimulus in a delayed paired-associate task and learning with a recurrent network to reproduce a temporally compressed version of a sequence. We discuss the potential role of the learning mechanism in classical trace conditioning. In the special case that the signal to be predicted encodes reward, the neuron learns to predict the discounted future reward and learning is closely related to the temporal difference learning algorithm TD(λ). 
27335404	Dopamine D2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D2, D3, or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [(11)C]-(+)-PHNO was used to quantify individual differences in putative D3 receptor availability in rodents trained on a novel three-choice spatial acquisition and reversal-learning task with probabilistic reinforcement. Binding of [(11)C]-(+)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [(11)C]-(+)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D3-preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D3 receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D3 receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D3 receptor in decision-making processes that are altered in psychiatric disorders.Flexible decision-making behavior is dependent upon dopamine D2/3 signaling in corticostriatal brain regions. However, the role of D3 receptors in adaptive, goal-directed behavior has not been thoroughly investigated. By combining PET imaging with the D3-preferring radioligand [(11)C]-(+)-PHNO, pharmacology, a novel three-choice probabilistic discrimination and reversal task and computational modeling of behavior in rats, we report that naturally occurring variation in [(11)C]-(+)-PHNO receptor availability relates to specific aspects of flexible decision making. We confirm these relationships using a D3-preferring agonist, thus identifying a unique role of midbrain D3 receptors in decision-making processes.	
27335401	In operant learning, initial reward-associated memories are thought to be distinct from subsequent extinction-associated memories. Memories formed during operant learning are thought to be stored in "neuronal ensembles." Thus, we hypothesize that different neuronal ensembles encode reward- and extinction-associated memories. Here, we examined prefrontal cortex neuronal ensembles involved in the recall of reward and extinction memories of food self-administration. We first trained rats to lever press for palatable food pellets for 7 d (1 h/d) and then exposed them to 0, 2, or 7 daily extinction sessions in which lever presses were not reinforced. Twenty-four hours after the last training or extinction session, we exposed the rats to either a short 15 min extinction test session or left them in their homecage (a control condition). We found maximal Fos (a neuronal activity marker) immunoreactivity in the ventral medial prefrontal cortex of rats that previously received 2 extinction sessions, suggesting that neuronal ensembles in this area encode extinction memories. We then used the Daun02 inactivation procedure to selectively disrupt ventral medial prefrontal cortex neuronal ensembles that were activated during the 15 min extinction session following 0 (no extinction) or 2 prior extinction sessions to determine the effects of inactivating the putative food reward and extinction ensembles, respectively, on subsequent nonreinforced food seeking 2 d later. Inactivation of the food reward ensembles decreased food seeking, whereas inactivation of the extinction ensembles increased food seeking. Our results indicate that distinct neuronal ensembles encoding operant reward and extinction memories intermingle within the same cortical area.A current popular hypothesis is that neuronal ensembles in different prefrontal cortex areas control reward-associated versus extinction-associated memories: the dorsal medial prefrontal cortex (mPFC) promotes reward seeking, whereas the ventral mPFC inhibits reward seeking. In this paper, we use the Daun02 chemogenetic inactivation procedure to demonstrate that Fos-expressing neuronal ensembles mediating both food reward and extinction memories intermingle within the same ventral mPFC area.	
27334699	Decisions involving the use of tools may require an agent to consider more levels of relational complexity than merely deciding between an immediate and a delayed option. Using a new experimental approach featuring two different types of tools, two apparatuses as well as two different types of reward, we investigated the Goffin cockatoos' ability to make flexible and profitable decisions within five different setups. Paralleling previous results in primates, most birds overcame immediate drives in favor of future gains; some did so even if tool use involved additional work effort. Furthermore, at the group level subjects maximized their profit by simultaneously considering both the quality of an immediate versus a delayed food reward (accessible with a tool) and the functionality of the available tool. As their performance levels remained stable across trials in all testing setups, this was unlikely the result of a learning effect. The Goffin cockatoos' ability to focus on relevant information was constrained when all task components (both food qualities, both apparatuses and both tools) were presented at the same time. 
27330233	Disease phenotyping by omics data has become a popular approach that potentially can lead to better personalized treatment. Identifying disease subtypes via unsupervised machine learning is the first step towards this goal. In this paper, we extend a sparse K-means method towards a meta-analytic framework to identify novel disease subtypes when expression profiles of multiple cohorts are available. The lasso regularization and meta-analysis identify a unique set of gene features for subtype characterization. An additional pattern matching reward function guarantees consistent subtype signatures across studies. The method was evaluated by simulations and leukemia and breast cancer data sets. The identified disease subtypes from meta-analysis were characterized with improved accuracy and stability compared to single study analysis. The breast cancer model was applied to an independent METABRIC dataset and generated improved survival difference between subtypes. These results provide a basis for diagnosis and development of targeted treatments for disease subgroups.
27329532	Although specific brain regions have been implicated in long-term memory processes, the brain function responsible for correctly recollecting information remains incompletely understood. This study used a remember-recollection-recognition task to explore brain activities specifically associated with correct recollection. Seventy-eight subjects were first asked to remember 40 items and recollect them in the scanner. Comparison of correctly recollected trials to incorrectly recollected trials (when participants mistakenly believed they had recollected information correctly) identified greater activation of the caudate bilaterally. The involvement of caudate activation appears important in recollecting information correctly. Potential explanations and implications are discussed. Hum Brain Mapp 37:3999-4005, 2016. © 2016 Wiley Periodicals, Inc.
27328320	Goal-directed behavior involves distributed neuronal circuits in the mammalian brain, including diverse regions of neocortex. However, the cellular basis of long-range cortico-cortical signaling during goal-directed behavior is poorly understood. Here, we recorded membrane potential of excitatory layer 2/3 pyramidal neurons in primary somatosensory barrel cortex (S1) projecting to either primary motor cortex (M1) or secondary somatosensory cortex (S2) during a whisker detection task, in which thirsty mice learn to lick for water reward in response to a whisker deflection. Whisker stimulation in 'Good performer' mice, but not 'Naive' mice, evoked long-lasting biphasic depolarization correlated with task performance in S2-projecting (S2-p) neurons, but not M1-projecting (M1-p) neurons. Furthermore, S2-p neurons, but not M1-p neurons, became excited during spontaneous unrewarded licking in 'Good performer' mice, but not in 'Naive' mice. Thus, a learning-induced, projection-specific signal from S1 to S2 may contribute to goal-directed sensorimotor transformation of whisker sensation into licking motor output. 
27324322	Mixed-method study.Describe caregiver perspectives on the rewards of parenting youth with spinal cord injury (SCI) and explore the relationships between rewards and child/caregiver demographic characteristics and child psychosocial outcomes.	Data collection occurred at three pediatric specialty hospitals within a single hospital system in the United States.	Self-identified primary caregivers (n=178) of children aged 1-18 years answered the question: 'What has been most rewarding in parenting a child with SCI'? and completed a questionnaire about their child's health-related quality of life (HRQOL). Participants aged 7-18 years (n=134) also completed tools assessing their community participation, anxiety, depression and HRQOL.	Four reward themes emerged: Enhanced Resilience (for example, resilience in my child, self and family), Caregiver-Child Relationship, Connecting with Others, and Learning. Caregivers of children with lower self-reported school and overall psychosocial HRQOL were more likely to report Enhanced Resilience in their child. Caregivers whose children had fewer depressive symptoms, lower levels of participation and who were older at injury and interview felt rewarded by an enhanced Caregiver-Child Relationship. Caregivers of children with a broader context of participation and higher school and psychosocial HRQOL reported Connecting with Others. Finally, unemployed caregivers and those with less education were more likely to report Learning.	Caregivers reported a variety of rewards from parenting their children with SCI, and several relationships emerged between rewards and demographics and child psychosocial outcomes. Future research should further examine the positive experiences of caregivers and whether focusing on strengths might yield better long-term outcomes for children with SCI.	
27324266	Although fear-conditioning research has demonstrated that certain survival-threatening stimuli, namely prepared fear stimuli, are readily associated with fearful events, little research has explored whether a parallel category exists for safety stimuli. We examined whether social-support figures, who have typically benefited survival, can serve as prepared safety stimuli, a category that has not been explored previously. Across three experiments, we uncovered three key findings. First, social-support figures were less readily associated with fear than were strangers or neutral stimuli (in a retardation-of-acquisition test). Second, social-support stimuli inhibited conditional fear responses to other cues (in a summation test), and this inhibition continued even after the support stimulus was removed. Finally, these effects were not simply due to familiarity or reward because both familiar and rewarding stimuli were readily associated with fear, whereas social-support stimuli were not. These findings suggest that social-support figures are one category of prepared safety stimuli that may have long-lasting effects on fear-learning processes. 
27322574	Adolescence is a period of life characterised by changes in learning and decision-making. Learning and decision-making do not rely on a unitary system, but instead require the coordination of different cognitive processes that can be mathematically formalised as dissociable computational modules. Here, we aimed to trace the developmental time-course of the computational modules responsible for learning from reward or punishment, and learning from counterfactual feedback. Adolescents and adults carried out a novel reinforcement learning paradigm in which participants learned the association between cues and probabilistic outcomes, where the outcomes differed in valence (reward versus punishment) and feedback was either partial or complete (either the outcome of the chosen option only, or the outcomes of both the chosen and unchosen option, were displayed). Computational strategies changed during development: whereas adolescents' behaviour was better explained by a basic reinforcement learning algorithm, adults' behaviour integrated increasingly complex computational features, namely a counterfactual learning module (enabling enhanced performance in the presence of complete feedback) and a value contextualisation module (enabling symmetrical reward and punishment learning). Unlike adults, adolescent performance did not benefit from counterfactual (complete) feedback. In addition, while adults learned symmetrically from both reward and punishment, adolescents learned from reward but were less likely to learn from punishment. This tendency to rely on rewards and not to consider alternative consequences of actions might contribute to our understanding of decision-making in adolescence.
27318659	Impaired attentional flexibility is considered to be one of the core cognitive deficits in Parkinson's disease (PD). However, the mechanisms that underlie this impairment are contested. Progress in resolving this dispute has also been hindered by the fact that cognitive deficits in PD are heterogeneous; therefore, it is unclear whether attentional impairments are only present in a subgroup of patients. Here, we demonstrate that what differentiates PD patients from age-matched controls is an inability to shift attention away from previously relevant information (perseveration) and an inability to shift attention towards previously irrelevant information (learned irrelevance). In contrast, there was no evidence that PD patients, compared to controls, were impaired in being able to appropriately attend to, or ignore, novel information. Furthermore, when patients were stratified according to their level of executive impairment, the executively impaired group showed a selective deficit in set formation compared to the unimpaired group, a behavioural pattern reminiscent of cortical dopamine depletion. Cumulatively, these results suggest that cognitive inflexibility in PD relates to a specific form of attentional dysfunction, in which learned attentional biases cannot be overcome. 
27318102	Problemgambling is thought to be comorbid with attention-deficit hyperactivity disorder (ADHD). We tested whether gamblers and ADHD patients exhibit similar reward-related brain activity in response to feedback in a gambling task. A series of brain electrical responses can be observed in the electroencephalogram (EEG) and the stimulus-locked event-related potentials (ERP), when participants in a gambling task are given feedback regardless of winning or losing the previous bet. Here, we used a simplified computerized version of the Iowa Gambling Task (IGT) to assess differences in reinforcement-driven choice adaptation between unmedicated ADHD patients with or without problem gambling traits and contrasted with a sex- and age-matched control group. EEG was recorded from the participants while they were engaged in the task which contained two choice options with different net payouts and win/loss probabilities. Learning trend which shows the ability to acquire and use knowledge of the reward outcomes to obtain a positive financial outcome was not observed in ADHD gamblers versus nongamblers. Induced theta-band (4-8Hz) power over frontal cortex was significantly higher in gamblers versus nongamblers in all different high-risk/low-risk win/lose conditions. Whereas induced low alpha (9-11Hz) power at frontal electrodes could only differentiate high-risk lose between gamblers and nongamblers but not the other three conditions between the two groups. The results indicate that ADHD nongamblers do not share with problem gamblers underlying deficits in reward learning. These pilot data highlight the need for studies of ADHD in gambling to elucidate how motivational states are represented during feedback processing. 
27317193	Balancing habitual and deliberate forms of choice entails a comparison of their respective merits-the former being faster but inflexible, and the latter slower but more versatile. Here, we show that arbitration between these two forms of control can be derived from first principles within an Active Inference scheme. We illustrate our arguments with simulations that reproduce rodent spatial decisions in T-mazes. In this context, deliberation has been associated with vicarious trial and error (VTE) behavior (i.e., the fact that rodents sometimes stop at decision points as if deliberating between choice alternatives), whose neurophysiological correlates are "forward sweeps" of hippocampal place cells in the arms of the maze under consideration. Crucially, forward sweeps arise early in learning and disappear shortly after, marking a transition from deliberative to habitual choice. Our simulations show that this transition emerges as the optimal solution to the trade-off between policies that maximize reward or extrinsic value (habitual policies) and those that also consider the epistemic value of exploratory behavior (deliberative or epistemic policies)-the latter requiring VTE and the retrieval of episodic information via forward sweeps. We thus offer a novel perspective on the optimality principles that engender forward sweeps and VTE, and on their role on deliberate choice. 
27316344	The cholinergic system plays important roles in both learning and addiction. Medications that modify cholinergic tone can have pronounced effects on behaviors reinforced by natural and drug reinforcers. Importantly, enhancing the action of acetylcholine (ACh) in the nucleus accumbens and ventral tegmental area (VTA) dopamine system can either augment or diminish these behaviors. A threshold model is presented that can explain these seemingly contradictory results. Relatively low levels of ACh rise above a lower threshold, facilitating behaviors supported by drugs or natural reinforcers. Further increases in cholinergic tone that rise above a second upper threshold oppose the same behaviors. Accordingly, cholinesterase inhibitors, or agonists for nicotinic or muscarinic receptors, each have the potential to produce biphasic effects on reward behaviors. Pretreatment with either nicotinic or muscarinic antagonists can block drug- or food- reinforced behavior by maintaining cholinergic tone below its lower threshold. Potential threshold mediators include desensitization of nicotinic receptors and biphasic effects of ACh on the firing of medium spiny neurons. Nicotinic receptors with high- and low- affinity appear to play greater roles in reward enhancement and inhibition, respectively. Cholinergic inhibition of natural and drug rewards may serve as mediators of previously described opponent processes. Future studies should evaluate cholinergic agents across a broader range of doses, and include a variety of reinforced behaviors. 
27314496	Information processing in the striatum requires the postsynaptic integration of glutamatergic and dopaminergic signals, which are then relayed to the output nuclei of the basal ganglia to influence behavior. Although cellularly homogeneous in appearance, the striatum contains several rare interneuron populations which tightly modulate striatal function. Of these, cholinergic interneurons (CINs) have been recently shown to play a critical role in the control of reward-related learning; however how the striatal cholinergic network is functionally organized at the mesoscopic level and the way this organization influences striatal function remains poorly understood. Here, we systematically mapped and digitally reconstructed the entire ensemble of CINs in the mouse striatum and quantitatively assessed differences in densities, spatial arrangement and neuropil content across striatal functional territories. This approach demonstrated that the rostral portion of the striatum contained a higher concentration of CINs than the caudal striatum and that the cholinergic content in the core of the ventral striatum was significantly lower than in the rest of the regions. Additionally, statistical comparison of spatial point patterns in the striatal cholinergic ensemble revealed that only a minor portion of CINs (17%) aggregated into cluster and that they were predominantly organized in a random fashion. Furthermore, we used a fluorescence reporter to estimate the activity of over two thousand CINs in naïve mice and found that there was a decreasing gradient of CIN overall function along the dorsomedial-to-ventrolateral axis, which appeared to be independent of their propensity to aggregate within the striatum. Altogether this work suggests that the regulation of striatal function by acetylcholine across the striatum is highly heterogeneous, and that signals originating in external afferent systems may be principally determining the function of CINs in the striatum. 
27313048	Cocaine addiction is a major public health problem that is particularly difficult to treat. Without medically proven pharmacological treatments, interventions to change the maladaptive behavior of addicted individuals mainly rely on psychosocial approaches. Here we report on impairments in cocaine-addicted patients to act purposefully toward a given goal and on the influence of extended training on their behavior. When patients were rewarded for their behavior, prolonged training improved their response rate toward the goal but simultaneously rendered them insensitive to the consequences of their actions. By contrast, overtraining of avoidance behavior had no effect on patient performance. Our findings illustrate the ineffectiveness of punitive approaches and highlight the potential for interventions that focus on improving goal-directed behavior and implementing more desirable habits to replace habitual drug-taking. 
27307055	Two critical neurotransmitter systems regulating ethanol (EtOH) reward are serotonin (5-HT) and dopamine (DA). Within the posterior ventral tegmental area (pVTA), 5-HT receptors have been shown to regulate DA neuronal activity. Increased pVTA neuronal activity has been linked to drug reinforcement. The current experiment sought to determine the effect of EtOH on 5-HT and DA levels within the pVTA.Wistar rats were implanted with cannula aimed at the pVTA. Neurochemical levels were determined using standard microdialysis procedures with concentric probes. Rats were randomly assigned to one of the five groups (n = 41; 7-9 per group) that were treated with 0-3.0 g/kg EtOH (intraperitoneally).	Ethanol produced increased extracellular DA levels in the pVTA that resembled an inverted U-shape dose-response curve with peak levels (~200% of baseline) at the 2.25 g/kg dose. The increase in DA levels was observed for an extended period of time (~100 minutes). The effects of EtOH on extracellular 5-HT levels in the pVTA also resembled an inverted U-shape dose-response curve. However, increased 5-HT levels were only observed during the initial post-injection sample. The increases in extracellular DA and 5-HT levels were significantly correlated.	The data indicate intraperitoneal EtOH administration stimulated the release of both 5-HT and DA within the pVTA, the levels of which were significantly correlated. Overall, the current findings suggest that the ability of EtOH to stimulate DA activity within the mesolimbic system may be modulated by increases in 5-HT release within the pVTA.	Two critical neurotransmitter systems regulating ethanol reward are serotonin and dopamine. The current experiment determined that intraperitoneal ethanol administration increased serotonin and dopamine levels within the pVTA (levels were significantly correlated). The current findings suggest the ability of EtOH to stimulate serotonin and dopamine activity within the mesolimbic system.	
27301653	There is evidence that people with eating disorders display altered intertemporal choice behavior (the degree of preference for immediate rewards over delayed rewards). Compared to healthy controls (HC), individuals with anorexia nervosa and binge-eating disorder show decreased and increased rates of temporal discounting (TD; the devaluation of delayed rewards), respectively. This is the first study to investigate TD in people with bulimia nervosa (BN).Thirty-nine individuals with BN (2 men) and 53 HC (9 men) completed a hypothetical monetary TD task. Over 80 binary choices, participants chose whether they would prefer to receive a smaller amount of money available immediately or a larger amount available in 3 months. Self-reported ability to delay gratification (the behavioral opposite of TD) was also measured.	Individuals with BN showed greater TD (i.e., a preference for smaller-sooner rewards) and a decreased self-reported capacity to delay gratification relative to HC. Experimental groups did not differ in age, gender ratio, or BMI.	Increased rates of TD may contribute to some of the core symptoms of BN that appear to involve making choices between immediate and delayed rewards (i.e., binge-eating and compensatory behaviors). Altered intertemporal choice behavior could therefore be a relevant target for intervention in this patient group. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:1077-1081).	
27301429	Despite its clinical relevance and the recent recognition as a diagnostic category in the DSM-5, binge eating disorder (BED) has rarely been investigated from a cognitive neuroscientific perspective targeting a more precise neurocognitive profiling of the disorder. BED patients suffer from a lack of behavioral control during recurrent binge eating episodes and thus fail to adapt their behavior in the face of negative consequences, eg, high risk for obesity. To examine impairments in flexible reward-based decision-making, we exposed BED patients (n=22) and matched healthy individuals (n=22) to a reward-guided decision-making task during functional resonance imaging (fMRI). Performing fMRI analysis informed via computational modeling of choice behavior, we were able to identify specific signatures of altered decision-making in BED. On the behavioral level, we observed impaired behavioral adaptation in BED, which was due to enhanced switching behavior, a putative deficit in striking a balance between exploration and exploitation appropriately. This was accompanied by diminished activation related to exploratory decisions in the anterior insula/ventro-lateral prefrontal cortex. Moreover, although so-called model-free reward prediction errors remained intact, representation of ventro-medial prefrontal learning signatures, incorporating inference on unchosen options, was reduced in BED, which was associated with successful decision-making in the task. On the basis of a computational psychiatry account, the presented findings contribute to defining a neurocognitive phenotype of BED.
27298234	Exposing rats to an upshift from a small reward to a larger reward sometimes yields evidence of consummatory successive positive contrast (cSPC), an effect that could be a suitable animal model of positive emotion. However, cSPC is an unreliable effect. Ten experiments explored the effects of an upshift in sucrose or saccharin concentration on consummatory behavior under several conditions. There was occasional evidence of cSPC, but mostly a combination of increased consummatory behavior relative to preshift reward concentrations and a reduced behavioral level relative to unshifted controls. Such a pattern is consistent with processes causing opposite changes on behavior. Reward upshift may induce processes that suppress behavior, such as taste neophobia (induced by an intense sucrose taste) and generalization decrement (induced by novelty in reward conditions after the upshift). An experiment tested the role of such novelty-related effects by preexposing animals to either the upshift concentration (12% sucrose) or water during three days before the start of the experiment. Sucrose-preexposed animals drank significantly more than water-preexposed animals during the upshift, but just as much as unshifted controls (i.e., no evidence of cSPC). These results suggest that cSPC may be difficult to obtain reliably because reward upshift induces opposing processes. However, they also seriously question the ontological status of cSPC. 
27298233	Recent studies of delay of gratification in capuchin monkeys using a rotating tray (RT) task have shown improved self-control performance in these animals in comparison to the accumulation (AC) task. In this study, we investigated whether this improvement resulted from the difference in methods between the rotating tray task and previous tests, or whether it was the result of greater overall experience with delay of gratification tasks. Experiment 1 produced similar performance levels by capuchins monkeys in the RT and AC tasks when identical reward and temporal parameters were used. Experiment 2 demonstrated a similar result using reward amounts that were more similar to previous AC experiments with these monkeys. In Experiment 3, monkeys performed multiple versions of the AC task with varied reward and temporal parameters. Their self-control behavior was found to be dependent on the overall delay to reward consumption, rather than the overall reward amount ultimately consumed. These findings indicate that these capuchin monkeys' self-control capacities were more likely to have improved across studies because of the greater experience they had with delay of gratification tasks. Experiment 4 and Experiment 5 tested new, task-naïve monkeys on both tasks, finding more limited evidence of self-control, and no evidence that one task was more beneficial than the other in promoting self-control. The results of this study suggest that future testing of this kind should focus on temporal parameters and reward magnitude parameters to establish accurate measures of delay of gratification capacity and development in this species and perhaps others. 
27295244	Mental illness is a huge problem many people face in the U.S. and around the world. The American Psychiatric Nurses Association indicates there is a shortage of nurses in every level and role in psychiatric-mental health nursing. Raising up a generation of nurses who want to work with the mentally ill is a challenge for nurse educators. The use of role playing and simulation in the learning lab prior to entering the clinical setting and reflective journaling in the clinical rotation can improve undergraduate nursing students' mental health clinical experience. 
27294197	Plasticity of the brain's dopamine system plays a crucial role in adaptive behavior by regulating appetitive motivation and the control of reinforcement learning. In this study, we investigated drug- and natural-reward conditioned behaviors in a mouse model in which the NMDA receptor-dependent plasticity of dopaminoceptive neurons was disrupted. We generated a transgenic mouse line with inducible selective inactivation of the NR1 subunit in neurons expressing dopamine D1 receptors (the NR1(D1CreERT2) mice). Whole-cell recordings of spontaneous EPSCs on neurons in the nucleus accumbens confirmed that a population of neurons lacked the NMDA receptor-dependent component of the current. This effect was accompanied by impaired long-term potentiation in the nucleus accumbens and in the CA1 area of the ventral, but not the dorsal, hippocampus. Mutant mice did not differ from control animals when tested for pavlovian or instrumental conditioning. However, NR1(D1CreERT2) mice acquired no preference for a context associated with administration of drugs of abuse. In the conditioned place preference paradigm, mutant mice did not spend more time in the context paired with cocaine, morphine, or ethanol, although these mice acquired a preference for sucrose jelly and an aversion to naloxone injections, as normal. Thus, we observed that the selective inducible ablation of the NMDA receptors specifically blocks drug-associated context memory with no effect on positive reinforcement in general. 
27292410	It is widely known that the catecholamine group is formed by dopamine, noradrenaline and adrenaline. Its synthesis is regulated by the enzyme called tyrosine hydroxylase. 3-hydroxytyramine/dopamine (DA) is a precursor of noradrenaline and adrenaline synthesis and acts as a neurotransmitter in the central nervous system. The three main nuclei, being the retrorubral field (A8 group), the substantia nigra pars compacta (A9 group) and the ventral tegmental area (A10 group), are arranged in the die-mesencephalic portion and are involved in three complex circuitries - the mesostriatal, mesolimbic and mesocortical pathways. These pathways are involved in behavioral manifestations, motricity, learning, reward and also in pathological conditions such as Parkinson's disease and schizophrenia. The aim of this study was to perform a morphological analysis of the A8, A9 and A10 groups in the common marmoset (Callithrix jacchus - a neotropical primate), whose morphological and functional characteristics support its suitability for use in biomedical research. Coronal sections of the marmoset brain were submitted to Nissl staining and TH-immunohistochemistry. The morphology of the neurons made it possible to subdivide the A10 group into seven distinct regions: interfascicular nucleus, raphe rostral linear nucleus and raphe caudal linear nucleus in the middle line; paranigral and parainterfascicular nucleus in the middle zone; the rostral portion of the ventral tegmental area nucleus and parabrachial pigmented nucleus located in the dorsolateral portion of the mesencephalic tegmentum. The A9 group was divided into four regions: substantia nigra compacta dorsal and ventral tiers; substantia nigra compacta lateral and medial clusters. No subdivisions were made for the A8 group. These results reveal that A8, A9 and A10 are phylogenetically stable across species. As such, further studies concerning such divisions are necessary in order to evaluate the occurrence of subdivisions that express DA in other primate species, with the aim of characterizing its functional relevance.
27289274	LVV-hemorphin 7 (LVVYPWTQRF; LVV-H7), an N-terminal fragment of the β-chain of hemoglobin cleaved by cathepsin D/pepsin, is an atypical endogenous opioid peptide that is found in high concentration in blood. LVV-H7 acts as a μ-opioid agonist and an inhibitor of insulin-regulated aminopeptidase. Subchronic administration of anabolic androgenic steroids (AAS) has been clinically proven to induce the synthesis of erythrocytes and increase hemoglobin concentrations. Patients with a history of AAS abuse are more susceptible to opioid abuse. We hypothesized that this association could be at least partially attributed to the sensitization of the mesocorticolimbic dopaminergic pathway by LVV-H7. Using the conditioned place preference test and neurochemical analysis, we investigated the possible mechanism underlying the effect of chronic nandrolone administration on morphine-induced reward and its correlation with LVV-H7 in rats. Either LVV-H7 may not sensitize the rewarding neural circuits or its inhibition on locomotor activity could mask reward-related behaviors. Chronic nandrolone pretreatment indeed caused a significant reward by low dose morphine, which did not cause any reward in control rats. However, coadministration of anti-LVV-H7 antiserum with nandrolone did not block this effect. This may rule out the possibility of the involvement of LVV-H7 in the action of nandrolone to intensify morphine-induced reward. Moreover, the serum level of LVV-H7 was mildly increased in response to chronic nandrolone administration in our animal model. According to the current clinical observations, we may conclude that the chronic administration of nandrolone can increase susceptibility to morphine dependence, but that this effect is not related to elevated LVV-H7.
27287793	This study aimed to evaluate the current sleep disorder status of nurses in general hospitals and analyze its influencing factors.A total of 2,033 nurses who have worked for 6 months in 3 general hospitals, namely, The First Affiliated Hospital of Harbin Medical University, The Second Affiliated Hospital of Harbin Medical University, and The Third Affiliated Hospital of Harbin Medical University, were selected by random sampling from April 2015 to November 2015 and investigated. The Effort-Reward Imbalance Questionnaire (ERI) and Job Content Questionnaire (JCQ) were applied to evaluate occupational stress. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep disorder status of the research subjects. Logistic regression analysis was adopted to determine the influencing factors of nurses' sleep disorders.	The average PSQI score of 2,003 research subjects is 7.26±3.56, including 860 subjects with PSQI ≥8, accounting for 42.9%. The female research subjects in the department of gynecology and obstetrics, emergency department, and ICU show high risks of sleep disorders (i.e., many years of working; job title: registered nurse; many times of night shift per month; no frequent exercise; many efforts and few rewards; high decision-making autonomy). Educational background and marital status did not exhibit statistical relevance with sleep disorders.	The sleep disorder status of nurses in general hospitals is closely related to occupational stress. As such, nurse managers should focus more attention to the influencing factors of nurses' sleep disorders and relieve their occupational stress to reduce the occurrence rate of sleep disorders.	
27287667	The purpose of this study was to evaluate the effectiveness of token reinforcement, using an ABAB reversal design, for increasing distance walked for adults with mild to moderate intellectual disabilities at an adult day-training center. Five participants earned tokens for walking 50-m laps and exchanged tokens for back-up reinforcers that had been identified through preference assessments. Token reinforcement resulted in a substantial increase from baseline in laps walked for 4 participants.
27284696	Decision-making is a flexible process dependent on the accumulation of various kinds of information; however, the corresponding neural mechanisms are far from clear. We extended a layered model of the frontal eye field to a learning-based model, using computational simulations to explain the cognitive process of choice tasks. The core of this extended model has three aspects: direction-preferred populations that cluster together the neurons with the same orientation preference, rule modules that control different rule-dependent activities, and reward-based synaptic plasticity that modulates connections to flexibly change the decision according to task demands. After repeated attempts in a number of trials, the network successfully simulated three decision choice tasks: an anti-saccade task, a no-go task, and an associative task. We found that synaptic plasticity could modulate the competition of choices by suppressing erroneous choices while enhancing the correct (rewarding) choice. In addition, the trained model captured some properties exhibited in animal and human experiments, such as the latency of the reaction time distribution of anti-saccades, the stop signal mechanism for canceling a reflexive saccade, and the variation of latency to half-max selectivity. Furthermore, the trained model was capable of reproducing the re-learning procedures when switching tasks and reversing the cue-saccade association. 
27284531	It has been suggested that positive psychotic symptoms reflect 'aberrant salience'. Previously we provided support for this hypothesis in first-episode schizophrenia patients, demonstrating that delusional symptoms were associated with aberrant reward processing, indexed by the Salience Attribution Test (SAT). Here we tested whether salience processing is abnormal in schizophrenia patients with long-standing treatment-refractory persistent delusions (TRS).Eighteen medicated TRS patients and 31 healthy volunteers completed the SAT, on which participants made a speeded response to earn money in the presence of cues. Each cue comprised two visual dimensions, colour and form. Reinforcement probability varied over one of these dimensions (task-relevant), but not the other (task-irrelevant).	Participants responded significantly faster on high-probability relative to low-probability trials, representing implicit adaptive salience; this effect was intact in TRS patients. By contrast, TRS patients were impaired on the explicit adaptive salience measure, rating high-probability stimuli less likely to be associated with reward than controls. There was little evidence for elevated aberrant salience in the TRS group.	These findings do not support the hypothesis that persistent delusions are related to aberrant motivational salience processing in TRS patients. However, they do support the view that patients with schizophrenia have impaired reward learning.	
27284278	Reversal learning has proven to be a valuable task in assessing the inhibitory process that is central to executive control. Psycho-stimulants and music are prevalent factors that influence cognition.The present study aimed at investigating the influences of dexamphetamine and music on inhibitory control.	This experimental study was conducted between May and June 2014 in the laboratory animal center of Shiraz University of Medical Sciences, Shiraz, Iran. Thirty mice were divided to five groups including a control group, a witness group, and three experimental groups. Food availability was restricted in order to maintain the subjects at 85% of their free-feeding body weight for behavioral testing. After discrimination learning, animals received four injections of 2 mg/kg dexamphetamine at two-hour intervals. The music group was exposed to music half an hour before reversal learning.	According to the results of the repeated measure analysis of variance (ANOVA), music increased errors (mean difference: -2.40, 95% CI: -3.59 to -1.22), yet dexamphetamine had no significant effect on reversal learning. Due to various advantages, we transited to the mixed model that showed increasing (Beta: 2.2 95% CI: 0.26 to 4.13) and borderline (Beta: 1.8 95% CI: -0.13 to 3.73) effects on the number of errors for dexamphetamine and music group, respectively.	Drug-treated subjects were impaired in their ability to modulate behavior, based upon changing information about stimulus-reward associations, possibly due to the inability to inhibit their response. These effects may have relevance to some mental disorders such as drug-abuse, schizophrenia, and obsessive-compulsive disorder.	
27284021	Sound is an invisible but powerful force that is central to everyday life. Studies in the neurobiology of everyday communication seek to elucidate the neural mechanisms underlying sound processing, their stability, their plasticity, and their links to language abilities and disabilities. This sound processing lies at the nexus of cognitive, sensorimotor, and reward networks. Music provides a powerful experimental model to understand these biological foundations of communication, especially with regard to auditory learning. We review studies of music training that employ a biological approach to reveal the integrity of sound processing in the brain, the bearing these mechanisms have on everyday communication, and how these processes are shaped by experience. Together, these experiments illustrate that music works in synergistic partnerships with language skills and the ability to make sense of speech in complex, everyday listening environments. The active, repeated engagement with sound demanded by music making augments the neural processing of speech, eventually cascading to listening and language. This generalization from music to everyday communications illustrates both that these auditory brain mechanisms have a profound potential for plasticity and that sound processing is biologically intertwined with listening and language skills. A new wave of studies has pushed neuroscience beyond the traditional laboratory by revealing the effects of community music training in underserved populations. These community-based studies reinforce laboratory work highlight how the auditory system achieves a remarkable balance between stability and flexibility in processing speech. Moreover, these community studies have the potential to inform health care, education, and social policy by lending a neurobiological perspective to their efficacy.
27283976	Studies on motor planning and action selection in object use reveal that what we choose to do in the present moment depends on our next planned action. In particular, many studies have shown that adult humans initially adopt uncomfortable hand postures to accommodate later task demands (i.e., the end-state comfort effect). Recent studies on action planning in different non-human primates species have provided contrasting results. Here, we tested whether capuchin monkeys (Sapajus spp.), natural tool users, would show planning abilities in two tasks with varying complexity: (i) an object-retrieval task involving self-directed actions (Experiment 1) and (ii) a tool-using task involving actions directed toward an external target (Experiment 2). In Experiment 1, six of 10 monkeys preferentially used a radial grip (i.e., with the thumb-side oriented towards the baited end) to grasp a horizontal dowel with either the left- or right-end baited and bring it to their mouth. In Experiment 2, all six tested capuchins preferentially used a radial grip (i.e., with the thumb-side oriented towards the center of the dowel) to grasp a dowel that was positioned horizontally at different orientations and to dislodge an out-of-reach food reward. Thus, we found that the capuchins showed second-order planning abilities in both tasks, but performance differences emerged in relation to hand preference and learning across sessions. Our findings support the idea that second-order motor planning occurred in an early stage of the primate lineage. Factors affecting the ability of nonhuman primates to estimate motor costs in action selection are discussed. 
27282865	GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics.Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17days (0.6mg for 7days, 1.2mg for 7days and 1.8mg for 3days) of treatment, we also studied changes in fMRI responses to food cues.	By design, to avoid any confounding by weight changes, subjects were studied for 17days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA.	We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that could over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials.	
27280962	Bipolar disorder (BD) is a severe mental illness that can have high costs for youths (<18 years old) and adults. Relative to healthy controls (HC), individuals with BD often show impaired attention, working memory, executive function, and cognitive flexibility (the ability to adapt to changing reward/punishment contingencies). In our study of youths and young adults with BD, we investigated 1) how cognitive flexibility varies developmentally in BD, and 2) whether it is independent of other executive function deficits associated with BD.We measured errors on a reversal-learning task, as well as spatial working memory and other executive function, among participants with BD (N=75) and HC (N=130), 7-27 years old. Regression analyses focused on the effects of diagnosis on reversal-learning errors, controlling for age, gender, IQ, spatial span, and executive function. Similar analyses examined non-reversal errors to rule out general task impairment.	Participants with BD, regardless of age, gender, or cognitive ability, showed more errors than HC on the response reversal stages of the cognitive flexibility task. However, participants with BD did not show more errors on non-reversal stages, even when controlling for other variables.	Study limitations include the cross-sectional, rather than longitudinal, design; inability to measure non-linear age effects; and inclusion of medicated participants and those with psychiatric comorbidity.	Individuals with BD show a specific impairment in reversing a previously rewarded response, which persists across the transition from childhood to young adulthood. Tailored interventions targeting this deficit may be effective throughout this developmentally turbulent time.	

27277868	Research on the neural substrates of drug reward, withdrawal and relapse has yet to be translated into significant advances in the treatment of addiction. One potential reason is that this research has not captured a common feature of human addiction: progressive social exclusion and marginalization. We propose that research aimed at understanding the neural mechanisms that link these processes to drug seeking and drug taking would help to make addiction neuroscience research more clinically relevant.
27277802	When conditions change, organisms need to learn about the changed conditions without interfering with what they already know. To do so, they can assign the new learning to a new "state" and the old learning to a previous state. This state assignment is fundamental to behavioral flexibility. Cholinergic interneurons (CINs) in the dorsomedial striatum (DMS) are necessary for associative information to be compartmentalized in this way, but the mechanism by which they do so is unknown. Here we addressed this question by recording putative CINs from the DMS in rats performing a task consisting of a series of trial blocks, or states, that required the recall and application of contradictory associative information. We found that individual CINs in the DMS represented the current state throughout each trial. These state correlates were not observed in dorsolateral striatal CINs recorded in the same rats. Notably, DMS CIN ensembles tracked rats' beliefs about the current state such that, when states were miscoded, rats tended to make suboptimal choices reflecting the miscoding. State information held by the DMS CINs also depended completely on the orbitofrontal cortex, an area that has been proposed to signal environmental states. These results suggest that CINs set the stage for recalling associative information relevant to the current environment by maintaining a real-time representation of the current state. Such a role has novel implications for understanding the neural basis of a variety of psychiatric diseases, such as addiction or anxiety disorders, in which patients generalize inappropriately (or fail to generalize) between different environments.Striatal cholinergic interneurons (CINs) are thought to be identical to tonically active neurons. These neurons have long been thought to have an important influence on striatal processing during reward-related learning. Recently, a more specific function for striatal CINs has been suggested, which is that they are necessary for striatal learning to be compartmentalized into different states as the state of the environment changes. Here we report that putative CINs appear to track rats' beliefs about which environmental state is current. We further show that this property of CINs depends on orbitofrontal cortex input and is correlated with choices made by rats. These findings could provide new insight into neuropsychiatric diseases that involve improper generalization between different contexts.	
27272616	The learning process involved in achieving brain self-regulation is presumed to be related to several factors, such as type of feedback, reward, mental imagery, duration of training, among others. Explicitly instructing participants to use mental imagery and monetary reward are common practices in real-time fMRI (rtfMRI) neurofeedback (NF), under the assumption that they will enhance and accelerate the learning process. However, it is still not clear what the optimal strategy is for improving volitional control. We investigated the differential effect of feedback, explicit instructions and monetary reward while training healthy individuals to up-regulate the blood-oxygen-level dependent (BOLD) signal in the supplementary motor area (SMA). Four groups were trained in a two-day rtfMRI-NF protocol: GF with NF only, GF,I with NF + explicit instructions (motor imagery), GF,R with NF + monetary reward, and GF,I,R with NF + explicit instructions (motor imagery) + monetary reward. Our results showed that GF increased significantly their BOLD self-regulation from day-1 to day-2 and GF,R showed the highest BOLD signal amplitude in SMA during the training. The two groups who were instructed to use motor imagery did not show a significant learning effect over the 2 days. The additional factors, namely motor imagery and reward, tended to increase the intersubject variability in the SMA during the course of training. Whole brain univariate and functional connectivity analyses showed common as well as distinct patterns in the four groups, representing the varied influences of feedback, reward, and instructions on the brain. Hum Brain Mapp 37:3153-3171, 2016. © 2016 Wiley Periodicals, Inc. 
27271505	Adaptation to sensorimotor transformations has received much attention in recent years. However, the role of motivation and its relation to the implicit and explicit processes underlying adaptation has been neglected thus far. Here, we examine the influence of extrinsic motivation on adaptation to a visuomotor rotation by way of providing financial incentives for accurate movements. Participants in the experimental group "bonus" received a defined amount of money for high end-point accuracy in a visuomotor rotation task; participants in the control group "no bonus" did not receive a financial incentive. Results showed better overall adaptation to the visuomotor transformation in participants who were extrinsically motivated. However, there was no beneficial effect of financial incentives on the implicit component, as assessed by the after-effects, and on separately assessed explicit knowledge. These findings suggest that the positive influence of financial incentives on adaptation is due to a component which cannot be measured by after-effects or by our test of explicit knowledge. A likely candidate is model-free learning based on reward-prediction errors, which could be enhanced by the financial bonuses. 

27270595	How does reward guide spatial attention during visual search? In the present study, we examine whether and how two types of reward information-magnitude and frequency-guide search behavior. Observers were asked to find a target among distractors in a search display to earn points. We manipulated multiple levels of value across the search display quadrants in two ways: For reward magnitude, targets appeared equally often in each quadrant, and the value of each quadrant was determined by the average points earned per target; for reward frequency, we varied how often the target appeared in each quadrant but held the average points earned per target constant across the quadrants. In Experiment 1, we found that observers were highly sensitive to the reward frequency information, and prioritized their search accordingly, whereas we did not find much prioritization based on magnitude information. In Experiment 2, we found that magnitude information for a nonspatial feature (color) could bias search performance, showing that the relative insensitivity to magnitude information during visual search is not generalized across all types of information. In Experiment 3, we replicated the negligible use of spatial magnitude information even when we used limited-exposure displays to incentivize the expression of learning. In Experiment 4, we found participants used the spatial magnitude information during a modified choice task-but again not during search. Taken together, these findings suggest that the visual search apparatus does not equally exploit all potential sources of spatial value information; instead, it favors spatial reward frequency information over spatial reward magnitude information. 
27263278	In the present paper usingthe method of delay discounting three groups of animals were discovered: a) those that at choice between immediate weak and delayed strong rewards have chosen an immediate reinforcement (high impulsive rats); b) those that were able to inhibit its own behavior and get the delayed reinforcement (low impulsive rats); and c) the rats with both types of reactions. In the water maze the different groups of rats did find a hidden platform for different time, swum various distance and with different speed. The differences however were significant only at overall comparison (for all days and trials) of the above mentioned parameters of the water maze learning. ANOVAs Group x Days, Group x Trials, and Groups x Days x Trials interactions were insignificant. The data obtained indicate that the difference between groups was appeared evidently due to the difference in general motor activity, rather than difference in their cognitive abilities assessed by reference and working memory tasks.
27263273	According to psychological research erotic images are evaluated in the context of positive emotions as the most intense, most associated with emotional arousal, among the variety of pleasant and unpleasant stimuli. However it is difficult to separate areas of the brain that are related to the general emotional process from the activity of the brain areas involved in neuronal representations of reward system. The purpose of this study was to determine differences in the brain activity using functional magnetic resonance imaging (fMRI) in male subjects in evaluating an intensity of pleasant images, including erotic, or unpleasant and neutral pictures. When comparing the condition with evaluation of the pleasant erotic images with conditions containing neutral or unpleasant stimuli, a significant activation was observed in the posterior cingulate cortex; the prefrontal cortex and the right globus pallidus. An increased activity of the right anterior central gyrus was observed in the conditions related to evaluation of pleasant and neutral stimuli. Thus, in the process of evaluating the intensity of emotional images of an erotic nature the active brain areas were related not only to neuronal representations of emotions, but also to motivations and control system of emotional arousal, which should be taken into account while using erotic pictures as intensive positive emotional stimuli.
27256354	The ability to adjust response strategies when faced with changes in the environment is critical for normal adaptive behavior. Such behavioral flexibility is compromised by experimental disruption of cortical GABAergic signaling, as well as in conditions such as schizophrenia and normal aging that are characterized by cortical hyperexcitability. The current studies were designed to determine whether stimulation of GABAergic signaling using the GABA(B) receptor agonist baclofen can facilitate behavioral flexibility.Male Fischer 344 rats were trained in a set-shifting task in which they learned to discriminate between two response levers to obtain a food reward. Correct levers were signaled in accordance with two distinct response rules (rule 1: correct lever signaled by a cue light; rule 2: correct lever signaled by its left/right position). The order of rule presentation varied, but they were always presented sequentially, with the trials and errors to reach criterion performance on the second (set shift) rule providing the measure of behavioral flexibility. Experiments determined the effects of the GABA(B) receptor agonist baclofen (intraperitoneal, 0, 1.0, 2.5, and 4.0 mg/kg) administered acutely before the shift to the second rule.	Baclofen enhanced set-shifting performance. Control experiments demonstrated that this enhancement was not simply due to improved discrimination learning, nor was it due to impaired recall of the initial discrimination rule.	The results demonstrate that baclofen can facilitate behavioral flexibility, suggesting that GABA(B) receptor agonists may have utility for treating behavioral dysfunction in neuropsychiatric disorders.	
27247404	When a person fails to obtain an expected reward from an object in the environment, they face a credit assignment problem: Did the absence of reward reflect an extrinsic property of the environment or an intrinsic error in motor execution? To explore this problem, we modified a popular decision-making task used in studies of reinforcement learning, the two-armed bandit task. We compared a version in which choices were indicated by key presses, the standard response in such tasks, to a version in which the choices were indicated by reaching movements, which affords execution failures. In the key press condition, participants exhibited a strong risk aversion bias; strikingly, this bias reversed in the reaching condition. This result can be explained by a reinforcement model wherein movement errors influence decision-making, either by gating reward prediction errors or by modifying an implicit representation of motor competence. Two further experiments support the gating hypothesis. First, we used a condition in which we provided visual cues indicative of movement errors but informed the participants that trial outcomes were independent of their actual movements. The main result was replicated, indicating that the gating process is independent of participants' explicit sense of control. Second, individuals with cerebellar degeneration failed to modulate their behavior between the key press and reach conditions, providing converging evidence of an implicit influence of movement error signals on reinforcement learning. These results provide a mechanistically tractable solution to the credit assignment problem.
27247125	We investigated a unique way in which adolescent peer influence occurs on social media. We developed a novel functional MRI (fMRI) paradigm to simulate Instagram, a popular social photo-sharing tool, and measured adolescents' behavioral and neural responses to likes, a quantifiable form of social endorsement and potential source of peer influence. Adolescents underwent fMRI while viewing photos ostensibly submitted to Instagram. They were more likely to like photos depicted with many likes than photos with few likes; this finding showed the influence of virtual peer endorsement and held for both neutral photos and photos of risky behaviors (e.g., drinking, smoking). Viewing photos with many (compared with few) likes was associated with greater activity in neural regions implicated in reward processing, social cognition, imitation, and attention. Furthermore, when adolescents viewed risky photos (as opposed to neutral photos), activation in the cognitive-control network decreased. These findings highlight possible mechanisms underlying peer influence during adolescence. 
27246576	This study investigated whether individual behavioural characteristics of piglets and stress induced by experience with humans can influence learning performance. After weaning, piglets received a chronic experience with humans to modulate their emotional state: rough (ROU), gentle (GEN), or minimal (MIN) experience. Simultaneously, they were trained on a discrimination task. Afterward, their behaviour during challenge tests was assessed. The first learning step of the task involved associating a positive sound cue with a response (approach a trough) and success of piglets depended mostly on motivation to seek for reward. Although the experience with humans did not have direct effect, the degree of fear of handler, measured based on their reactivity to a human approach test, was related to motivation to seek rewards and learning speed of this first step in stressed ROU piglets, but not in MIN and GEN piglets. In contrast, the second learning step was more cognitively challenging, since it involved discrimination learning, including negative cues during which piglets had to learn to avoid the trough. Locomotion activity, measured during an open-field test, was associated with performance of the discrimination learning. To conclude, fearfulness towards humans and locomotion activity are linked with learning performance in relation to task complexity, highlighting the necessity to take into account these factors in animal research and management. 
27245703	Stimuli associated with monetary reward can become powerful cues that effectively capture visual attention. We examined whether such value-driven attentional capture can be induced with monetary feedback in the absence of an expected cash payout. To this end, we implemented images of U.S. dollar bills as reward feedback. Participants knew in advance that they would not receive any money based on their performance. Our reward stimuli-$5 and $20 bill images-were thus dissociated from any practical utility. Strikingly, we observed a reliable attentional capture effect for the mere images of bills. Moreover, this finding generalized to Monopoly money. In two control experiments, we found no evidence in favor of nominal or symbolic monetary value. Hence, we claim that bill images are special monetary representations, such that there are strong associations between the defining visual features of bills and reward, probably due to a lifelong learning history. Together, we show that the motivation to earn cash plays a minor role when it comes to monetary rewards, while bill-defining visual features seem to be sufficient. These findings have the potential to influence human factor applications, such as gamification, and can be extended to novel value systems, such as the electronic cash Bitcoin being developed for use in mobile banking. Finally, our procedure represents a proof of concept on how images of money can be used to conserve expenditures in the experimental context. 
27242888	A central goal in understanding brain function is to link specific cell populations to behavioral outputs. In recent years, the selective targeting of specific neural circuits has been made possible with the development of new experimental approaches, including chemogenetics. This technique allows for the control of molecularly defined subsets of cells through engineered G protein-coupled receptors (GPCRs), which have the ability to activate or silence neuronal firing. Through chemogenetics, neural circuits are being linked to behavioral outputs at an unprecedented rate. Further, the coupling of chemogenetics with imaging techniques to monitor neural activity in freely moving animals now makes it possible to deconstruct the complex whole-brain networks that are fundamental to behavioral states. In this review, we highlight a specific chemogenetic application known as DREADDs (designer receptors exclusively activated by designer drugs). DREADDs are used ubiquitously to modulate GPCR activity in vivo and have been widely applied in the basic sciences, particularly in the field of behavioral neuroscience. Here, we focus on the impact and utility of DREADD technology in dissecting the neural circuitry of various behaviors including memory, cognition, reward, feeding, anxiety and pain. By using DREADDs to monitor the electrophysiological, biochemical, and behavioral outputs of specific neuronal types, researchers can better understand the links between brain activity and behavior. Additionally, DREADDs are useful in studying the pathogenesis of disease and may ultimately have therapeutic potential. 
27242574	Cocaine use disorder is associated with maladaptive decision-making behavior, which strongly contributes to the harmful consequences of chronic drug use. Prior research has shown that cocaine users exhibit impaired neuropsychological test performances, particularly with regard to attention, learning, and memory but also in executive functions such as decision-making and impulse control. However, to what extent cocaine users show impaired decision-making under risk without feedback has not yet been investigated systematically. Therefore, to examine risk-taking behavior, 31 chronic cocaine users and 26 stimulant-naïve healthy controls who were part of the Zurich Cocaine Cognition Study, performed the Randomized Lottery Task (RALT) with winning lotteries consisting of an uncertain and a certain prospect. Results revealed that risky decisions were associated with male sex, increased cocaine use in the past year, higher cocaine concentrations in the hair, and younger age. In addition, higher levels of cocaine in the hair and cumulative lifetime consumption were associated with risky decisions, whereas potentially confounding factors including cognition and psychiatric symptoms had no significant effect. Taken together, our results indicate that cocaine users who increased their consumption over a period of 1 year show deficits in the processing of risky information accompanied with increased risk-taking. Future research should analyse whether risky decisions could potentially serve as a prognostic marker for cocaine use disorder. 
27241710	Dopaminergic therapy improves some cognitive functions and worsens others in patients with Parkinson's disease (PD). These paradoxical effects are explained by the dopamine overdose hypothesis, which proposes that effects of dopaminergic therapy on a cognitive function is determined by the baseline dopamine levels in brain regions mediating that function.We directly tested this prevalent hypothesis, evaluating the effects of levodopa on stimulus-reward learning in healthy young adults, who presumably have optimal baseline dopamine levels and dopamine regulation.	Twenty-six healthy, young adults completed a probabilistic reversal learning task in a randomized, double-blind, placebo-controlled, crossover design. Participants completed one session on levodopa 100 mg/carbidopa 25 mg and another session on placebo.	We found that levodopa impaired reversal learning relative to placebo. Further analyses revealed that levodopa impaired learning from both punishment and reward.	Exogenous dopamine impairs stimulus-reward learning, independent of PD pathology and prior to sensitization through repeated exposure, in healthy adults with normal cognition and baseline dopamine function. Our findings support the dopamine overdose hypothesis and caution clinicians about detrimental effects of levodopa in all clinical populations (e.g., early PD, restless leg syndrome) regardless of baseline cognitive and dopaminergic system function.	
27238864	Projections from the lateral hypothalamus (LH) to the ventral tegmental area (VTA), containing both GABAergic and glutamatergic components, encode conditioned responses and control compulsive reward-seeking behavior. GABAergic neurons in the LH have been shown to mediate appetitive and feeding-related behaviors. Here we show that the GABAergic component of the LH-VTA pathway supports positive reinforcement and place preference, while the glutamatergic component mediates place avoidance. In addition, our results indicate that photoactivation of these projections modulates other behaviors, such as social interaction and perseverant investigation of a novel object. We provide evidence that photostimulation of the GABAergic LH-VTA component, but not the glutamatergic component, increases dopamine (DA) release in the nucleus accumbens (NAc) via inhibition of local VTA GABAergic neurons. Our study clarifies how GABAergic LH inputs to the VTA can contribute to generalized behavioral activation across multiple contexts, consistent with a role in increasing motivational salience. VIDEO ABSTRACT. 
27235078	The striatum has been involved in complex behaviors such as motor control, learning, decision-making, reward and aversion. The striatum is mainly composed of medium spiny neurons (MSNs), typically divided into those expressing dopamine receptor D1, forming the so-called direct pathway, and those expressing D2 receptor (indirect pathway). For decades it has been proposed that these two populations exhibit opposing control over motor output, and recently, the same dichotomy has been proposed for valenced behaviors. Whereas D1-MSNs mediate reinforcement and reward, D2-MSNs have been associated with punishment and aversion. In this review we will discuss pharmacological, genetic and optogenetic studies that indicate that there is still controversy to what concerns the role of striatal D1- and D2-MSNs in this type of behaviors, highlighting the need to reconsider the early view that they mediate solely opposing aspects of valenced behaviour. 
27234192	Schizophrenia involves marked motivational and learning deficits that may reflect abnormalities in reward processing. The purpose of this study was to examine positive and negative feedback sensitivity in schizophrenia using computational modeling derived from the Wisconsin Card Sorting Test (WCST). We also aimed to explore feedback sensitivity in a sample with bipolar disorder.Eighty-three individuals with schizophrenia and 27 with bipolar disorder were included. Demographic, clinical and cognitive outcomes, together with the WCST, were considered in both samples. Computational modeling was performed using the R syntax to calculate 3 parameters based on trial-by-trial execution on the WCST: reward sensitivity (R), punishment sensitivity (P), and choice consistency (D). The associations between outcome variables and the parameters were investigated.	Positive and negative sensitivity showed deficits, but P parameter was clearly diminished in schizophrenia. Cognitive variables, age, and symptoms were associated with R, P, and D parameters in schizophrenia. The sample with bipolar disorder would show cognitive deficits and feedback abnormalities to a lesser extent than individuals with schizophrenia.	Negative feedback sensitivity demonstrated greater deficit in both samples. Idiosyncratic cognitive requirements in the WCST might introduce confusion when supposing model-free reinforcement learning. Negative symptoms of schizophrenia were related to lower feedback sensitivity and less goal-directed patterns of choice.	
27234176	In spite of the revived interest in compulsive buying disorder (CBD), its classification into the contemporary nosologic systems continues to be debated, and scarce studies have addressed heterogeneity in the clinical phenotype through methodologies based on a person-centered approach.To identify empirical clusters of CBD employing personality traits, as well as patients' sex, age and the age of CBD onset as indicators.	An agglomerative hierarchical clustering method defining a combination of the Schwarz Bayesian Information Criterion and log-likelihood was used.	Three clusters were identified in a sample of n=110 patients attending a specialized CBD unit a) "male compulsive buyers" reported the highest prevalence of comorbid gambling disorder and the lowest levels of reward dependence; b) "female low-dysfunctional" mainly included employed women, with the highest level of education, the oldest age of onset, the lowest scores in harm avoidance and the highest levels of persistence, self-directedness and cooperativeness; and c) "female highly-dysfunctional" with the youngest age of onset, the highest levels of comorbid psychopathology and harm avoidance, and the lowest score in self-directedness.	Sociodemographic characteristics and personality traits can be used to determine CBD clusters which represent different clinical subtypes. These subtypes should be considered when developing assessment instruments, preventive programs and treatment interventions.	

27221149	Orienting biases refer to consistent, trait-like direction of attention or locomotion toward one side of space. Recent studies suggest that such hemispatial biases may determine how well people memorize information presented in the left or right hemifield. Moreover, lesion studies indicate that learning rewarded stimuli in one hemispace depends on the integrity of the contralateral striatum. However, the exact neural and computational mechanisms underlying the influence of individual orienting biases on reward learning remain unclear. Because reward-based behavioural adaptation depends on the dopaminergic system and prediction error (PE) encoding in the ventral striatum, we hypothesized that hemispheric asymmetries in dopamine (DA) function may determine individual spatial biases in reward learning. To test this prediction, we acquired fMRI in 33 healthy human participants while they performed a lateralized reward task. Learning differences between hemispaces were assessed by presenting stimuli, assigned to different reward probabilities, to the left or right of central fixation, i.e. presented in the left or right visual hemifield. Hemispheric differences in DA function were estimated through differential fMRI responses to positive vs. negative feedback in the left vs. right ventral striatum, and a computational approach was used to identify the neural correlates of PEs. Our results show that spatial biases favoring reward learning in the right (vs. left) hemifield were associated with increased reward responses in the left hemisphere and relatively better neural encoding of PEs for stimuli presented in the right (vs. left) hemifield. These findings demonstrate that trait-like spatial biases implicate hemisphere-specific learning mechanisms, with individual differences between hemispheres contributing to reinforcing spatial biases. 
27219099	Drug and alcohol abusers develop strong memories for drug-related stimuli. Preclinical studies suggest that such memories are a result of drug actions on reward pathways, which facilitate learning about drug-related stimuli. However, few controlled studies have investigated how drugs affect memory for drug-related stimuli in humans.The current study examined the direct effect of alcohol on memory for images of alcohol-related or neutral beverages. Participants received alcohol (0.8 g/kg) either before viewing visual images (encoding condition; n = 20) or immediately after viewing them (consolidation condition; n = 20). A third group received placebo both before and after viewing the images (control condition; n = 19). Memory retrieval was tested exactly 48 hours later, in a drug-free state.	Alcohol impaired memory in the encoding condition and enhanced memory in the consolidation condition, but these effects did not differ for alcohol-related and neutral beverage stimuli. However, in the encoding condition, participants who experienced greater alcohol-induced stimulation exhibited better memory for alcohol-related, but not neutral beverage stimuli.	These findings suggest that individual differences in sensitivity to the positive, rewarding effects of alcohol are associated with greater propensity to remember alcohol-related stimuli encountered while intoxicated. As such, stimulant responders may form stronger memory associations with alcohol-related stimuli, which might then influence their drinking behavior.	
27217105	The current study utilized resting-state functional magnetic resonance imaging (fMRI) to examine how two important non-cognitive skills, grit and growth mindset, are associated with cortico-striatal networks important for learning. Whole-brain seed-to-voxel connectivity was examined for dorsal and ventral striatal seeds. While both grit and growth mindset were associated with functional connectivity between ventral striatal and bilateral prefrontal networks thought to be important for cognitive-behavioral control. There were also clear dissociations between the neural correlates of the two constructs. Grit, the long-term perseverance towards a goal or set of goals, was associated with ventral striatal networks including connectivity to regions such as the medial prefrontal and rostral anterior cingulate cortices implicated in perseverance, delay and receipt of reward. Growth mindset, the belief that effort can improve talents, notably intelligence, was associated with both ventral and dorsal striatal connectivity with regions thought to be important for error-monitoring, such as dorsal anterior cingulate cortex. Our findings may help construct neurocognitive models of these non-cognitive skills and have critical implications for character education. Such education is a key component of social and emotional learning, ensuring that children can rise to challenges in the classroom and in life. 
27217103	GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the brain are known to have an important role in drug-associated learning and memory. Selective blockage of GluN2B-containing NMDA receptors (GluN2B-NMDARs) has been shown to impair morphine-induced conditioned place preference (CPP) without affecting natural reward-induced CPP. In the present study, GluN2B transgenic rats with over-expressed GluN2B-subunits in the forebrain were used to assess the susceptibility to CPP induced by morphine and natural rewards as well as to naloxone-induced conditioned place aversion (CPA). The results showed that GluN2B transgenic rats exhibited a relatively higher susceptibility to morphine-induced CPP and naloxone-induced CPA than their wild-type littermates did, while they retained the similar sensitivity as wild-type rats to CPP induced by natural reinforcers (food and sucrose). These findings suggest that increased level of GluN2B-NMDARs in forebrain facilitates formation of drug-related memory, but not that associated with natural rewards. GluN2B-NMDARs might be a potential target for the treatment of drug abuse. 
27214500	Prior research has demonstrated that sleep enhances memory for future-relevant information, including memory for information that is salient due to emotion, reward, or knowledge of a later memory test. Although sleep has been shown to prioritize information with any of these characteristics, the present study investigates the novel question of how sleep prioritizes information when multiple salience cues exist. Participants encoded scenes that were future-relevant based on emotion (emotional vs. neutral), reward (rewarded vs. unrewarded), and instructed learning (intentionally vs. incidentally encoded), preceding a delay consisting of a nap, an equivalent time period spent awake, or a nap followed by wakefulness (to control for effects of interference). Recognition testing revealed that when multiple dimensions of future relevance co-occur, sleep prioritizes top-down, goal-directed cues (instructed learning, and to a lesser degree, reward) over bottom-up, stimulus-driven characteristics (emotion). Further, results showed that these factors interact; the effect of a nap on intentionally encoded information was especially strong for neutral (relative to emotional) information, suggesting that once one cue for future relevance is present, there are diminishing returns with additional cues. Sleep may binarize information based on whether it is future-relevant or not, preferentially consolidating memory for the former category. Potential neural mechanisms underlying these selective effects and the implications of this research for educational and vocational domains are discussed. (PsycINFO Database Record 
27199791	Humor operates through a variety of techniques, which first generate surprise and then amusement and laughter once the unexpected incongruity is resolved. As different types of jokes use different techniques, the corresponding humor processes also differ. The present study builds on the framework of the 'tri-component theory of humor,' which details the mechanisms involved in cognition (comprehension), affect (appreciation), and laughter (expression). This study seeks to identify differences among joke types and between sexes/genders in the neural mechanisms underlying humor processing. Three types of verbal jokes, bridging-inference jokes (BJs), exaggeration jokes (EJs), and ambiguity jokes (AJs), were used as stimuli. The findings revealed differences in brain activity for an interaction between sex/gender and joke type. For BJs, women displayed greater activation in the temporoparietal-mesocortical-motor network than men, demonstrating the importance of the temporoparietal junction (TPJ) presumably for 'theory of mind' processing, the orbitofrontal cortex for motivational functions and reward coding, and the supplementary motor area for laughter. Women also showed greater activation than men in the frontal-mesolimbic network associated with EJs, including the anterior (frontopolar) prefrontal cortex (aPFC, BA 10) for executive control processes, and the amygdala and midbrain for reward anticipation and salience processes. Conversely, AJs elicited greater activation in men than women in the frontal-paralimbic network, including the dorsal prefrontal cortex (dPFC) and parahippocampal gyrus. All joke types elicited greater activation in the aPFC of women than of men, whereas men showed greater activation than women in the dPFC. To confirm the findings related to sex/gender differences, random group analysis and within group variance analysis were also performed. These findings help further establish the mechanisms underlying the processing of different joke types for the sexes/genders and provide a neural foundation for a theory of sex/gender differences in humor. 

27193188	Recent theoretical models underline reward sensitivity as a potential endophenotype for major depressive disorder. Neural and behavioral evidence reveals depression is associated with reduced reward sensitivity. However, reward dysfunction is not unique to depression, as it is also common across disorders of poor impulse control. We examined the interrelationships of depression (Depression, Anxiety, and Stress Scale [DASS-21]) and impulsivity (UPPS-P Impulsive Behavior Scale) with reward sensitivity among a large, representative sample (N = 260). ERPs were recorded to isolate two neural indicators of consummatory reward processing: initial evaluation of rewards in the 250-350 ms time window postonset of feedback (reward positivity [RewP]), and salience to monetary outcomes (P3). Significant interactions were observed between depression and impulsivity facets across these two stages of reward processing: depression and positive urgency predicted RewP amplitude to reward outcomes (win vs. loss); depression and one other impulsivity trait, (lack of) premeditation, predicted P3 amplitude to monetary outcomes. Conversely, high symptoms of depression were related to three biobehavioral profiles: (1) blunted RewP in conjunction with high positive urgency, (2) combination of blunted RewP and low (lack of) premeditation, and (3) blunted P3 to monetary wins/losses, in conjunction with low (lack of) premeditation. Findings illustrate that reward-related dysfunctions may be optimally conceptualized when examining the interactions between dimensions of internalizing and externalizing psychopathology. 
27191219	Working memory (WM) impacts a gamut of cognitive abilities, but implicit WM is typically not considered in assessment or treatment, which may explain the variability of results in reviews of WM training. The role of implicit WM in adaptive behavior is reviewed. All we do is action based. Explicit WM plays a major role when we are required to "think"; that is, when we apply previously learned perception-action linkages in new ways to unique situations. Implicit WM is involved in the automation of behavior, which occurs through interaction with cortical and subcortical systems that guide sensory-motor anticipation and the prediction of reward. This article reviews evidence that implicit WM interacts with cortical-cerebellar and cortical-basal ganglia connections to form perception-action linkages. The cerebellum forms an internal model of cortical WM, corrects the content of this internal model, and then projects the improved representation back to the cortex, where it is retained for future use. The basal ganglia also form an anticipatory system, controlling cortical access to WM by allowing or restricting the information that is released based on the probability of reward. This framework is applied to the assessment and treatment of individuals with WM deficits. The ability to automate behavior can be assessed through repeated trials of existing testing instruments, such as the Trails B and Stroop tasks. Application of skill learning emphasizing automation as an end goal offers a model for the development of new types of WM training. 
27190012	Adaptive behaviour entails the capacity to select actions as a function of their energy cost and expected value and the disruption of this faculty is now viewed as a possible cause of the symptoms of Parkinson's disease. Indirect evidence points to the involvement of the subthalamic nucleus-the most common target for deep brain stimulation in Parkinson's disease-in cost-benefit computation. However, this putative function appears at odds with the current view that the subthalamic nucleus is important for adjusting behaviour to conflict. Here we tested these contrasting hypotheses by recording the neuronal activity of the subthalamic nucleus of patients with Parkinson's disease during an effort-based decision task. Local field potentials were recorded from the subthalamic nucleus of 12 patients with advanced Parkinson's disease (mean age 63.8 years ± 6.8; mean disease duration 9.4 years ± 2.5) both OFF and ON levodopa while they had to decide whether to engage in an effort task based on the level of effort required and the value of the reward promised in return. The data were analysed using generalized linear mixed models and cluster-based permutation methods. Behaviourally, the probability of trial acceptance increased with the reward value and decreased with the required effort level. Dopamine replacement therapy increased the rate of acceptance for efforts associated with low rewards. When recording the subthalamic nucleus activity, we found a clear neural response to both reward and effort cues in the 1-10 Hz range. In addition these responses were informative of the subjective value of reward and level of effort rather than their actual quantities, such that they were predictive of the participant's decisions. OFF levodopa, this link with acceptance was weakened. Finally, we found that these responses did not index conflict, as they did not vary as a function of the distance from indifference in the acceptance decision. These findings show that low-frequency neuronal activity in the subthalamic nucleus may encode the information required to make cost-benefit comparisons, rather than signal conflict. The link between these neural responses and behaviour was stronger under dopamine replacement therapy. Our findings are consistent with the view that Parkinson's disease symptoms may be caused by a disruption of the processes involved in balancing the value of actions with their associated effort cost. 
27185487	Striatal dopamine (DA) plays a central role in reward-related learning and behavioral adaptation to changing environments. Recent studies suggest that rather than being broadcast as a uniform signal throughout the entire region, DA release dynamics diverge between different striatal regions. In a previous study, we showed that phasic DA release patterns in the ventromedial striatum (VMS) rapidly adapt during reversal learning. However, it is unknown how DA dynamics in the dorsolateral striatum (DLS) are modulated during such adaptive behavior. Here, we used fast-scan cyclic voltammetry to measure phasic DA release in the DLS during spatial reversal learning. In the DLS, we observed minor DA release after the onset of a visual cue signaling reward availability, followed by more pronounced DA release during more proximal reward cues (e.g., lever extension) and execution of the operant response (i.e., lever press), both in rewarded and non-rewarded trials. These release dynamics (minor DA after onset of the predictive visual cue, prominent DA during the operant response) did not change significantly during or following a reversal of response-reward contingencies. Notably, the DA increase to the lever press did not reflect a general signal related to the initiation of any motivated motor response, as we did not observe DA release when rats initiated nose pokes into the food receptacle during inter-trial intervals. This suggests that DA release in the DLS occurs selectively during the initiation and execution of a learned operant response. Together with our previous results obtained in the VMS, these findings reveal distinct phasic DA release patterns during adaptation of established behavior in DLS and VMS. The VMS DA signal, which is highly sensitive to reversal of response-reward contingences, may provide a teaching signal to guide reward-related learning and facilitate behavioral adaptation, whereas DLS DA may reflect a 'response execution signal' largely independent of outcome, that may be involved in initiation and energizing of operant behavior.
27184070	The reward positivity is a component of the human ERP elicited by feedback stimuli in trial-and-error learning and guessing tasks. A prominent theory holds that the reward positivity reflects a reward prediction error signal that is sensitive to outcome valence, being larger for unexpected positive events relative to unexpected negative events (Holroyd & Coles, 2002). Although the theory has found substantial empirical support, most of these studies have utilized either monetary or performance feedback to test the hypothesis. However, in apparent contradiction to the theory, a recent study found that unexpected physical punishments also elicit the reward positivity (Talmi, Atkinson, & El-Deredy, 2013). The authors of this report argued that the reward positivity reflects a salience prediction error rather than a reward prediction error. To investigate this finding further, in the present study participants navigated a virtual T maze and received feedback on each trial under two conditions. In a reward condition, the feedback indicated that they would either receive a monetary reward or not and in a punishment condition the feedback indicated that they would receive a small shock or not. We found that the feedback stimuli elicited a typical reward positivity in the reward condition and an apparently delayed reward positivity in the punishment condition. Importantly, this signal was more positive to the stimuli that predicted the omission of a possible punishment relative to stimuli that predicted a forthcoming punishment, which is inconsistent with the salience hypothesis. 
27184056	Recent research has shown that reward learning can modulate oculomotor and attentional capture by physically salient and task-irrelevant distractor stimuli, even when directing gaze to those stimuli is directly counterproductive to receiving reward. This value-modulated oculomotor capture effect may reflect biased competition in the oculomotor system, such that the relationship between a stimulus feature and reward enhances that feature's representation on an internal priority map. However, it is also possible that this effect is a result of reward reducing the threshold for a saccade to be made to salient items. Here, we demonstrate value-modulated oculomotor capture when two reward-associated distractor stimuli are presented simultaneously in the same search display. The influence of reward on oculomotor capture is found to be most prominent at the shortest saccade latencies. We conclude that the value-modulated oculomotor capture effect is a consequence of biased competition on the saccade priority map and cannot be explained by a general reduction in saccadic threshold. 
27181908	A non-reward attractor theory of depression is proposed based on the operation of the lateral orbitofrontal cortex and supracallosal cingulate cortex. The orbitofrontal cortex contains error neurons that respond to non-reward for many seconds in an attractor state that maintains a memory of the non-reward. The human lateral orbitofrontal cortex is activated by non-reward during reward reversal, and by a signal to stop a response that is now incorrect. Damage to the human orbitofrontal cortex impairs reward reversal learning. Not receiving reward can produce depression. The theory proposed is that in depression, this lateral orbitofrontal cortex non-reward system is more easily triggered, and maintains its attractor-related firing for longer. This triggers negative cognitive states, which in turn have positive feedback top-down effects on the orbitofrontal cortex non-reward system. Treatments for depression, including ketamine, may act in part by quashing this attractor. The mania of bipolar disorder is hypothesized to be associated with oversensitivity and overactivity in the reciprocally related reward system in the medial orbitofrontal cortex and pregenual cingulate cortex. 
27181060	Effective error-driven learning benefits from scaling of prediction errors to reward variability. Such behavioral adaptation may be facilitated by neurons coding prediction errors relative to the standard deviation (SD) of reward distributions. To investigate this hypothesis, we required participants to predict the magnitude of upcoming reward drawn from distributions with different SDs. After each prediction, participants received a reward, yielding trial-by-trial prediction errors. In line with the notion of adaptive coding, BOLD response slopes in the Substantia Nigra/Ventral Tegmental Area (SN/VTA) and ventral striatum were steeper for prediction errors occurring in distributions with smaller SDs. SN/VTA adaptation was not instantaneous but developed across trials. Adaptive prediction error coding was paralleled by behavioral adaptation, as reflected by SD-dependent changes in learning rate. Crucially, increased SN/VTA and ventral striatal adaptation was related to improved task performance. These results suggest that adaptive coding facilitates behavioral adaptation and supports efficient learning. 
27180319	Social defeat (SD) induces a long-lasting increase in the rewarding effects of psychostimulants measured using the self-administration and conditioned place procedures (CPP). However, little is known about the epigenetic changes induced by social stress and about their role in the increased response to the rewarding effects of psychostimulants. Considering that histone acetylation regulates transcriptional activity and contributes to drug-induced behavioral changes, we addressed the hypothesis that SD induces transcriptional changes by histone modifications associated with the acquisition of place conditioning. After a fourth defeat, H3(K9) acetylation was decreased in the hippocampus, while there was an increase of HAT and a decrease of HDAC levels in the cortex. Three weeks after the last defeat, mice displayed an increase in histone H4(K12) acetylation and an upregulation of histone acetyl transferase (HAT) activity in the hippocampus. In addition, H3(K4)me3, which is closely associated with transcriptional initiation, was also augmented in the hippocampus three weeks after the last defeat. Inhibition of HAT by curcumin (100mg/kg) before each SD blocked the increase in the conditioned reinforcing effects of 1mg/kg of cocaine, while inhibition of HDAC by valproic acid (500mg/kg) before social stress potentiated cocaine-induced CPP. Preference was reinstated when animals received a priming dose of 0.5mg/kg of cocaine, an effect that was absent in untreated defeated mice. These results suggest that the experience of SD induces chromatin remodeling, alters histone acetylation and methylation, and modifies the effects of cocaine on place conditioning. They also point to epigenetic mechanisms as potential avenues leading to new treatments for the long-term effects of social stress on drug addiction.
27179761	Steep discounting of delayed rewards is linked with a variety of unhealthy behaviors that contribute to the major causes of preventable death and disease. Growing evidence suggests that decreases in delay discounting contribute to healthier preferences. This study sought to provide preliminary evidence for the viability of developing a brief priming task to reduce delay discounting in a large, diverse group of individuals. Participants (n=1,122) were randomized to one of three conditions: Future Focus (FF), Present Focus (PF), and Non-Temporal Focus (NTF) intended respectively to decrease, increase, or have no effect on delay discounting. Participants then completed the Monetary Choice Questionnaire, a brief assessment of delay discounting rate. Participants randomized to FF exhibited significantly lower discounting rates than those randomized to PF or NTF conditions. Race, Hispanic background, social self-monitoring, education, and cigarette smoking also accounted for a significant amount of variance in the discounting model. These findings provide support for the development of a brief priming intervention that might be examined in clinical or public health contexts to decrease discounting and support healthy choices. 
27179526	Although the use of neuroimaging techniques has revealed much about the neural correlates of social decision making (SDM) in humans, it remains poorly understood how social stimuli are represented, and how social decisions are implemented at the neural level in humans and in other species. To address this issue, the establishment of novel animal paradigms allowing a broad spectrum of neurobiological causal manipulations and neurophysiological recordings provides an exciting tool to investigate the neural implementation of social valuation in the brain. Here, we discuss the potential of a rodent model, Rattus norvegicus, for the understanding of SDM and its neural underpinnings. Particularly, we consider recent data collected in a rodent prosocial choice task within a social reinforcement framework and discuss factors that could drive SDM in rodents.
27175986	Dysfunctional reward processing has long been considered an important feature of major depressive disorder (MDD). However, depression is a heterogeneous construct and the nature of this heterogeneity may contribute to some of the inconsistent empirical findings on reward dysfunction in MDD. The current study examined 1 source of heterogeneity, melancholic symptoms, and its association with reward processing. In individuals with MDD (N = 141) and MDD-free controls (N = 113), electroencephalogram (EEG) alpha asymmetry was measured during a behavioral reward task that probed reward anticipation. Melancholic depression was measured both categorically (Diagnostic and Statistical Manual of Mental Disorders [DSM] diagnosis) and dimensionally (Hamilton Endogenomorphy Scale [HES]). Results showed that a dimensional (and not categorical) definition of melancholia predicted reward processing, with higher melancholic symptoms predicting reduced reward anticipation. Importantly, the effects of melancholic symptoms on reduced reward anticipation remained above and beyond overall depression severity. These results suggest that dysfunctional reward processing may only be associated with melancholic symptoms, not depression in general. (PsycINFO Database Record
27175984	Individuals with schizophrenia have a diminished ability to use reward history to adaptively guide behavior. However, tasks traditionally used to assess such deficits often rely on multiple cognitive and neural processes, leaving etiology unresolved. In the current study, we adopted recent computational formalisms of reinforcement learning to distinguish between model-based and model-free decision-making in hopes of specifying mechanisms associated with reinforcement-learning dysfunction in schizophrenia. Under this framework, decision-making is model-free to the extent that it relies solely on prior reward history, and model-based if it relies on prospective information such as motivational state, future consequences, and the likelihood of obtaining various outcomes. Model-based and model-free decision-making was assessed in 33 schizophrenia patients and 30 controls using a 2-stage 2-alternative forced choice task previously demonstrated to discern individual differences in reliance on the 2 forms of reinforcement-learning. We show that, compared with controls, schizophrenia patients demonstrate decreased reliance on model-based decision-making. Further, parameter estimates of model-based behavior correlate positively with IQ and working memory measures, suggesting that model-based deficits seen in schizophrenia may be partially explained by higher-order cognitive deficits. These findings demonstrate specific reinforcement-learning and decision-making deficits and thereby provide valuable insights for understanding disordered behavior in schizophrenia. (PsycINFO Database Record
27175326	The prevalence of comorbid cannabis and tobacco use has been increasing among adolescents and adults and has been shown to be associated with a range of changes or deficits in physical, psychological and behavioral outcomes. Moreover, comorbid use has been shown to have a differential effect on the structure and function of the brain, especially as it relates to the reward circuitry and learning and memory. This interaction might be mediated by the involvement of the endocannabinoid system and alterations in dopamine signaling in regions associated with reward and cognitive functioning. While current findings demonstrate a differential effect of comorbid use on neurobiological and behavioral correlates compared with single substance use, additional studies are needed controlling for potential psychiatric comorbidities, age of onset of use and use of other substances. Understanding the neurobiological mechanisms associated with comorbid cannabis and tobacco use will be important in developing successful treatment outcomes in the future.
27175079	Decision-making is the process of forming preferences for possible options, selecting and executing actions, and evaluating the outcome. This study used the Iowa Gambling Task (IGT) and the Prospect Valence Learning (PVL) model to investigate deficits in risk-reward related decision-making in patients with chronic schizophrenia, and to identify decision-making processes that contribute to poor IGT performance in these patients.Thirty-nine patients with schizophrenia and 31 healthy controls participated. Decision-making was measured by total net score, block net scores, and the total number of cards selected from each deck of the IGT. PVL parameters were estimated with the Markov chain Monte Carlo sampling scheme in OpenBugs and BRugs, its interface to R, and the estimated parameters were analyzed with the Mann-Whitney U-test.	The schizophrenia group received significantly lower total net scores compared to the control group. In terms of block net scores, an interaction effect of group × block was observed. The block net scores of the schizophrenia group did not differ across the five blocks, whereas those of the control group increased as the blocks progressed. The schizophrenia group obtained significantly lower block net scores in the fourth and fifth blocks of the IGT and selected cards from deck D (advantageous) less frequently than the control group. Additionally, the schizophrenia group had significantly lower values on the utility-shape, loss-aversion, recency, and consistency parameters of the PVL model.	These results indicate that patients with schizophrenia experience deficits in decision-making, possibly due to failure in learning the expected value of each deck, and incorporating outcome experiences of previous trials into expectancies about options in the present trial.	
27174576	In 1990, Blum and associates provided the first confirmed genetic link between the DRD2 polymorphisms and alcoholism. This finding was based on an earlier conceptual framework, which served as a blueprint for their seminal genetic association discovery they termed "Brain Reward Cascade." These findings were followed by a new way of understanding all addictive behaviors (substance and non-substance) termed "Reward Deficiency Syndrome" (RDS). RDS incorporates a complex multifaceted array of inheritable behaviors that are polygenic.In this review article, we attempt to clarify these terms and provide a working model to accurately diagnose and treat these unwanted behaviors.	We are hereby proposing the development of a translational model we term "Reward Deficiency Solution System™" that incorporates neurogenetic testing and meso-limbic manipulation of a "hypodopaminergic" trait/state, which provides dopamine agonistic therapy (DAT) as well as reduced "dopamine resistance," while embracing "dopamine homeostasis."	The result is better recovery and relapse prevention, despite DNA antecedents, which could impact the recovery process and relapse. Understanding the commonality of mental illness will transform erroneous labeling based on symptomatology, into a genetic and anatomical etiology. WC: 184.	
27174440	We examined the effects of delayed reinforcement on the responding of individuals with intellectual disabilities. Three conditions were evaluated: (a) food reinforcement, (b) token reinforcement with a postsession exchange opportunity, and (c) token reinforcement with a posttrial exchange opportunity. Within each condition, we assessed responding given (a) a no-reinforcement baseline, (b) immediate reinforcement, and (c) delayed reinforcement, in which responses produced a reinforcer after 1 of 6 delays. Results suggest that delayed food produced greater response persistence than did delayed tokens.
27173430	Value-based action selection has been suggested to be realized in the corticostriatal local circuits through competition among neural populations. In this article, we review theoretical and experimental studies that have constructed and verified this notion, and provide new perspectives on how the local-circuit selection mechanisms implement reinforcement learning (RL) algorithms and computations beyond them. The striatal neurons are mostly inhibitory, and lateral inhibition among them has been classically proposed to realize "Winner-Take-All (WTA)" selection of the maximum-valued action (i.e., 'max' operation). Although this view has been challenged by the revealed weakness, sparseness, and asymmetry of lateral inhibition, which suggest more complex dynamics, WTA-like competition could still occur on short time scales. Unlike the striatal circuit, the cortical circuit contains recurrent excitation, which may enable retention or temporal integration of information and probabilistic "soft-max" selection. The striatal "max" circuit and the cortical "soft-max" circuit might co-implement an RL algorithm called Q-learning; the cortical circuit might also similarly serve for other algorithms such as SARSA. In these implementations, the cortical circuit presumably sustains activity representing the executed action, which negatively impacts dopamine neurons so that they can calculate reward-prediction-error. Regarding the suggested more complex dynamics of striatal, as well as cortical, circuits on long time scales, which could be viewed as a sequence of short WTA fragments, computational roles remain open: such a sequence might represent (1) sequential state-action-state transitions, constituting replay or simulation of the internal model, (2) a single state/action by the whole trajectory, or (3) probabilistic sampling of state/action. 
27171199	Socially-conveyed rules and instructions strongly shape expectations and emotions. Yet most neuroscientific studies of learning consider reinforcement history alone, irrespective of knowledge acquired through other means. We examined fear conditioning and reversal in humans to test whether instructed knowledge modulates the neural mechanisms of feedback-driven learning. One group was informed about contingencies and reversals. A second group learned only from reinforcement. We combined quantitative models with functional magnetic resonance imaging and found that instructions induced dissociations in the neural systems of aversive learning. Responses in striatum and orbitofrontal cortex updated with instructions and correlated with prefrontal responses to instructions. Amygdala responses were influenced by reinforcement similarly in both groups and did not update with instructions. Results extend work on instructed reward learning and reveal novel dissociations that have not been observed with punishments or rewards. Findings support theories of specialized threat-detection and may have implications for fear maintenance in anxiety. 
27170428	Dysfunctional reward processing is known to play a central role for the development of psychiatric disorders. Glucocorticoids that are secreted in response to stress have been shown to attenuate reward sensitivity and thereby might promote the onset of psychopathology. However, the underlying neurobiological mechanisms mediating stress hormone effects on reward processing as well as potential sex differences remain elusive. In this neuroimaging study, we administered 30mg cortisol or a placebo to 30 men and 30 women and subsequently tested them in the Monetary Incentive Delay Task. Cortisol attenuated anticipatory neural responses to a verbal and a monetary reward in the left pallidum and the right anterior parahippocampal gyrus. Furthermore, in men, activation in the amygdala, the precuneus, the anterior cingulate, and in hippocampal regions was reduced under cortisol, whereas in cortisol-treated women a signal increase was observed in these regions. Behavioral performance also indicated that reward learning in men is impaired under high cortisol concentrations, while it is augmented in women. These findings illustrate that the stress hormone cortisol substantially diminishes reward anticipation and provide first evidence that cortisol effects on the neural reward system are sensitive to sex differences, which might translate into different vulnerabilities for psychiatric disorders. 
27169834	Short-chain fatty acids (SCFAs), metabolites produced through the microbial fermentation of nondigestible dietary components, have key roles in energy homeostasis. Animal research suggests that colon-derived SCFAs modulate feeding behavior via central mechanisms. In humans, increased colonic production of the SCFA propionate acutely reduces energy intake. However, evidence of an effect of colonic propionate on the human brain or reward-based eating behavior is currently unavailable.We investigated the effect of increased colonic propionate production on brain anticipatory reward responses during food picture evaluation. We hypothesized that elevated colonic propionate would reduce both reward responses and ad libitum energy intake via stimulation of anorexigenic gut hormone secretion.	In a randomized crossover design, 20 healthy nonobese men completed a functional magnetic resonance imaging (fMRI) food picture evaluation task after consumption of control inulin or inulin-propionate ester, a unique dietary compound that selectively augments colonic propionate production. The blood oxygen level-dependent (BOLD) signal was measured in a priori brain regions involved in reward processing, including the caudate, nucleus accumbens, amygdala, anterior insula, and orbitofrontal cortex (n = 18 had analyzable fMRI data).	Increasing colonic propionate production reduced BOLD signal during food picture evaluation in the caudate and nucleus accumbens. In the caudate, the reduction in BOLD signal was driven specifically by a lowering of the response to high-energy food. These central effects were partnered with a decrease in subjective appeal of high-energy food pictures and reduced energy intake during an ad libitum meal. These observations were not related to changes in blood peptide YY (PYY), glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations.	
27166166	We have an incomplete picture of how the brain links object representations to reward value, and how this information is stored and later retrieved. The orbitofrontal cortex (OFC), medial frontal cortex (MFC), and ventrolateral prefrontal cortex (VLPFC), together with the amygdala, are thought to play key roles in these processes. There is an apparent discrepancy, however, regarding frontal areas thought to encode value in macaque monkeys versus humans. To address this issue, we used fMRI in macaque monkeys to localize brain areas encoding recently learned image values. Each week, monkeys learned to associate images of novel objects with a high or low probability of water reward. Areas responding to the value of recently learned reward-predictive images included MFC area 10 m/32, VLPFC area 12, and inferior temporal visual cortex (IT). The amygdala and OFC, each thought to be involved in value encoding, showed little such effect. Instead, these 2 areas primarily responded to visual stimulation and reward receipt, respectively. Strong image value encoding in monkey MFC compared with OFC is surprising, but agrees with results from human imaging studies. Our findings demonstrate the importance of VLPFC, MFC, and IT in representing the values of recently learned visual images.
27164607	Learning from demonstrations is a paradigm by which an apprentice agent learns a control policy for a dynamic environment by observing demonstrations delivered by an expert agent. It is usually implemented as either imitation learning (IL) or inverse reinforcement learning (IRL) in the literature. On the one hand, IRL is a paradigm relying on the Markov decision processes, where the goal of the apprentice agent is to find a reward function from the expert demonstrations that could explain the expert behavior. On the other hand, IL consists in directly generalizing the expert strategy, observed in the demonstrations, to unvisited states (and it is therefore close to classification, when there is a finite set of possible decisions). While these two visions are often considered as opposite to each other, the purpose of this paper is to exhibit a formal link between these approaches from which new algorithms can be derived. We show that IL and IRL can be redefined in a way that they are equivalent, in the sense that there exists an explicit bijective operator (namely, the inverse optimal Bellman operator) between their respective spaces of solutions. To do so, we introduce the set-policy framework that creates a clear link between the IL and the IRL. As a result, the IL and IRL solutions making the best of both worlds are obtained. In addition, it is a unifying framework from which existing IL and IRL algorithms can be derived and which opens the way for the IL methods able to deal with the environment's dynamics. Finally, the IRL algorithms derived from the set-policy framework are compared with the algorithms belonging to the more common trajectory-matching family. Experiments demonstrate that the set-policy-based algorithms outperform both the standard IRL and IL ones and result in more robust solutions.
27163585	Besides motor function, the basal ganglia have been implicated in feedback learning. In patients with chronic basal ganglia infarcts, deficits in reward-based reversal learning have previously been described.We re-examined the acquisition and reversal of stimulus-stimulus-reward associations and acquired equivalence in eleven patients with acute basal ganglia stroke (8 men, 3 women; 57.8±13.3 years), whose performance was compared eleven healthy subjects of comparable age, sex distribution and education, who were recruited outside the hospital. Eleven hospitalized patients with a similar vascular risk profile as the stroke patients but without stroke history served as clinical control group.	In a neuropsychological assessment 7±3 days post-stroke, verbal and spatial short-term and working memory and inhibition control did not differ between groups. Compared with healthy subjects, control patients with vascular risk factors exhibited significantly reduced performance in the reversal phase (F[2,30] = 3.47; p = 0.044; post-hoc comparison between risk factor controls and healthy controls: p = 0.030), but not the acquisition phase (F[2,30] = 1.01; p = 0.376) and the acquired equivalence (F[2,30] = 1.04; p = 0.367) tasks. In all tasks, the performance of vascular risk factor patients closely resembled that of basal ganglia stroke patients. Correlation studies revealed a significant association of the number of vascular risk factors with reversal learning (r = -0.33, p = 0.012), but not acquisition learning (r = -0.20, p = 0.121) or acquired equivalence (r = -0.22, p = 0.096).	The previously reported impairment of reward-based learning may be attributed to vascular risk factors and associated diseases, which are enriched in stroke patients. This study emphasizes the necessity of appropriate control subjects in cognition studies.	
27163379	Principles of negative reinforcement learning may play a critical role in the etiology and treatment of depression. We examined the integrity of positive reinforcement learning in congenitally helpless (cH) rats, an animal model of depression, using a random ratio schedule and a devaluation-extinction procedure. Furthermore, we tested whether an antidepressant dose of the monoamine oxidase (MAO)-B inhibitor deprenyl would reverse any deficits in positive reinforcement learning. We found that cH rats (n=9) were impaired in the acquisition of even simple operant contingencies, such as a fixed interval (FI) 20 schedule. cH rats exhibited no apparent deficits in appetite or reward sensitivity. They reacted to the devaluation of food in a manner consistent with a dose-response relationship. Reinforcer motivation as assessed by lever pressing across sessions with progressively decreasing reward probabilities was highest in congenitally non-helpless (cNH, n=10) rats as long as the reward probabilities remained relatively high. cNH compared to wild-type (n=10) rats were also more resistant to extinction across sessions. Compared to saline (n=5), deprenyl (n=5) reduced the duration of immobility of cH rats in the forced swimming test, indicative of antidepressant effects, but did not restore any deficits in the acquisition of a FI 20 schedule. We conclude that positive reinforcement learning was impaired in rats bred for helplessness, possibly due to motivational impairments but not deficits in reward sensitivity, and that deprenyl exerted antidepressant effects but did not reverse the deficits in positive reinforcement learning. 
27162098	Theta oscillations in the electroencephalogram (EEG) are associated with learning and behavioral adaptation.To investigate the effects of theta transcranial alternating current stimulation (tACS) applied to the frontal cortex on reversal learning.	Healthy volunteers participated in a sham-controlled between subjects design. TACS at 1 mA peak-to-peak was administered during a reward-punishment reversal learning task. Resting state EEG was measured before and after tACS and the task.	Active tACS improved learning ability, but at the same time interfered with applying the rule to optimize behavior. Furthermore, a significant decrease in frontal theta-beta EEG ratios was observed following active tACS.	Results provide behavioral and electrophysiological evidence for influencing reversal learning with exogenous oscillatory electric field potentials applied to the frontal cortex.	
27160060	Reward has repeatedly been shown to influence cognitive control. More precisely, performance contingent reward is known to increase preparatory, proactive control. In comparison, performance non-contingent reward, that is, reward that is not dependent on a pre-specified performance criterion but is given unconditional for any response, even errors, is a rather understudied topic. Recently, Fröber and Dreisbach (2014) compared performance contingent and non-contingent reward in a single experiment. They found that non-contingent reward seems to modulate cognitive control in an oppositional way than contingent reward, namely by reducing proactive control. In the present paper, the authors further investigate this dissociation in two experiments with a reward manipulation that facilitated adaptations to changes in reward availability: reward - with performance contingency varying between subjects - was manipulated not trial-by-trial but in mini-blocks of 20 consecutive trials in an AX-Continuous Performance Task. Performance contingent reward significantly increased proactive control. The repeated experience of non-contingent reward even for errors did not result in increased error rates, but instead was indicative of stable compliance with task rules over time and with less reliance on proactive control. 
27150924	Childhood maltreatment, which markedly increases risks for psychopathology, is associated with structural and functional brain differences. Especially, exposure to parental verbal abuse (PVA) or interparental violence during childhood is associated with negative outcomes such as depression, posttraumatic stress disorder (PTSD), and reduced cognitive abilities. Other forms of childhood maltreatment have been associated with brain structure or developmental alteration. Our earlier studies elucidated potential discernible effects of PVA and witnessing domestic violence during childhood on brain morphology, including gray matter volume or cortical thickness. Brain regions that process and convey the adverse sensory input of the abuse might be modified specifically by such experiences, particularly in subjects exposed to a single type of maltreatment. Exposure to multiple types of maltreatment is more commonly associated with morphological alterations in the corticolimbic regions. These findings fit with preclinical studies showing that sensory cortices are highly plastic structures. Using tasks with high and low monetary rewards while subjects underwent functional MRI, we also examined whether neural activity during reward processing was altered, or not, in children and adolescents with reactive attachment disorder (RAD). Significantly reduced activity in the caudate and nucleus accumbens was observed during a high monetary reward condition in the RAD group compared to the typically developed group. The striatal neural reward activity in the RAD group was also markedly decreased. The present results suggest that dopaminergic dysfunction occurred in the striatum in children and adolescents with RAD, potentially leading to a future risk of psychiatric disorders such as dependence. 
27150400	Although it is challenging for individuals with cocaine addiction to achieve abstinence, the greatest difficulty is avoiding relapse to drug taking, which is often triggered by cues associated with prior cocaine use. This vulnerability to relapse persists for long periods (months to years) after abstinence is achieved. Here, I discuss rodent studies of cue-induced cocaine craving during abstinence, with a focus on neuronal plasticity in the reward circuitry that maintains high levels of craving. Such work has the potential to identify new therapeutic targets and to further our understanding of experience-dependent plasticity in the adult brain under normal circumstances and in the context of addiction.
27149935	Although the impact of dopamine on reward learning is well documented, its influence on other aspects of behavior remains the subject of much ongoing work. Dopaminergic drugs are known to increase risk-taking behavior, but the underlying mechanisms for this effect are not clear. We probed dopamine's role by examining the effect of its precursor L-DOPA on the choices of healthy human participants in an experimental paradigm that allowed particular components of risk to be distinguished. We show that choice behavior depended on a baseline (ie, value-independent) gambling propensity, a gambling preference scaling with the amount/variance, and a value normalization factor. Boosting dopamine levels specifically increased just the value-independent baseline gambling propensity, leaving the other components unaffected. Our results indicate that the influence of dopamine on choice behavior involves a specific modulation of the attractiveness of risky options-a finding with implications for understanding a range of reward-related psychopathologies including addiction. 
27148628	Cognitive control covers a broad range of cognitive functions, but its research and theories typically remain tied to a single domain. Here we outline and review an associative learning perspective on cognitive control in which control emerges from associative networks containing perceptual, motor, and goal representations. Our review identifies 3 trending research themes that are shared between the domains of conflict adaptation, task switching, response inhibition, and attentional control: Cognitive control is context-specific, can operate in the absence of awareness, and is modulated by reward. As these research themes can be envisaged as key characteristics of learning, we propose that their joint emergence across domains is not coincidental but rather reflects a (latent) growth of interest in learning-based control. Associative learning has the potential for providing broad-scaled integration to cognitive control theory, and offers a promising avenue for understanding cognitive control as a self-regulating system without postulating an ill-defined set of homunculi. We discuss novel predictions, theoretical implications, and immediate challenges that accompany an associative learning perspective on cognitive control. (PsycINFO Database Record 
27147653	Most real-life cues exhibit certain inherent values that may interfere with or facilitate the acquisition of new expected values during associative learning. In particular, when inherent and acquired values are congruent, learning may progress more rapidly. Here we investigated such an influence through a 2 × 2 factorial design, using attractiveness (high/low) of the facial picture as a proxy for the inherent value of the cue and its reward probability (high/low) as a surrogate for the acquired value. Each picture was paired with a monetary win or loss either congruently or incongruently. Behavioral results from 32 human participants indicated both faster response time and faster learning rate for value-congruent cue-outcome pairings. Model-based fMRI analysis revealed a fractionation of reinforcement learning (RL) signals in the ventral striatum, including a strong and novel correlation between the cue-specific decaying learning rate and BOLD activity in the ventral caudate. Additionally, we detected a functional link between neural signals of both learning rate and reward prediction error in the ventral striatum, and the signal of expected value in the ventromedial prefrontal cortex, showing a novel confirmation of the mathematical RL model via functional connectivity.Most real-world decisions require the integration of inherent value and sensitivity to outcomes to facilitate adaptive learning. Inherent value is drawing increasing interest from decision scientists because it influences decisions in contexts ranging from advertising to investing. This study provides novel insight into how inherent value influences the acquisition of new expected value during associative learning. Specifically, we find that the congruence between the inherent value and the acquired reward influences the neural coding of learning rate. We also show for the first time that neuroimaging signals coding the learning rate, prediction error, and acquired value follow the multiplicative Rescorla-Wagner learning rule, a finding predicted by reinforcement learning theory.	
27146401	Disorders of behavioral regulation, including attention deficit hyperactivity disorder (ADHD) and drug addiction, are in part due to poor inhibitory control, attentional deficits, and hyper-responsivity to reward-associated cues.To determine whether these traits are related, we tested genetically variable male and female heterogeneous stock rats in the choice reaction time (CRT) task and Pavlovian conditioned approach (PavCA). Sex differences in the response to methylphenidate during the CRT were also assessed.	In the CRT task, rats were required to withhold responding until one of two lights indicated whether responses into a left or right port would be reinforced with water. Reaction time on correct trials and premature responses were the operational definitions of attention and response inhibition, respectively. Rats were also pretreated with oral methylphenidate (0, 2, 4 mg/kg) during the CRT task to determine whether this drug would improve performance. Subsequently, during PavCA, presentation of an illuminated lever predicted the delivery of a food pellet into a food-cup. Lever-directed approach (sign-tracking) and food-cup approach (goal-tracking) were the primary measures, and rats were categorized as "sign-trackers" and "goal-trackers" using an index based on these measures.	Sign-trackers made more premature responses than goal-trackers but showed no differences in reaction time. There were sex differences in both tasks, with females having higher sign-tracking, completing more CRT trials, and making more premature responses after methylphenidate administration.	These results indicate that response inhibition is related to reward-cue responsivity, suggesting that these traits are influenced by common genetic factors.	
27146018	The taste cortex in the anterior insula provides separate and combined representations of the taste, temperature, and texture of food in the mouth independently of hunger and thus of reward value and pleasantness. One synapse on, in the orbitofrontal cortex, these sensory inputs are combined by associative learning with olfactory and visual inputs for some neurons, and these neurons encode food reward value in that they respond to food only when hunger is present and in that activations correlate linearly with subjective pleasantness. Cognitive factors, including word-level descriptions and selective attention to affective value, modulate the representation of the reward value of taste, olfactory, and flavor stimuli in the orbitofrontal cortex and a region to which it projects, the anterior cingulate cortex. These food reward representations are important in the control of appetite and food intake. Individual differences in reward representations may contribute to obesity, and there are age-related differences in these reward representations. Implications of how reward systems in the brain operate for understanding, preventing, and treating obesity are described. 
27145766	It has been questioned that the more than 300 mental disorders currently listed in international disease classification systems all have a distinct neurobiological correlate. Here, we support the idea that basic dimensions of mental dysfunctions, such as alterations in reinforcement learning, can be identified, which interact with individual vulnerability and psychosocial stress factors and, thus, contribute to syndromes of distress across traditional nosological boundaries. We further suggest that computational modeling of learning behavior can help to identify specific alterations in reinforcement-based decision-making and their associated neurobiological correlates. For example, attribution of salience to drug-related cues associated with dopamine dysfunction in addiction can increase habitual decision-making via promotion of Pavlovian-to-instrumental transfer as indicated by computational modeling of the effect of Pavlovian-conditioned stimuli (here affectively positive or alcohol-related cues) on instrumental approach and avoidance behavior. In schizophrenia, reward prediction errors can be modeled computationally and associated with functional brain activation, thus revealing reduced encoding of such learning signals in the ventral striatum and compensatory activation in the frontal cortex. With respect to negative mood states, it has been shown that both reduced functional activation of the ventral striatum elicited by reward-predicting stimuli and stress-associated activation of the hypothalamic-pituitary-adrenal axis in interaction with reduced serotonin transporter availability and increased amygdala activation by aversive cues contribute to clinical depression; altogether these observations support the notion that basic learning mechanisms, such as Pavlovian and instrumental conditioning and Pavlovian-to-instrumental transfer, represent a basic dimension of mental disorders that can be mechanistically characterized using computational modeling and associated with specific clinical syndromes across established nosological boundaries. Instead of pursuing a narrow focus on single disorders defined by clinical tradition, we suggest that neurobiological research should focus on such basic dimensions, which can be studied in and compared among several mental disorders. 

27138112	Identifying mechanisms through which individual differences in reward learning emerge offers an opportunity to understand both a fundamental form of adaptive responding as well as etiological pathways through which aberrant reward learning may contribute to maladaptive behaviors and psychopathology. One candidate mechanism through which individual differences in reward learning may emerge is variability in dopaminergic reinforcement signaling. A common functional polymorphism within the catechol-O-methyl transferase gene (COMT; rs4680, Val(158) Met) has been linked to reward learning, where homozygosity for the Met allele (linked to heightened prefrontal dopamine function and decreased dopamine synthesis in the midbrain) has been associated with relatively increased reward learning. Here, we used a probabilistic reward learning task to asses response bias, a behavioral form of reward learning, across three separate samples that were combined for analyses (age: 21.80 ± 3.95; n = 392; 268 female; European-American: n = 208). We replicate prior reports that COMT rs4680 Met allele homozygosity is associated with increased reward learning in European-American participants (β = 0.20, t = 2.75, P < 0.01; ΔR(2) = 0.04). Moreover, a meta-analysis of 4 studies, including the current one, confirmed the association between COMT rs4680 genotype and reward learning (95% CI -0.11 to -0.03; z = 3.2; P < 0.01). These results suggest that variability in dopamine signaling associated with COMT rs4680 influences individual differences in reward which may potentially contribute to psychopathology characterized by reward dysfunction.
27137964	Anorexia nervosa (AN) is a disorder characterized by restricted eating, fears of gaining weight, and body image distortions. The etiology remains unknown; however impairments in social cognition and reward circuits contribute to the onset and maintenance of the disorder. One possibility is that AN is associated with reduced perceived pleasantness during social interactions. We therefore examined the perception of interpersonal, 'affective touch' and its social modulation in AN. We measured the perceived pleasantness of light, dynamic stroking touches applied to the forearm of 25 AN patients and 30 healthy controls using C Tactile (CT) afferents-optimal (3cm/s) and non-optimal (18cm/s) velocities, while simultaneously displaying images of faces showing rejecting, neutral and accepting expressions. CT-optimal touch, but not CT non-optimal touch, elicited significantly lower pleasantness ratings in AN patients compared with healthy controls. Pleasantness ratings were modulated by facial expressions in both groups in a similar fashion; namely, presenting socially accepting faces increased the perception of touch pleasantness more than neutral and rejecting faces. Our findings suggest that individuals with AN have a disordered, CT-based affective touch system. This impairment may be linked to their weakened interoceptive perception and distorted body representation.
27136677	Adaptive decision-making uses information gained when exploring alternative options to decide whether to update the current choice strategy. Magnocellular mediodorsal thalamus (MDmc) supports adaptive decision-making, but its causal contribution is not well understood. Monkeys with excitotoxic MDmc damage were tested on probabilistic three-choice decision-making tasks. They could learn and track the changing values in object-reward associations, but they were severely impaired at updating choices after reversals in reward contingencies or when there were multiple options associated with reward. These deficits were not caused by perseveration or insensitivity to negative feedback though. Instead, monkeys with MDmc lesions exhibited an inability to use reward to promote choice repetition after switching to an alternative option due to a diminished influence of recent past choices and the last outcome to guide future behavior. Together, these data suggest MDmc allows for the rapid discovery and persistence with rewarding options, particularly in uncertain or changing environments. 
27135927	For goal-directed behaviour it is critical that we can both select the appropriate action and learn to modify the underlying movements (for example, the pitch of a note or velocity of a reach) to improve outcomes. The basal ganglia are a critical nexus where circuits necessary for the production of behaviour, such as the neocortex and thalamus, are integrated with reward signalling to reinforce successful, purposive actions. The dorsal striatum, a major input structure of basal ganglia, is composed of two opponent pathways, direct and indirect, thought to select actions that elicit positive outcomes and suppress actions that do not, respectively. Activity-dependent plasticity modulated by reward is thought to be sufficient for selecting actions in the striatum. Although perturbations of basal ganglia function produce profound changes in movement, it remains unknown whether activity-dependent plasticity is sufficient to produce learned changes in movement kinematics, such as velocity. Here we use cell-type-specific stimulation in mice delivered in closed loop during movement to demonstrate that activity in either the direct or indirect pathway is sufficient to produce specific and sustained increases or decreases in velocity, without affecting action selection or motivation. These behavioural changes were a form of learning that accumulated over trials, persisted after the cessation of stimulation, and were abolished in the presence of dopamine antagonists. Our results reveal that the direct and indirect pathways can each bidirectionally control movement velocity, demonstrating unprecedented specificity and flexibility in the control of volition by the basal ganglia.
27133871	Many animals, including insects, make decisions using both personally gathered information and social information derived from the behavior of other, usually conspecific, individuals [1]. Moreover, animals adjust use of social versus personal information appropriately under a variety of experimental conditions [2-5]. An important factor in how information is used is the information's reliability, that is, how consistently the information is correlated with something of relevance in the environment [6]. The reliability of information determines which signals should be attended to during communication [6-9], which types of stimuli animals should learn about, and even whether learning should evolve [10, 11]. Here, we show that bumble bees (Bombus impatiens) account for the reliability of personally acquired information (which flower color was previously associated with reward) and social information (which flowers are chosen by other bees) in making foraging decisions; however, the two types of information are not treated equally. Bees prefer to use social information if it predicts a reward at all, but if social information becomes entirely unreliable, flower color will be used instead. This greater sensitivity to the reliability of social information, and avoidance of conspecifics in some cases, may reflect the specific ecological circumstances of bee foraging. Overall, the bees' ability to make decisions based on both personally acquired and socially derived information, and the relative reliability of both, demonstrates a new level of sophistication and flexibility in animal, particularly insect, decision-making. 
27132706	Classical appetitive conditioning constitutes a basic learning process through which environmental stimuli can be associated with reward. Previous studies showed that individual differences in neuroticism and extraversion influence emotional processing and have been shown to modulate neural activity in subcortical and prefrontal areas in response to emotional stimuli. However, the role of individual differences in appetitive conditioning has so far not been investigated in detail. The aim of this study was to assess the association between neuroticism and extraversion with neural activity and connectivity during appetitive conditioning. The conditioned stimulus (CS) was either a picture of a dish or a cup. One stimulus (CS+) was paired with a monetary reward and the other stimulus (CS-) was associated with its absence while hemodynamic activity was measured by means of functional magnetic resonance imaging. A significant negative correlation of neuroticism scores with amygdala activity was observed during appetitive conditioning. Further, extraversion was positively associated with responses in the hippocampus and the thalamus. In addition, effective connectivity between the amygdala as a seed region and the anterior cingulate cortex, the insula, and the thalamus was negatively correlated with neuroticism scores and positively correlated with extraversion scores. The results may indicate a neural correlate for the deficits in appetitive learning in subjects with high neuroticism scores and point to a facilitating effect of extraversion on reward-related learning. Hum Brain Mapp 37:2992-3002, 2016. © 2016 Wiley Periodicals, Inc. 
27132202	Obesity is a major health problem characterized by accumulated fat mass. The availability of an energy-dense, highly palatable diet plays an important role in obesity development. Neuropeptide Y (NPY), an orexigenic peptide, is affected by dietary composition and NPY can affect dietary preference. The hypothalamic NPY system is well characterized and has been studied in several models of obesity. However, findings from models of diet-induced obesity are not straightforward. In addition, NPY plays a role in (food-)motivated behaviors and interacts with the mesolimbic dopamine system, both of which are altered in obesity. We here review the effect of obesogenic diets on NPY levels in the hypothalamus and reward-related regions. 
27129788	Adolescents display weaker taste avoidance induced by both abused and non-abused drugs than adults. Drug history attenuates avoidance learning in adults (the drug pre-exposure effect), but little is known about this phenomenon in adolescents. Given that the weaker taste avoidance in adolescence is thought to be a function of their relative insensitivity to the drug's aversive effects, it might be expected that the drug pre-exposure effect would be weaker in adolescents given that for some drugs this effect is mediated by associative blocking that depends on the association of environmental cues with the drug's aversive effects. To address this, in the present studies male adolescent (Experiment 1) and adult (Experiment 2) rats were given five spaced injections of LiCl prior to subsequent taste avoidance conditioning with LiCl. Consistent with past reports, adolescents displayed weaker taste avoidance than adults. While adults displayed attenuated LiCl-induced taste avoidance following LiCl pre-exposure, adolescents showed no evidence of this pre-exposure. This work is consistent with the view that adolescents are relatively insensitive to the aversive effects of drugs, an insensitivity potentially important in subsequent intake of drugs of abuse given that such intake is a function of the balance of their rewarding and aversive effects.
27129616	The consolidation of new associations is thought to depend in part on physiological processes engaged during non-REM (NREM) sleep, such as slow oscillations and sleep spindles. Moreover, NREM sleep is thought to selectively benefit associations that are adaptive for the future. In line with this, the current study investigated whether different reward cues at encoding are associated with changes in sleep physiology and memory retention. Participants' associative memory was tested after learning a list of arbitrarily paired words both before and after taking a 90-min nap. During learning, word-pairs were preceded by a cue indicating either a high or a low reward for correct memory performance at test. The motivation manipulation successfully impacted retention such that memory declined to a greater extent from pre- to post sleep for low rewarded than for high rewarded word-pairs. In line with previous studies, positive correlations between spindle density during NREM sleep and general memory performance pre- and post-sleep were found. In addition to this, however, a selective positive relationship between memory performance for highly rewarded word-pairs at posttest and spindle density during NREM sleep was also observed. These results support the view that motivationally salient memories are preferentially consolidated and that sleep spindles may be an important underlying mechanism for selective consolidation.
27128170	Reward properties of stimuli can undergo sudden changes, and the detection of these 'reversals' is often made difficult by the probabilistic nature of rewards/punishments. Here we tested whether and how humans use social information (someone else's choices) to overcome uncertainty during reversal learning. We show a substantial social influence during reversal learning, which was modulated by the type of observed behavior. Participants frequently followed observed conservative choices (no switches after punishment) made by the (fictitious) other player but ignored impulsive choices (switches), even though the experiment was set up so that both types of response behavior would be similarly beneficial/detrimental (Study 1). Computational modeling showed that participants integrated the observed choices as a 'social prediction error' instead of ignoring or blindly following the other player. Modeling also confirmed higher learning rates for 'conservative' versus 'impulsive' social prediction errors. Importantly, this 'conservative bias' was boosted by interpersonal similarity, which in conjunction with the lack of effects observed in a non-social control experiment (Study 2) confirmed its social nature. A third study suggested that relative weighting of observed impulsive responses increased with increased volatility (frequency of reversals). Finally, simulations showed that in the present paradigm integrating social and reward information was not necessarily more adaptive to maximize earnings than learning from reward alone. Moreover, integrating social information increased accuracy only when conservative and impulsive choices were weighted similarly during learning. These findings suggest that to guide decisions in choice contexts that involve reward reversals humans utilize social cues conforming with their preconceptions more strongly than cues conflicting with them, especially when the other is similar.
27122637	Rates of innovative foraging behaviours and success on problem-solving tasks are often used to assay differences in cognition, both within and across species. Yet the cognitive features of some problem-solving tasks can be unclear. As such, explanations that attribute cognitive mechanisms to individual variation in problem-solving performance have revealed conflicting results. We investigated individual consistency in problem-solving performances in captive-reared pheasant chicks, Phasianus colchicus, and addressed whether success depends on cognitive processes, such as trial-and-error associative learning, or whether performances may be driven solely via noncognitive motivational mechanisms, revealed through subjects' willingness to approach, engage with and persist in their interactions with an apparatus, or via physiological traits such as body condition. While subjects' participation and success were consistent within the same problems and across similar tasks, their performances were inconsistent across different types of task. Moreover, subjects' latencies to approach each test apparatus and their attempts to access the reward were not repeatable across trials. Successful individuals did not improve their performances with experience, nor were they consistent in their techniques in repeated presentations of a task. However, individuals that were highly motivated to enter the experimental chamber were more likely to participate. Successful individuals were also faster to approach each test apparatus and more persistent in their attempts to solve the tasks than unsuccessful individuals. Our findings therefore suggest that individual differences in problem-solving success can arise from inherent motivational differences alone and hence be achieved without inferring more complex cognitive processes.
27122037	Exchange protein directly activated by cAMP (Epac) and protein kinase A (PKA) are intracellular receptors for cAMP. Although PKA and its downstream effectors have been studied extensively in the context of drug addiction, whether and how Epac regulates cellular and behavioral effects of drugs of abuse remain essentially unknown. Epac is known to regulate AMPA receptor (AMPAR) trafficking. Previous studies have shown that a single cocaine exposure in vivo leads to an increase in GluA2-lacking AMPARs in dopamine neurons of the ventral tegmental area (VTA). We tested the hypothesis that Epac mediates cocaine-induced changes in AMPAR subunit composition in the VTA. We report that a single cocaine injection in vivo in wild-type mice leads to inward rectification of EPSCs and renders EPSCs sensitive to a GluA2-lacking AMPAR blocker in VTA dopamine neurons. The cocaine-induced increase in GluA2-lacking AMPARs was absent in Epac2-deficient mice but not in Epac1-deficient mice. In addition, activation of Epac with the selective Epac agonist 8-CPT-2Me-cAMP (8-CPT) recapitulated the cocaine-induced increase in GluA2-lacking AMPARs, and the effects of 8-CPT were mediated by Epac2. We also show that conditioned place preference to cocaine was impaired in Epac2-deficient mice and in mice in which Epac2 was knocked down in the VTA but was not significantly altered in Epac1-deficient mice. Together, these results suggest that Epac2 is critically involved in the cocaine-induced change in AMPAR subunit composition and drug-cue associative learning.Addictive drugs, such as cocaine, induce long-lasting adaptions in the reward circuits of the brain. A single intraperitoneal injection of cocaine leads to changes in the composition and property of the AMPAR that carries excitatory inputs to dopamine neurons. Here, we provide evidence that exchange protein directly activated by cAMP (Epac), a cAMP sensor protein, is required for the cocaine-induced changes of the AMPAR. We found that the effects of cocaine were mimicked by activation of Epac but were blocked by genetic deletion of Epac. Furthermore, cocaine-cue associative learning was impaired in mice lacking Epac. These findings uncovered a critical role of Epac in regulating the cellular and behavioral actions of cocaine.	
27120563	Recently, Sui, He, and Humphreys (2012) introduced a new paradigm to measure perceptual self-prioritization processes. It seems that arbitrarily tagging shapes to self-relevant words (I, my, me, and so on) leads to speeded verification times when matching self-relevant word shape pairings (e.g., me - triangle) as compared to non-self-relevant word shape pairings (e.g., stranger - circle). In order to analyze the level at which self-prioritization takes place we analyzed whether the self-prioritization effect is due to a tagging of the self-relevant label and the particular associated shape or due to a tagging of the self with an abstract concept. In two experiments participants showed standard self-prioritization effects with varying stimulus features or different exemplars of a particular stimulus-category suggesting that self-prioritization also works at a conceptual level.
27120562	We constructed an online cheating paradigm that could be used to validate the Crosswise Model ( Yu, Tian, & Tang, 2008 ), a promising indirect questioning technique designed to control for socially desirable responding on sensitive questions. Participants qualified for a reward only if they could identify the target words from three anagrams, one of which was virtually unsolvable as shown on a pretest. Of the 664 participants, 15.5% overreported their performance and were categorized as cheaters. When participants were asked to report whether they had cheated, a conventional direct question resulted in a substantial underestimate (5.1%) of the known prevalence of cheaters. Using a CWM question resulted in a more accurate estimate (13.0%). This result shows that the CWM can be used to control for socially desirable responding and provides estimates that are much closer to the known prevalence of a sensitive personal attribute than those obtained using a direct question.
27116758	A data-driven adaptive tracking control approach is proposed for a class of continuous-time nonlinear systems using a recent developed goal representation heuristic dynamic programming (GrHDP) architecture. The major focus of this paper is on designing a multivariable tracking scheme, including the filter-based action network (FAN) architecture, and the stability analysis in continuous-time fashion. In this design, the FAN is used to observe the system function, and then generates the corresponding control action together with the reference signals. The goal network will provide an internal reward signal adaptively based on the current system states and the control action. This internal reward signal is assigned as the input for the critic network, which approximates the cost function over time. We demonstrate its improved tracking performance in comparison with the existing heuristic dynamic programming (HDP) approach under the same parameter and environment settings. The simulation results of the multivariable tracking control on two examples have been presented to show that the proposed scheme can achieve better control in terms of learning speed and overall performance.
27116102	Decision making often requires simultaneously learning about and combining evidence from various sources of information. However, when making inferences from these sources, humans show systematic biases that are often attributed to heuristics or limitations in cognitive processes. Here we use a combination of experimental and modelling approaches to reveal neural substrates of probabilistic inference and corresponding biases. We find systematic deviations from normative accounts of inference when alternative options are not equally rewarding; subjects' choice behaviour is biased towards the more rewarding option, whereas their inferences about individual cues show the opposite bias. Moreover, inference bias about combinations of cues depends on the number of cues. Using a biophysically plausible model, we link these biases to synaptic plasticity mechanisms modulated by reward expectation and attention. We demonstrate that inference relies on direct estimation of posteriors, not on combination of likelihoods and prior. Our work reveals novel mechanisms underlying cognitive biases and contributions of interactions between reward-dependent learning, decision making and attention to high-level reasoning. 
27114896	Reward/behavioral approach system hypersensitivity is implicated in bipolar disorders (BD) and in normative development during adolescence. Pediatric onset of BD is associated with a more severe illness course. However, little is known about neural processing of rewards in adolescents with BD or developmental (i.e., age) associations with activation of these neural systems. The present study aims to address this knowledge gap. The present sample included 21 adolescents with BD and 26 healthy adolescents, ages 13 to 19. Participants completed a functional magnetic resonance imaging (fMRI) protocol using the Monetary Incentive Delay (MID) task. Behavioral performance was similar between groups. Group differences in BOLD activation during target anticipation and feedback anticipation periods of the task were examined using whole-brain analyses, as were group differences in age effects. During both target anticipation and feedback anticipation, adolescents with BD, compared to adolescents without psychopathology, exhibited decreased engagement of frontal regions involved in cognitive control (i.e., dorsolateral prefrontal cortex). Healthy adolescents exhibited age-related decreases, while adolescents with BD exhibited age-related increases, in activity of other cognitive control frontal areas (i.e., right inferior frontal gyrus), suggesting altered development in the BD group. Longitudinal research is needed to examine potentially abnormal development of cognitive control during reward pursuit in adolescent BD and whether early therapeutic interventions can prevent these potential deviations from normative development. 
27113327	Amphetamine and other drugs of abuse have both short-term and long-lasting effects on brain function, and drug sensitization paradigms often result in chronic impairments in behavioral flexibility. Here we show that acute amphetamine administration temporarily renders rats less sensitive to reward omission, as revealed by a decrease in lose-shift responding during a binary choice task. Intracerebral infusions of amphetamine into the ventral striatum did not affect lose-shift responding but did increase impulsive behavior in which rats chose to check both reward feeders before beginning the next trial. In contrast to acute systemic and intracerebral infusions, sensitization through repeated exposure induced long-lasting increased sensitivity to reward omission. These treatments did not affect choices on trials following reward delivery (i.e. win-stay responding), and sensitization increased spine density in the sensorimotor striatum. The dichotomous effects of amphetamine on short-term and long-term loss sensitivity, and the null effect on win-stay responding, are consistent with a shift of behavioral control to the sensorimotor striatum after drug sensitization. These data provide a new demonstration of such a shift in a novel task unrelated to drug administration, and suggests that the dominance of sensorimotor control persists over many hundreds of trials after sensitization.
27112968	Our everyday-life comprises a multitude of decisions that we take whilst trying to maximize advantageous outcomes, limit risks and update current needs. The cognitive processes that guide decision making as well as the brain circuits they are based on are only poorly understood. Numerous studies point to a potential role of dopamine and nicotine in decision making but less is known about their interactions. Here, 26 healthy male subjects performed the Iowa Gambling Task (IGT) in two sessions following the administration of either nicotine or placebo. Striatal dopamine transporter (DAT) binding was measured by single-photon emission computed tomography (SPECT). Results indicate that lower DAT levels were associated with better performance in the IGT (p=0.0004). Cognitive modelling analysis using the prospect valence learning (PVL) model indicated that low DAT subjects' performance deteriorated following nicotine administration as indicated by an increased learning rate and a decreased response consistency. Our results shed light on the neurochemistry underlying reward-based decision making in humans by demonstrating a significant interaction between nicotine and the DAT. The observed interaction is consistent with the hypothesized associations between DAT expression and extracellular dopamine levels, suggestive of an inverted U-shape relationship between baseline dopamine and magnitude in response to a pro-dopaminergic compound. Our findings are of particular interest in the context of psychiatric disorders where aberrant decision making represents a part of the core symptomatology, such as addiction, schizophrenia or depression. 
27111213	This study assessed the association between indirectly measured behavioural approach- and avoidance-related tendencies on the one hand, and reactive versus proactive aggression on the other hand. Reactive aggression (i.e. the impulsive, anger-driven aggression expressed in response to threatening stimuli) was differentiated from proactive aggression (i.e. the more controlled aggression motivated towards obtaining specific goals). A mixed sample of 118 patients and healthy controls filled out a self-report measure to assess their degree of reactive and proactive aggression, and then performed an Approach Avoidance Task in which they were asked to pull or push a joystick in response to a format-feature of a series of pictures, irrespective of their contents. The pictorial stimuli used in this task included attack-related scenes and angry faces, along with neutral, positive and negative control stimuli. The results were controlled for the level of personality disorder pathology, gender, and age. The findings indicated that reactive but not proactive aggression was related to the relative behavioural tendency to approach attack-related scenes, along with positive stimuli. These findings reflect the hyper-reactivity of the approach-related reward system in reactive aggression, and further our knowledge into the distinct correlates and precursors of reactive and proactive aggression.
27110917	Dopaminergic (DA) neurons in the midbrain provide rich topographic innervation of the striatum and are central to learning and to generating actions. Despite the importance of this DA innervation, it remains unclear whether and how DA neurons are specialized on the basis of the location of their striatal target. Thus, we sought to compare the function of subpopulations of DA neurons that target distinct striatal subregions in the context of an instrumental reversal learning task. We identified key differences in the encoding of reward and choice in dopamine terminals in dorsal versus ventral striatum: DA terminals in ventral striatum responded more strongly to reward consumption and reward-predicting cues, whereas DA terminals in dorsomedial striatum responded more strongly to contralateral choices. In both cases the terminals encoded a reward prediction error. Our results suggest that the DA modulation of the striatum is spatially organized to support the specialized function of the targeted subregion. 
27107297	Reward feedback following visual search causes the visual characteristics of targets to become salient and attention-drawing, but little is known about the mechanisms underlying this value-driven capture effect. Here, we use transcranial random noise stimulation (tRNS) to demonstrate that such reward potentiation involves induced plasticity in visual cortex. Human participants completed a feature-search reward-learning task involving the selection of a red or green colored target presented among distractors of various color. Each correct trial garnered reward and the magnitude of reward was determined by the color of the target. Three groups completed this task: two groups received tRNS over either occipital or frontal cortex, and the third group received sham stimulation as a control. In a subsequent test phase of the experiment participants searched for a unique shape presented among colored distractors. During the test phase, no tRNS was applied and no reward was available. However, in some trials a single distractor had color matching that associated with reward during training. Search for the target was impacted by the presence of such reward-associated distractors in the occipital stimulation group, demonstrating that plasticity in visual cortex contributes to value-driven attentional capture. 
27104548	Mainstream psychological stress theory claims that it is important to include information on people's ways of coping with work stress when assessing the impact of stressful psychosocial work environments on health. Yet, some widely used respective theoretical models focus exclusively on extrinsic factors. The model of effort-reward imbalance (ERI) differs from them as it explicitly combines information on extrinsic and intrinsic factors in studying workers' health. As a growing number of studies used the ERI model in recent past, we conducted a systematic review of available evidence, with a special focus on the distinct contribution of its intrinsic component, the coping pattern "over-commitment", towards explaining health. Moreover, we explore whether the interaction of intrinsic and extrinsic components exceeds the size of effects on health attributable to single components. Results based on 51 reports document an independent explanatory role of "over-commitment" in explaining workers' health in a majority of studies. However, support in favour of the interaction hypothesis is limited and requires further exploration. In conclusion, the findings of this review support the usefulness of a work stress model that combines extrinsic and intrinsic components in terms of scientific explanation and of designing more comprehensive worksite stress prevention programs. 
27100197	The mesopontine tegmentum, including the pedunculopontine and laterodorsal tegmental nuclei (PPN and LDT), provides major cholinergic inputs to midbrain and regulates locomotion and reward. To delineate the underlying projection-specific circuit mechanisms, we employed optogenetics to control mesopontine cholinergic neurons at somata and at divergent projections within distinct midbrain areas. Bidirectional manipulation of PPN cholinergic cell bodies exerted opposing effects on locomotor behavior and reinforcement learning. These motor and reward effects were separable via limiting photostimulation to PPN cholinergic terminals in the ventral substantia nigra pars compacta (vSNc) or to the ventral tegmental area (VTA), respectively. LDT cholinergic neurons also form connections with vSNc and VTA neurons; however, although photo-excitation of LDT cholinergic terminals in the VTA caused positive reinforcement, LDT-to-vSNc modulation did not alter locomotion or reward. Therefore, the selective targeting of projection-specific mesopontine cholinergic pathways may offer increased benefit in treating movement and addiction disorders. 
27100081	This study investigated the influence of personality characteristics and gender on adolescents' perception of risk and their risk-taking behaviour. Male and female participants (157 females: 116 males, aged 13-20) completed self-report measures on risk perception, risk-taking and personality. Male participants perceived behaviours as less risky, reportedly took more risks, were less sensitive to negative outcomes and less socially anxious than female participants. Path analysis identified a model in which age, behavioural inhibition and impulsiveness directly influenced risk perception, while age, social anxiety, impulsiveness, sensitivity to reward, behavioural inhibition and risk perception itself were directly or indirectly associated with risk-taking behaviour. Age and behavioural inhibition had direct relationships with social anxiety, and reward sensitivity was associated with impulsiveness. The model was representative for the whole sample and male and female groups separately. The observed relationship between age and social anxiety and the influence this may have on risk-taking behaviour could be key for reducing adolescent risk-taking behaviour. Even though adolescents may understand the riskiness of their behaviour and estimate their vulnerability to risk at a similar level to adults, factors such as anxiety regarding social situations, sensitivity to reward and impulsiveness may exert their influence and make these individuals prone to taking risks. If these associations are proven causal, these factors are, and will continue to be, important targets in prevention and intervention efforts. 
27099987	Evidence increasingly suggests that dopaminergic neurons play a more sophisticated role in predicting rewards than previously thought.
27101627	In this paper, we propose a multiagent reinforcement learning algorithm dealing with fully cooperative tasks. The algorithm is called frequency of the maximum reward Q-learning (FMRQ). FMRQ aims to achieve one of the optimal Nash equilibria so as to optimize the performance index in multiagent systems. The frequency of obtaining the highest global immediate reward instead of immediate reward is used as the reinforcement signal. With FMRQ each agent does not need the observation of the other agents' actions and only shares its state and reward at each step. We validate FMRQ through case studies of repeated games: four cases of two-player two-action and one case of three-player two-action. It is demonstrated that FMRQ can converge to one of the optimal Nash equilibria in these cases. Moreover, comparison experiments on tasks with multiple states and finite steps are conducted. One is box-pushing and the other one is distributed sensor network problem. Experimental results show that the proposed algorithm outperforms others with higher performance.
27101365	When people anticipate uncertain future outcomes, they often prefer to know their fate in advance. Inspired by an idea in behavioral economics that the anticipation of rewards is itself attractive, we hypothesized that this preference of advance information arises because reward prediction errors carried by such information can boost the level of anticipation. We designed new empirical behavioral studies to test this proposal, and confirmed that subjects preferred advance reward information more strongly when they had to wait for rewards for a longer time. We formulated our proposal in a reinforcement-learning model, and we showed that our model could account for a wide range of existing neuronal and behavioral data, without appealing to ambiguous notions such as an explicit value for information. We suggest that such boosted anticipation significantly drives risk-seeking behaviors, most pertinently in gambling. 
27098701	An essential component of goal-directed decision-making is the ability to maintain flexible responding based on the value of a given reward, or "reinforcer." The medial orbitofrontal cortex (mOFC), a subregion of the ventromedial prefrontal cortex, is uniquely positioned to regulate this process. We trained mice to nose poke for food reinforcers and then stimulated this region using CaMKII-driven Gs-coupled designer receptors exclusively activated by designer drugs (DREADDs). In other mice, we silenced the neuroplasticity-associated neurotrophin brain-derived neurotrophic factor (BDNF). Activation of Gs-DREADDs increased behavioral sensitivity to reinforcer devaluation, whereas Bdnf knockdown blocked sensitivity. These changes were accompanied by modifications in breakpoint ratios in a progressive ratio task, and they were recapitulated in Bdnf(+/-)mice. Replacement of BDNF selectively in the mOFC in Bdnf(+/-)mice rescued behavioral deficiencies, as well as phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2). Thus, BDNF expression in the mOFC is both necessary and sufficient for the expression of typical effort allocation relative to an anticipated reinforcer. Additional experiments indicated that expression of the immediate-early gene c-fos was aberrantly elevated in the Bdnf(+/-)dorsal striatum, and BDNF replacement in the mOFC normalized expression. Also, systemic administration of an MAP kinase kinase inhibitor increased breakpoint ratios, whereas the addition of discrete cues bridging the response-outcome contingency rescued breakpoints in Bdnf(+/-)mice. We argue that BDNF-ERK1/2 in the mOFC is a key regulator of "online" goal-directed action selection.Goal-directed response selection often involves predicting the consequences of one's actions and the value of potential payoffs. Lesions or chemogenetic inactivation of the medial orbitofrontal cortex (mOFC) in rats induces failures in retrieving outcome identity memories (Bradfield et al., 2015), suggesting that the healthy mOFC serves to access outcome value information when it is not immediately observable and thereby guide goal-directed decision-making. Our findings suggest that the mOFC also bidirectionally regulates effort allocation for a given reward and that expression of the neurotrophin BDNF in the mOFC is both necessary and sufficient for mice to sustain stable representations of reinforcer value.	
27098451	Among other approaches, the modulation of the dopaminergic pathway has been advocated in the therapeutic management of Alcohol Use Disorders (AUD). A potential avenue toward the modulation of the dopaminergic pathway across varying substance disorders seems to be provided by aripiprazole, a second-generation antipsychotic characterized by a peculiar pharmacodynamics signature.In this review, the authors provided a qualitative synthesis and a critical perspective on the efficacy of aripiprazole in relapse prevention and craving in AUD. A systematic search was carried out through MEDLINE/Embase/PsycINFO/Cochrane Library from inception until September 2015, combining free terms and MESH headings for the topics of AUD and aripiprazole as following: (((Alcohol use Disorder) OR (Alcohol use)) AND aripiprazole).	Based both on a qualitative synthesis and a critical interpretation of the evidence, the authors submit that aripiprazole would promote alcohol abstinence and reduce the alcohol seeking behaviour possibly via dopaminergic and serotoninergic modulations at the fronto-subcortical circuits underpinning alcohol reward and craving, impulsive behaviour as well as reduce alcohol-related anxiety/low mood and anhedonia. However, due to the lack of published studies, a conclusive statement about any direct effect of aripiprazole in the prevention of craving and/or alcohol consumption is not possible.	
27096576	Although the prevalence of adolescent smoking has declined over the past two decades, the rate of decline has slowed. Electronic videogames show promise as an effective tool for health behavior change; however, the current state of tobacco prevention and cessation games has not been previously reviewed or evaluated.Currently available tobacco-related videogames were identified through online searches and in smartphone application stores. In total, 88 games were systematically coded for characteristics, content, and quality using a reliable and valid coding instrument developed for this research.	The majority of games included at least two components of interactivity (75.0 percent) and at least one mechanism for rewarding (69.3 percent). However, most games lacked a story line (97.7 percent) and components for sense of control (25.0 percent). There were an average of 3.54 (standard deviation = 2.20) theoretical constructs in the games, with attitudes (83.0 percent), knowledge (78.4 percent), and perceived severity (55.7 percent) being the most common. The most common educational approach used was the affective education model (83.0 percent). Most games included at least one tobacco message (90.9 percent), with a majority of messages being loss-framed (63.6 percent) and/or one-sided (75.0 percent).	Although today's anti-tobacco videogames contain many effective features, numerous qualities and best practices for changing behaviors through games are not present. Future games should seek to address these best practices in their development and evaluation to increase the likelihood they will be effective.	
27091566	Scratch card games are incredibly popular in the Canadian marketplace. However, only recently have researchers started to systematically analyze their structural characteristics and how these in turn affect the gambler. We present two studies designed to further understand the underlying physiological and psychological effects that scratch cards have on gamblers. We had gamblers (63 in Experiment 1, 68 in Experiment 2) play custom made scratch cards involving a small win, a regular loss and a near-miss-where they uncovered two out of the three symbols needed to win the top prize. Our predictions were that despite near-misses and losses being objectively equivalent (the gambler wins nothing) gamblers' reactions to these outcomes would differ dramatically. During game play, skin conductance levels and heart rate were recorded, as well as how long gamblers paused between each game. Gamblers' subjective reactions to the different outcomes were then assessed. In both studies, near-misses triggered higher levels of physiological arousal (skin conductance levels and heart rates) than losses. Gamblers paused significantly longer following small wins than other outcomes, and reported high arousal, positive affect and urge to gamble-a constellation of results consistent with their rewarding properties. Importantly near-miss outcomes were rated as highly arousing, negative in emotional tone, and the most frustrating of all three outcome types examined. In Experiment 2, when we measured subjective urge to gamble immediately after each outcome, urge to gamble was significantly higher following near-misses than regular losses. Thus, despite not rewarding the gambler with any monetary gain, these outcomes nevertheless triggered higher arousal and larger urges to gamble than regular losses, a finding that may explain in part, the allure of scratch cards as a gambling activity.
27091565	The feedback-related negativity (FRN) provides a reliable ERP marker of performance monitoring (PM). It is usually larger for negative compared to positive feedback, and for unexpected relative to expected feedback. In two experiments, we assessed whether these effects could be modulated by goal relevance, defined as feedback informativeness (reliability) and/or impact on a person's goals. EEG (64-channel) was recorded while 30 participants (in each experiment) performed a speeded go/no-go task across blocks in which the feedback on task performance was deemed either relevant or not. At the ERP level, the FRN component was larger for (frequent) negative compared to (deviant) positive feedback exclusively when the feedback was relevant (Experiment 1). When the probability of positive and negative feedback was balanced (Experiment 2), this valence-driven FRN effect was absent. However, across these two experiments, the FRN was always larger for irrelevant than relevant feedback. Moreover, the subsequent P300 component was larger for feedback in the relevant than the irrelevant blocks. This effect was valence unspecific in Experiment 1, while in Experiment 2 larger P3 amplitudes were recorded for negative than positive (relevant) feedback. Across the two experiments, a larger correct-related negativity in the irrelevant than relevant context was also observed, suggesting that PM is flexible. These ERP findings indicate that goal relevance influences feedback (and response) processing during PM, with two nonoverlapping neurophysiological effects: It gates reward prediction error brain mechanisms (FRN effect), before enhancing subsequent motivational processes (P300 effect). 
27091300	Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner. 
27090501	Positive social interactions contribute to the sense that one's life has meaning. Enjoyment of feelings associated through social interaction motivates humans to build social connections according to their personal preferences. Therefore, we hypothesized that social interaction itself activates the reward system in a manner that depends upon individual interaction preferences. To test this hypothesis, we conducted a functional magnetic resonance imaging (fMRI) study in which 38 participants played a virtual ball-toss game in which the number of ball tosses to the participant was either similar to (normal-frequency condition) or higher than (high-frequency condition) the number of tosses to the other players. Participants reported greater-than-anticipated enjoyment during the high-frequency condition, suggesting that receiving a social reward led to unexpected positive feelings. Consistent with this, the high-frequency condition produced stronger activation in the ventral striatum, which is part of the reward system, and the precuneus, representing positive self-image, which might be translated to social reward. Furthermore, ventral striatal activation covaried with individual participants' preference for interactions with others. These findings suggest that an elevated frequency of social interaction is represented as a social reward, which might motivate individuals to promote social interaction in a manner that is modulated by personal preference. 
27090229	Understanding factors that contribute to the etiology of obesity is critical for minimizing the effects of obesity-related adverse physical health outcomes. Emotional eating or the inability to control intake of calorically dense diets (CDD) under conditions of psychosocial stress exposure is a potential risk factor for the development of obesity in people. Decreases in dopamine 2 receptors (D2R) availability have been documented in substance abuse and obesity in humans, as well as animal models of chronic stressor exposure. Social subordination in macaques is a well-established animal model of a chronic psychogenic stressor that results in stress axis dysregulation, attenuated striatal D2R levels, and stress-induced hyperphagia in complex dietary environment. However, it remains unclear how these phenotypes emerge as the stressor becomes chronic during the formation of new social groups. Thus, the goal of the current study was to assess how the imposition of social subordination over a four-month period would affect food intake, socioemotional behavior, and D2R binding potential (D2R-BP) in female rhesus monkeys maintained on a typical laboratory chow diet (LCD) compared with those having a choice between a LCD and a CDD. Results showed that access to a CDD leads to increased total caloric intake and preference for a CDD over a LCD. For the dietary choice condition, females directing less aggression towards group mates during the four-month period, a characteristic of lower social status, consumed progressively more calories over the four-month period than more aggressive females. This relation between agonistic behavior and appetite was not observed for females in LCD-only condition. Finally, decreased D2R-BP in the orbitofrontal cortex was predictive of increased overall caloric intake in all females regardless of dietary environment, suggesting that reduced availability of D2R within the prefrontal cortex is associated with unrestrained eating. Studies are continuing to determine how newly imposed dominance ranks continue to affect reward neurochemistry and appetite over time, and how this is influenced by the dietary environment. 
27090211	Work stress may impair physicians' ability to provide high quality patient care. Prior research remains however sparse and has insufficiently explored explanations for this relationship. It has been suggested that physicians' poor mental health is one potential explanatory factor. We drew on a well-established model to measure work stress (the effort-reward imbalance [ERI] model) in order to test this hypothesis. Further, to address another research gap and to potentially inform the development of better-targeted interventions, we aimed to examine associations of individual ERI constructs with the quality of care.We used cross-sectional data, which had been collected in 2014 among 416 physicians in Germany. ERI constructs (i.e. effort, reward, the ERI ratio, and overcommitment) were measured by the established 23-item questionnaire. Physicians' perceptions of quality of care were assessed by a six-item instrument inquiring after poor care practices or attitudes. Physicians' mental health was operationalized by the state scale of the Spielberger's State-Trait Depression Scales. We used both continuous and categorized dependent and independent variables in multivariable linear and logistic regression analyses.	Both an increasing ERI ratio and increasing effort were associated with poorer quality of care while increasing rewards were related to better care. Physicians' depressive symptoms did not affect these associations substantially. Associations with overcommitment were weak and attenuated to non-significant levels by correction for depressive symptoms. The level of overcommitment did not modify associations between the ERI ratio and quality of care.	Our study suggests that high work-related efforts and low rewards are associated with reports of poorer patient care among physicians, irrespectively of physicians' depressive symptoms. Quality of patient care may thus be improved by concurrently reducing effort and increasing rewards among physicians.	
27090067	Several factors, such as cold exposure, aging, the number of experiences and viral infection, have been shown to affect learning ability in different organisms. Wolbachia has been found worldwide as an arthropod parasite/mutualist symbiont in a wide range of species, including insects. Differing effects have been identified on physiology and behavior by Wolbachia. However, the effect of Wolbachia infection on the learning ability of their host had never previously been studied. The current study carried out to compare learning ability and memory duration in 2 strains of the parasitoid Trichogramma brassicae: 1 uninfected and 1 infected by Wolbachia. Both strains were able to associate the novel odors with the reward of an oviposition into a host egg. However, the percentage of females that responded to the experimental design and displayed an ability to learn in these conditions was higher in the uninfected strain. Memory duration was longer in uninfected wasps (23.8 and 21.4 h after conditioning with peppermint and lemon, respectively) than in infected wasps (18.9 and 16.2 h after conditioning with peppermint and lemon, respectively). Memory retention increased in response to the number of conditioning sessions in both strains, but memory retention was always shorter in the infected wasps than in the uninfected ones. Wolbachia infection may select for reduced memory retention because shorter memory induces infected wasps to disperse in new environments and avoid competition with uninfected wasps by forgetting cues related to previously visited environments, thus increasing transmission of Wolbachia in new environments.
27089981	Endogenous opioid signaling in ventral cortico-striatal-pallidal circuitry is implicated in elevated alcohol consumption and relapse to alcohol seeking. Mu-opioid receptor activation in the medial shell of the nucleus accumbens (NAc), a region implicated in multiple aspects of reward processing, elevates alcohol consumption while NAc opioid antagonists reduce it. However, the precise nature of the increases in alcohol consumption, and the effects of mu-opioid agonists on alcohol seeking and relapse are not clear. Here, we tested the effects of the mu-opioid agonist [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) in rat NAc shell on lick microstructure in a free-drinking test, alcohol seeking during operant self-administration, extinction learning and expression, and cue-reinforced reinstatement of alcohol seeking. DAMGO enhanced the number, but not the size of drinking bouts. DAMGO also enhanced operant alcohol self-administration and cue-induced reinstatement, but did not affect extinction learning or elicit reinstatement in the absence of cues. Our results suggest that mu-opioid agonism in NAc shell elevates alcohol consumption, seeking and conditioned reinforcement primarily by enhancing the incentive motivational properties of alcohol and alcohol-paired cues, rather than by modulating palatability, satiety, or reinforcement. 
27085908	There is a well-established literature linking obesity to altered dopamine signaling and brain response to food-related stimuli. Neuroimaging studies frequently report enhanced responses in dopaminergic regions during food anticipation and decreased responses during reward receipt. This has been interpreted as reflecting anticipatory "reward surfeit", and consummatory "reward deficiency". In particular, attenuated response in the dorsal striatum to primary food rewards is proposed to reflect anhedonia, which leads to overeating in an attempt to compensate for the reward deficit. In this paper, we propose an alternative view. We consider brain response to food-related stimuli in a reinforcement-learning framework, which can be employed to separate the contributions of reward sensitivity and reward-related learning that are typically entangled in the brain response to reward. Consequently, we posit that decreased striatal responses to milkshake receipt reflect reduced reward-related learning rather than reward deficiency or anhedonia because reduced reward sensitivity would translate uniformly into reduced anticipatory and consummatory responses to reward. By re-conceptualizing reward deficiency as a shift in learning about subjective value of rewards, we attempt to reconcile neuroimaging findings with the putative role of dopamine in effort, energy expenditure and exploration and suggest that attenuated brain responses to energy dense foods reflect the "fuel", not the fun entailed by the reward. 
27085777	Appetite and body weight regulation are controlled by the central nervous system (CNS) in a rather complicated manner. The human brain plays a central role in integrating internal and external inputs to modulate energy homeostasis. Although homeostatic control by the hypothalamus is currently considered to be primarily responsible for controlling appetite, most of the available evidence derives from experiments in rodents, and the role of this system in regulating appetite in states of hunger/starvation and in the pathogenesis of overeating/obesity remains to be fully elucidated in humans. Further, cognitive and affective processes have been implicated in the dysregulation of eating behavior in humans, but their exact relative contributions as well as the respective underlying mechanisms remain unclear. We briefly review each of these systems here and present the current state of research in an attempt to update clinicians and clinical researchers alike on the status and future directions of obesity research. 
27084852	Theoretical models distinguish two decision-making strategies that have been formalized in reinforcement-learning theory. A model-based strategy leverages a cognitive model of potential actions and their consequences to make goal-directed choices, whereas a model-free strategy evaluates actions based solely on their reward history. Research in adults has begun to elucidate the psychological mechanisms and neural substrates underlying these learning processes and factors that influence their relative recruitment. However, the developmental trajectory of these evaluative strategies has not been well characterized. In this study, children, adolescents, and adults performed a sequential reinforcement-learning task that enabled estimation of model-based and model-free contributions to choice. Whereas a model-free strategy was apparent in choice behavior across all age groups, a model-based strategy was absent in children, became evident in adolescents, and strengthened in adults. These results suggest that recruitment of model-based valuation systems represents a critical cognitive component underlying the gradual maturation of goal-directed behavior. 
27083529	Adaptive actions build on internal probabilistic models of possible outcomes that are tuned according to the errors of their predictions when experiencing an actual outcome. Prediction errors (PEs) inform choice behavior across a diversity of outcome domains and dimensions, yet neuroimaging studies have so far only investigated such signals in singular experimental contexts. It is thus unclear whether the neuroanatomical distribution of PE encoding reported previously pertains to computational features that are invariant with respect to outcome valence, sensory domain, or some combination of the two. We acquired functional MRI data while volunteers performed four probabilistic reversal learning tasks which differed in terms of outcome valence (reward-seeking versus punishment-avoidance) and domain (abstract symbols versus facial expressions) of outcomes. We found that ventral striatum and frontopolar cortex coded increasingly positive PEs, whereas dorsal anterior cingulate cortex (dACC) traced increasingly negative PEs, irrespectively of the outcome dimension. Individual reversal behavior was unaffected by context manipulations and was predicted by activity in dACC and right inferior frontal gyrus (IFG). The stronger the response to negative PEs in these areas, the lower was the tendency to reverse choice behavior in response to negative events, suggesting that these regions enforce a rule-based strategy across outcome dimensions. Outcome valence influenced PE-related activity in left amygdala, IFG, and dorsomedial prefrontal cortex, where activity selectively scaled with increasingly positive PEs in the reward-seeking but not punishment-avoidance context, irrespective of sensory domain. Left amygdala displayed an additional influence of sensory domain. In the context of avoiding punishment, amygdala activity increased with increasingly negative PEs, but only for facial stimuli, indicating an integration of outcome valence and sensory domain during probabilistic choices. 
27083126	In the present study we assessed alterations in cognitive functions in a chronic mild stress (CMS) rat model of depression. Cognitive functions were assessed in two different tasks applying the translational operant platform touchscreen technology; the visual discrimination/acquisition task was used to assess the ability to perceive and distinguish visual stimuli and to assess associative stimulus-reward learning. The visual discrimination/reversal learning task was used to assess functional brain plasticity or reprogramming of previously acquired stimulus-reward associations. These tasks permit the dissociation of multiple cognitive domains. The CMS model is a validated depression model with the useful feature that rats upon stress exposure show a graduated, individual stress response allowing the segregation of rats into different phenotypes including stress-resilient and anhedonic-like subgroups. Anhedonic-like rats are less likely to acquire the pairwise discrimination task, and they have a slower acquisition rate than controls. In the reversal learning task, resilient rats performed significantly better than anhedonic-like rats over time and 50% passed criterion as opposed to 25% for controls and only 14% for anhedonic-like rats. This indicates that resilient rats have higher cognitive flexibility than anhedonic-like rats. Thus they perform better in learning a novel task, which at the same time potentially implies an increased ability to inhibit previously rewarded behavior.
27083122	Rats avoid intake of a taste cue when paired with a drug of abuse or with the illness-inducing agent, lithium chloride (LiCl). Although progress has been made, it is difficult to compare the suppressive effects of abused agents and LiCl on intake of a gustatory conditioned stimulus (CS) because of the cross-laboratory use of different CSs, different unconditioned stimuli (USs), and different doses of the drugs, different conditioning regimens, and different restriction states. Here we have attempted to unify these variables by comparing the suppressive effects of a range of doses of morphine, cocaine, and LiCl on intake of a saccharin CS using a common regimen in non-restricted, food restricted, or water restricted male Sprague-Dawley rats. The results showed that, while the putatively aversive agent, LiCl, was effective in suppressing intake of the taste cue across nearly all doses, regardless of restriction state, the suppressive effects of both morphine and cocaine were greatly reduced when evaluated in either food or water restricted rats. Greater sensitivity to drug was revealed, at very low doses, when testing occurred in the absence of need (i.e., when the rats were non-restricted). Together, these results provide the first uniform and comprehensive analysis of the suppressive effects of morphine, cocaine, and LiCl as a function of dose and restriction state. In the present case, the suppressive effects of morphine and cocaine are found to differ from those of LiCl and, in some respects, from one another as well.
27082659	Often the world is structured such that distinct sensory contexts signify the same abstract rule set. Learning from feedback thus informs us not only about the value of stimulus-action associations but also about which rule set applies. Hierarchical clustering models suggest that learners discover structure in the environment, clustering distinct sensory events into a single latent rule set. Such structure enables a learner to transfer any newly acquired information to other contexts linked to the same rule set, and facilitates re-use of learned knowledge in novel contexts. Here, we show that humans exhibit this transfer, generalization and clustering during learning. Trial-by-trial model-based analysis of EEG signals revealed that subjects' reward expectations incorporated this hierarchical structure; these structured neural signals were predictive of behavioral transfer and clustering. These results further our understanding of how humans learn and generalize flexibly by building abstract, behaviorally relevant representations of the complex, high-dimensional sensory environment.
27081852	Inequity aversion has been proposed to act as a limiting factor for cooperation, thus preventing subjects from disadvantageous cooperative interactions. While a recent study revealed that also dogs show some sensitivity to inequity, the underlying mechanisms of this behaviour are still unclear. The aim of the current study was threefold: 1) to replicate the study by Range et al. (2009, PNAS, 106, 340-345); 2) to investigate the emotional mechanisms involved in the inequity response by measuring the heart rate and 3) to explore the link between inequity aversion and cooperation in terms of behaviours shown towards the partner dog and towards the experimenter who caused the inequity. Dog tested in dyads were alternately asked to give their paw and were either equally or unequally rewarded by the experimenter. After each social test condition, we conducted food tolerance tests and free interaction tests in which the subjects' social behaviour towards the partner and the experimenter were observed. As in the previous study, subjects refused to continue giving their paw when only the partner was rewarded, but not when both dogs were rewarded with rewards of different quality. Although subjects did not react to this quality inequity during the test, we did find reduced durations of food sharing in the subsequent tolerance test, indicating that dogs perceived the inequity but were not able to react to it in the test context. Moreover, subjects avoided their partner and the experimenter more during the free interaction time following unequal compared to equal treatment. Despite the clear behavioural reactions to inequity, we could not detect any changes in heart rate. Results suggest that inequity aversion might in fact be mediated by simple emotional mechanisms: sharing a negative experience, like inequity, might reduce future cooperation by decreasing the likelihood of proximity being maintained between partners. 

27075431	Opioid therapy for pain is associated with an increased risk for substance use disorders. This study's purpose was to determine the association between opioid misuse propensity (Screener and Opioid Assessment for Patients in Pain-Revised) and delay discounting (DD), a behavioral process linked to substance use disorders, which quantifies the extent to which outcomes are devalued because of their delay. Participants reporting chronic pain (N = 249) answered pain and opioid use questions and then completed 4 DD tasks. Each of these tasks assessed either money or pain consequences, framed as either rewards or punishments. Each task involved hypothetical choices between immediate smaller vs delayed larger consequences. The extant Monetary Choice Questionnaire assessed DD of money rewards, and a modified version assessed discounting of money losses (immediate smaller loss vs larger delayed loss). Based on the Monetary Choice Questionnaire, the novel Pain Relief Choice Questionnaire assessed choices between an immediate short duration of pain relief vs a longer duration of pain relief. Similarly, the novel Additional Pain Choice Questionnaire assessed choices between an immediate short duration of additional pain vs a longer duration of additional pain. Discounting of both additional pain and money losses were significantly associated with high Screener and Opioid Assessment for Patients in Pain-Revised scores-indicating participants at greatest risk for opioid misuse discount future punishments rather than future rewards compared with those at low risk. Measures of DD may have promise in more accurately identifying individuals at highest risk for opioid misuse during chronic opioid therapy.
27072508	Habitual exercise could contribute to weight management by altering processes of food reward via the gut-brain axis. We investigated hedonic processes of food reward in active and inactive men and characterised relationships with gastric emptying and body fat. Forty-four men (active: n=22; inactive: n=22, BMI range 21-36kg/m(2); percent fat mass range 9-42%) were studied. Participants were provided with a standardised fixed breakfast and an ad libitum lunch meal 5h later. Explicit liking, implicit wanting and preference among high-fat, low-fat, sweet and savoury food items were assessed immediately post-breakfast (fed state) and again pre-lunch (hungry state) using the Leeds Food Preference Questionnaire. Gastric emptying was assessed by (13)C-octanoic acid breath test. Active individuals exhibited a lower liking for foods overall and a greater implicit wanting for low-fat savoury foods in the fed state, compared to inactive men. Differences in the fed state remained significant after adjusting for percent fat mass. Active men also had a greater increase in liking for savoury foods in the interval between breakfast and lunch. Faster gastric emptying was associated with liking for savoury foods and with an increase in liking for savoury foods in the postprandial interval. In contrast, greater implicit wanting for high-fat foods was associated with slower gastric emptying. These associations were independent of each other, activity status and body fat. In conclusion, active and inactive men differ in processes of food reward. The rate of gastric emptying may play a role in the association between physical activity status and food reward, via the gut-brain axis.
27071084	Recent advances in blood oxygen level-dependent-functional MRI (BOLD-fMRI)-based neurofeedback reveal that participants can modulate neuronal properties. However, it is unknown whether such training effects can be introduced in the absence of participants' awareness that they are being trained. Here, we show unconscious neurofeedback training, which consequently produced changes in functional connectivity, introduced in participants who received positive and negative rewards that were covertly coupled to activity in two category-selective visual cortex regions. The results indicate that brain networks can be modified even in the complete absence of intention and awareness of the learning situation, raising intriguing possibilities for clinical interventions. 
27070265	This study sought to assess associations between work stressors and work ability in a cohort (2009-2012) of 498 hospital workers. Time-dependent variables associated with the Work Ability Index (WAI) were evaluated using general linear mixed models. Analyses included effects of individual and work characteristics. Except for work demands, the work stressors (job control, social support, effort-reward imbalance, overcommitment and work-related activities that cause pain/injury) were associated with WAI (p < 0.050) at intercept and in the time interaction. Daytime work and morning shift work were associated with decreased WAI (p < 0.010). Work stressors negatively affected work ability over time independently of other variables. 
27069385	Le système de récompense dopaminergique mésolimbique est responsable de la symptomatologie affective négative de la schizophrénie, qui peut être liée à un faible tonus dopaminergique dans le striatum ventral. Le test du retard à l'incitation financière peut être utilisé pour étudier la réponse du striatum ventral aux stimuli incitatifs. Nous montrons que l'activation du striatum ventral est faible chez les schizophrènes et que cette faible activation est liée aux symptômes négatifs primaires et secondaires induits par les neuroleptiques, connus aussi comme antipsychotiques. Le passage des antipsychotiques de première génération (typiques) aux antipsychotiques de seconde génération (atypiques) augmente l'activation du striatum ventral due au moindre blocage des récepteurs de la dopamine D2. Cette étude et d'autres études similaires montrent que l'lRM fonctionnelle permet d'examiner les aspects importants des mécanismes antipsychotiques.El sistema de recompensa dopaminérgico mesolímbico es responsable de la sintomatología afectiva negativa de la esquizofrenia, la cual puede estar relacionada con un tono dopaminérgico bajo dentro del estriado ventral. La prueba del retardo del incentivo monetario (RIM) se puede emplear para estudiar la respuesta del estriado ventral al estímulo incentivador. Se muestra que la activación del estriado ventral es baja en pacientes con esquizofrenia y esta reducción de la activación está relacionada con síntomas negativos primarios y secundarios inducidos por los neurolépticos, también conocidos como antipsicóticos. El cambio de los antipsicóticos típicos o de primera generación a los atípicos o de segunda generación aumentó la activación del estriado ventral debido a un menor bloqueo de los receptores dopaminérgicos D2. Este y otros estudios similares muestran que las pruebas con imágenes de resonancia magnética funcional son adecuadas para investigar importantes aspectos de los mecanismos de los antipsicóticos.	The mesolimbic dopaminergic reward system is responsible for the negative affective symptomatology of schizophrenia, which may be related to a low dopamine tonus within the ventral striatum. The monetary incentive delay (MID) task can be used to study the response of the ventral striatum to incentive stimuli. We show that activation of the ventral striatum is low in patients with schizophrenia, and that this low activation is related to primary and secondary negative symptoms induced by neuroleptics, also known as antipsychotics. Switching from first-(typical) to second-generation (atypical) antipsychotics increased activation of the ventral striatum due to less blocking of dopamine D2 receptors. This and similar studies show that functional magnetic resonance imaging (fMRI) tasks are suitable to investigate important aspects of antipsychotic mechanisms. 	
27069382	La schizophrénie se caractérise par un taux élevé de dopamine striatale. Dans cet article, nous analysons les causes et les conséquences de cette modification de la dopamine striatale. Nous résumons tout d'abord les premiers résultats obtenus par neuro-imagerie fonctionnelle, concernant l'anticipation et le processus de récompense striatale. Deuxièmement, nous présentons une série d'études récentes emblématiques d'une recherche particulière: une association d'apprentissages par renforcement basés sur la théorie et de tests de prise de décision combinés à une modélisation informatique et à la neuro-imagerie fonctionnelle. Nous analysons pourquoi cette approche représente un outil prometteur pour la compréhension des mécanismes symptomatiques sous-jacents en étudiant l'apport de multiples systèmes de contrôle comportementaux travaillant en parallèle. Nous analysons aussi la façon dont cela peut améliorer notre compréhension de la mise en place neurobiologique de telles fonctions. Troisièmement, nous passons en revue les arguments sur la topographie de la dysfonction de la dopamine au sein du striatum. Enfin nous présentons nos conclusions et soulignons les aspects importants à considérer dans des études ultérieures.El aumento de la funcion dopaminergica estriatal es uno de los ha I la zg os mejor establecidos en la esquizofrenia. En esta revision se discuten las causas y consecuencias de esta alteration de la dopamina estriatal. inkialmente se resumen los primeros hallazgos en relation con los procesos de recompensa y anticipation en el estriado empleando neuroimage nes funcionales. En segundo lugar se presenta una serie de estudios recientes que ejemplifican una forma especial de investigation: una combination de aprendizaje por refuerzo basado en la teoria y tareas de toma de detisiones en combination con modelos computacionales y neuroimagenes funcionales. Se discute por que esta forma representa una herramienta promisor'! a para comprender los mecanismos subyacentes de dimensiones sintomatkas mediante la diseccion de la contribution de sistemas de control conductual multiple trabajando en paralelo. Tambien se discute como se puede avanzar en la comprension de la implementation neurobiologica de tales funciones. En tercer lugar, se revisa la evidencia relacionada con la to po gratia de la dis funcion dopaminergica dentro del estriado. Por ultimo se presentan las conclusiones y se destacan aspectos importantes para ser considerados en futuros estudios.	Elevated striatal dopamine function is one of the best-established findings in schizophrenia. In this review, we discuss causes and consequences of this striata! dopamine alteration. We first summarize earlier findings regarding striatal reward processing and anticipation using functional neuroimaging. Secondly, we present a series of recent studies that are exemplary for a particular research approach: a combination of theory-driven reinforcement learning and decision-making tasks in combination with computational modeling and functional neuroimaging. We discuss why this approach represents a promising tool to understand underlying mechanisms of symptom dimensions by dissecting the contribution of multiple behavioral control systems working in parallel. We also discuss how it can advance our understanding of the neurobiological implementation of such functions. Thirdly, we review evidence regarding the topography of dopamine dysfunction within the striatum. Finally, we present conclusions and outline important aspects to be considered in future studies. 	
27069379	Choisir nécessite de soupeser plusieurs variables de décision, comme l'utilité, l'incertitude, l'attente ou l'effort, qui se combinent pour définir une valeur subjective pour chaque option envisagée ou pour chaque plan d'action. Cette aptitude se fonde sur les expériences d'apprentissage lors des récompenses (et punitions) potentielles résultant d'actes antérieurs. Prises dans un contexte social, les décisions peuvent impliquer une pensée stratégique sur les intentions de l'autre et sur le rôle du comportement de l'autre sur notre propre choix. L'estimation est aussi influencée par différentes émotions qui servent à adapter nos choix afin de, par exemple, éviter les paris excessivement risqués, prévenir les regrets futurs ou échapper aux rejets personnels ou aux conflits. En nous appuyant sur une théorie économique et sur les avancées des études des mécanismes neuronaux, nous analysons les essais récents pertinents chez les primates non humains et les observations cliniques faites chez des patients atteints neurologiquement et souffrant d'une perturbation de l'aptitude à la prise de décision.La conducta de elección requiere sopesar múltiples variables de decisión, como la utilidad, la incertidumbre, el retraso o el esfuerzo que se combinan para definir un valor subjetivo para cada opción o curso de acción que se considere. Esta capacidad está basada en el aprendizaje previo acerca de las potencia les recompensas (y castigos) que resultan de las acciones anteriores. Cuando las decisiones se realizan en un contexto social pueden involucrar un pensamiento estratégico acerca de las intenciones de otros y acerca del impacto de las conductas de otros en el propio resultado de uno. La valoración también está influenciada por diferentes emociones que sirven para regular adaptativamente nuestras electiones con el fin de, por ejemplo, alejarse de juegos ex-cesivamente riesgosos, prevenir futuras lamentaciones o evitar rechazo o conflictos personales. Basándose en la teoría económica y en los avances en el estudio de los mecanismos neurales, se revisan experimentos relevantes recientes en primates no humanos y observaciones clínicas realizadas en pacientes deteriorados neurológicamente quienes tienen alteraciones en la capacidad de tomar decisiones.	Choice behavior requires weighing multiple decision variables, such as utility, uncertainty, delay, or effort, that combine to define a subjective value for each considered option or course of action. This capacity is based on prior learning about potential rewards (and punishments) that result from prior actions. When made in a social context, decisions can involve strategic thinking about the intentions of others and about the impact of others' behavior on one's own outcome. Valuation is also influenced by different emotions that serve to adaptively regulate our choices in order to, for example, stay away from excessively risky gambles, prevent future regrets, or avoid personal rejection or conflicts. Drawing on economic theory and on advances in the study of neuronal mechanisms, we review relevant recent experiments in nonhuman primates and clinical observations made in neurologically impaired patients suffering from impaired decision-making capacities. 	
27069377	Les erreurs de prédiction de la récompense consistent en différences entre la récompense reçue et celle prévue. Elles sont déterminates pour les formes basiques d'apprentissage concernant la récompense et nous font lutter pour plus de récompense, une caractéristique bénéfique de l'évolution. La plupart des neurones dopaminergiques du mésencéphale des humains, des singes et des rongeurs indiquent une erreur de prédiction de la récompense ; ils sont activés par plus de récompense que prévu (erreur de prédiction positive), restent dans l'activité initiale pour une récompense complètement prévue et montrent une activité diminuée en cas de moins de récompense que prévu (erreur de prédiction négative). Le signal dopaminergique augmente de façon non linéaire avec la récompense et code I'utilité économique formelle. Les médicaments addictifs génèrent, détournent et amplifient le signal de la récompense dopaminergique et induisent des effets dopaminergiques exagérés et non controlés sur la plasticité neuronale. Le striatum, I'amygdale et le cortex frontal manifestent aussi le codage erroné de la prédiction de la récompense, mais seulement dans des sous-populations de neurones. L'important concept d'erreurs de prédiction de la récompense est donc mis en œuvre dans le matériel neuronal.Los errores en la predicción de la recompensa se deben a las diferencias entre las recompensas recibidas y predichas. Ellos son cruciales para las formas básicas de aprendizaje acerca de las recompensas y nos hacen esforzarnos por más recompensas, lo que constituye un rasgo evolucionario beneficioso. La mayoría de las neuronas dopaminérgicas en el mesencéfalo de los humanos, monos y roedores dan información sobre el error en la predicción de la recompensa; ellas son activadas por más recompensa que la predicha (error de predicción positivo); se mantienen en una actividad basal para el total de las recompensas predichas, y muestran una actividad disminuida con menos recompensa que la predicha (error de predicción negativo). La señal de dopamina aumenta de forma no lineal con el valor de la recompensa y da claves sobre la utilidad económica formal. Las drogas adictivas generan, secuestran y amplifican la señal de recompensa dopaminérgica e inducen efectos dopaminérgicos exagerados y descontrolados en la plasticidad neuronal. El estriado, la amígdala y la corteza frontal también codifican errores en la predicción de la recompensa, pero solo en ciertas subpoblaciones de neuronas. Por lo tanto, el concepto importante de errores en la predicción de recompensa está implementado en el hardware neuronal.	Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards-an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware. 	
27069376	Les connexions cortico-striatales jouent un rôle central dans l'élaboration de comportements pertinents axés sur des objectifs, dont la motivation et la cognition, pour mettre en oeuvre des actions adaptées en vue d'un résultat spécifique. Le cortex se projette sur le striatum de façon topographique. Différentes régions du striatum ont donc été associées à ces différentes fonctions: le striatum ventral pour la récompense ; le noyau caudé pour la cognition ; et le putamen pour le contrôle moteur. Les connexions cortico-striatales sont néanmoins plus complexes et les interactions entre les territoires fonctionnels sont larges. Ces interactions surviennent dans des régions spécifiques où il y a convergence de territoires terminaux issus de régions corticales fonctionnelles différentes. Cet article offre une mise au point sur les connexions du cortex vers le striatum et sur leur rôle d'intégration de L'information par le biais des fonctions motrices, cognitives et de récompense. L'accent est mis sur L'interface entre les domaines fonctionnels au sein du striatum.Las conexiones cortico-estriatales juegan un papel central en el desarrollo de conductas adecuadas dirigidas a un objetivo, incluyendo la motivación y los aspectos cognitivos para desarrollar acciones apropiadas para obtener un resultado específico. La corteza se proyecta hacia el cuerpo estriado topográficamente. En consecuencia, se han asociado diferentes regiones del cuerpo estriado con estas diversas funciones: el estriado ventral con la recompensa, el núcleo caudado con la cognición y el putamen con el control motor. Sin embargo, las conexiones cortico-estritales son más complejas y las interacciones entre los territorios funcionales son amplias. Estas interacciones se producen en regiones específicas en las cuales se encuentra la convergencia de los campos terminales de diferentes regiones corticales funcionales. Este artículo proporciona una panorámica acerca de las conexiones de la corteza con el cuerpo estriado y su papel en la integración de la información en las funciones de recompensa, cognitiva y motora. Se hace hincapie en la interfaz entre los dominios funcionales dentro del cuerpo estriado.	Corticostriatal connections play a central role in developing appropriate goal-directed behaviors, including the motivation and cognition to develop appropriate actions to obtain a specific outcome. The cortex projects to the striatum topographically. Thus, different regions of the striatum have been associated with these different functions: the ventral striatum with reward; the caudate nucleus with cognition; and the putamen with motor control. However, corticostriatal connections are more complex, and interactions between functional territories are extensive. These interactions occur in specific regions in which convergence of terminal fields from different functional cortical regions are found. This article provides an overview of the connections of the cortex to the striatum and their role in integrating information across reward, cognitive, and motor functions. Emphasis is placed on the interface between functional domains within the striatum. 	
27069375	Many studies have suggested that the striatum, located at the interface of the cortico-basal ganglia-thalamic circuit, consists of separate circuits that serve distinct functions It plays an important role in motor planning, value processing, and decision making. 
27068462	Dopamine action in the nucleus accumbens (NAc) is thought to drive appetitive behavior and Pavlovian reward learning. However, it remains controversial how dopamine achieves these behavioral effects by regulating medium spiny projection neurons (MSNs) of the NAc, especially on a behaviorally relevant timescale. Metabotropic glutamate receptor (mGluR)-induced Ca(2+) signaling dependent on the Ca(2+)- releasing messenger inositol 1,4,5-triphosphate (IP3) plays a critical role in controlling neuronal excitability and synaptic plasticity. Here, we show that transient dopamine application facilitates mGluR/IP3-induced Ca(2+) signals within a time window of ∼2-10 s in a subpopulation of MSNs in the NAc core. Dopamine facilitation of IP3-induced Ca(2+) signaling is mediated by D1 dopamine receptors. In dopamine-insensitive MSNs, activation of A2A adenosine receptors causes enhancement of IP3-evoked Ca(2+) signals, which is reversed by D2 dopamine receptor activation. These results show that dopamine differentially regulates Ca(2+) signaling on the order of seconds in two distinct MSN subpopulations.
27068049	Initial antidepressant treatment can paradoxically worsen symptoms in depressed adolescents by undetermined mechanisms. Interestingly, antidepressants modulate GABAA receptors, which mediate paradoxical effects of other therapeutic drugs, particularly in females. Although the neuroanatomic site of action for this paradox is unknown, elevated GABAA receptor signaling in the nucleus accumbens can disrupt motivation. We assessed fluoxetine's effects on motivated behaviors in pubescent female hamsters - anhedonia in the reward investigational preference (RIP) test as well as anxiety in the anxiety-related feeding/exploration conflict (AFEC) test. We also assessed accumbal signaling by RT-PCR and electrophysiology. Fluoxetine initially worsened motivated behaviors at puberty, relative to adulthood. It also failed to improve these behaviors as pubescent hamsters transitioned into adulthood. Low accumbal mRNA levels of multiple GABAA receptor subunits and GABA-synthesizing enzyme, GAD67, assessed by RT-PCR, suggested low GABAergic tone at puberty. Nonetheless, rapid fluoxetine-induced reductions of α5GABAA receptor and BDNF mRNA levels at puberty were consistent with age-related differences in GABAergic responses to fluoxetine and disruption of the motivational state. Whole-cell patch clamping of accumbal slices also suggested low GABAergic tone by the low amplitude of miniature inhibitory postsynaptic currents (mIPSCs) at puberty. It also confirmed age-related differences in GABAergic responses to fluoxetine. Specifically, fluoxetine potentiated mIPSC amplitude and frequency at puberty, but attenuated the amplitude during adulthood. These results implicate GABAergic tone and GABAA receptor plasticity in adverse motivational responses and resistance to fluoxetine during adolescence.
27067889	Breast feeding can promote positive long-term and short-term health outcomes in infant and mother. The UK has one of the lowest breastfeeding rates (duration and exclusivity) in the world, resulting in preventable morbidities and associated healthcare costs. Breastfeeding rates are also socially patterned, thereby potentially contributing to health inequalities. Financial incentives have been shown to have a positive effect on health behaviours in previously published studies.Based on data from earlier development and feasibility stages, a cluster (electoral ward) randomised trial with mixed-method process and content evaluation was designed. The 'Nourishing Start for Health' (NOSH) intervention comprises a financial incentive programme of up to 6 months duration, delivered by front-line healthcare professionals, in addition to existing breastfeeding support. The intervention aims to increase the prevalence and duration of breast feeding in wards with low breastfeeding rates. The comparator is usual care (no offer of NOSH intervention). Routine data on breastfeeding rates at 6-8 weeks will be collected for 92 clusters (electoral wards) on an estimated 10,833 births. This sample is calculated to provide 80% power in determining a 4% point difference in breastfeeding rates between groups. Content and process evaluation will include interviews with mothers, healthcare providers, funders and commissioners of infant feeding services. The economic analyses, using a healthcare provider's perspective, will be twofold, including a within-trial cost-effectiveness analysis and beyond-trial modelling of longer term expectations for cost-effectiveness. Results of economic analyses will be expressed as cost per percentage point change in cluster level in breastfeeding rates between trial arms. In addition, we will present difference in resource use impacts for a range of acute conditions in babies aged 0-6 months.	Participating organisations Research and Governance departments approved the study. Results will be published in peer-reviewed journals and at conference presentations.	ISRCTN44898617; Pre-results.	
27067513	Zero-determinant (ZD) strategies, as discovered by Press and Dyson, can enforce a linear relationship between a pair of players' scores in the iterated prisoner's dilemma. Particularly, the extortionate ZD strategies can enforce and exploit cooperation, providing a player with a score advantage, and consequently higher scores than those from either mutual cooperation or generous ZD strategies. In laboratory experiments in which human subjects were paired with computer co-players, we demonstrate that both the generous and the extortionate ZD strategies indeed enforce a unilateral control of the reward. When the experimental setting is sufficiently long and the computerized nature of the opponent is known to human subjects, the extortionate strategy outperforms the generous strategy. Human subjects' cooperation rates when playing against extortionate and generous ZD strategies are similar after learning has occurred. More than half of extortionate strategists finally obtain an average score higher than that from mutual cooperation. 
27067122	The effort-reward imbalance (ERI) model of work stress has been widely applied in investigating association between psychosocial factors at work and health. This study examined associations between perceived psychosocial work stress as measured by the ERI model and self-rated health (SRH) among nurses and environmental health officers (EHOs) working in secondary public healthcare facilities in the Gambia.A cross-sectional study on a random sample of 287 health care professionals (201 nurses and 86 EHOs). A 22-item ERI questionnaire was used to collect data on the psychosocial factors defined by the ERI model. SRH was assessed using a single item measure.	The distribution of subjective health was not statistically different between nurses and EHOs. However, our study uncovered significant associations between perceived psychosocial work stress and subjective health. Specifically, we found that a perceived high effort-reward imbalance (ER-ratio > 1) is a significant risk factor for poor SRH, in both occupational groups. However, over-commitment was not significantly associated with poor SRH in the two groups. When efforts and rewards were considered as separate variables in the analysis, rewards were inversely associated with poor SRH in both groups.	Because of the high perceived Effort-Reward Imbalance among healthcare professionals at secondary public healthcare facilities, it is necessary to modify working conditions through improvement of psychosocial work environment, such as reasonable allocation of resources to increase pay, incentives or other forms of rewards from government. Interventions that could mitigate and prevent stress at work are worth considering in future healthcare policies.	
27066768	To thrive in a changing environment, organisms evolved strategies for rapidly modifying their behavioral responses to sensory stimuli. In this review, we investigate the role of sensory cortical circuits in these flexible behaviors. First, we provide a framework for classifying tasks in which flexibility is required. We then present studies in animal models which demonstrate that responses of sensory cortical neurons depend on the expected outcome associated with a stimulus. Last, we discuss inactivation studies which indicate that sensory cortex facilitates behavioral flexibility, but is not always required for adapting to changes in environmental conditions. This analysis provides insights into the contributions of cortical and subcortical sensory circuits to flexibility in behavior.
27064794	Learning in a new environment is influenced by prior learning and experience. Correctly applying a rule that maps a context to stimuli, actions, and outcomes enables faster learning and better outcomes compared to relying on strategies for learning that are ignorant of task structure. However, it is often difficult to know when and how to apply learned rules in new contexts. In our study we explored how subjects employ different strategies for learning the relationship between stimulus features and positive outcomes in a probabilistic task context. We test the hypothesis that task naive subjects will show enhanced learning of feature specific reward associations by switching to the use of an abstract rule that associates stimuli by feature type and restricts selections to that dimension. To test this hypothesis we designed a decision making task where subjects receive probabilistic feedback following choices between pairs of stimuli. In the task, trials are grouped in two contexts by blocks, where in one type of block there is no unique relationship between a specific feature dimension (stimulus shape or color) and positive outcomes, and following an un-cued transition, alternating blocks have outcomes that are linked to either stimulus shape or color. Two-thirds of subjects (n = 22/32) exhibited behavior that was best fit by a hierarchical feature-rule model. Supporting the prediction of the model mechanism these subjects showed significantly enhanced performance in feature-reward blocks, and rapidly switched their choice strategy to using abstract feature rules when reward contingencies changed. Choice behavior of other subjects (n = 10/32) was fit by a range of alternative reinforcement learning models representing strategies that do not benefit from applying previously learned rules. In summary, these results show that untrained subjects are capable of flexibly shifting between behavioral rules by leveraging simple model-free reinforcement learning and context-specific selections to drive responses. 

27063080	Interventions focusing on the prevention and treatment of chronic non-communicable diseases are on rise. In the current article, we propose that dysfunction of the mesocortico-limbic reward system contributes to the emergence of the WHO-identified risk behaviors (tobacco use, unhealthy diet, physical inactivity and harmful use of alcohol), behaviors that underlie the evolution of major non-communicable diseases (e.g. cardiovascular diseases, cancer, diabetes and chronic respiratory diseases). Given that dopaminergic neurons of the mesocortico-limbic system are tightly associated with reward-related processes and motivation, their dysfunction may fundamentally influence behavior. While nicotine and alcohol alter dopamine neuron function by influencing some receptors, mesocortico-limbic system dysfunction was associated with elevation of metabolic set-point leading to hedonic over-eating. Although there is some empirical evidence, precise molecular mechanism for linking physical inactivity and mesocortico-limbic dysfunction per se seems to be missing; identification of which may contribute to higher success rates for interventions targeting lifestyle changes pertaining to physical activity. In the current article, we compile evidence in support of a link between exercise and the mesocortico-limbic system by elucidating interactions on the axis of muscle - irisin - brain derived neurotrophic factor (BDNF) - and dopaminergic function of the midbrain. Irisin is a contraction-regulated myokine formed primarily in skeletal muscle but also in the brain. Irisin stirred considerable interest, when its ability to induce browning of white adipose tissue parallel to increasing thermogenesis was discovered. Furthermore, it may also play a role in the regulation of behavior given it readily enters the central nervous system, where it induces BDNF expression in several brain areas linked to reward processing, e.g. the ventral tegmental area and the hippocampus. BDNF is a neurotropic factor that increases neuronal dopamine content, modulates dopamine release relevant for neuronal plasticity and increased neuronal survival as well as learning and memory. Further linking BDNF to dopaminergic function is BDNF's ability to activate tropomyosin-related kinase B receptor that shares signalization with presynaptic dopamine-3 receptors in the ventral tegmental area. Summarizing, we propose that the skeletal muscle derived irisin may be the link between physical activity and reward-related processes and motivation. Moreover alteration of this axis may contribute to sedentary lifestyle and subsequent non-communicable diseases. Preclinical and clinical experimental models to test this hypothesis are also proposed. 
27060505	Recent work has shown that attentional deficits following stroke can be modulated by motivational stimulation, particularly anticipated monetary reward. Here we examined the effects of anticipated reward on the pathological attentional blink (AB), an index of temporal selective attention, which is prolonged in patients with right hemisphere damage and a history of left neglect. We specifically compared the effects of reward versus feedback-without-reward on the AB in 17 patients. We found that the patients all manifested impaired performance compared to healthy controls and that reward modulated the pathological blink in the patient group, but only in the second experimental session. When the performance of patients whose neglect had recovered was compared with that of patients who had ongoing or persistent neglect, reward appeared to only influence the AB in the former. These results have implications for our understanding of motivation-attention interactions following right hemisphere stroke, and how they may impact upon recovery from spatial neglect.
27059320	Adapting behavior to dynamic stimulus-reward contingences is a core feature of reversal learning and a capacity thought to be critical to socio-emotional behavior. Impairment in reversal learning has been linked to multiple psychiatric outcomes, including depression, Parkinson's disorder, and substance abuse. A recent influential study introduced an innovative laboratory reversal-learning paradigm capable of disentangling the roles of feedback valence and expectancy. Here, we sought to use this paradigm in order to examine the time-course of reward and punishment learning using event-related potentials among a large, representative sample (N=101). Three distinct phases of processing were examined: initial feedback evaluation (reward positivity, or RewP), allocation of attention (P3), and sustained processing (late positive potential, or LPP). Results indicate a differential pattern of valence and expectancy across these processing stages: the RewP was uniquely related to valence (i.e., positive vs. negative feedback), the P3 was uniquely associated with expectancy (i.e., unexpected vs. expected feedback), and the LPP was sensitive to both valence and expectancy (i.e., main effects of each, but no interaction). The link between ERP amplitudes and behavioral performance was strongest for the P3, and this association was valence-specific. Overall, these findings highlight the potential utility of the P3 as a neural marker for feedback processing in reversal-based learning and establish a foundation for future research in clinical populations.
27056740	Drug addiction shares brain mechanisms and molecular substrates with learning and memory processes, such as the stimulation of glutamate receptors and their downstream signalling pathways. In the present work we provide an up-to-date review of studies that have demonstrated the implication of the main memory-related calcium-dependent protein kinases in opiate and cocaine addiction. The effects of these drugs of abuse in different animal models of drug reward, dependence and addiction are altered by manipulation of the mitogen-activated protein kinase (MAPK) family, particularly extracellular signal regulated kinase (ERK), calcium/calmodulin-dependent kinase II (CaMKII), the protein kinase C (PKC) family (including PKMζ), cAMP-dependent protein kinase A (PKA), cGMP-dependent protein kinase G (PKG), the phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target mammalian target of Rapamycin (mTOR), cyclin-dependent kinase 5 (Cdk5), heat-shock proteins (Hsp) and other enzymes and proteins. Research suggests that drugs of abuse induce dependence and addiction by modifying the signalling pathways that involve these memory-related protein kinases, and supports the idea that drug addiction is an excessive aberrant learning disorder in which the maladaptive memory of drug-associated cues maintains compulsive drug use and contributes to relapse. Moreover, the studies we review offer new pharmacological strategies to treat opiate and cocaine dependence based on the manipulation of these protein kinases. In particular, disruption of reconsolidation of drug-related memories may have a high therapeutic value in the treatment of drug addiction. 
27054684	Reward learning has a powerful influence on the attention system, causing previously reward-associated stimuli to automatically capture attention. Difficulty ignoring stimuli associated with drug reward has been linked to addiction relapse, and the attention system of drug-dependent patients seems especially influenced by reward history. This and other evidence suggests that value-driven attention has consequences for behavior and decision-making, facilitating a bias to approach and consume the previously reward-associated stimulus even when doing so runs counter to current goals and priorities. Yet, a mechanism linking value-driven attention to behavioral responding and a general approach bias is lacking. Here we show that previously reward-associated stimuli escape inhibitory processing in a go/no-go task. Control experiments confirmed that this value-dependent failure of goal-directed inhibition could not be explained by search history or residual motivation, but depended specifically on the learned association between particular stimuli and reward outcome. When a previously high-value stimulus is encountered, the response codes generated by that stimulus are automatically afforded high priority, bypassing goal-directed cognitive processes involved in suppressing task-irrelevant behavior. (PsycINFO Database Record 
27053349	Glutamate receptors in mesolimbic areas such as the nucleus accumbens, ventral tegmental area, prefrontal cortex (PFC), and hippocampus (HIP) are a component of the mechanisms of drug-induced reward and can modulate the firing pattern of dopaminergic neurons in the reward system. In addition, several lines of study have indicated that cAMP response element-binding protein (CREB) and c-fos have important role in morphine-induced conditioned place preference (CPP) induced by drugs of abuse, such as morphine, cocaine, nicotine, and alcohol. Therefore, in the present study, we investigated the changes in phosphorylated CREB (p-CREB) and c-fos induction within the nucleus accumbens (NAc), HIP, and PFC after intracerebroventricular (ICV) administration of different doses of CNQX or vehicle during extinction period or reinstatement of morphine-induced CPP. In all groups, the CPP procedure was done; afterward, the conditioning scores were recorded by Ethovision software. After behavioral test recording, we dissected out the NAc, HIP, and PFC regions and measured the p-CREB/CREB ratio and c-fos level by Western blot analysis. Our results showed that administration of CNQX significantly shortened the extinction of morphine CPP. Besides, ICV microinjection of CNQX following extinction period decreased the reinstatement of morphine CPP in extinguished rats. In molecular section, in treatment group, all mentioned factors were dose-dependently decreased in comparison with vehicle group (DMSO) after ICV microinjection of different doses of CNQX but not in pre-extinction microinjection. These findings suggested that antagonism of AMPA receptor decreased p-CREB/CREB ratio and c-fos level in the PFC, NAc, and HIP. Modulation of the drug memory reconsolidation may be useful for faster extinction of drug-induced reward and attenuation of drug-seeking behavior.
27053203	ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Baz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins.We show that BAZ1B, a component of chromatin remodeling complexes, in the nucleus accumbens regulates reward-related behaviors in response to chronic exposure to both rewarding and aversive stimuli by regulating largely distinct subsets of genes.	
27052943	Anterior insular and orbitofrontal cortex (AIC and OFC, respectively) are known to play important roles in decision making under risk. However, risk-related AIC neural activity has not been investigated and it is controversial whether the rodent OFC conveys genuine risk signals. To address these issues, we examined AIC and OFC neuronal activity in rats responding to five distinct auditory cues predicting water reward with different probabilities. Both structures conveyed significant neural signals for reward, value and risk, with value and risk signals conjunctively coded. However, value signals were stronger and appeared earlier in the OFC, and many risk-coding OFC neurons responded only to the cue predicting certain (100%) reward. Also, AIC neurons tended to increase their activity for a prolonged time following a negative outcome and according to previously expected value. These results show that both the AIC and OFC convey neural signals related to reward uncertainty, but in different ways. The OFC might play an important role in encoding certain reward-biased, risk-modulated subjective value, whereas the AIC might convey prolonged negative outcome and disappointment signals. 
27052578	A major open question is whether computational strategies thought to be used during experiential learning, specifically model-based and model-free reinforcement learning, also support observational learning. Furthermore, the question of how observational learning occurs when observers must learn about the value of options from observing outcomes in the absence of choice has not been addressed. In the present study we used a multi-armed bandit task that encouraged human participants to employ both experiential and observational learning while they underwent functional magnetic resonance imaging (fMRI). We found evidence for the presence of model-based learning signals during both observational and experiential learning in the intraparietal sulcus. However, unlike during experiential learning, model-free learning signals in the ventral striatum were not detectable during this form of observational learning. These results provide insight into the flexibility of the model-based learning system, implicating this system in learning during observation as well as from direct experience, and further suggest that the model-free reinforcement learning system may be less flexible with regard to its involvement in observational learning. 
27050518	Mesolimbic dopamine encodes the benefits of a course of action. However, the value of an appetitive reward depends strongly on an animal's current state. To investigate the relationship between dopamine, value, and physiological state, we monitored sub-second dopamine release in the nucleus accumbens core while rats made choices between food and sucrose solution following selective satiation on one of these reinforcers. Dopamine signals reflected preference for the reinforcers in the new state, decreasing to the devalued reward and, after satiation on food, increasing for the valued sucrose solution. These changes were rapid and selective, with dopamine release returning to pre-satiation patterns when the animals were re-tested in a standard food-restricted state. Such rapid and selective adaptation of dopamine-associated value signals could provide an important signal to promote efficient foraging for a varied diet. 

27048158	Orexinergic system is involved in reward processing and drug addiction.Here, we investigated the effect of intrahippocampal CA1 administration of orexin-2 receptor (OX2r) antagonist on the acquisition, expression, and extinction of morphine-induced place preference in rats.	Conditioned place preference (CPP) was induced by subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Three experimental plots were designed; TCS OX2 29 as a selective antagonist of orexin-2 receptors (OX2rs) was dissolved in DMSO, prepared in solutions with different concentrations (1, 3, 10, and 30 nM), and was bilaterally microinjected into the CA1 and some neighboring regions (0.5 μl/side). Conditioning scores and locomotor activities were recorded during the test.	Results demonstrate that intra-CA1 administration of the OX2r antagonist attenuates the induction of morphine CPP during the acquisition and expression phases. Effect of TCS OX2 29 on reduction of morphine CPP was dose-dependent and was more pronounced during the acquisition than the expression. Furthermore, higher concentrations of TCS OX2 29 facilitated the extinction of morphine-induced CPP and reduced extinction latency period. Nevertheless, administration of TCS OX2 29 solutions did not have any influence on locomotor activity of all phases.	Our findings suggest that OX2rs in the CA1 region of hippocampus are involved in the development of the acquisition and expression of morphine CPP. Moreover, blockade of OX2rs could facilitate extinction and may abrogate or extinguish the ability of drug-related cues, implying that the antagonist might be considered as a propitious therapeutic agent in suppressing drug-seeking behavior.	
27047400	It has been proposed that compulsive drug seeking reflects an underlying dysregulation in adaptive behavior that favors habitual (automatic and inflexible) over goal-directed (deliberative and highly flexible) action selection. Rodent studies have established that repeated exposure to cocaine or amphetamine facilitates the development of habits, producing behavior that becomes unusually insensitive to a reduction in the value of its outcome. The current study more directly investigated the effects of cocaine pre-exposure on goal-directed learning and action selection using an approach that discourages habitual performance. After undergoing a 15-day series of cocaine (15 or 30 mg/kg, i.p.) or saline injections and a drug withdrawal period, rats were trained to perform two different lever-press actions for distinct reward options. During a subsequent outcome devaluation test, both cocaine- and saline-treated rats showed a robust bias in their choice between the two actions, preferring whichever action had been trained with the reward that retained its value. Thus, it appears that the tendency for repeated cocaine exposure to promote habit formation does not extend to a more complex behavioral scenario that encourages goal-directed control. To further explore this issue, we assessed how prior cocaine treatment would affect the rats' ability to learn about a selective reduction in the predictive relationship between one of the two actions and its outcome, which is another fundamental feature of goal-directed behavior. Interestingly, we found that cocaine-treated rats showed enhanced, rather than diminished, sensitivity to this action-outcome contingency degradation manipulation. Given their mutual dependence on striatal dopamine signaling, we suggest that cocaine's effects on habit formation and contingency learning may stem from a common adaptation in this neurochemical system. 
27046310	Addiction is often conceptualized as a behavioral strategy for avoiding negative experiences. In rodents, opioid intake has been associated with abnormal acquisition and extinction of avoidance behavior. Here, we tested the hypothesis that these findings would generalize to human opioid-dependent subjects.Adults meeting DSM-IV criteria for heroin dependence and treated with opioid medication (n = 27) and healthy controls (n = 26) were recruited between March 2013 and October 2013 and given a computer-based task to assess avoidance behavior. For this task, subjects controlled a spaceship and could either gain points by shooting an enemy spaceship or hide in safe areas to avoid on-screen aversive events. Hiding duration during different periods of the task was used to measure avoidance behavior.	While groups did not differ on escape responding (hiding) during the aversive event, heroin-dependent men (but not women) made more avoidance responses during a warning signal that predicted the aversive event (analysis of variance, sex × group interaction, P = .007). Heroin-dependent men were also slower to extinguish the avoidance response when the aversive event no longer followed the warning signal (P = .011). This behavioral pattern resulted in reduced opportunity to obtain reward without reducing risk of punishment. Results suggest that, in male patients, differences in avoidance behavior cannot be easily explained by impaired task performance or by exaggerated motor activity.	This study provides evidence for abnormal acquisition and extinction of avoidance behavior in opioid-dependent patients. Interestingly, data suggest that abnormal avoidance is demonstrated only by male patients. Findings shed light on cognitive and behavioral manifestations of opioid addiction and may facilitate development of therapeutic approaches to help affected individuals.	
27045841	Little is known about the causes of individual differences in reward sensitivity. We investigated gene-environment interactions (GxE) on behavioral and neural measures of reward sensitivity, in light of the differential susceptibility theory. This theory states that individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments. Reward responses were assessed during a monetary incentive delay task in 178 participants with and 265 without attention-deficit/hyperactivity disorder (ADHD), from N=261 families. We examined interactions between variants in candidate plasticity genes (DAT1, 5-HTT and DRD4) and social environments (maternal expressed emotion and peer affiliation). HTTLPR short allele carriers showed the least reward speeding when exposed to high positive peer affiliation, but the most when faced with low positive peer affiliation or low maternal warmth. DAT1 10-repeat homozygotes displayed similar GxE patterns toward maternal warmth on general task performance. At the neural level, DRD4 7-repeat carriers showed the least striatal activation during reward anticipation when exposed to high maternal warmth, but the most when exposed to low warmth. Findings were independent of ADHD severity. Our results partially confirm the differential susceptibility theory and indicate the importance of positive social environments in reward sensitivity and general task performance for persons with specific genotypes. 
27044354	Melanin-concentrating hormone (MCH) is involved in the regulation of food intake and has recently been associated with alcohol-related behaviors. Blockade of MCH-1 receptors (MCH1-Rs) attenuates operant alcohol self-administration and decreases cue-induced reinstatement, but the mechanism through which the MCH1-R influences these behaviors remains unknown. MCH1-Rs are highly expressed in the nucleus accumbens shell (NAcSh) where they are co-expressed with dopamine (DA) receptors. MCH has been shown to potentiate responses to dopamine and to increase phosphorylation of DARPP-32, an intracellular marker of DA receptor activation, in the NAcSh.In the present study, we investigated the role of the MCH1-R in alcohol reward using the conditioned place preference (CPP) paradigm. We then used immunohistochemistry (IHC) to assess activation of downstream signaling after administration of a rewarding dose of alcohol.	We found that alcohol-induced CPP was markedly decreased in mice with a genetic deletion of the MCH1-R as well as after pharmacological treatment with an MCH1-R antagonist, GW803430. In contrast, an isocaloric dose of dextrose did not produce CPP. The increase in DARPP-32 phosphorylation seen in wildtype (WT) mice after acute alcohol administration in the NAcSh was markedly reduced in MCH1-R knock-out (KO) mice.	Our results suggest that MCH1-Rs regulate the rewarding properties of alcohol through interactions with signaling cascades downstream of DA receptors in the NAcSh.	
27044008	The negative symptoms of schizophrenia (SZ) are associated with a pattern of reinforcement learning (RL) deficits likely related to degraded representations of reward values. However, the RL tasks used to date have required active responses to both reward and punishing stimuli. Pavlovian biases have been shown to affect performance on these tasks through invigoration of action to reward and inhibition of action to punishment, and may be partially responsible for the effects found in patients. Forty-five patients with schizophrenia and 30 demographically-matched controls completed a four-stimulus reinforcement learning task that crossed action ("Go" or "NoGo") and the valence of the optimal outcome (reward or punishment-avoidance), such that all combinations of action and outcome valence were tested. Behaviour was modelled using a six-parameter RL model and EEG was simultaneously recorded. Patients demonstrated a reduction in Pavlovian performance bias that was evident in a reduced Go bias across the full group. In a subset of patients administered clozapine, the reduction in Pavlovian bias was enhanced. The reduction in Pavlovian bias in SZ patients was accompanied by feedback processing differences at the time of the P3a component. The reduced Pavlovian bias in patients is suggested to be due to reduced fidelity in the communication between striatal regions and frontal cortex. It may also partially account for previous findings of poorer "Go-learning" in schizophrenia where "Go" responses or Pavlovian consistent responses are required for optimal performance. An attenuated P3a component dynamic in patients is consistent with a view that deficits in operant learning are due to impairments in adaptively using feedback to update representations of stimulus value. 
27041499	Although the basolateral amygdala (BLA) is known to play a critical role in the formation of memories of both positive and negative valence, the coding and routing of valence-related information is poorly understood. Here, we recorded BLA neurons during the retrieval of associative memories and used optogenetic-mediated phototagging to identify populations of neurons that synapse in the nucleus accumbens (NAc), the central amygdala (CeA), or ventral hippocampus (vHPC). We found that despite heterogeneous neural responses within each population, the proportions of BLA-NAc neurons excited by reward predictive cues and of BLA-CeA neurons excited by aversion predictive cues were higher than within the entire BLA. Although the BLA-vHPC projection is known to drive behaviors of innate negative valence, these neurons did not preferentially code for learned negative valence. Together, these findings suggest that valence encoding in the BLA is at least partially mediated via divergent activity of anatomically defined neural populations. 
27038816	This paper presents the Hierarchy of Gambling Choices (HGC), which is a consumer-oriented framework for understanding the key environmental and contextual features that influence peoples' selections of online and venue-based electronic gaming machines (EGMs). The HGC framework proposes that EGM gamblers make choices in selection of EGM gambling experiences utilising Tversky's (Psychol Rev 79(4):281-299, 1972). Elimination-by-Aspects model, and organise their choice in a hierarchical manner by virtue of EGMs being an "experience good" (Nelson in J Polit Econ 78(2):311-329, 1970). EGM features are divided into three levels: the platform-including, online, mobile or land-based; the provider or specific venue in which the gambling occurs; and the game or machine characteristics, such as graphical themes and bonus features. This framework will contribute to the gambling field by providing a manner in which to systematically explore the environment surrounding EGM gambling and how it affects behaviour.
27038750	In humans, bromocriptine (BRO) is used as a treatment for many disorders, such as prolactinomas, even during pregnancy and lactation. Previously we demonstrated that maternal BRO treatment at the end of lactation programs offspring for obesity and several endocrine dysfunctions. Here, we studied the long-term effects of direct BRO injection in neonatal Wistar rats on their dopaminergic pathway, anxiety-like behavior and locomotor activity at adulthood. Male pups were either s.c. injected with BRO (0.1μg/once daily) from postnatal day (PN) 1 to 10 or from PN11 to 20. Controls were injected with methanol-saline. Body mass, food intake, neuropeptides, dopamine pathway parameters, anxiety-like behavior and locomotor activity were analyzed. The dopamine pathway was analyzed in the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal striatum (DS) at PN180. PN1-10 BRO-treated animals had normal body mass and adiposity but lower food intake and plasma prolactin (PRL). This group had higher POMC in the arcuate nucleus (ARC), higher tyrosine hydroxylase (TH) in the VTA, higher dopa decarboxylase (DDc), higher D2R and μu-opioid receptor in the NAc. Concerning behavior in elevated plus maze (EPM), BRO-treated animals displayed more anxiety-like behaviors. PN11-20 BRO-treated showed normal body mass and adiposity but higher food intake and plasma PRL. This group had lower POMC in the ARC, lower TH in the VTA and lower DAT in the NAc. BRO-treated animals showed less anxiety-like behaviors in the EPM. Thus, neonatal BRO injection, depending on the time of treatment, leads to different long-term dysfunctions in the dopaminergic reward system, food intake behavior and anxiety levels, findings that could be partially due to PRL and POMC changes. 
27038409	Cognitive behavioral therapy (CBT) is a well-established treatment for anxiety and depression; however, response to CBT is heterogeneous across patients and many remain symptomatic after therapy, raising the need to identify prospective predictors for treatment planning. Altered neural processing of reward has been implicated in both depression and anxiety, and improving hedonic capacity is a goal of CBT. However, little is known about how neural response to reward relates to CBT outcomes in depression and anxiety. The current study used the reward positivity (RewP) event-related potential (ERP) component to examine whether neural reactivity to reward would predict CBT response in a sample of patients with anxiety without depression (n = 30) and comorbid anxiety and depression (CAD, n = 22).Participants completed a guessing reward ERP paradigm before completing 12 weeks of standard CBT.	The majority of the sample (68%; 35 out of 52 patients) responded to treatment, and those with a reduced RewP at baseline were more likely to respond to treatment. A reduced RewP was also associated with a greater pre-to-post CBT reduction in depressive symptoms among individuals with CAD, but not among individuals with pure anxiety.	CBT may be most beneficial in reducing depressive symptoms for individuals who demonstrate decreased reward reactivity prior to treatment. CBT may target reward brain function, leading to greater improvement in symptoms. These effects may be strongest, and therefore most meaningful, for individuals with reward-processing deficits prior to treatment.	
27037939	Methamphetamine (meth) addiction is a chronically relapsing disorder that often produces persistent cognitive deficits. These include decreased cognitive flexibility, which may prevent meth addicts from altering their habitual drug abuse and leave them more susceptible to relapse. Multiple factors including low rates of compliance with research study participation and varied drug use patterns make the relationship between cognitive flexibility and relapse difficult to establish in clinical populations.Here, we combined an extended-access meth self-administration paradigm with an automated set-shifting task in rats to directly compare cognitive flexibility performance with meth-seeking behavior.	Rats were pre-trained on an automated visual discrimination task, followed by 14 days of extended access (6 h/day) of meth or sucrose self-administration. They were then tested in the set-shifting task on strategy shift and reversal and subsequently assessed for cue-induced reinstatement of meth seeking.	Rats with a history of meth, but not sucrose, self-administration had selective deficits in reversal learning. Specifically, meth rats had an increase in the total number of errors and perseverative errors (corresponding to the old stimulus-reward association) following the reversal shift, which correlated with prior stable meth self-administration. However, no relationship was seen between errors during the reversal and cue-induced reinstatement.	The lack of association between meth-induced reversal deficits and cue-induced reinstatement to meth seeking indicates that these two domains may constitute independent pathologies of meth addiction.	

27031875	Objects that are rare are often perceived to be inherently more valuable than objects that are abundant - a bias brought about in part by the scarcity heuristic. In the present study, we sought to test whether perception of rarity impacted reward evaluation within the human medial-frontal cortex. Here, participants played a gambling game in which they flipped rare and abundant 'cards' on a computer screen to win financial rewards while electroencephalographic data were recorded. Unbeknownst to participants, reward outcome and frequency was random and equivalent for both rare and abundant cards; thus, only a perception of scarcity was true. Analysis of the electroencephalographic data indicated that the P300 component of the event-related brain potential differed in amplitude for wins and losses following the selection of rare cards, but not following the selection of abundant cards. Importantly, then, we found that the perception of card rarity impacted reward processing even though reward feedback was independent of and subsequent to card selection. Our data indicate a top-down influence of the scarcity heuristic on reward evaluation, and specifically the processing of reward magnitude, within the human medial-frontal cortex. 
27031872	We have investigated in adolescent mice the effect of subchronic leptin on (i) leptin receptor expression and functionality, and (ii) dopamine-related gene expression (tyrosine hydroxylase, Th; dopamine type-1 receptor, Drd1; dopamine type-2 receptor, Drd2) within the prefrontal cortex (PFC), which is involved in sensory perception of food and reward sensitivity, and the hippocampus, a brain area sensitive to food composition and pivotal in learning and memory processes related to feeding behaviour. Here, we show that leptin treatment triggered leptin resistance both in the hippocampus and in the PFC. In contrast, leptin induced the upregulation of dopamine-related genes in the PFC, whereas it failed to modify the expression of these genes in the hippocampus. The effect of leptin was similar irrespective of the time elapsed since the last leptin administration (either 2 or 14 h), indicating that the effect detected was not associated with leptin withdrawal. Our data show that leptin receptor desensitization is coincident with the upregulation of dopamine-related genes in the PFC of adolescent mice undergoing hyperleptinaemia triggered by exogenous leptin. 
27031567	Behavioral control is influenced not only by learning from the choices made and the rewards obtained but also by "what might have happened," that is, inference about unchosen options and their fictive outcomes. Substantial progress has been made in understanding the neural signatures of direct learning from choices that are actually made and their associated rewards via reward prediction errors (RPEs). However, electrophysiological correlates of abstract inference in decision-making are less clear. One seminal theory suggests that the so-called feedback-related negativity (FRN), an ERP peaking 200-300 msec after a feedback stimulus at frontocentral sites of the scalp, codes RPEs. Hitherto, the FRN has been predominantly related to a so-called "model-free" RPE: The difference between the observed outcome and what had been expected. Here, by means of computational modeling of choice behavior, we show that individuals employ abstract, "double-update" inference on the task structure by concurrently tracking values of chosen stimuli (associated with observed outcomes) and unchosen stimuli (linked to fictive outcomes). In a parametric analysis, model-free RPEs as well as their modification because of abstract inference were regressed against single-trial FRN amplitudes. We demonstrate that components related to abstract inference uniquely explain variance in the FRN beyond model-free RPEs. These findings advance our understanding of the FRN and its role in behavioral adaptation. This might further the investigation of disturbed abstract inference, as proposed, for example, for psychiatric disorders, and its underlying neural correlates. 
27030510	Human altruism is often expressed through charitable donation-supporting a cause that benefits others in society, at cost to oneself. The underlying mechanisms of this other-regarding behavior remain imperfectly understood. By recording event-related-potential (ERP) measures of brain activity from human participants during a social gambling task, we identified markers of differential responses to receipt of monetary outcomes for oneself vs for a charitable cause. We focused our ERP analyses on the frontocentral feedback-related negativity (FRN) and three subcomponents of the attention-related P300 (P3) brain wave: the frontocentral P2 and P3a and the parietal P3b. The FRN distinguished between gains and losses for both self and charity outcomes. Importantly, this effect of outcome valence was greater for self than charity for both groups and was independent of two altruism-related measures: participants' pre-declared intended donations and the actual donations resulting from their choices. In contrast, differences in P3 subcomponents for outcomes for self vs charity strongly predicted both of our laboratory measures of altruism-as well as self-reported engagement in real-life altruistic behaviors. These results indicate that individual differences in altruism are linked to individual differences in the relative deployment of attention (as indexed by the P3) toward outcomes affecting other people.


27029021	Addictive drugs modulate synaptic transmission in the meso-corticolimbic system by hijacking normal adaptive forms of experience-dependent synaptic plasticity. Psychostimulants such as METH have been shown to affect hippocampal synaptic plasticity, albeit with a less understood synaptic mechanism. METH is one of the most addictive drugs that elicit long-term alterations in the synaptic plasticity in brain areas involved in reinforcement learning and reward processing. Dopamine transporter (DAT) is one of the main targets of METH. As a substrate for DAT, METH decreases dopamine uptake and increases dopamine efflux via the transporter in the target brain regions such as nucleus accumbens (NAc) and hippocampus. Due to cross talk between NAc and hippocampus, stimulation of NAc has been shown to alter hippocampal plasticity. In this study, we tested the hypothesis that manipulation of glutamatergic and GABA-ergic systems in the shell-NAc modulates METH-induced enhancement of long term potentiation (LTP) in the hippocampus. Rats treated with METH (four injections of 5 mg/kg) exhibited enhanced LTP as compared to saline-treated animals. Intra-NAc infusion of muscimol (GABA receptor agonist) decreased METH-induced enhancement of dentate gyrus (DG)-LTP, while infusion of AP5 (NMDA receptor antagonist) prevented METH-induced enhancement of LTP. These data support the interpretation that reducing NAc activity can ameliorate METH-induced hippocampal LTP through a hippocampus-NAc-VTA circuit loop. Synapse 70:325-335, 2016. © 2016 Wiley Periodicals, Inc. 
27023366	Measures of neuronal activation are a natural and parsimonious translational biomarker to consider in the context of neuropsychiatric drug discovery studies. In this regard, functional neuroimaging using the BOLD fMRI technique is becoming more frequently employed to not only probe aberrant brain regions and circuits in disease, but also to assess the effects of novel pharmacological agents on these processes. In the ideal situation, these types of studies would first be conducted pre-clinically in rodents to confirm a measurable functional response on relevant brain circuits before seeking to replicate the findings in an analogous fMRI paradigm in humans. However, the need for animal immobilization during the scanning procedure precludes all but the simplest behavioural task-based paradigms in rodent BOLD fMRI. This chapter considers how in vivo oxygen amperometry may represent a viable and valid proxy for BOLD fMRI in freely moving rodents engaged in behavioural tasks. The amperometric technique and several examples of emerging evidence are described to show how the technique can deliver results that translate to pharmacological, event-related and functional connectivity variants of fMRI. In vivo oxygen amperometry holds great promise as a technique that may help to bridge the gap between basic drug discovery research in rodents and applied efficacy testing in humans. 
27021283	It is well established that learning can occur without external feedback, yet normative reinforcement learning theories have difficulties explaining such instances of learning. Here, we propose that human observers are capable of generating their own feedback signals by monitoring internal decision variables. We investigated this hypothesis in a visual perceptual learning task using fMRI and confidence reports as a measure for this monitoring process. Employing a novel computational model in which learning is guided by confidence-based reinforcement signals, we found that mesolimbic brain areas encoded both anticipation and prediction error of confidence-in remarkable similarity to previous findings for external reward-based feedback. We demonstrate that the model accounts for choice and confidence reports and show that the mesolimbic confidence prediction error modulation derived through the model predicts individual learning success. These results provide a mechanistic neurobiological explanation for learning without external feedback by augmenting reinforcement models with confidence-based feedback. 
27016362	Learning and motivation are two psychological processes allowing animals to form and express Pavlovian associations between a conditioned stimulus (CS) and an unconditioned stimulus (UCS). However, most models have attempted to capture the mechanisms of learning while neglecting the role that motivation (or incentive salience) may actively play in the expression of behaviour. There is now a body of neurobehavioural evidence showing that incentive salience represents a major determinant of Pavlovian performance. This article presents a motivational model of sign-tracking behaviour whose aim is to explain a wide range of behavioural effects, including those related to partial reinforcement, physiological changes, competition between CSs, and individual differences in responding to a CS. In this model, associative learning is assumed to determine the ability to produce a Pavlovian conditioned response rather than to control the strength and the quality of that response. The model is in keeping with the incentive salience hypothesis and will therefore be discussed in the context of dopamine's role in the brain. 
27016155	Delay discounting describes the tendency for organisms to devalue outcomes because they are delayed. Robust, positive correlations exist between excessive delay discounting and many maladaptive behaviors (e.g., substance abuse, obesity). Several studies have demonstrated that delay discounting can be reduced and this may hold promise for improving treatment outcomes. One method of reducing delay discounting provides rats with extended training with delayed reinforcement (i.e., delay-exposure training) and this significantly reduces impulsive choices, relative to rats trained with an equal number of immediate-reinforcement sessions (i.e., immediate-exposure training). To evaluate the stability of this effect, 12 weanling male Wistar rats were randomly assigned to receive either delay-exposure or immediate-exposure training for 120 sessions. Impulsive choice was assessed using an increasing-delay procedure immediately following training and 120 days after completion of the initial assessment. Delay-exposed rats discounted delayed food rewards significantly less than immediate-exposed rats in the initial assessment and the reassessment conducted 120 days later. These results are encouraging as they suggest that the effects of delay-exposure training are robust to the passage of time and intervening experience.
27015893	Spermine and spermidine are natural polyamines that are produced mainly via decarboxylation of l-ornithine and the sequential transfer of aminopropyl groups from S-adenosylmethionine to putrescine by spermidine synthase and spermine synthase. Spermine and spermidine interact with intracellular and extracellular acidic residues of different nature, including nucleic acids, phospholipids, acidic proteins, carboxyl- and sulfate-containing polysaccharides. Therefore, multiple actions have been suggested for these polycations, including modulation of the activity of ionic channels, protein synthesis, protein kinases, and cell proliferation/death, within others. In this review we summarize these neurochemical/neurophysiological/morphological findings, particularly those that have been implicated in the improving and deleterious effects of spermine and spermidine on learning and memory of naïve animals in shock-motivated and nonshock-motivated tasks, from a historical perspective. The interaction with the opioid system, the facilitation and disruption of morphine-induced reward and the effect of polyamines and putative polyamine antagonists on animal models of cognitive diseases, such as Alzheimer's, Huntington, acute neuroinflammation and brain trauma are also reviewed and discussed. The increased production of polyamines in Alzheimer's disease and the biphasic nature of the effects of polyamines on memory and on the NMDA receptor are also considered. In light of the current literature on polyamines, which include the description of an inborn error of the metabolism characterized by mild-to moderate mental retardation and polyamine metabolism alterations in suicide completers, we can anticipate that polyamine targets may be important for the development of novel strategies and approaches for understanding the etiopathogenesis of important central disorders and their pharmacological treatment.
27015724	Maternal major depressive disorder (MDD) increases risk for MDD and predicts reduced reward responding in adolescent offspring. However, it is unclear whether alterations in neural response to reward can be detected in school-aged children at high risk before the typical increase in reward response observed in adolescence.To assess relationships between neural response to gain/loss feedback, MDD risk, and child depressive symptoms, 47 psychiatrically healthy 7- to 10-year-old children (16 at high risk given maternal MDD) completed questionnaires and a functional magnetic resonance imaging (fMRI) card-guessing game in which candy was gained and lost.	High-risk children showed both blunted response to gain and greater deactivation/reduced activation to loss within the ventral striatum and anterior insula. Within the striatum, risk-group differences in response to loss feedback were significantly larger than for gain, with greater deactivation to loss predicting risk-group status above and beyond blunted gain activation. Anhedonia was related to reduced deactivation to loss (i.e., reduced sensitivity to loss), whereas negative mood was related to enhanced deactivation to loss (i.e., enhanced sensitivity to loss) in the ventral striatum.	High-risk children showed blunted ventral striatal activation to gain feedback, but ventral striatal deactivation to loss was a stronger predictor of MDD risk. Furthermore, relationships between response to loss and elevated depressive symptoms within the ventral striatum and cingulate differed depending on the type of depressive symptom. Together these results highlight the potentially important role of response to loss of reward in childhood risk for depression.	
27014885	To investigate the correlation of occupational stress with the serum levels of immunoglobulins(IgG, IgM, and IgA) and complement(C3 and C4).In May 2011, convenience sampling and cluster sampling were used to select 225 policemen from a local police station as study subjects. A questionnaire was used to investigate demographic features and occupational stress, and the immunoturbidimetric assay was applied to measure the serum levels of IgG, IgM, IgA, and complement C3 and C4.	Positive affectivity was positively correlated with the concentration of IgG(r=0.084, P<0.01); positive affectivity, coping strategy, and sleep quality were positively correlated with the concentration of IgM(r= 0.146, 0.155, and 0.203, all P<0.05); negative affectivity was negatively correlated with the concentration of IgM(r=-0.185, P<0.05). Reward and sleep quality were positively correlated with the concentration of C3(r= 0.172 and 0.285, both P<0.05), and negative affectivity was negatively correlated with the concentration of C3 (r=-0.174, P<0.05); sleep quality was positively correlated with the concentration of C4(r= 0.173, P<0.05), and negative affectivity was negatively correlated with the concentration of C4(r=-0.164, P<0.05). The logistic regression analysis revealed that the risks for a reduced concentration of IgG in the groups with high scores of social support and positive affectivity were 0.460 and 0.495 times those in the groups with low scores, while the risk for a reduced concentration of IgM in the group with a high score of coping strategy was 0.482 times that in the group with a low score.	Occupational stress is correlated with the serum levels of immunoglobulins and complement.	
27014102	Auditory verbal hallucinations (AVHs) are a hallmark of schizophrenia and can significantly impair patients' emotional, social, and occupational functioning. Despite progress in psychopharmacology, over 25% of schizophrenia patients suffer from treatment-resistant hallucinations. In the search for alternative treatment methods, neurofeedback (NF) emerges as a promising therapy tool. NF based on real-time functional magnetic resonance imaging (rt-fMRI) allows voluntarily change of the activity in a selected brain region - even in patients with schizophrenia. This study explored effects of NF on ongoing AVHs. The selected participants were trained in the self-regulation of activity in the anterior cingulate cortex (ACC), a key monitoring region involved in generation and intensity modulation of AVHs. Using rt-fMRI, three right-handed patients, suffering from schizophrenia and ongoing, treatment-resistant AVHs, learned control over ACC activity on three separate days. The effect of NF training on hallucinations' severity was assessed with the Auditory Vocal Hallucination Rating Scale (AVHRS) and on the affective state - with the Positive and Negative Affect Schedule (PANAS). All patients yielded significant upregulation of the ACC and reported subjective improvement in some aspects of AVHs (AVHRS) such as disturbance and suffering from the voices. In general, mood (PANAS) improved during NF training, though two patients reported worse mood after NF on the third day. ACC and reward system activity during NF learning and specific effects on mood and symptoms varied across the participants. None of them profited from the last training set in the prolonged three-session training. Moreover, individual differences emerged in brain networks activated with NF and in symptom changes, which were related to the patients' symptomatology and disease history. NF based on rt-fMRI seems a promising tool in therapy of AVHs. The patients, who suffered from continuous hallucinations for years, experienced symptom changes that may be attributed to the NF training. In order to assess the effectiveness of NF as a therapeutic method, this effect has to be studied systematically in larger groups; further, long-term effects need to be assessed. Particularly in schizophrenia, future NF studies should take into account the individual differences in reward processing, fatigue, and motivation to develop individualized training protocols. 
27013685	Midline thalamus is implicated in linking visceral and exteroceptive sensory information with behavior. However, whether neuronal activity is modulated with temporal precision by cues and actions in real time is unknown. Using single-neuron recording and a Pavlovian visual-cue/liquid-reward association task in rats, we discovered phasic responses to sensory cues, appropriately timed to modify information processing in output targets, as well as tonic modulations within and between trials that were differentially reward modulated, which may have distinct arousal functions. Many of the cue-responsive neurons also responded to repetitive licks, consistent with sensorimotor integration. Further, some lick-related neurons were activated only by the first rewarded lick and only if that lick were also part of a conditioned response sequence initiated earlier, consistent with binding action decisions to their ensuing outcome. This rich repertoire of responses provides electrophysiological evidence for midline thalamus as a site of complex information integration for reward-mediated behavior.Disparate brain circuits are involved in sensation, movement, and reward information. These must interact in order for the relationships between cues, actions, and outcomes to be learned. We found that responses of single neurons in midline thalamus to sensory cues are increased when associated with reward. This output may amplify similar signals generated in parallel by the dopamine system. In addition, some neurons coded a three-factor decision in which the neuron fired only if there was a movement, if it was the first one after the reward becoming available, and if it was part of a sequence triggered in response to a preceding cue. These data highlight midline thalamus as an important node integrating multiple types of information for linking sensation, actions, and rewards.	
27013677	The neurobiological processes underpinning the natural forgetting of long-term memories are poorly understood. Based on the critical role of GluA2-containing AMPA receptors (GluA2/AMPARs) in long-term memory persistence, we tested in rats whether their synaptic removal underpins time-dependent memory loss. We found that blocking GluA2/AMPAR removal with the interference peptides GluA23Y or G2CT in the dorsal hippocampus during a memory retention interval prevented the normal forgetting of established, long-term object location memories, but did not affect their acquisition. The same intervention also preserved associative memories of food-reward conditioned place preference that would otherwise be lost over time. We then explored whether this forgetting process could play a part in behavioral phenomena involving time-dependent memory change. We found that infusing GluA23Y into the dorsal hippocampus during a 2 week retention interval blocked generalization of contextual fear expression, whereas infusing it into the infralimbic cortex after extinction of auditory fear prevented spontaneous recovery of the conditioned response. Exploring possible physiological mechanisms that could be involved in this form of memory decay, we found that bath application of GluA23Y prevented depotentiation, but not induction of long-term potentiation, in a hippocampal slice preparation. Together, these findings suggest that a decay-like forgetting process that involves the synaptic removal of GluA2/AMPARs erases consolidated long-term memories in the hippocampus and other brain structures over time. This well regulated forgetting process may critically contribute to establishing adaptive behavior, whereas its dysregulation could promote the decline of memory and cognition in neuropathological disorders.The neurobiological mechanisms involved in the natural forgetting of long-term memory and its possible functions are not fully understood. Based on our previous work describing the role of GluA2-containing AMPA receptors in memory maintenance, here, we tested their role in forgetting of long-term memory. We found that blocking their synaptic removal after long-term memory formation extended the natural lifetime of several forms of memory. In the hippocampus, it preserved spatial memories and inhibited contextual fear generalization; in the infralimbic cortex, it blocked the spontaneous recovery of extinguished fear. These findings suggest that a constitutive decay-like forgetting process erases long-term memories over time, which, depending on the memory removed, may critically contribute to developing adaptive behavioral responses.	


27012303	G protein-gated inwardly rectifying potassium (GIRK) channels contribute to the effects of a number of drugs of abuse, including ethanol. However, the roles of individual subunits in the rewarding effects of ethanol are poorly understood.We compare conditioned place preference (CPP) in GIRK3 subunit knock-out (GIRK3(-/-)), heterozygote (GIRK3(+/-)), and wild-type (WT) mice. In addition, the development of locomotor tolerance/sensitization and the effects of EtOH intoxication on associative learning (fear conditioning) are also assessed.	Our data show significant EtOH CPP in GIRK3(-/-) and GIRK3(+/-) mice, but not in the WT littermates. In addition, we demonstrate that these effects are not due to differences in EtOH metabolism, the development of EtOH tolerance/sensitivity, or associative learning abilities. While there were no consistent genotype differences in the fear conditioning assay, our data do show a selective sensitization of the impairing effects of EtOH intoxication on contextual learning, but no effect on cued learning.	These findings suggest that GIRK3 plays a role in EtOH reward. Furthermore, the selectivity of this effect suggests that GIRK channels could be an effective therapeutic target for the prevention and/or treatment of alcoholism.	
27012102	I think that medicine for patients with severe motor and intellectual disabilities (SMID) should aim to help them and their families to promote a better quality of life in their communities by building multidisciplinary networks. Below, I mention four personal opinions on why I find working with medicine for SMID patients attractive: 1. Sharing in the joy experienced by SMID patients and their family members as they learn to cope with SMID and grow as people. When I see how patients who are affected by SMID and their family members grow and lead fulfilling lives, I feel that my work has been richly rewarded. 2. The joy of being considered reliable and appreciated. I feel highly rewarded when I earn the trust of the family members, and I get a word of gratitude from them. 3. Enjoying the experience of working with ingenious and team medicine. I experience a feeling of accomplishment after engaging in intense discussions on successful preventive innominate transections. 4. The opportunity to make a social contribution. I believe that I can contribute to making our world more livable to a greater number of people. To spread awareness about the attractiveness of SMID medicine, I provide SMID medicine education at Nagoya University. My lectures and training are attended by patients with SMID and their families. I also hope that many young doctors become interested in SMID medicine and find it an enjoyable experience.
27011364	A growing body of research suggests that bipolar disorders (BD) are associated with high impulsivity. Using a multi-method approach, the current study provided the first examination of the hypothesis that impulsivity would prospectively predict shorter time to onset of DSM-IV-TR or RDC hypomanic or manic episodes in a sample selected based on reward sensitivity, a biobehavioral trait shown to predict onset and course of BD.163 participants with high reward sensitivity and 114 participants with moderate reward sensitivity were followed every six months for an average of 2.68 years. Participants completed the Barratt Impulsiveness Scale - Version 11 (BIS-11), Balloon Analog Risk Task (BART), Beck Depression Inventory, Altman Self-Rating Mania Scale, and an expanded Schedule for Affective Disorders and Schizophrenia (exp-SADS) - Lifetime Version at baseline and were followed prospectively with the exp-SADS - Change Version to assess onset of hypomanic or manic episodes and treatment seeking for mood problems.	Cox proportional hazard regression analyses indicated that impulsivity as measured by a behavioral task (BART; OR=1.04, p=.03) and a self-report measure (BIS-11 Attentional Impulsiveness subscale; OR=1.16, p=.01) predicted shorter time to hypomania/mania onset, after controlling for baseline depressive and manic symptoms, family history of mood disorder, treatment seeking for mood problems, and reward sensitivity.	The study was limited by non-comprehensive assessment of impulsivity and unknown generalizability to clinical samples.	Impulsivity confers vulnerability to hypomania or mania. Future studies would benefit from considering how impulsivity can be integrated into existing biopsychosocial models of BD.	
27010492	Pediatric obesity is a growing public health concern that contributes to high rates of negative long-term physical and mental health outcomes. Research focused on identifying risk for pediatric obesity has linked delay discounting, or an inclination for immediate rewards, as well as weight concern to individuals with greater Body Mass Index (BMI). The current study seeks to fill a void in the literature by examining how these two variables interact to promote higher BMI in female adolescents.Adolescent (n=60) females between the ages of 13-19years (mage=17.45, SD=1.74) of age completed the Eating Disorder Examination Questionnaire (EDE-Q) and the Delay Discounting Questionnaire.	A mediation model examined whether delay discounting accounted for the relationship between weight concern and BMI. Results indicate that in the current study weight concern was negatively related to delay discounting and delay discounting was negatively related to BMI. The overall model revealed that a partial mediation occurred [b=1.28, t(60)=4.92, p<0.01].	These results suggest that while impulsivity is an important factor to consider, other constructs may also be influential in how weight concerns contribute to greater BMI. Nevertheless, the results indicate that prevention and interventions should identify females with high levels of both weight concern and impulsivity as an increased risk for experiencing pediatric obesity and long-term negative health outcomes.	
27009582	With the expiry of the Health Accords, provincial governments must face the challenge of improving performance in the context of ageing demographics, increasing multi-morbidity, and real concerns about financial stability. The Institute for Healthcare Improvement Triple Aim articulates fundamental goals that can guide health system transformation: improved population health, enhanced patient experience and reduced or stable per capita costs. Advancing fragmented and costly health systems in pursuit of these goals requires transformative, as opposed to iterative, change. Provincial governments are ideally suited to lead this change by acting as "integrators" who link healthcare organizations and align incentives across the spectrum of delivery. Although there is very limited evidence regarding the effectiveness of system-level reforms, we draw on initiatives from around the world to suggest policies that can promote system-level Triple Aim innovation. We categorize these policies within the classic functions ascribed to health systems: financing, stewardship and resource generation. As healthcare financers, governments should orient procurement policy towards the Triple Aim innovation and reform payment to reward value not volume. As health system stewards, governments should define a Triple Aim vision; measure and report outcomes, patient experience, and costs; integrate across sectors; and facilitate learning from failure and spread of successful innovation. As resource generators, governments should invest in health information technology to exploit "big data" and ensure that professional education equips front-line clinicians with skills necessary to improve systems. There are a number of barriers to system-level Triple Aim innovation. There is a lack of evidence for macro-level policy changes, innovation is costly and complicated, and system reform may not be politically appealing. Triple Aim innovation may also be conflated with organization-level quality improvement initiatives. These barriers can be overcome with effective leadership. A mandate and funding to evaluate reforms can be built into laws. Innovation can be funded by shared savings and health gains. Reform may be more politically viable in the current climate of austerity. The Triple Aim framework offers aspirational and concrete objectives that should be integrated into the health system design by Canadian provincial governments to improve health system performance. 
27007845	A marked bias towards risk aversion has been observed in nearly every species tested. A minority of individuals, however, instead seem to prefer risk (repeatedly choosing uncertain large rewards over certain but smaller rewards), and even risk-averse individuals sometimes opt for riskier alternatives. It is not known how neural activity underlies such important shifts in decision-making--either as a stable trait across individuals or at the level of variability within individuals. Here we describe a model of risk-preference in rats, in which stable individual differences, trial-by-trial choices, and responses to pharmacological agents all parallel human behaviour. By combining new genetic targeting strategies with optical recording of neural activity during behaviour in this model, we identify relevant temporally specific signals from a genetically and anatomically defined population of neurons. This activity occurred within dopamine receptor type-2 (D2R)-expressing cells in the nucleus accumbens (NAc), signalled unfavourable outcomes from the recent past at a time appropriate for influencing subsequent decisions, and also predicted subsequent choices made. Having uncovered this naturally occurring neural correlate of risk selection, we then mimicked the temporally specific signal with optogenetic control during decision-making and demonstrated its causal effect in driving risk-preference. Specifically, risk-preferring rats could be instantaneously converted to risk-averse rats with precisely timed phasic stimulation of NAc D2R cells. These findings suggest that individual differences in risk-preference, as well as real-time risky decision-making, can be largely explained by the encoding in D2R-expressing NAc cells of prior unfavourable outcomes during decision-making.
27005734	The prevalence rates of overweight and obesity are, internationally as well as in Switzerland, increasing in recent years. The neurobiology tries to explore an improved understanding of the central nervous causes of obesity. Findings from addiction research seem very useful because there are certain similarities between addiction and obesity in terms of neurobiological causes. An improved understanding of the disease of obesity could help to develop more effective therapies for obese patients in the future. Further research, e. g. in the field of stress regulation, is thus urgently needed.
27005398	Honey bees have the ability to detect the Earth's magnetic field, and the suspected magnetoreceptors are the iron granules in the abdomens of the bees. To identify the sensing route of honey bee magnetoreception, we conducted a classical conditioning experiment in which the responses of the proboscis extension reflex (PER) were monitored. Honey bees were successfully trained to associate the magnetic stimulus with a sucrose reward after two days of training. When the neural connection of the ventral nerve cord (VNC) between the abdomen and the thorax was cut, the honey bees no longer associated the magnetic stimulus with the sucrose reward but still responded to an olfactory PER task. The neural responses elicited in response to the change of magnetic field were also recorded at the VNC. Our results suggest that the honey bee is a new model animal for the investigation of magnetite-based magnetoreception. 
27003189	Anxiety and social deficits, often involving communication impairment, are fundamental clinical features of fragile X syndrome. There is growing evidence that dysregulation in reward processing is a contributing factor to the social deficits observed in many psychiatric disorders. Hence, we hypothesized that transgenic fragile X mental retardation 1 gene (fmr1) KO (FX) rats would display alterations in reward processing. To this end, awake control and FX rats were imaged for changes in blood oxygen level dependent (BOLD) signal intensity in response to the odor of almond, a stimulus to elicit the innate reward response. Subjects were 'odor naive' to this evolutionarily conserved stimulus. The resulting changes in brain activity were registered to a three-dimensional segmented, annotated rat atlas delineating 171 brain regions. Both wild-type (WT) and FX rats showed robust brain activation to a rewarding almond odor, though FX rats showed an altered temporal pattern and tended to have a higher number of voxels with negative BOLD signal change from baseline. This pattern of greater negative BOLD was especially apparent in the Papez circuit, critical to emotional processing and the mesolimbic/habenular reward circuit. WT rats showed greater positive BOLD response in the supramammillary area, whereas FX rats showed greater positive BOLD response in the dorsal lateral striatum, and greater negative BOLD response in the retrosplenial cortices, the core of the accumbens and the lateral preoptic area. When tested in a freely behaving odor-investigation paradigm, FX rats failed to show the preference for almond odor which typifies WT rats. However, FX rats showed investigation profiles similar to WT when presented with social odors. These data speak to an altered processing of this highly salient novel odor in the FX phenotype and lend further support to the notion that altered reward systems in the brain may contribute to fragile X syndrome symptomology. 
27001827	Dysfunctional reward processing is implicated in various mental disorders, including attention deficit hyperactivity disorder (ADHD) and addictions. Such impairments might involve different components of the reward process, including brain activity during reward anticipation. We examined brain nodes engaged by reward anticipation in 1,544 adolescents and identified a network containing a core striatal node and cortical nodes facilitating outcome prediction and response preparation. Distinct nodes and functional connections were preferentially associated with either adolescent hyperactivity or alcohol consumption, thus conveying specificity of reward processing to clinically relevant behavior. We observed associations between the striatal node, hyperactivity, and the vacuolar protein sorting-associated protein 4A (VPS4A) gene in humans, and the causal role of Vps4 for hyperactivity was validated in Drosophila Our data provide a neurobehavioral model explaining the heterogeneity of reward-related behaviors and generate a hypothesis accounting for their enduring nature. 
27001642	Addiction to a wide range of substances of abuse has been suggested to reflect a 'Reward Deficiency Syndrome'. That is, drugs are said to stimulate the reward mechanisms so intensely that, to compensate, the population of dopamine D2 receptors (DD2R) declines. The result is that an increased intake is necessary to experience the same degree of reward. Without an additional intake, cravings and withdrawal symptoms result. A suggestion is that food addiction, in a similar manner to drugs of abuse, decrease DD2R. The role of DD2R in obesity was therefore examined by examining the association between body mass index (BMI) and the Taq1A polymorphism, as the A1 allele is associated with a 30-40% lower number of DD2R, and is a risk factor for drug addiction. If a lower density of DD2R is indicative of physical addiction, it was argued that if food addiction occurs, those with the A1 allele should have a higher BMI. A systematic review found 33 studies that compared the BMI of those who did and did not have the A1 allele. A meta-analysis of the studies compared those with (A1/A1 and A1/A2) or without (A2/A2) the A1 allele; no difference in BMI was found (standardized mean difference 0.004 (s.e. 0.021), variance 0.000, Z=0.196, P<0.845). It was concluded that there was no support for a reward deficiency theory of food addiction. In contrast, there are several reports that those with the A1 allele are less able to benefit from an intervention that aimed to reduce weight, possibly a reflection of increased impulsivity. 
26999282	Motivational deficits in schizophrenia are proposed to be attributable in part to abnormal effort-cost computations. Inflated subjective cognitive effort costs may explain diminished functioning in schizophrenia to the extent that they drive avoidance of complex decision-making and planning. Although previous data support inflated subjective physical effort costs for individuals with schizophrenia, evidence on cognitive effort is mixed. We exploited the methodological advantages of a recently developed cognitive effort-discounting paradigm (Westbrook, Kester, & Braver, 2013) to examine effort-cost computations in schizophrenia. The paradigm quantifies subjective costs in terms of explicit, continuous discounting of monetary rewards based on parametrically varied demands (levels N of the N-back working memory task), holding objective features of task duration and reward likelihood constant. Both healthy participants (N = 25) and schizophrenia patients (N = 25) showed systematic influences of reward and task demands on choice patterns. Critically, however, participants with schizophrenia discounted rewards more steeply as a function of effort, indicating that effort was more costly for this group. Moreover, discounting varied robustly with symptomatology, such that schizophrenia patients with greater clinically rated negative symptom severity discounted rewards more steeply. These findings extend the current literature on abnormal-effort cost computations in schizophrenia by establishing a clear relationship between the costliness of cognitive effort and negative symptoms. (PsycINFO Database Record
26999046	Prior research illustrates that memory can guide value-based decision-making. For example, previous work has implicated both working memory and procedural memory (i.e., reinforcement learning) in guiding choice. However, other types of memories, such as episodic memory, may also influence decision-making. Here we test the role for episodic memory-specifically item versus associative memory-in supporting value-based choice. Participants completed a task where they first learned the value associated with trial unique lotteries. After a short delay, they completed a decision-making task where they could choose to reengage with previously encountered lotteries, or new never before seen lotteries. Finally, participants completed a surprise memory test for the lotteries and their associated values. Results indicate that participants chose to reengage more often with lotteries that resulted in high versus low rewards. Critically, participants not only formed detailed, associative memories for the reward values coupled with individual lotteries, but also exhibited adaptive decision-making only when they had intact associative memory. We further found that the relationship between adaptive choice and associative memory generalized to more complex, ecologically valid choice behavior, such as social decision-making. However, individuals more strongly encode experiences of social violations-such as being treated unfairly, suggesting a bias for how individuals form associative memories within social contexts. Together, these findings provide an important integration of episodic memory and decision-making literatures to better understand key mechanisms supporting adaptive behavior.
26997364	Reward is known to affect visual search performance. Rewarding targets can increase search performance, whereas rewarding distractors can decrease search performance. We used subcomponents of the N2pc in the event-related EEG, the NT (target negativity) and ND /PD (distractor negativity/positivity), in a visual search task to disentangle target and distractor processing related to reward. The visual search task comprised homogeneous and heterogeneous contexts in which a target and a colored distractor were embedded. After each correct trial, participants were given a monetary reward that depended on the color of the distractor. We found longer response times for displays with high-reward distractors compared to displays with low-reward distractors, indicating reward-induced interference, however, only for heterogeneous contexts. The NT component, indicative of attention deployment to the target, showed that target selection was impaired by high-reward distractors, regardless of the context homogeneity. Processing of distractors was not affected by reward in homogeneous contexts. In heterogeneous contexts, however, high-reward distractors were more likely to capture attention (ND ) and required more effort to be suppressed (PD ) than low-reward distractors. In sum the results showed that, despite the fact that target selection is impaired by high-reward distractors in both homogeneous and heterogeneous background contexts, high-reward distractors capture attention only in scenarios that foster attentional capture. 

26996511	In a continuously changing environment, in which behavioral outcomes are rarely certain, animals must be able to learn to integrate feedback from their choices over time and adapt to changing reward contingencies to maintain flexible behavior. The orbitofrontal region of prefrontal cortex (OFC) has been widely implicated as playing a role in the ability to flexibly control behavior. We used a probabilistic reversal learning task to measure rats' behavioral flexibility and its neural basis in the activity of single neurons in OFC. In this task, one lever, designated as 'correct', was rewarded at a high probability (80%) and a second, spatially distinct lever, designated as 'incorrect', was rewarded at a low probability (20%). Once rats reached a learning criterion for reliably selecting the correct lever, reward contingencies of the two levers were switched, and daily sessions were conducted until rats reliably selected the new correct lever. All rats performed the initial Acquisition and subsequent Reversal successfully, with more sessions needed to learn the Reversal. OFC neurons were recorded during five behavioral sessions spanning Acquisition and Reversal learning. The dominant pattern of neural responding in OFC, identified by principal component analysis of the population of neurons recorded, was modulated by reward outcome across behavioral sessions. Generally, activity was higher following rewarded choices than unrewarded. However, there was a correlation between reduced responses to reward following incorrect choices and the establishment of the preference for the correct lever. These results show how signaling by individual OFC neurons may participate in the flexible adaptation of behavior under changing reward contingencies.
26995186	How unappealing are individuals who behave badly towards others? We show here that children and even infants, although motivated by material rewards, are nonetheless willing to incur costs to avoid "doing business" with a wrongdoer. When given the choice to accept a smaller offering from a do-gooder or a larger offering from a wrongdoer, children and infants chose to accept the smaller offering. It was only when the difference between the offerings was very large that their aversion to the wrongdoer was overcome by personal incentives. These findings show that a willingness to forgo self-interests when faced with wrongdoers is a fundamental aspect of human nature. 
26993471	Diabetes is an increasing public health problem in the UK and globally. Diabetic retinopathy is a microvascular complication of diabetes, and is one of the leading causes of blindness in the UK working age population. The diabetic eye screening programme in England aims to invite all people with diabetes aged 12 or over for retinal photography to screen for the presence of diabetic retinopathy. However, attendance rates are only 81 %, leaving many people at risk of preventable sight loss.This is a three arm randomized controlled trial to investigate the impact of different types of financial incentives (based on principles from behavioral economics) on increasing attendance at diabetic eye screening appointments in London. Eligible participants will be aged 16 or over, and are those who have been invited to screening appointments annually, but who have not attended, or telephoned to rearrange an appointment, within the last 24 months. Eligible participants will be randomized to one of three conditions: 1. Control condition (usual invitation letter) 2. Fixed incentive condition (usual invitation letter, including a voucher for £10 if they attend their appointment) 3. Probabilistic incentive condition (invitation letter, including a voucher for a 1 in 100 chance of winning £1000 if they attend their appointment). Participants will be sent invitation letters, and the primary outcome will be whether or not they attend their appointment. One thousand participants will be included in total, randomized with a ratio of 1.4:1:1. In order to test whether the incentive scheme has a differential impact on patients from different demographic or socio-economic groups, information will be recorded on age, gender, distance from screening center, socio-economic status and length of time since they were last screened. A cost-effectiveness analysis will also be performed.	This study will be the first trial of financial incentives for improving uptake of diabetic eye screening. If effective, the intervention may suggest a cost-effective way to increase screening rates, thus reducing unnecessary blindness.	ISRCTN14896403, 25 February 2016.	
26993372	Despite numerous clinical trials no efficacious medications for methamphetamine (MA) have been identified. Neuroinflammation, which has a role in MA-related reward and neurodegeneration, is a novel MA pharmacotherapy target. Ibudilast inhibits activation of microglia and pro-inflammatory cytokines and has reduced MA self-administration in preclinical research. This study examined whether ibudilast would reduce subjective effects of MA in humans.Adult, non-treatment seeking, MA-dependent volunteers (N=11) received oral placebo, moderate ibudilast (40 mg), and high-dose ibudilast (100mg) via twice-daily dosing for 7 days each in an inpatient setting. Following infusions of saline, MA 15 mg, and MA 30 mg participants rated 12 subjective drug effects on a visual analog scale (VAS).	As demonstrated by statistically-significant ibudilast × MA condition interactions (p<.05), ibudilast reduced several MA-related subjective effects including High, Effect (i.e., any drug effect), Good, Stimulated and Like. The ibudilast-related reductions were most pronounced in the MA 30 mg infusions, with ibudilast 100mg significantly reducing Effect (97.5% CI [-12.54, -2.27]), High (97.5% CI [-12.01, -1.65]), and Good (97.5% CI [-11.20, -0.21]), compared to placebo.	Ibudilast appeared to reduce reward-related subjective effects of MA in this early-stage study, possibly due to altering the processes of neuroinflammation involved in MA reward. Given this novel mechanism of action and the absence of an efficacious medication for MA dependence, ibudilast warrants further study to evaluate its clinical efficacy.	
26993151	Behavioral economics and neuroeconomics bring together perspectives and methods from psychology, economics, and cognitive neuroscience to understand decision making and choice behavior. Extending an operant behavioral theoretical framework, these perspectives have increasingly been applied to understand the alcohol use disorders (AUDs), and this review surveys the theory, methods, and findings from this approach. The focus is on 3 key behavioral economic concepts: delay discounting (i.e., preferences for smaller immediate rewards relative to larger delayed rewards), alcohol demand (i.e., alcohol's reinforcing value), and proportionate alcohol-related reinforcement (i.e., relative amount of psychosocial reinforcement associated with alcohol use).Delay discounting has been linked to AUDs in both cross-sectional and longitudinal studies and has been investigated cross-sectionally using neuroimaging. Alcohol demand and proportionate alcohol-related reinforcement have both been robustly associated with drinking and alcohol misuse cross-sectionally, but not over time. Both have also been found to predict treatment response to brief interventions. Alcohol demand has also been used to enhance the measurement of acute motivation for alcohol in laboratory studies. Interventions that focus on reducing the value of alcohol by increasing alternative reinforcement and response cost have been found to be efficacious, albeit in relatively small numbers of randomized controlled trials (RCTs). Mediators and moderators of response to these interventions have not been extensively investigated.	The application of behavioral economics and neuroeconomics to AUDs has given rise to an extensive body of empirical work, although significant gaps in knowledge remain. In particular, there is a need for more longitudinal investigations to clarify the etiological roles of these behavioral economic processes, especially alcohol demand and proportionate alcohol reinforcement. Additional RCTs are needed to extend and generalize the findings for reinforcement-based interventions and to investigate mediators and moderators of treatment success for optimization. Applying neuroeconomics to AUDs remains at an early stage and has been primarily descriptive to date, but has high potential for important translational insights into the future. The same is true for using these behavioral economic indicators to understand genetic influences on AUDs.	
26990962	We evaluated the usefulness of 2 assessments to guide treatment selection for individuals whose prior functional analysis indicated that automatic reinforcement maintained their problem behavior. In the 1st assessment, we compared levels of problem behavior during a noncontingent play condition and an alone or ignore condition. In the 2nd, we assessed participants' relative preferences for automatic reinforcement and social reinforcers in a concurrent-operants arrangement. We used the results of these 2 assessments to assign 5 participants to a treatment based on noncontingent access to social reinforcers or to a treatment based on differential access to social reinforcers. We conducted monthly probes with the participants over 10 to 12 months to evaluate the effects of the treatment procedures. All participants showed reductions in problem behavior over this period.
26990882	Kratom (Mitragyna speciosa) is a widely abused herbal drug preparation in Southeast Asia. It is often consumed as a substitute for heroin, but imposing itself unknown harms and addictive burdens. Mitragynine is the major psychostimulant constituent of kratom that has recently been reported to induce morphine-like behavioural and cognitive effects in rodents. The effects of chronic consumption on non-drug related behaviours are still unclear. In the present study, we investigated the effects of chronic mitragynine treatment on spontaneous activity, reward-related behaviour and cognition in mice in an IntelliCage® system, and compared them with those of morphine and Δ-9-tetrahydrocannabinol (THC). We found that chronic mitragynine treatment significantly potentiated horizontal exploratory activity. It enhanced spontaneous sucrose preference and also its persistence when the preference had aversive consequences. Furthermore, mitragynine impaired place learning and its reversal. Thereby, mitragynine effects closely resembled that of morphine and THC sensitisation. These findings suggest that chronic mitragynine exposure enhances spontaneous locomotor activity and the preference for natural rewards, but impairs learning and memory. These findings confirm pleiotropic effects of mitragynine (kratom) on human lifestyle, but may also support the recognition of the drug's harm potential.
26987308	Resting-state magnetic resonance imaging has uncovered abnormal functional connectivity in heroin-dependent individuals (HDIs). However, it remains unclear how brain regions implicated in addictions are related in baseline state without conditioned cues in heroin dependent individuals during opioid maintenance treatment (HDIs-OMT). Previous connectivity analysis assessed the strength of correlated activity between brain regions but lacked the ability to infer directional neural interactions. In the current study, we employed Granger causality analysis to investigate directional causal influences among the brain circuits in HDIs-OMT and non-opioid users. The results revealed a weaker effective connectivity between the caudate nucleus implicated in mediating the reward circuit and other brain regions and also a weaker connectivity between the anterior cingulate cortex and medial prefrontal cortex implicated in mediating inhibitory control. Conversely, HDIs-OMT exhibited stronger effective connectivity between the hippocampus and amygdala implicated in mediating learning-memory, and the anterior cingulate cortex involved in mediating inhibitory control while the putamen mediated learned habits, suggesting that the hippocampus and amygdala may propel the memory circuit to override the control circuit and drive the learned habit in HDIs-OMT. Alterations in learning-memory and inhibitory control may contribute jointly and form a basis for relapse risk even after a period of heroin abstinence. Sustained neural effect of opioid dependence on methadone maintenance including hyperactivation in the memory circuit and impairment in the control circuit support the role of the memory circuitry in relapse and may help redefine targets for treatment.
26985023	Repeated exposure to psychostimulants induces locomotor sensitization and leads to persistent changes in the circuitry of the mesocorticolimbic dopamine (DA) system. G-protein-gated inwardly rectifying potassium (GIRK; also known as Kir3) channels mediate a slow IPSC and control the excitability of DA neurons. Repeated 5 d exposure to psychostimulants decreases the size of the GABAB receptor (GABABR)-activated GIRK currents (IBaclofen) in ventral tegmental area (VTA) DA neurons of mice, but the mechanism underlying this plasticity is poorly understood. Here, we show that methamphetamine-dependent attenuation of GABABR-GIRK currents in VTA DA neurons required activation of both D1R-like and D2R-like receptors. The methamphetamine-dependent decrease in GABABR-GIRK currents in VTA DA neurons did not depend on a mechanism of dephosphorylation of the GABAB R2 subunit found previously for other neurons in the reward pathway. Rather, the presence of the GIRK3 subunit appeared critical for the methamphetamine-dependent decrease of GABABR-GIRK current in VTA DA neurons. Together, these results highlight different regulatory mechanisms in the learning-evoked changes that occur in the VTA with repeated exposure to psychostimulants.Exposure to addictive drugs such as psychostimulants produces persistent adaptations in inhibitory circuits within the mesolimbic dopamine system, suggesting that addictive behaviors are encoded by changes in the reward neural circuitry. One form of neuroadaptation that occurs with repeated exposure to psychostimulants is a decrease in slow inhibition, mediated by a GABAB receptor and a potassium channel. Here, we examine the subcellular mechanism that links psychostimulant exposure with changes in slow inhibition and reveal that one type of potassium channel subunit is important for mediating the effect of repeated psychostimulant exposure. Dissecting out the components of drug-dependent plasticity and uncovering novel protein targets in the reward circuit may lead to the development of new therapeutics for treating addiction.	
26980782	Appetitive sign-tracking, in which reward-paired cues elicit approach that can result in cue interaction, demonstrates how cues acquire motivational value. For example, rats will approach and subsequently interact with a lever insertion cue that signals food delivery upon its retraction. However, lever deflections are rapidly reduced once rats are trained on an omission schedule in which lever interactions cancel food delivery. Here we evaluated the change in sign-tracking response topography in rats exposed to such an omission procedure. Lever deflections dropped precipitously when they canceled reward. However, rats that were on an omission schedule continued to approach, sniff, and contact the lever without pressing it, and did so at comparable rates to rats that were not under an omission schedule. Thus, sign-tracking was maintained, albeit in a different manner, following omission. Such findings show that the motivational attraction to reward cues can be expressed with remarkable persistence and flexibility. 
26979761	Autism spectrum disorder (ASD) is marked by impairments in social-emotional situations, executive functioning, and behavioral regulation. These symptoms may be related to deficits in performance monitoring, i.e., the ability to observe and evaluate one's own behavior and performance which is necessary for the regulation of future behavior. The present literature review investigated electroencephalic correlates of performance monitoring in ASD. Event-related potentials (ERPs) considered in this review included internal performance monitoring components (error-related negativity, error positivity), external performance monitoring components (feedback-related negativity, feedback-P3), and observational performance monitoring components (observer error-related negativity, observer feedback-related negativity). The majority of studies point to reduced internal performance monitoring in ASD. External performance monitoring in reward-processing paradigms, where rewards are independent of performance, seems to be intact in ASD. So far, no studies have investigated the observer error-related negativity in ASD. Available data on the observer feedback-related negativity are inconclusive, since only two studies with differential study results investigated this construct in ASD. In general, results suggest that individuals with ASD have problems with internal performance monitoring and with learning from external, abstract feedback. In contrast, the processing of external, concrete feedback seems to be largely intact in ASD. 
26979137	Since the 1990 s strenuous attempts have been made to rebuild trust in childhood immunisations. This study aimed to understand if financial incentives (FI) or quasi-mandatory schemes (QMS), e.g. mandating immunisations for entry to universal services such as day care or school, might be acceptable interventions to increase immunisations uptake for preschool children.Parents and carers of preschool children (n=91); health and other professionals (n=18); and those responsible for developing and commissioning immunisation services (n=6) took part in the study. Qualitative methods were employed to explore the acceptability of FI/QMS with stakeholders. Framework analysis was used to develop a coding framework that was applied to the whole dataset. Interpretations of the emergent themes were verified between researchers and presented to the project's Parent Reference Group to ensure coherence and relevance.	(1) FI: parents and professionals felt introducing FI was inappropriate. It was acknowledged FI may encourage families living in disadvantage to prioritise immunisation, but unintended consequences could outweigh any advantage. FI essentially changes behaviour into a cash transaction which many equated to bribery that could inadvertently create inequalities. (2) QMS: parents and professionals highlighted the positives of introducing QMS, stating it felt natural, fair and less likely to create inequality. Despite QMS' potential to positively impact on uptake there were concerns about the implementation and workability of such schemes.	FI for preschool immunisation may not be acceptable, within a UK context. Introducing FI could have detrimental effects on uptake if it were associated with bribery and coercion. Quasi-mandatory schemes, mandating immunisation for universal service entry, was the most acceptable option and could contribute to the normalising of immunisation. Future work would be needed to assess how this could be successfully implemented and if it did indeed increase uptake.	
26976089	Recent findings indicate that pedunculopontine tegmental nucleus (PPTg) neurons encode reward-related information that is context-dependent. This information is critical for behavioral flexibility when reward outcomes change signaling a shift in response patterns should occur. The present experiment investigated whether NMDA lesions of the PPTg affects the acquisition and/or reversal learning of a spatial discrimination using probabilistic reinforcement. Male Long-Evans rats received a bilateral infusion of NMDA (30nmoles/side) or saline into the PPTg. Subsequently, rats were tested in a spatial discrimination test using a probabilistic learning procedure. One spatial location was rewarded with an 80% probability and the other spatial location rewarded with a 20% probability. After reaching acquisition criterion of 10 consecutive correct trials, the spatial location - reward contingencies were reversed in the following test session. Bilateral and unilateral PPTg-lesioned rats acquired the spatial discrimination test comparable to that as sham controls. In contrast, bilateral PPTg lesions, but not unilateral PPTg lesions, impaired reversal learning. The reversal learning deficit occurred because of increased regressions to the previously 'correct' spatial location after initially selecting the new, 'correct' choice. PPTg lesions also reduced the frequency of win-stay behavior early in the reversal learning session, but did not modify the frequency of lose-shift behavior during reversal learning. The present results suggest that the PPTg contributes to behavioral flexibility under conditions in which outcomes are uncertain, e.g. probabilistic reinforcement, by facilitating sensitivity to positive reward outcomes that allows the reliable execution of a new choice pattern. 
26971947	When an organism receives a reward, it is crucial to know which of many candidate actions caused this reward. However, recent work suggests that learning is possible even when this most fundamental assumption is not met. We used novel reward-guided learning paradigms in two fMRI studies to show that humans deploy separable learning mechanisms that operate in parallel. While behavior was dominated by precise contingent learning, it also revealed hallmarks of noncontingent learning strategies. These learning mechanisms were separable behaviorally and neurally. Lateral orbitofrontal cortex supported contingent learning and reflected contingencies between outcomes and their causal choices. Amygdala responses around reward times related to statistical patterns of learning. Time-based heuristic mechanisms were related to activity in sensorimotor corticostriatal circuitry. Our data point to the existence of several learning mechanisms in the human brain, of which only one relies on applying known rules about the causal structure of the task. 
26970240	Alcohol-associated stimuli contribute to relapse risk. Therefore, understanding the behavioural and neural mechanisms underlying the ability of such stimuli to promote alcohol-seeking is important for developing effective treatments for alcohol-use disorders. The Pavlovian-instrumental transfer (PIT) paradigm can be used to study the influence of Pavlovian cues on independently-trained instrumental responses earning reward. The effects can be either general, increasing the vigour of reward-related behaviours, or specific to responses that earn a common outcome. These different forms of PIT are mediated by distinct neural circuits involving the nucleus accumbens (NAC) core and shell, respectively. Here we examined the effects of pharmacological inactivation of either the NAC core or shell on PIT generated by alcohol-predictive and sucrose-predictive stimuli in rats. We found that presentations of a stimulus predicting sucrose enhanced responding for sucrose but not alcohol, suggesting an outcome-specific effect. In contrast, presentations of an alcohol-predictive stimulus enhanced responding for both alcohol and sucrose, suggesting a generally arousing effect. Inactivation of the NAC core reduced PIT and, in particular, the effect of the alcohol stimulus. Inactivation of the NAC shell reduced the specificity of the stimulus effects but left the ability of the stimuli to non-specifically invigorate responding intact, consistent with a role in mediating the specificity of PIT. Together, these results suggest that the NAC core plays a particularly important role in mediating the influence of alcohol-predictive cues on reward-seeking behaviours. 
26969866	Changed reward functions have been proposed as a core feature of stimulant addiction, typically observed as reduced neural responses to non-drug-related rewards. However, it was unclear yet how specific this deficit is for different types of non-drug rewards arising from social and non-social reinforcements. We used functional neuroimaging in cocaine users to investigate explicit social reward as modeled by agreement of music preferences with music experts. In addition, we investigated non-social reward as modeled by winning desired music pieces. The study included 17 chronic cocaine users and 17 matched stimulant-naive healthy controls. Cocaine users, compared with controls, showed blunted neural responses to both social and non-social reward. Activation differences were located in the ventromedial prefrontal cortex overlapping for both reward types and, thus, suggesting a non-specific deficit in the processing of non-drug rewards. Interestingly, in the posterior lateral orbitofrontal cortex, social reward responses of cocaine users decreased with the degree to which they were influenced by social feedback from the experts, a response pattern that was opposite to that observed in healthy controls. The present results suggest that cocaine users likely suffer from a generalized impairment in value representation as well as from an aberrant processing of social feedback.
26968195	A promising approach in treating cocaine abuse is to metabolize cocaine in the blood using a mutated butyrylcholinesterase (BChE) that functions as a cocaine hydrolase (CocH). In rats, a helper-dependent adenoviral (hdAD) vector-mediated delivery of CocH abolished ongoing cocaine use and cocaine-primed reinstatement of drug-seeking for several months. This enzyme also metabolizes ghrelin, an effect that may be beneficial in maintaining healthy weights. The effect of a single hdAD-CocH vector injection was examined in rats on measures of anxiety, body weight, cocaine self-administration, and cocaine-induced locomotor activity. To examine anxiety, periadolescent rats were tested in an elevated-plus maze. Weight gain was then examined under four rodent diets. Ten months after CocH-injection, adult rats were trained to self-administer cocaine intravenously and, subsequently, cocaine-induced locomotion was tested. Viral gene transfer produced sustained plasma levels of CocH for over 13 months of testing. CocH-treated rats did not differ from controls in measures of anxiety, and only showed a transient reduction in weight gain during the first 3 weeks postinjection. However, CocH-treated rats were insensitive to cocaine. At 10 months postinjection, none of the CocH-treated rats initiated cocaine self-administration, unlike 90% of the control rats. At 13 months postinjection, CocH-treated rats showed no cocaine-induced locomotion, whereas control rats showed a dose-dependent enhancement of locomotion. CocH vector produced a long-term blockade of the rewarding and behavioral effects of cocaine in rats, emphasizing its role as a promising therapeutic intervention in cocaine abuse. 
26967472	It is thought that rewarding experiences with drugs create strong contextual associations and encourage repeated intake. In turn, repeated exposures to drugs of abuse make lasting alterations in the brain function of vulnerable individuals, and these persistent alterations likely serve to maintain the maladaptive drug seeking and taking behaviors characteristic of addiction/dependence(2). In rodents, reward experience and contextual associations are frequently measured using the conditioned place preference assay, or CPP, wherein preference for a previously drug-paired context is measured. Behavioral sensitization, on the other hand, is an increase in a drug-induced behavior that develops progressively over repeated exposures. Since sensitized behaviors can often be measured after several months of drug abstinence, depending on the dose and length of initial exposure, they are considered observable correlates of lasting drug-induced plasticity. Researchers have found these assays useful in determining the neurobiological substrates mediating aspects of addiction as well as assessing the potential of different interventions in disrupting these behaviors. This manuscript describes basic, effective protocols for mouse CPP and locomotor behavioral sensitization to cocaine. 
26966157	Humans uniquely appreciate aesthetics, experiencing pleasurable responses to complex stimuli that confer no clear intrinsic value for survival. However, substantial variability exists in the frequency and specificity of aesthetic responses. While pleasure from aesthetics is attributed to the neural circuitry for reward, what accounts for individual differences in aesthetic reward sensitivity remains unclear. Using a combination of survey data, behavioral and psychophysiological measures and diffusion tensor imaging, we found that white matter connectivity between sensory processing areas in the superior temporal gyrus and emotional and social processing areas in the insula and medial prefrontal cortex explains individual differences in reward sensitivity to music. Our findings provide the first evidence for a neural basis of individual differences in sensory access to the reward system, and suggest that social-emotional communication through the auditory channel may offer an evolutionary basis for music making as an aesthetically rewarding function in humans.
26965571	The medial prefrontal cortex (mPFC) plays a major role in goal-directed behaviours, but it is unclear whether it plays a role in breaking away from a high-value reward in order to explore for better options. To address this question, we designed a novel 3-arm Bandit Task in which rats were required to choose one of three potential reward arms, each of which was associated with a different amount of food reward and time-out punishment. After a variable number of choice trials the reward locations were shuffled and animals had to disengage from the now devalued arm and explore the other options in order to optimise payout. Lesion and control groups' behaviours on the task were then analysed by fitting data with a reinforcement learning model. As expected, lesioned animals obtained less reward overall due to an inability to flexibly adapt their behaviours after a change in reward location. However, modelling results showed that lesioned animals were no more likely to explore than control animals. We also discovered that all animals showed a strong preference for certain maze arms, at the expense of reward. This tendency was exacerbated in the lesioned animals, with the strongest effects seen in a subset of animals with damage to dorsal mPFC. The results confirm a role for mPFC in goal-directed behaviours but suggest that rats rely on other areas to resolve the explore-exploit dilemma. 
26964905	Impulsive choice is a diagnostic feature and/or complicating factor for several psychological disorders and may be examined in the laboratory using delay-discounting procedures. Recent investigators have proposed using quantitative measures of analysis to examine the behavioral processes contributing to impulsive choice. The purpose of this study was to examine the effects of physical activity (i.e., wheel running) on impulsive choice in a single-response, discrete-trial procedure using two quantitative methods of analysis. To this end, rats were assigned to physical activity or sedentary groups and trained to respond in a delay-discounting procedure. In this procedure, one lever always produced one food pellet immediately, whereas a second lever produced three food pellets after a 0, 10, 20, 40, or 80-s delay. Estimates of sensitivity to reinforcement amount and sensitivity to reinforcement delay were determined using (1) a simple linear analysis and (2) an analysis of logarithmically transformed response ratios. Both analyses revealed that physical activity decreased sensitivity to reinforcement amount and sensitivity to reinforcement delay. These findings indicate that (1) physical activity has significant but functionally opposing effects on the behavioral processes that contribute to impulsive choice and (2) both quantitative methods of analysis are appropriate for use in single-response, discrete-trial procedures. 
26964376	Previous studies have reported that lesions of the orbitofrontal cortex (OFC) in rats induce impulsive choices in delayed reinforcement tasks. However, some studies have suggested that the OFC is not related to impulsivity but instead to compulsivity. In this study, we investigated the effects of OFC lesions on choice in a T-maze. First, 14 rats were trained to discriminate spatially between a high-reward arm with a delay of 15 seconds and a low-reward arm without a delay. The high-reward arm contained 10 food pellets, whereas the low-reward arm contained only one pellet. In the presurgery test, all rats chose the high-reward arm in most trials. In the postsurgery test, both OFC lesioned (n = 7) and control (sham-lesioned and intact; n = 7) rats continued to choose the high-reward arm in most trials. Following the postsurgery test, the high- and low-reward arms were reversed. In the reversal test, OFC lesioned rats made significantly fewer high-reward choices than did control rats. These results indicate that OFC lesions induced compulsive choices rather than impulsive choices.
26961951	Electrical stimulation of the lateral hypothalamus (LH) has two motivational effects: long trains of stimulation induce drive-like effects such as eating, and short trains are rewarding. It has not been clear whether a single set of activated fibers subserves the two effects. Previous optogenetic stimulation studies have confirmed that reinforcement and induction of feeding can each be induced by selective stimulation of GABAergic fibers originating in the bed nucleus of the LH and projecting to the ventral tegmental area (VTA). In the present study we determined the optimal stimulation parameters for each of the two optogenetically induced effects in food-sated mice. Stimulation-induced eating was strongest with 5 Hz and progressively weaker with 10 and 20 Hz. Stimulation-induced reward was strongest with 40 Hz and progressively weaker with lower or higher frequencies. Mean preferred duration for continuous 40 Hz stimulation was 61.6 s in a "real-time" place preference task; mean preferred duration for 5 Hz stimulation was 45.6 s. The differential effects of high- and low-frequency stimulation of this pathway seem most likely to be due to differential effects on downstream targets.
26961950	Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (α4)3(β2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)2(β2)3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway.
26961943	Rewarding experiences exert a strong influence on later decision making. While decades of neuroscience research have shown how reinforcement gradually shapes preferences, decisions are often influenced by single past experiences. Surprisingly, relatively little is known about the influence of single learning episodes. Although recent work has proposed a role for episodes in decision making, it is largely unknown whether and how episodic experiences contribute to value-based decision making and how the values of single episodes are represented in the brain. In multiple behavioral experiments and an fMRI experiment, we tested whether and how rewarding episodes could support later decision making. Participants experienced episodes of high reward or low reward in conjunction with incidental, trial-unique neutral pictures. In a surprise test phase, we found that participants could indeed remember the associated level of reward, as evidenced by accurate source memory for value and preferences to re-engage with rewarded objects. Further, in a separate experiment, we found that high-reward objects shown as primes before a gambling task increased financial risk taking. Neurally, re-exposure to objects in the test phase led to significant reactivation of reward-related patterns. Importantly, individual variability in the strength of reactivation predicted value memory performance. Our results provide a novel demonstration that affect-related neural patterns are reactivated during later experience. Reactivation of value information represents a mechanism by which memory can guide decision making.
26960696	Clinical and preclinical evidence indicates that the setting of drug use affects drug reward in a substance-specific manner. Heroin and cocaine co-abusers, for example, indicated distinct settings for the two drugs: heroin being used preferentially at home and cocaine preferentially outside the home. Similar results were obtained in rats that were given the opportunity to self-administer intravenously both heroin and cocaine.The goal of the present study was to investigate the possibility that the positive affective state induced by cocaine is enhanced when the drug is taken at home relative to a non-home environment, and vice versa for heroin.	To test this hypothesis, we trained male rats to self-administer both heroin and cocaine on alternate days and simultaneously recorded the emission of ultrasonic vocalizations (USVs), as it has been reported that rats emit 50-kHz USVs when exposed to rewarding stimuli, suggesting that these USVs reflect positive affective states.	We found that Non-Resident rats emitted more 50-kHz USVs when they self-administered cocaine than when self-administered heroin whereas Resident rats emitted more 50-kHz USVs when self-administering heroin than when self-administering cocaine. Differences in USVs in Non-Resident rats were more pronounced during the first self-administration (SA) session, when the SA chambers were completely novel to them. In contrast, the differences in USVs in Resident rats were more pronounced during the last SA sessions.	These findings indicate that the setting of drug taking exerts a substance-specific influence on the ability of drugs to induce positive affective states.	
26959371	Marine recreational fishing is a popular outdoor activity. However, knowledge about the magnitude of recreational catches relative to commercial catches in coastal fisheries is generally sparse. Coastal Atlantic cod (Gadus morhua) is a target species for recreational fishers in the North Atlantic. In Norway, recreational fishers are allowed to use a variety of traps and nets as well as long-line and rod and line when fishing for cod. From 2005 to 2013, 9729 cod (mean size: 40 cm, range: 15-93 cm) were tagged and released in coastal Skagerrak, southeast Norway. Both high-reward (NOK 500) and low-reward tags (NOK 50) were used in this study. Because some harvested fish (even those posting high-reward tags) may go unreported by fishers, reporting rates were estimated from mark-recovery models that incorporate detection parameters in their structure, in addition to survival and mortality estimates. During 2005 to 2013, a total of 1707 tagged cod were recovered and reported by fishers. We estimate the overall annual survival to be 33% (SE 1.5). Recreational rod and line fishing were responsible for 33.7% (SE 2.4) of total mortality, followed by commercial fisheries (15.1% SE 0.8) and recreational fixed gear (6.8% SE 0.4). Natural mortality was 44.4% (SE 2.5) of total mortality. Our findings suggest that recreational fishing-rod and line fishing in particular-is responsible for a substantial part of fishing mortality exerted on coastal cod in southern Norway. 
26959336	The resurgence of interest in anhedonia within major depression has been fuelled by clinical trials demonstrating its utility in predicting antidepressant response as well as recent conceptualizations focused on the role and manifestation of anhedonia in depression. Historically, anhedonia has been understood as a "loss of pleasure", yet neuropsychological and neurobiological studies reveal a multifaceted reconceptualization that emphasizes different facets of hedonic function, including desire, effort/motivation, anticipation and consummatory pleasure. To ensure generalizability across studies, evaluation of the available subjective and objective methods to assess anhedonia is necessary. The majority of research regarding anhedonia and its neurobiological underpinnings comes from preclinical research, which uses primary reward (e.g. food) to probe hedonic responding. In contrast, behavioural studies in humans primarily use secondary reward (e.g. money) to measure many aspects of reward responding, including delay discounting, response bias, prediction error, probabilistic reversal learning, effort, anticipation and consummatory pleasure. The development of subjective scales to measure anhedonia has also increased in the last decade. This review will assess the current methodology to measure anhedonia, with a focus on scales and behavioural tasks in humans. Limitations of current work and recommendations for future studies are discussed. 
26956807	The present research explored the cortical correlates of rewarding mechanisms and cortical 'unbalance' effect in internet addiction (IA) vulnerability.Internet Addiction Inventory (IAT) and personality trait (Behavioural Inhibition System, BIS; Behavioural Activation System, BAS) were applied to 28 subjects. Electroencephalographic (EEG, alpha frequency band) and response times (RTs) were registered during a Go-NoGo task execution in response to different online stimuli: gambling videos, videogames or neutral stimuli. Higher-IAT (more than 50 score, with moderate or severe internet addiction) and lower-IAT (<50 score, with no internet addiction).	Alpha band and RTs were affected by IAT, with significant bias (reduced RTs) for high-IAT in response to gambling videos and videogames; and by BAS, BAS-Reward subscale (BAS-R), since not only higher-IAT, but also BAS and BAS-R values determined an increasing of left prefrontal cortex (PFC) activity (alpha reduction) in response to videogames and gambling stimuli for both Go and NoGo conditions, in addition to decreased RTs for these stimuli categories.	The increased PFC responsiveness and the lateralisation (left PFC hemisphere) effect in NoGo condition was explained on the basis of a 'rewarding bias' towards more rewarding cues and a deficit in inhibitory control in higher-IAT and higher-BAS subjects. In contrast lower-IAT and lower-BAS predicted a decreased PFC response and increased RTs for NoGo (inhibitory mechanism). These results may support the significance of personality (BAS) and IAT measures for explaining future internet addiction behaviour based on this observed 'vulnerability'.	
26955839	Nicotine dependence is characterized as a neural circuit dysfunction, particularly with regard to the reward circuit. Although dependence severity moderates cue reactivity in the brain regions involved in reward processing, the direction of its influence remains controversial.Investigating the functional organization of the reward circuit may provide complementary information. Here, we used resting-state functional connectivity (rsFC) to evaluate the integrity of the reward circuit in smokers with different severities of nicotine dependence.	Totals of 65 smokers and 37 non-smokers underwent resting-state functional magnetic resonance imaging (fMRI). The smokers were divided into low-dependent (FTND < 5, n = 26) and high-dependent smoker groups (FTND ≥ 5, n = 39) based on their nicotine-dependence severity (as measured by the Fagerström test for nicotine dependence [FTND]). The region of interest (ROI)-wise rsFC within the reward circuit was compared between smokers and non-smokers as well as between low-dependent and high-dependent smokers and then correlated with smokers' FTND scores.	Widespread rsFC attenuation was observed in the reward circuit of smokers compared with non-smokers. Compared with low-dependent smokers, high-dependent smokers showed greater rsFC between the right amygdala and the left nucleus accumbens (NAcc) as well as between the bilateral hippocampus. Furthermore, a positive correlation between the inter-hippocampus rsFC and the severity of nicotine dependence (FTND) was detected among all smokers (r = 0.416, p = 0.001).	Our results indicate a dysfunction of the reward circuit in nicotine-dependent individuals. Moreover, our study improves the understanding of the neuroplastic changes that occur during the development of nicotine dependence.	

26952196	Cognitive neuroscience suffers from a unique and pervasive problem of generalizability. Since neural findings are often interpreted in the context of a specific manipulation during a carefully controlled task, it is hard to transfer knowledge from one task to another. In this report we address problems of generalizability with two methodological advancements. First, we aimed to transcend status quo experimental procedures with a continuous, engaging task environment. To this end, we created a novel 8-bit style continuous space shooter video game that elicits a multitude of goal-oriented events, such as crashing into a wall or blowing up an enemy with a missile. Second, we aimed to objectively define the psychological significance of these events. To achieve this aim, we used pattern classification of EEG data to derive predictive weights from carefully controlled pre-game exemplar events (oddball target detection and gambling wins and losses) and transferred those weights to EEG activities during video game events. All major goal-oriented events (crashes into the wall, crashes into an enemy, missile hit on an enemy) had a significant between-task transfer bias towards oddball target weights in the time range of the canonical P3, indicating the presence of similar salience detection processes. Missile hits on an enemy were specifically identified as gambling wins, confirming the hypothesis that this goal-oriented event was appetitive. These findings suggest that it is possible to identify the contribution of canonical neural activities during otherwise ambiguous and uncontrolled task performance. 
26949878	The main aim of this study was to examine the measurement invariance of the Work Organization Assessment Questionnaire (WOAQ) across genders in a group of health care employees, using bifactor modeling. There is a very limited research that uses invariance testing of bifactor models, despite their usefulness. Establishing validity of the WOAQ in this way is important for demonstrating its relevance for both men and women.A bifactor modeling procedure was used here to examine the validity of the WOAQ with a sample of 946 paramedics employed in a large Australian organization in the health care sector.	The results of this study show that the WOAQ has good psychometric properties across genders in health care settings. In addition, there were significant mean differences between men and women in their perceptions of "quality of relationships with colleagues," and "reward and recognition." There were no differences between men and women in the remaining factors: "quality of relationships with the management," "quality of relationships with colleagues," and "quality of the physical environment."	The use of bifactor modeling to establish the cross-validity of the WOAQ across male and female paramedics adds to evidence for the measure's good psychometric properties. The findings confirm those of previous research that has used higher order confirmatory factor analysis. Moreover, mean differences between men and women were found to be significant in two of the five WOAQ subscales. These findings have practical implications for health care organizations, in terms of assessing work characteristics and developing activities to support the health and well-being of their employees.	
26949249	Midbrain dopamine neurons have been proposed to signal reward prediction errors as defined in temporal difference (TD) learning algorithms. While these models have been extremely powerful in interpreting dopamine activity, they typically do not use value derived through inference in computing errors. This is important because much real world behavior - and thus many opportunities for error-driven learning - is based on such predictions. Here, we show that error-signaling rat dopamine neurons respond to the inferred, model-based value of cues that have not been paired with reward and do so in the same framework as they track the putative cached value of cues previously paired with reward. This suggests that dopamine neurons access a wider variety of information than contemplated by standard TD models and that, while their firing conforms to predictions of TD models in some cases, they may not be restricted to signaling errors from TD predictions. 
26949122	Rules encompass cue-action-outcome associations used to guide decisions and strategies in a specific context. Subregions of the frontal cortex including the orbitofrontal cortex (OFC) and dorsomedial prefrontal cortex (dmPFC) are implicated in rule learning, although changes in structural connectivity underlying rule learning are poorly understood. We imaged OFC axonal projections to dmPFC during training in a multiple choice foraging task and used a reinforcement learning model to quantify explore-exploit strategy use and prediction error magnitude. Here we show that rule training, but not experience of reward alone, enhances OFC bouton plasticity. Baseline bouton density and gains during training correlate with rule exploitation, while bouton loss correlates with exploration and scales with the magnitude of experienced prediction errors. We conclude that rule learning sculpts frontal cortex interconnectivity and adjusts a thermostat for the explore-exploit balance. 
26948895	Complex cognitive processes require sophisticated local processing but also interactions between distant brain regions. It is therefore critical to be able to study distant interactions between local computations and the neural representations they act on. Here we report two anatomically and computationally distinct learning signals in lateral orbitofrontal cortex (lOFC) and the dopaminergic ventral midbrain (VM) that predict trial-by-trial changes to a basic internal model in hippocampus. To measure local computations during learning and their interaction with neural representations, we coupled computational fMRI with trial-by-trial fMRI suppression. We find that suppression in a medial temporal lobe network changes trial-by-trial in proportion to stimulus-outcome associations. During interleaved choice trials, we identify learning signals that relate to outcome type in lOFC and to reward value in VM. These intervening choice feedback signals predicted the subsequent change to hippocampal suppression, suggesting a convergence of signals that update the flexible representation of stimulus-outcome associations. 
26948894	Activation of the ventral tegmental area (VTA) and mesolimbic networks is essential to motivation, performance, and learning. Humans routinely attempt to motivate themselves, with unclear efficacy or impact on VTA networks. Using fMRI, we found untrained participants' motivational strategies failed to consistently activate VTA. After real-time VTA neurofeedback training, however, participants volitionally induced VTA activation without external aids, relative to baseline, Pre-test, and control groups. VTA self-activation was accompanied by increased mesolimbic network connectivity. Among two comparison groups (no neurofeedback, false neurofeedback) and an alternate neurofeedback group (nucleus accumbens), none sustained activation in target regions of interest nor increased VTA functional connectivity. The results comprise two novel demonstrations: learning and generalization after VTA neurofeedback training and the ability to sustain VTA activation without external reward or reward cues. These findings suggest theoretical alignment of ideas about motivation and midbrain physiology and the potential for generalizable interventions to improve performance and learning.
26948120	Cocaine experience affects motivation structures such as the nucleus accumbens (NAc) and its major output target, the ventral pallidum (VP). Previous studies demonstrated that both NAc activity and hedonic responses change reliably as a taste cue comes to predict cocaine availability. Here we extended this investigation to examine drug-experience induced changes in hedonic encoding in the VP. VP activity was first characterized in adult male Sprague-Dawley rats in response to intraoral infusions of palatable saccharin and unpalatable quinine solutions. Next, rats received 7 daily pairings of saccharin that predicted either a cocaine (20mg/kg, ip) or saline injection. Finally, the responses to saccharin and quinine were again assessed. Of 109 units recorded in 11 rats that received saccharin-cocaine pairings, 71% of responsive units significantly reduced firing rate during saccharin infusions and 64% increased firing rate during quinine exposure. However, as saccharin came to predict cocaine, and elicited aversive taste reactivity, VP responses changed to resemble quinine. After conditioning, 70% of saccharin-responsive units increased firing rate. Most units that encoded the palatable taste (predominantly reduced firing rate) were located in the anterior VP, while most units that were responsive to aversive tastes were located in the posterior VP. This study reveals an anatomical complexity to the nature of hedonic encoding in the VP. 
26946306	Previous studies showed that exposure to certain types of stressors enhance the rewarding effects of many drugs of abuse, including alcohol; however, no systematic study has investigated the role of single prolonged stress (SPS) in acquisition of alcohol conditioned place preference (CPP). The purpose of this study was to examine whether SPS would facilitate the acquisition of alcohol CPP in rats.Male Sprague-Dawley rats were randomly assigned to either SPS exposure condition or no exposure condition. Freezing behavior and Elevated plus maze (EPM) were employed to evaluate PTSD-like symptoms induced by SPS. Further, using unbiased procedure, CPP conditioning was conducted with alcohol (2g/kg).	SPS significantly enhanced freezing behavior of rats, decreased percentages (%) of both time spent and number of entry into the open arms, and facilitated the acquisition of alcohol CPP without inhibiting rats' activity.	Our findings suggest that SPS plays an important role in alcohol dependence, and CPP paradigm with SPS may be useful for exploring the rewarding mechanism of alcohol with regard to the interaction between alcohol and post-traumatic stress disorder (PTSD).	
26946109	Flexible goal-directed behavior requires monitor-control networks to detect the need for behavioral adjustments and to implement the required regulations. Among event-related brain potentials related to the function of such networks is the feedback-related negativity (FRN), which is detected in trial-and-error learning tasks. Conflict monitoring theory (CMT) as one of the influential theories of such networks cannot describe the FRN. Recently, we have proposed a cost-conflict monitoring system that extends the CMT. The cost-conflict monitoring holds that the monitoring system can detect conflict signal, but the conflict is over the costs of alternative outcomes of the selected action rather than the response conflict as proposed by the CMT. In the cost-conflict monitoring, cost functions are computed based on waiting times from the response to feedback delivery and from these quantities a conflict signal is derived. Here, we present a computational realization of such cost-conflict monitor-controller network. We utilize this computational model to simulate existing human performance and ERP data of a trial-and-error learning task. The model successfully simulated the behavioral data and FRN signals under different conditions in this task. 
26944283	Chronic exposure to cocaine in vivo induces long-term synaptic plasticity associated with the brain's circuitry that underlies development of repetitive and automatic behaviors called habits. In fact, prolonged drug consumption results in aberrant expression of protein-coding genes and small regulatory RNAs, including miRNAs that are involved in synaptic plasticity and neuroadaptations. However, the mechanisms mediating cocaine use disorder are still not fully understood. The present study is designed to examine the expression of miR-124, miR-132, miR-134, and miR-212, as well as the levels of the Ago2, Pum2, and REST mRNAs and proteins implicated in their regulation. We applied rat cocaine self-administration (SA) and extinction training procedures with a yoked triad to assess the changes in the levels of four miRNAs and three protein-coding genes and corresponding proteins in the dorsal striatum. We demonstrated that elevated expression of mature miR-212 and miR-132 is long-lasting and persists in the drug-free period (till 10-day abstinence). Moreover, mRNA and protein of REST, a regulator of neuronal transcription, was raised selectively in cocaine self-administering rats and Ago2 transcript decreased after cocaine treatment. Unexpectedly, the expression level of Ago2 and Pum2 proteins changed only in the active cocaine-receiving animals. These results point out the important aspects of long-lasting alterations in microRNAs, genes, and protein expressions involved in the control of synaptic plasticity associated with reward and motivation learning related to cocaine addiction.
26943941	Previous studies have shown that high effort-reward imbalance (ERI) at work is a risk factor for the onset of self-reported depressive symptoms. In this study, we examined whether ERI predicts risk of treatment with antidepressant medication in a representative sample of the Danish workforce.We linked survey data on ERI and covariates of 4541 participants from the Danish Work Environment Cohort Study 2000 with the Danish National Prescription Registry that includes all legally purchased prescription drugs at pharmacies in Denmark since 1995. Participants with a history of antidepressant treatment or with self-reported depressive symptoms at baseline were excluded. Using Cox proportional hazard analyses we examined the prospective association between ERI at baseline and incident antidepressant treatment while adjusting for potential confounders. Time of follow-up was 5 years.	A total of 309 (6.8%) participants started antidepressant treatment during follow-up. Exposure to ERI at baseline was not related to risk of antidepressant treatment (hazard ratio: 0.91, 95% CI=0.81-1.03 after adjustment for potential confounders).	The use of antidepressant treatment as an indicator for onset of depression might have led to misclassification, because (a) antidepressants are also used to treat other conditions than depression and (b) a considerable proportion of individuals with depression are not treated with antidepressants.	ERI did not predict incident antidepressant treatment, contradicting previous findings on ERI and self-reported depression. To clarify the association of ERI with risk of depression, we recommend further prospective studies using non-self-reported measures of ERI, clinical assessments of depression, or both.	
26942317	We previously demonstrated that predictive motor timing (i.e., timing requiring visuomotor coordination in anticipation of a future event, such as catching or batting a ball) is impaired in patients with spinocerebellar ataxia (SCA) types 6 and 8 relative to healthy controls. Specifically, SCA patients had difficulties postponing their motor response while estimating the target kinematics. This behavioral difference relied on the activation of both cerebellum and striatum in healthy controls, but not in cerebellar patients, despite both groups activating certain parts of cerebellum during the task. However, the role of these two key structures in the dynamic adaptation of the motor timing to target kinematic properties remained unexplored. In the current paper, we analyzed these data with the aim of characterizing the trial-by-trial changes in brain activation. We found that in healthy controls alone, and in comparison with SCA patients, the activation in bilateral striatum was exclusively associated with past successes and that in the left putamen, with maintaining a successful performance across successive trials. In healthy controls, relative to SCA patients, a larger network was involved in maintaining a successful trial-by-trial strategy; this included cerebellum and fronto-parieto-temporo-occipital regions that are typically part of attentional network and action monitoring. Cerebellum was also part of a network of regions activated when healthy participants postponed their motor response from one trial to the next; SCA patients showed reduced activation relative to healthy controls in both cerebellum and striatum in the same contrast. These findings support the idea that cerebellum and striatum play complementary roles in the trial-by-trial adaptation in predictive motor timing. In addition to expanding our knowledge of brain structures involved in time processing, our results have implications for the understanding of BG disorders, such as Parkinson disease where feedback processing or reward learning is affected. 
26939060	Human social interactions are regulated by moral norms that define individual obligations and rights. These norms are enforced by punishment of transgressors and reward of followers. Yet, the generality and strength of this drive to punish or reward is unclear, especially when people are not personally involved in the situation and when the actual impact of their sanction is only indirect, i.e., when it diminishes or promotes the social status of the punished or rewarded individual. In a real-life study, we investigated if people are inclined to anonymously punish or reward a person for her past deeds in a different social context. Participants from three socio-professional categories voted anonymously for early career violinists in an important violin competition. We found that participants did not punish an immoral violin candidate, nor did they reward another hyper-moral candidate. On the contrary, one socio-professional category sanctioned hyper-morality. Hence, salient moral information about past behavior did not elicit punishment or reward in an impersonal situation where the impact of the sanction was indirect. We conclude that contextual features play an important role in human motivation to enforce moral norms. 
26936075	There has been growing interest in a better understanding of the etiology of compulsive sexual behavior (CSB). It is assumed that facilitated appetitive conditioning might be an important mechanism for the development and maintenance of CSB, but no study thus far has investigated these processes.To explore group differences in neural activity associated with appetitive conditioning and connectivity in subjects with CSB and a healthy control group.	Two groups (20 subjects with CSB and 20 controls) were exposed to an appetitive conditioning paradigm during a functional magnetic resonance imaging experiment, in which a neutral stimulus (CS+) predicted visual sexual stimuli and a second stimulus (CS-) did not.	Blood oxygen level-dependent responses and psychophysiologic interaction.	As a main result, we found increased amygdala activity during appetitive conditioning for the CS+ vs the CS- and decreased coupling between the ventral striatum and prefrontal cortex in the CSB vs control group.	The findings show that neural correlates of appetitive conditioning and neural connectivity are altered in patients with CSB. The increased amygdala activation might reflect facilitated conditioning processes in patients with CSB. In addition, the observed decreased coupling could be interpreted as a marker for impaired emotion regulation success in this group.	
26935020	Cannabinoids are the active ingredients in marijuana, which is among the most widely used addictive drugs despite the well-documented harmfulness related to its abuse. The mechanism underlying cannabinoid addiction remains unclear, which is attributed partially to the difficulty in behavioral testing of high-dose cannabinoids using the conditioned place preference (CPP) model. Here, we optimized conditions for establishing CPP with the synthetic cannabinoid HU210 intraperitoneally administered at a high dose. We found that the natural place preference of rats could be exploited for establishing a biased CPP model, and that the adverse effect of HU210 could be ameliorated by adding four daily pre-injections before the conditioning program. Thus, 0.1 mg/kg HU210 induced CPP when pre-injections were administered before traditional conditioning with HU210 administration paired with the non-preferred compartment. The present study provides a useful CPP model for behavioral measurement of the rewarding effects of cannabinoids. 

26932552	The neuropeptide oxytocin plays a role in reward, stress, social affiliation, learning, and memory processes. As such, there is increasing interest in oxytocin as a potential treatment for addictions. The endogenous oxytocin system is itself altered by short- or long-term exposure to drugs of abuse. A large number of preclinical studies in rodents have investigated the effect of oxytocin administration on various drug-induced behaviors to determine whether oxytocin can reverse the neuroadaptations occurring with repeated drug and alcohol use. In addition, the mechanisms by which oxytocin acts to modify the behavioral response to drugs of abuse are beginning to be understood. More recently, a few small clinical studies have been conducted in cocaine, cannabis, and alcohol dependence. This review summarizes the preclinical as well as clinical literature to date on the oxytocin system and its relevance to drug and alcohol addiction. 
26932139	Major depressive disorder (MDD) is widely prevalent and severely disabling, mainly due to its recurrent nature. A better understanding of the mechanisms underlying MDD-recurrence may help to identify high-risk patients and to improve the preventive treatment they need. MDD-recurrence has been considered from various levels of perspective including symptomatology, affective neuropsychology, brain circuitry and endocrinology/metabolism. However, MDD-recurrence understanding is limited, because these perspectives have been studied mainly in isolation, cross-sectionally in depressed patients. Therefore, we aim at improving MDD-recurrence understanding by studying these four selected perspectives in combination and prospectively during remission.In a cohort design, we will include 60 remitted, unipolar, unmedicated, recurrent MDD-participants (35-65 years) with ≥ 2 MDD-episodes. At baseline, we will compare the MDD-participants with 40 matched controls. Subsequently, we will follow-up the MDD-participants for 2.5 years while monitoring recurrences. We will invite participants with a recurrence to repeat baseline measurements, together with matched remitted MDD-participants. Measurements include questionnaires, sad mood-induction, lifestyle/diet, 3 T structural (T1-weighted and diffusion tensor imaging) and blood-oxygen-level-dependent functional MRI (fMRI) and MR-spectroscopy. fMRI focusses on resting state, reward/aversive-related learning and emotion regulation. With affective neuropsychological tasks we will test emotional processing. Moreover, we will assess endocrinology (salivary hypothalamic-pituitary-adrenal-axis cortisol and dehydroepiandrosterone-sulfate) and metabolism (metabolomics including polyunsaturated fatty acids), and store blood for, for example, inflammation analyses, genomics and proteomics. Finally, we will perform repeated momentary daily assessments using experience sampling methods at baseline. We will integrate measures to test: (1) differences between MDD-participants and controls; (2) associations of baseline measures with retro/prospective recurrence-rates; and (3) repeated measures changes during follow-up recurrence. This data set will allow us to study different predictors of recurrence in combination.	The local ethics committee approved this study (AMC-METC-Nr.:11/050). We will submit results for publication in peer-reviewed journals and presentation at (inter)national scientific meetings.	NTR3768.	
26929353	According to normative theories, reward-maximizing agents should have consistent preferences. Thus, when faced with alternatives A, B, and C, an individual preferring A to B and B to C should prefer A to C. However, it has been widely argued that humans can incur losses by violating this axiom of transitivity, despite strong evolutionary pressure for reward-maximizing choices. Here, adopting a biologically plausible computational framework, we show that intransitive (and thus economically irrational) choices paradoxically improve accuracy (and subsequent economic rewards) when decision formation is corrupted by internal neural noise. Over three experiments, we show that humans accumulate evidence over time using a "selective integration" policy that discards information about alternatives with momentarily lower value. This policy predicts violations of the axiom of transitivity when three equally valued alternatives differ circularly in their number of winning samples. We confirm this prediction in a fourth experiment reporting significant violations of weak stochastic transitivity in human observers. Crucially, we show that relying on selective integration protects choices against "late" noise that otherwise corrupts decision formation beyond the sensory stage. Indeed, we report that individuals with higher late noise relied more strongly on selective integration. These findings suggest that violations of rational choice theory reflect adaptive computations that have evolved in response to irreducible noise during neural information processing. 
26928431	The time to initiate a movement can, even implicitly, be influenced by the environment. All primates, including humans, respond faster and with greater accuracy to stimuli that are brighter, louder or associated with larger reward, than to neutral stimuli. Whether this environment also modulates the executive functions which allow ongoing actions to be suppressed remains an issue of debate. In this study, we investigated the implicit learning of spatial selectivity of movement inhibition in humans and macaque monkeys performing a saccade-countermanding task. The occurrence of stop trials, in which subjects were visually instructed to cancel a prepared movement, was manipulated according to the target location. One visual target was associated with higher probability of stop signal appearance (e.g., 80 %), while the second target was associated with low fraction of stop (e.g., 20 %). The absolute occurrence of stop trials across the two targets (50 %) remains constant. The results show that human and macaque monkeys can selectively adapt their behaviors according to the implicit probability of stopping. Behavioral adjustments were larger when targets were in different hemifields and for larger distances between targets. Reduced selective inhibitory behaviors were observed when 15° of visual angle separated the targets, and this effect vanished when targets were separated by only 2°. Overall, our study shows that both response and inhibition times can be modulated by the relative spatial occurrence of stop signals. We speculate that beyond the particular effect we observed in the context of the saccade paradigm, selective motor execution may imply a disinhibitory mechanism that modulates the motor pathways associated with the fronto-median cortex and basal ganglia circuits. 
26926962	Intrauterine growth restriction (IUGR) is associated with increased preference for palatable foods. The hedonic response to sweet taste, modulated by the nucleus accumbens μ-opioid-receptors, may be involved. We investigated hedonic responses and receptor levels in IUGR and Control animals. From pregnancy day 10, Sprague-Dawley dams received either an ad libitum (Control), or a 50% food restricted (FR) diet. At birth, pups were cross-fostered, and nursed by Adlib fed dams. The hedonic response was evaluated at 1 day after birth and at 90 days of life, by giving sucrose solution or water and analyzing the hedonic facial responses (within 60s). Control pups exposed either to water or sucrose resolved their hedonic responses after 16 and 18s, respectively, while FR hedonic responses to sucrose persisted over 20s. FR pups had deceased phospho-μ-opioid-receptor (p=0.009) and reduced phosphor:total mu opioid receptor ratio compared to controls pups (p=0.003). In adults, there was an interaction between group and solution at the end of the evaluation (p=0.044): Control decreased the response after sucrose solution, FR did not change over time. There were no differences in phosphorylation of μ-opioid-receptor in adults. These results demonstrate IUGR newborn rats exhibit alterations in hedonic response accompanied by a decrease in μ-opioid-receptor phosphorylation, though these alterations do not persist at 3 months of age. Opioid system alterations in early life may contribute to the development of preference for highly palatable foods and contribute to rapid weight gain and obesity in IUGR offspring.
26924971	Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene are linked to obesity, but how these SNPs influence resting-state neural activation is unknown. Few brain-imaging studies have investigated the influence of obesity-related SNPs on neural activity, and no study has investigated resting-state connectivity patterns. We tested connectivity within three, main resting-state networks: default mode (DMN), sensorimotor (SMN), and salience network (SN) in 30 male participants, grouped based on genotype for the rs9939609 FTO SNP, as well as punishment and reward sensitivity measured by the Behavioral Inhibition (BIS) and Behavioral Activation System (BAS) questionnaires. Because obesity is associated with anomalies in both systems, we calculated a BIS/BAS ratio (BBr) accounting for features of both scores. A prominence of BIS over BAS (higher BBr) resulted in increased connectivity in frontal and paralimbic regions. These alterations were more evident in the obesity-associated AA genotype, where a high BBr was also associated with increased SN connectivity in dopaminergic circuitries, and in a subnetwork involved in somatosensory integration regarding food. Participants with AA genotype and high BBr, compared to corresponding participants in the TT genotype, also showed greater DMN connectivity in regions involved in the processing of food cues, and in the SMN for regions involved in visceral perception and reward-based learning. These findings suggest that neural connectivity patterns influence the sensitivity toward punishment and reward more closely in the AA carriers, predisposing them to developing obesity. Our work explains a complex interaction between genetics, neural patterns, and behavioral measures in determining the risk for obesity and may help develop individually-tailored strategies for obesity prevention. 

26923993	Brain-derived neurotrophic factor (BDNF) affects synaptic plasticity and neural structure and plays key roles in learning and memory processes. Recent evidence also points to important, yet complex, roles for BDNF in rodent models of cocaine abuse and addiction. Here we examine the role of prefrontal cortical (PFC) BDNF in reward-related decision making and behavioral sensitivity to, and responding for, cocaine. We focus on BDNF within the medial and orbital PFC, its regulation by cocaine during early postnatal development and in adulthood, and how BDNF in turn influences responding for drug reinforcement, including in reinstatement models. When relevant, we draw comparisons and contrasts with experiments using natural (food) reinforcers. We also summarize findings supporting, or refuting, the possibility that BDNF in the medial and orbital PFC regulate the development and maintenance of stimulus-response habits. Further investigation could assist in the development of novel treatment approaches for cocaine use disorders. 
26923851	Acute stress and elevated glucocorticoid hormone levels are well known to impair the retrieval of hippocampus-dependent 'declarative' memory. Recent findings suggest that stress might also impair the retrieval of non-hippocampal memories. In particular, stress shortly before retention testing was shown to impair the retrieval of striatal stimulus-response associations in humans. However, the mechanism underlying this stress-induced retrieval impairment of non-hippocampal stimulus-response memory remains elusive. In the present study, we investigated whether an acute elevation in glucocorticoid levels mediates the impairing effects of stress on retrieval of stimulus-response memory. Male Sprague-Dawley rats were trained on a stimulus-response task in an eight-arm radial maze until they learned to associate a stimulus, i.e., cue, with a food reward in one of the arms. Twenty-four hours after successful acquisition, they received a systemic injection of vehicle, corticosterone (1mg/kg), the corticosterone-synthesis inhibitor metyrapone (35mg/kg) or were left untreated 1h before retention testing. We found that the corticosterone injection impaired the retrieval of stimulus-response memory. We further found that the systemic injection procedure per se was stressful as the vehicle administration also increased plasma corticosterone levels and impaired the retrieval of stimulus-response memory. However, memory retrieval was not impaired when rats were tested 2min after the systemic vehicle injection, before any stress-induced elevation in corticosterone levels had occurred. Moreover, metyrapone treatment blocked the effect of injection stress on both plasma corticosterone levels and memory retrieval impairment, indicating that the endogenous corticosterone response mediates the stress-induced memory retrieval impairment. None of the treatments affected rats' locomotor activity or motivation to search for the food reward within the maze. These findings show that stress may affect memory processes beyond the hippocampus and that these stress effects are due to the action of glucocorticoids. 
26922160	Cue-reactivity is thought to play a fundamental role in the maintenance of addiction. The incentive sensitization theory proposes that conditioned responses are related to increased sensitivity of the reward-related dopaminergic pathways in the brain. However, neuroimaging studies on alcohol cue-reactivity show inconsistent results.Stimuli content of 26 alcohol cue-reactivity studies was systematically reviewed.	No differences were found between alcoholic beverage stimuli and non-alcoholic beverage stimuli in human display and brand factors; however, alcoholic beverage stimuli were more likely to display social interaction compared to non-alcoholic beverage stimuli.	Given that processing of social information activates brain areas that partly overlap with reward-related brain areas associated with cue-reactivity, such differences between conditions can introduce noise in the findings. We therefore suggest matching stimuli sets on the reviewed factors carefully to improve reliability of neuroimaging studies investigating alcohol-related cue-reactivity.	
26921725	The objective of this study was to examine the relation between affects linked to avoidance/withstanding options and distress tolerance in heavy drinkers. It has been suggested that the expected rewards of taking withstanding options and the expected punishments of taking avoidance options could have an influence on judgment regarding withstanding ongoing distress. However, there are no studies that have tested this hypothesis. Thus, we measured the affects linked to each option and examined their relations with distress tolerance based on the theoretical/empirical evidence that proves that affects reflect the expected rewards and punishments of certain options. We hypothesized that affects linked to avoidance/withstanding options are closely related to distress tolerance in heavy drinkers.Forty heavy drinkers completed a self-report measure that assessed the affective associations of options and took a behavioral task indexing distress tolerance.	Hierarchical regression analyses revealed that affects linked to avoidance/withstanding options are closely associated with distress tolerance, even after controlling for negative emotional experiences and alcohol use problems.	Our findings indicate that affects linked to avoidance/withstanding options may have an important influence on distress tolerance and therefore deserve further explorations.	
26919475	In the philosophical literature, self-deception is mainly approached through the analysis of paradoxes. Yet, it is agreed that self-deception is motivated by protection from distress. In this paper, we argue, with the help of findings from cognitive neuroscience and psychology, that self-deception is a type of affective coping. First, we criticize the main solutions to the paradoxes of self-deception. We then present a new approach to self-deception. Self-deception, we argue, involves three appraisals of the distressing evidence: (a) appraisal of the strength of evidence as uncertain, (b) low coping potential and (c) negative anticipation along the lines of Damasio's somatic marker hypothesis. At the same time, desire impacts the treatment of flattering evidence via dopamine. Our main proposal is that self-deception involves emotional mechanisms provoking a preference for immediate reward despite possible long-term negative repercussions. In the last part, we use this emotional model to revisit the philosophical paradoxes. 
26919132	In Southeast Asia the native honey bee species Apis cerana is often attacked by hornets (Vespa velutina), mainly in the period from April to November. During the co-evolution of these two species honey bees have developed several strategies to defend themselves such as learning the odors of hornets and releasing alarm components to inform other mates. However, so far little is known about whether and how honey bees modulate their olfactory learning in the presence of the hornet predator and alarm components of honey bee itself. In the present study, we test for associative olfactory learning of A. cerana in the presence of predator odors, the alarm pheromone component isopentyl acetate (IPA), or a floral odor (hexanal) as a control. The results show that bees can detect live hornet odors, that there is almost no association between the innately aversive hornet odor and the appetitive stimulus sucrose, and that IPA is less well associated with an appetitive stimulus when compared with a floral odor. In order to imitate natural conditions, e.g. when bees are foraging on flowers and a predator shows up, or alarm pheromone is released by a captured mate, we tested combinations of the hornet odor and floral odor, or IPA and floral odor. Both of these combinations led to reduced learning scores. This study aims to contribute to a better understanding of the prey-predator system between A. cerana and V. velutina.
26919058	Amotivation, or decisional anhedonia, is a prominent and disabling feature of depression. However, this aspect of depression remains understudied, and no prior work has applied objective laboratory tests of motivation in both unipolar and bipolar depression.We assessed motivation deficits using a Progressive Ratio Task (PRT) that indexes willingness to exert effort for monetary reward. The PRT was administered to 96 adults ages 18-60 including 25 participants with a current episode of unipolar depression, 28 with bipolar disorder (current episode depressed), and 43 controls without any Axis I psychiatric disorders.	Depressed participants exhibited significantly lower motivation than control participants as objectively defined by progressive ratio breakpoints. Both the unipolar and bipolar groups were lower than controls but did not differ from each other.	Medication use differed across groups, and we did not have a separate control task to measure psychomotor activity; however neither medication effects or psychomotor slowing are likely to explain our findings.	Our study fills an important gap in the literature by providing evidence that diminished effort on the PRT is present across depressed patients who experience either unipolar or bipolar depression. This adds to growing evidence for shared mechanisms of reward and motivation dysfunction, and highlights the importance of improving the assessment and treatment of motivation deficits across the mood disorders spectrum.	
26919056	Whether personality features affect the development of somatoform disorders and their psychopathologies is an important issue. Aim of this study was to resolve this issue by comparing indicators of psychopathology and personality features in subjects with somatoform disorders and healthy controls.This study recruited 148 subjects with somatoform disorders and 146 healthy controls. The severity of psychopathology was measured with the Patient Health Questionnaire-15 (PHQ-15), Health Anxiety Questionnaire (HAQ), Beck Depression Inventory-II (BDI-II), and Beck Anxiety Inventory (BAI). The Tridimensional Personality Questionnaire (TPQ) was used to assess personality features. Demographic data, psychopathology indicators, and TPQ scores were compared between groups. Correlation and multivariate linear regression analysis were used to identify the personality dimensions or demographic variables associated with psychopathology.	The somatoform group had lower novelty seeking (NS) and reward dependence (RD) and higher harm avoidance (HA) and severity of psychopathologies. Multiple regression analysis revealed that fatigability, persistence, gender, and education level were predictive of PHQ-15; HA, educational level, persistence, and dependence were predictive of HAQ; HA, persistence, education level, and NS were predictive of BDII-II; and fatigability, education level, persistence, and anticipatory worry were predictive of BAI. The development of somatoform disorders was associated with fatigability, age, residence location, education level, and attachment.	The limitations include heterogeneity of the diagnosis, the high proportion of undifferentiated somatoform disorder, and the cross-sectional study design.	HA/fatigability, persistence, and education level are associated with each type of psychopathology. Fatigability is a powerful predictor of somatoform disorder development.	
26918742	Dual-systems frameworks propose that moral judgments are derived from both an immediate emotional response, and controlled/rational cognition. Recently Cushman (2013) proposed a new dual-system theory based on model-free and model-based reinforcement learning. Model-free learning attaches values to actions based on their history of reward and punishment, and explains some deontological, non-utilitarian judgments. Model-based learning involves the construction of a causal model of the world and allows for far-sighted planning; this form of learning fits well with utilitarian considerations that seek to maximize certain kinds of outcomes. I present three concerns regarding the use of model-free reinforcement learning to explain deontological moral judgment. First, many actions that humans find aversive from model-free learning are not judged to be morally wrong. Moral judgment must require something in addition to model-free learning. Second, there is a dearth of evidence for central predictions of the reinforcement account-e.g., that people with different reinforcement histories will, all else equal, make different moral judgments. Finally, to account for the effect of intention within the framework requires certain assumptions which lack support. These challenges are reasonable foci for future empirical/theoretical work on the model-free/model-based framework. 
26918236	The medial prefrontal cortex (mPFC) is a part of brain reward system involved in cognitive functions such as learning and memory. The mPFC receives strong dopaminergic innervations from ventral tegmental area (VTA) that comprises a portion of the mesolimbic dopaminergic system (MLDS), and sends glutamatergic projections to both the VTA and nucleus accumbens (NAc).In this study, male Wister rats weighing 250-350 g were used. The effect of medial prefrontal cortex (mPFC) electrical stimulation with different current intensities (25, 50,100, and 150 μA) in healthy and addicted rats on passive avoidance memory was studied here.	This study showed that 25 and 150 μA had no effect on improving avoidance memory in rats. Current intensities of 50 and 100 μA differ significantly with 25 and 150 μA. The PL of mPFC contributes to memory processing.	The electrical stimulations of prelimbic with 50 and 100 μA current intensities were improved avoidance memory in addicted rats while learning impairment is caused in healthy rats while the electrical stimulation with these used current intensities.	

26917214	Self-affirmation (reflecting on important personal values) has been shown to have a range of positive effects; however, the neural basis of self-affirmation is not known. Building on studies showing that thinking about self-preferences activates neural reward pathways, we hypothesized that self-affirmation would activate brain reward circuitry during functional MRI (fMRI) studies. In Study 1, with college students, making judgments about important personal values during self-affirmation activated neural reward regions (i.e., ventral striatum), whereas making preference judgments that were not self-relevant did not. Study 2 replicated these results in a community sample, again showing that self-affirmation activated the ventral striatum. These are among the first fMRI studies to identify neural processes during self-affirmation. The findings extend theory by showing that self-affirmation may be rewarding and may provide a first step toward identifying a neural mechanism by which self-affirmation may produce a wide range of beneficial effects. 
26916640	Researchers have shown that both differential reinforcement and response cost within token economies are similarly effective for changing the behavior of individuals in a group context (e.g., Donaldson, DeLeon, Fisher, & Kahng, 2014; Iwata & Bailey, 1974). In addition, these researchers have empirically evaluated preference for these procedures. However, few previous studies have evaluated the individual effects of these procedures both in group contexts and in the absence of peers. Therefore, we replicated and extended previous research by determining the individual effects and preferences of differential reinforcement and response cost under both group and individualized conditions. Results demonstrated that the procedures were equally effective for increasing on-task behavior during group and individual instruction for most children, and preference varied across participants. In addition, results were consistent across participants who experienced the procedures in group and individualized settings.
26916080	The aim of this study was to test the psychometric properties of a short questionnaire for work-related stress entitled Work Well index (WWi) and its interaction with different variables of self-reported health. An online survey was conducted in a sample of 1,218 employees (51% female) in four countries of an international insurance company. Internal consistency reliability, factorial validity, convergent validity and criterion validity of the 10-item WWi were analyzed. Good internal consistency reliability of the WWi was obtained (Cronbach's α coefficient = 0.85). Confirmatory factor analysis showed a satisfactory model fit of the data (AGFI = 0.92). The WWi was highly correlated to conceptually close constructs such as demand-control, effort-reward imbalance and workplace social capital (p < 0.001). Moreover, the 10-item WWi was significantly (p < 0.001) associated with elevated risk of self-rated health, absenteeism, presenteeism and depression (odds ratio 1.63, 1.36, 2.08, 2.95, respectively). We conclude that this short questionnaire is a reliable and valid instrument measuring psychosocial stress at work. Copyright © 2016 John Wiley & Sons, Ltd.
26915673	Striatal-enriched protein tyrosine phosphatase (STEP) is abundantly expressed in the striatum, which strongly expresses dopamine and opioid receptors and mediates the effects of many drugs of abuse. However, little is known about the role of STEP in opioid receptor function. In the present study, we generated STEP-targeted mice carrying a nonsense mutation (C230X) in the kinase interaction domain of STEP by screening the N-ethyl-N-nitrosourea (ENU)-driven mutant mouse genomic DNA library and subsequent in vitro fertilization. It was confirmed that the C230X nonsense mutation completely abolished functional STEP protein expression in the brain. STEP(C230X-/-) mice showed attenuated acute morphine-induced psychomotor activity and withdrawal symptoms, whereas morphine-induced analgesia, tolerance and reward behaviors were unaffected. STEP(C230X-/-) mice displayed reduced hyperlocomotion in response to intrastriatal injection of the μ-opioid receptor agonist DAMGO, but the behavioral responses to δ- and κ-opioid receptor agonists remained intact. These results suggest that STEP has a key role in the regulation of psychomotor action and physical dependency to morphine. These data suggest that STEP inhibition may be a critical target for the treatment of withdrawal symptoms associated with morphine. 
26915426	Correctly directing social behaviour towards a specific individual requires an ability to discriminate between conspecifics. The mechanisms of individual recognition include phenotype matching and familiarity-based recognition. Communication-based recognition is a subset of familiarity-based recognition wherein the classification is based on behavioural or distinctive signalling properties. Male fowl (Gallus gallus) produce a visual display (tidbitting) upon finding food in the presence of a female. Females typically approach displaying males. However, males may tidbit without food. We used the distinctiveness of the visual display and the unreliability of some males to test for communication-based recognition in female fowl. We manipulated the prior experience of the hens with the males to create two classes of males: S(+) wherein the tidbitting signal was paired with a food reward to the female, and S (-) wherein the tidbitting signal occurred without food reward. We then conducted a sequential discrimination test with hens using a live video feed of a familiar male. The results of the discrimination tests revealed that hens discriminated between categories of males based on their signalling behaviour. These results suggest that fowl possess a communication-based recognition system. This is the first demonstration of live-to-video transfer of recognition in any species of bird. 
26914457	The interaction of working and reference memory was studied in rats on an eight-arm radial maze. In two experiments, rats were trained to perform working memory and reference memory tasks. On working memory trials, they were allowed to enter four randomly chosen arms for reward in a study phase and then had to choose the unentered arms for reward in a test phase. On reference memory trials, they had to learn to visit the same four arms on the maze on every trial for reward. Retention was tested on working memory trials in which the interval between the study and test phase was 15 s, 15 min, or 30 min. At each retention interval, tests were performed in which the correct WM arms were either congruent or incongruent with the correct RM arms. Both experiments showed that congruency interacted with retention interval, yielding more forgetting at 30 min on incongruent trials than on congruent trials. The effect of reference memory strength on the congruency effect was examined in Experiment 1, and the effect of associating different contexts with working and reference memory on the congruency effect was studied in Experiment 2.
26914228	As obesity has become a pressing health issue for American children, greater attention has been focused on how schools can be used to improve how students eat. Previously, we piloted the use of small prizes in an elementary school cafeteria to improve healthful food selection. We hoped to increase healthful food selection in all the elementary schools of a small school district participating in the United States Department of Agriculture Lunch Program by offering prizes to children who selected a Power Plate (PP), which consisted of an entrée with whole grains, a fruit, a vegetable, and plain low-fat milk. In this study, the PP program was introduced to 3 schools sequentially over an academic year. During the kickoff week, green, smiley-faced emoticons were placed by preferred foods, and children were given a prize daily if they chose a PP on that day. After the first week, students were given a sticker or temporary tattoo 2 days a week if they selected a PP. Combining data from the 3 schools in the program, students increased PP selection from 4.5% at baseline to 49.4% (p < 0.0001) during an intervention period of 2.5 school weeks. The school with the longest intervention period, 6 months, showed a PP selection increase of from 3.9% to 26.4% (p < 0.0001). In conclusion, giving small prizes as rewards dramatically improves short-term healthful food selection in elementary school children. 
26913540	Technological advances over the last decade are changing the face of behavioral neuroscience research. Here we review recent work on the use of one such transformative tool in behavioral neuroscience research, chemogenetics (or Designer Receptors Exclusively Activated by Designer Drugs, DREADDS). As transformative technologies such as DREADDs are introduced, applied, and refined, their utility in addressing complex questions about behavior and cognition becomes clear and exciting. In the behavioral neuroscience field, remarkable new findings now regularly appear as a result of the ability to monitor and intervene in neural processes with high anatomical precision as animals behave in complex task environments. As these new tools are applied to behavioral questions, individualized procedures for their use find their way into diverse labs. Thus, "tips of the trade" become important for wide dissemination not only for laboratories that are using the tools but also for those who are interested in incorporating them into their own work. Our aim is to provide an up-to-date perspective on how the DREADD technique is being used for research on learning and memory, decision making, and goal-directed behavior, as well as to provide suggestions and considerations for current and future users based on our collective experience. (PsycINFO Database Record 
26911787	In addition to the neuromodulatory role of cholinergic systems, brief, temporally discrete cholinergic release events, or "transients", have been associated with the detection of cues in attention tasks. Here we review four main findings about cholinergic transients during cognitive processing. Cholinergic transients are: (1) associated with the detection of a cue and influenced by cognitive state; (2) not dependent on reward outcome, although the timing of the transient peak co-varies with the temporal relationship between detection and reward delivery; (3) correlated with the mobilization of the cue-evoked response; (4) causal mediators of shifts from monitoring to cue detection. We next discuss some of the key questions concerning the timing and occurrence of transients within the framework of available evidence including: (1) Why does the shift from monitoring to cue detection require a transient? (2) What determines whether a cholinergic transient will be generated? (3) How can cognitive state influence transient occurrence? (4) Why do cholinergic transients peak at around the time of reward delivery? (5) Is there evidence of cholinergic transients in humans? We conclude by outlining future research studies necessary to more fully understand the role of cholinergic transients in mediating cue detection. 
26911379	Establishing a behavioral model for the effect of social environment on nicotine intake in rodents facilitates the investigation of molecular mechanisms critical for the interaction between social environment and cigarette smoking.Our main objective was to test the hypothesis that nicotine is the primary reinforcer in the socially acquired nicotine intravenous self-administration (IVSA) model by using an aversive flavor cue.	Adolescent female rats were placed in operant conditioning chambers equipped with two lickometers. Operant licking triggered concurrent deliveries of a flavor (i.e., taste and odor) cue containing either quinine or saccharin and an i.v. infusion (30 μg/kg nicotine or saline). An audiovisual cue was provided for some groups of rats. A second rat that did not receive nicotine was placed in the operant conditioning chambers to provide either a neutral or an inducing (i.e., by consuming the flavored solution) social environment. These two rats were separated by a divider that allowed orofacial interactions.	Rats acquired stable nicotine IVSA with either the aversive or the appetitive flavor cue in the inducing social environment, and obtained similar amounts of infusions. The neutral social environment did not support nicotine IVSA with either cue. The audiovisual cue per se did not support nicotine IVSA but enhanced nicotine intake. Nicotine increased the number of concurrent nose pokes by the two rats into the center divider, a measure of social interaction.	Despite its aversive effects, nicotine is the primary reinforcer for the operant responses in the socially acquired nicotine IVSA model.	
26911263	Prospective studies and intervention evaluations that examine change over time assume that measurement tools measure the same construct at each occasion. In the area of parent-child feeding practices, longitudinal measurement properties of the questionnaires used are rarely verified. To ascertain that measured change in feeding practices reflects true change rather than change in the assessment, structure, or conceptualisation of the constructs over time, this study examined longitudinal measurement invariance of the Feeding Practices and Structure Questionnaire (FPSQ) subscales (9 constructs; 40 items) across 3 time points. Mothers participating in the NOURISH trial reported their feeding practices when children were aged 2, 3.7, and 5 years (N = 404). Confirmatory Factor Analysis (CFA) within a structural equation modelling framework was used. Comparisons of initial cross-sectional models followed by longitudinal modelling of subscales, resulted in the removal of 12 items, including two redundant or poorly performing subscales. The resulting 28-item FPSQ-28 comprised 7 multi-item subscales: Reward for Behaviour, Reward for Eating, Persuasive Feeding, Overt Restriction, Covert Restriction, Structured Meal Setting and Structured Meal Timing. All subscales showed good fit over 3 time points and each displayed at least partial scalar (thresholds equal) longitudinal measurement invariance. We recommend the use of a separate single item indicator to assess the family meal setting. This is the first study to examine longitudinal measurement invariance in a feeding practices questionnaire. Invariance was established, indicating that the subscales of the shortened FPSQ-28 can be used with mothers to validly assess change in 7 feeding constructs in samples of children aged 2-5 years of age. 
26909847	Elucidating the neurobiological mechanisms underlying individual differences in the extent to which reward cues acquire the ability to act as incentive stimuli may contribute to the development of successful treatments for addiction and related disorders. We used the sign-tracker/goal-tracker animal model to examine the role of dopamine D2 and D3 receptors in the propensity to attribute incentive salience to reward cues. Following Pavlovian training, wherein a discrete lever-cue was paired with food reward, rats were classified as sign- or goal-trackers based on the resultant conditioned response. We examined the effects of D2/D3 agonists, 7-OH-DPAT (0.01-0.32mg/kg) or pramipexole (0.032-0.32mg/kg), the D2/D3 antagonist raclopride (0.1mg/kg), and the selective D3 antagonist, SB-277011A (6 or 24mg/kg), on the expression of sign- and goal-tracking conditioned responses. The lever-cue acquired predictive value and elicited a conditioned response for sign- and goal-trackers, but only for sign-trackers did it also acquire incentive value. Following administration of either 7-OH-DPAT, pramipexole, or raclopride, the performance of the previously acquired conditioned response was attenuated for both sign- and goal-trackers. For sign-trackers, the D2/D3 agonist, 7-OH-DPAT, also attenuated the conditioned reinforcing properties of the lever-cue. The selective D3 antagonist did not affect either conditioned response. Alterations in D2/D3 receptor signaling, but not D3 signaling alone, transiently attenuate a previously acquired Pavlovian conditioned response, regardless of whether the response is a result of incentive motivational processes. These findings suggest activity at the dopamine D2 receptor is critical for a reward cue to maintain either its incentive or predictive qualities. 
26909674	This study examined sex differences in executive function in middle-aged gonadectomized marmosets (Callithrix jacchus) with or without hormonal replacement. We tested ten castrated male (mean age 5.5 years) marmosets treated with testosterone cypionate (T, n = 5) or vehicle (n = 5) on Reversal Learning, which contributes to cognitive flexibility, and the Delayed Response task, measuring working memory. Their performance was compared to that of 11 ovariectomized females (mean age = 3.7 years) treated with Silastic capsules filled with 17-β estradiol (E2, n = 6) or empty capsules (n = 5), previously tested on the same tasks (Lacreuse et al. in J Neuroendocrinol 26:296-309, 2014. doi: 10.1111/jne.12147). Behavioral observations were conducted daily. Females exhibited more locomotor behaviors than males. Males and females did not differ in the number of trials taken to reach criterion on the reversals, but males had significantly longer response latencies, regardless of hormone replacement. They also had a greater number of refusals than females. Additionally, both control and T-treated males, but not females, had slower responses on incorrect trials, suggesting that males were making errors due to distraction, lack of motivation or uncertainty. Furthermore, although both males and females had slower responding following an incorrect compared to a correct trial, the sex difference in response latencies was disproportionally large following an incorrect trial. No sex difference was found in the Delayed Response task. Overall, slower response latencies in males than females during Reversal Learning, especially during and following an incorrect trial, may reflect greater sensitivity to punishment (omission of reward) and greater performance monitoring in males, compared to females. Because these differences occurred in gonadectomized animals and regardless of hormone replacement, they may be organized early in life.
26908005	In Experiment 1, six capuchins lifted a weight during a 10-min session to receive a food piece. Across conditions, the weight was increased across six different amounts for three different food types. The number of food pieces obtained as a function of the weight lifted was fitted by a demand equation that is hypothesized to quantify food value. For most subjects, this analysis showed that the three food types differed little in value. In Experiment 2, these monkeys were given pairwise choices among these food types. In 13 of 18 comparisons, preferences at least equaled a 3-to-1 ratio; in seven comparisons, preference was absolute. There was no relation between values based on degree of preference versus values based on the demand equation. When choices in the present report were compared to similar data with these subjects from another study, between-study lability in preference emerged. This outcome contrasts with the finding in demand analysis that test-retest reliability is high. We attribute the unreliability and extreme assignment of value based on preference tests to high substitutability between foods. We suggest use of demand analysis instead of preference tests for studies that compare the values of different foods. A better strategy might be to avoid manipulating value by using different foods. Where possible, value should be manipulated by varying amounts of a single food type because, over an appropriate range, more food is consistently more valuable than less. Such an approach would be immune to problems in between-food substitutability. 

26905669	Interest is rising for animal modelling of Gambling disorder (GD), which is rapidly emerging as a mental health concern. In the present study, we assessed gambling proneness in male Wistar-Han rats using the "Probabilistic Delivery Task" (PDT). This operant protocol is based on choice between either certain, small amounts of food (SS) or larger amounts of food (LLL) delivered (or not) depending on a given (and progressively decreasing) probability. Here, we manipulated the ratio between large and small reward size to assess the impact of different magnitudes on rats' performance. Specifically, we drew a comparison between threefold (2 vs 6 pellets) and fivefold (1 vs 5 pellets) sizes. As a consequence, the "indifferent point" (IP, at which either choice is mathematically equivalent in terms of total foraging) was at 33% and 20% probability of delivery, respectively. Animals tested with the sharper contrast (i.e. fivefold ratio) exhibited sustained preference for LLL far beyond the IP, despite high uncertainty and low payoff, which rendered LLL a sub-optimal option. By contrast, animals facing a slighter contrast (i.e. threefold ratio) were increasingly disturbed by progressive rarefaction of rewards, as expressed by enhanced inadequate nose-poking: this was in accordance with their prompt shift in preference to SS, already shown around the IP. In conclusion, a five-folded LLL-to-SS ratio was not only more attractive, but also less frustrating than a three-folded one. Thus, a profile of gambling proneness in the PDT is more effectively induced by marked contrast between alternative options. 
26905190	Impaired social interaction is a hallmark symptom of many psychiatric diseases, including dependence syndromes (substance use disorders). Helping the addict reorient her/his behavior away from the drug of abuse toward social interaction would be of considerable therapeutic benefit. To study the neural basis of such a reorientation, we have developed several animal models in which the attractiveness of a dyadic (i.e. one-to-one) social interaction (DSI) can be compared directly with that of cocaine as a prototypical drug of abuse. Our models are based on the conditioned place preference (CPP) paradigm. In an ongoing effort to validate our experimental paradigms in C57BL/6 mice to make use of the plethora of transgenic models available in this genus, we found the following: (a) DSI with a live mouse produced CPP, whereas an interaction with an inanimate mouse-like object (i.e. a 'toy mouse'; toy mouse interaction) led to conditioned place aversion - but only in the Jackson substrain (C57BL/6J). (b) In the NIH substrain (C57BL/6N), both DSI and toy mouse interaction produced individual aversion in more than 50% of the tested mice. (c) Four 15 min DSI episodes did not result in the development of an observable hierarchy, that is, dominance/subordination behavior in the overwhelming majority (i.e. 30 of 32) of the tested Jackson mouse pairs. Therefore, dominance/subordination does not seem to be a confounding variable in our paradigm, at least not in C57BL/6J mice. Respective data for NIH mice were too limited to allow any conclusion. The present findings indicate that (a) DSI with a live mouse produces CPP to a greater degree than an interaction with an inanimate object resembling a mouse and that (b) certain substrain differences with respect to CPP/aversion to DSI do exist between the Jax and NIH substrain of C57BL/6 mice. These differences have to be considered when choosing a proper mouse substrain model for investigating the neural basis of DSI reward versus drug reward. 
26905044	Engage is a treatment for late-life depression developed to match the skills of community clinicians based on the theory that dysfunction in the Research Domain Criteria Project positive valence systems is a critical mechanism of late-life depression. Accordingly, it uses "reward exposure" (engagement in meaningful, rewarding activities) as its principal intervention. This study tests the hypothesis that change in behavioral activation, an index of positive valence systems function, during successive treatment periods with Engage and during follow-up predicts depression at the end of each period.Forty-eight nondemented, older adults with unipolar major depression were treated openly with 9 weekly sessions of Engage and assessed 36 weeks after entry. Depression severity was assessed with the 24-item Hamilton Depression Rating Scale (HAM-D) and behavioral activation with the Behavioral Activation for Depression Scale (BADS) at baseline, 6 weeks (mid-treatment), 9 weeks (end of treatment), and 36 weeks.	A mixed-effects model examined whether change in BADS in successive periods occurring during Engage treatment and during follow-up predicts depression at the end of each period. Both BADS change (F1,52 = 18.63, p < 0.0001) and time (F2,52 = 7.68, p = 0.0012) predicted HAM-D scores at the end of each observation period. Every point of increase in BADS change reduced the HAM-D by 0.105 points. HAM-D at each point did not predict subsequent change in BADS (F1,52 = 2.17, p = 0.146).	During Engage treatment and follow-up, change in behavioral activation is followed by improvement of depressive symptoms and signs.	
26904943	Dopamine release during reward-driven behaviors influences synaptic plasticity. However, dopamine innervation and release in the hippocampus and its role during aversive behaviors are controversial. Here, we show that in vivo hippocampal synaptic plasticity in the CA3-CA1 circuit underlies contextual learning during inhibitory avoidance (IA) training. Immunohistochemistry and molecular techniques verified sparse dopaminergic innervation of the hippocampus from the midbrain. The long-term synaptic potentiation (LTP) underlying the learning of IA was assessed with a D1-like dopamine receptor agonist or antagonist in ex vivo hippocampal slices and in vivo in freely moving mice. Inhibition of D1-like dopamine receptors impaired memory of the IA task and prevented the training-induced enhancement of both ex vivo and in vivo LTP induction. The results indicate that dopamine-receptor signaling during an aversive contextual task regulates aversive memory retention and regulates associated synaptic mechanisms in the hippocampus that likely underlie learning.
26904301	Exposure to drugs of abuse induces plasticity in the brain and creates persistent drug-related memories. These changes in plasticity and persistent drug memories are believed to produce aberrant motivation and reinforcement contributing to addiction. Most studies have explored the effect drugs of abuse have on pre- and postsynaptic cells and astrocytes; however, more recently, attention has shifted to explore the effect these drugs have on the extracellular matrix (ECM). Within the ECM are unique structures arranged in a net-like manner, surrounding a subset of neurons called perineuronal nets (PNNs). This review focuses on drug-induced changes in PNNs, the molecules that regulate PNNs, and the expression of PNNs within brain circuitry mediating motivation, reward, and reinforcement as it pertains to addiction. 
26900651	Altered inhibitory control (response inhibition, reward-based inhibition, cognitive inhibition, reversal learning) has been implicated in eating disorders (EDs) and obesity. It is unclear, however, how different types of inhibitory control contribute to eating and weight-control behaviours. This review evaluates the relationship between one aspect of inhibitory control (a reactive component of motor response inhibition measured by the stop signal task) and eating/weight in clinical and non-clinical populations. Sixty-two studies from 58 journal articles were included. Restrained eaters had diminished reactive inhibitory control compared to unrestrained eaters, and showed greatest benefit to their eating behaviour from manipulations of inhibitory control. Obese individuals may show less reactive inhibitory control but only in the context of food-specific inhibition or after executive resources are depleted. Of the limited studies in EDs, the majority found no impairment in reactive inhibitory control, although findings are inconsistent. Thus, altered reactive inhibitory control is related to some maladaptive eating behaviours, and hence may provide a therapeutic target for behavioural manipulations and/or neuromodulation. However, other types of inhibitory control may also contribute. Methodological and theoretical considerations are discussed. 
26900166	Metacognition, the monitoring of one's own mental states, is a fundamental aspect of human intellect. Despite tests in nonhuman animals suggestive of uncertainty monitoring, some authors interpret these results solely in terms of primitive psychological mechanisms and reinforcement regimes, where "reinforcement" is invariably considered to be the delivery and consumption of earned food rewards. Surprisingly, few studies have detailed the trial-by-trial behaviour of animals engaged in such tasks. Here we report ethology-based observations on a rhesus monkey completing sparse-dense discrimination problems, and given the option of escaping trials (i.e., responding "uncertain") at its own choosing. Uncertainty responses were generally made on trials of high objective difficulty, and were characterized by long latencies before beginning visible trials, long times taken for response, and, even after controlling for difficulty, high degrees of wavering during response. Incorrect responses were also common in trials of high objective difficulty, but were characterized by low degrees of wavering. This speaks to the likely adaptive nature of "hesitation," and is inconsistent with models which argue or predict implicit, inflexible information-seeking or "alternative option" behaviours whenever challenging problems present themselves, Confounding models which suggest that nonhuman behaviour in metacognition tasks is driven solely by food delivery/consumption, the monkey was also observed allowing pellets to accumulate and consuming them during and after trials of all response/outcome categories (i.e., whether correct, incorrect, or escaped). This study thus bolsters previous findings that rhesus monkey behaviour in metacognition tasks is in some respects disassociated from mere food delivery/consumption, or even the avoidance of punishment. These and other observations fit well with the evolutionary status and natural proclivities of rhesus monkeys, but weaken arguments that responses in such tests are solely associated with associative mechanisms, and instead suggest more derived and controlled cognitive processing. The latter interpretation appears particularly parsimonious given the neurological adaptations of primates, as well as their highly flexible social and ecological behaviour.
26900137	There is an apparent contradiction between experimental data showing that the basal ganglia are involved in goal-oriented and routine behaviors and clinical observations. Lesion or disruption by deep brain stimulation of the globus pallidus interna has been used for various therapeutic purposes ranging from the improvement of dystonia to the treatment of Tourette's syndrome. None of these approaches has reported any severe impairment in goal-oriented or automatic movement.To solve this conundrum, we trained 2 monkeys to perform a variant of a 2-armed bandit-task (with different reward contingencies). In the latter we alternated blocks of trials with choices between familiar rewarded targets that elicit routine behavior and blocks with novel pairs of targets that require an intentional learning process.	Bilateral inactivation of the globus pallidus interna, by injection of muscimol, prevents animals from learning new contingencies while performance remains intact, although slower for the familiar stimuli. We replicate in silico these data by adding lateral competition and Hebbian learning in the cortical layer of the theoretical model of the cortex-basal ganglia loop that provided the framework of our experimental approach.	The basal ganglia play a critical role in the deliberative process that underlies learning but are not necessary for the expression of routine movements. Our approach predicts that after pallidotomy or during stimulation, patients should have difficulty with complex decision-making processes or learning new goal-oriented behaviors. © 2016 Movement Disorder Society.	
26899746	This review paper is focused upon the involvement of mesolimbic dopamine (DA) and related brain systems in effort-based processes. Interference with DA transmission affects instrumental behavior in a manner that interacts with the response requirements of the task, such that rats with impaired DA transmission show a heightened sensitivity to ratio requirements. Impaired DA transmission also affects effort-related choice behavior, which is assessed by tasks that offer a choice between a preferred reinforcer that has a high work requirement vs. less preferred reinforcer that can be obtained with minimal effort. Rats and mice with impaired DA transmission reallocate instrumental behavior away from food-reinforced tasks with high response costs, and show increased selection of low reinforcement/low cost options. Tests of effort-related choice have been developed into models of pathological symptoms of motivation that are seen in disorders such as depression and schizophrenia. These models are being employed to explore the effects of conditions associated with various psychopathologies, and to assess drugs for their potential utility as treatments for effort-related symptoms. Studies of the pharmacology of effort-based choice may contribute to the development of treatments for symptoms such as psychomotor slowing, fatigue or anergia, which are seen in depression and other disorders. 
26898320	In the current study, the associations of reward sensitivity with weight related behaviors and body mass index were investigated in a general population sample of 443 Flemish children (50.3% boys) aged 5.5-12 years. Cross-sectional data on palatable food consumption frequency, screen time, physical activity, parental education level and measured length and weight were collected. The Drive subscale of the 'Behavioral Inhibition Scale/Behavioral Activation Scale' was used as a short method to measure reward sensitivity. A significant positive association of reward sensitivity with the fast food and sweet drink consumption frequency was found. Furthermore, a significant positive association of reward sensitivity with the z-score of body mass index was demonstrated, which explained additional variance to the variance explained by palatable food consumption frequency, screen time, physical activity and parental education level. Hence, the assessment of reward sensitivity may have an added value to the assessment of weight-related behavior indicators when evaluating the determinants of overweight in a child. In sum, children high in reward sensitivity might be more attracted to fast food and sweet drinks, and hence, might be more vulnerable to develop unfavorable food habits and overweight. These findings suggest that considering inter-individual differences in reward sensitivity is of importance in future childhood obesity prevention campaigns. 
26894884	In the psychological literature, many studies have investigated the neuropsychological and behavioral changes that occur developmentally during adolescence. These studies have consistently observed a deficit in the decision-making ability of children and adolescents. This deficit has been ascribed to incomplete brain development. The same deficit has also been observed in adult problem and pathological gamblers. However, to date, no study has examined decision-making in adolescents with and without gambling problems. Furthermore, no study has ever examined associations between problem gambling, decision-making, cognitive distortions and alcohol use in youth. To address these issues, 104 male adolescents participated in this study. They were equally divided in two groups, problem gamblers and non-problem gamblers, based on South Oaks Gambling Screen Revised for Adolescents scores. All participants performed the Iowa gambling task and completed the Gambling Related Cognitions Scale and the alcohol use disorders identification test. Adolescent problem gamblers displayed impaired decision-making, reported high cognitive distortions, and had more problematic alcohol use compared to non-problem gamblers. Strong correlations between problem gambling, alcohol use, and cognitive distortions were observed. Decision-making correlated with interpretative bias. This study demonstrated that adolescent problem gamblers appear to have the same psychological profile as adult problem gamblers and that gambling involvement can negatively impact on decision-making ability that, in adolescence, is still developing. The correlations between interpretative bias and decision-making suggested that the beliefs in the ability to influence gambling outcomes may facilitate decision-making impairment.
26894438	The relationship between impulse control disorder (ICD) behaviors and problematic Internet use (PIU) has been established in the literature. Our aim was to further investigate whether the ICDs of individuals suffering from PIU primarily involve an inability to delay gratification or a tendency to take risks. Using delay and probability discounting tasks, we compared the subjective value of discounting between PIU individuals and controls in conditions of gaining or losing different monetary amounts. The results of the present study revealed a significant positive relationship between PIU and impulsivity scores. PIU individuals discounted delayed amounts more steeply than controls, regardless of the reward sign and monetary amount. Conversely, there were no significant group differences in the probability discounting task. These findings suggest that PIU individuals may be more impulsive than controls when impulsivity is framed as insensitivity to delayed outcomes rather than as a tendency to take risks, which is inconsistent with the view of impulsivity as a general trait. 
26892860	Competition enhances learning under certain circumstances. However, little is known about how the neural mechanisms involved in a competition during the episodic encoding are modulated by the social distance of personal relationships with opponents. To investigate this issue, using functional magnetic resonance imaging (fMRI), we scanned healthy young adults during a competition with their familiar friends and unfamiliar others in the episodic encoding. Three major findings emerged from this study. First, activations in the right temporo-parietal junction (rTPJ) were significantly greater in the competition with familiar friends than with unfamiliar others, and the activations in this region were significantly correlated with the subjective ratings of motivation. Second, striatum and amygdala activations increased by the competition with familiar friends were significantly correlated with the increased ratings of pleasantness, which reflected emotionally positive feelings in victory for the competition with familiar opponents. Third, the functional connectivity between the rTPJ and reward-related regions, including the striatum and substantia nigra, was higher in the competition with familiar friends than with unfamiliar others. Taken together with our behavioral findings, in which memories encoded by competing with familiar friends were remembered more accurately than those with unfamiliar others, the interacting mechanisms between the rTPJ that is involved in social motivation and the reward-related regions that are involved in social reward could contribute to the enhancement of memories encoded in the competition with familiar others. 
26892856	Joint attention, the shared attentional focus of at least two people on a third significant object, is one of the earliest steps in social development and an essential aspect of reciprocal interaction. However, the neural basis of joint attention (JA) in the course of development is completely unknown. The present study made use of an interactive eye-tracking paradigm in order to examine the developmental trajectories of JA and the influence of a familiar interaction partner during the social encounter. Our results show that across children and adolescents JA elicits a similar network of "social brain" areas as well as attention and motor control associated areas as in adults. While other-initiated JA particularly recruited visual, attention and social processing areas, self-initiated JA specifically activated areas related to social cognition, decision-making, emotions and motivational/reward processes highlighting the rewarding character of self-initiated JA. Activation was further enhanced during self-initiated JA with a familiar interaction partner. With respect to developmental effects, activation of the precuneus declined from childhood to adolescence and additionally shifted from a general involvement in JA towards a more specific involvement for self-initiated JA. Similarly, the temporoparietal junction (TPJ) was broadly involved in JA in children and more specialized for self-initiated JA in adolescents. Taken together, this study provides first-time data on the developmental trajectories of JA and the effect of a familiar interaction partner incorporating the interactive character of JA, its reciprocity and motivational aspects. 
26890678	Cues that are contingently paired with unconditioned, rewarding stimuli can acquire rewarding properties themselves through a process known as the attribution of incentive salience, or the transformation of neutral stimuli into attractive, "wanted' stimuli capable of motivating behavior. Pavlovian conditioned approach (PCA) develops after the response-independent presentation of a conditioned stimulus (CS; e.g., a lever) that predicts the delivery of an unconditioned stimulus (US; e.g., a food pellet) and can be used to measure incentive salience. During training, three patterns of conditioned responses (CRs) can develop: sign-tracking behavior (CS-directed CR), goal-tracking behavior (US-directed CR), and an intermediate response (both CRs). Sign-trackers attribute incentive salience to reward-related cues and are more vulnerable to cue-induced reinstatement of drug-seeking as well as other addiction-related behaviors, making PCA a potentially valuable procedure for studying addiction vulnerability. Here, we describe materials and methods used to elicit PCA behavior from rats as well as analyze and interpret PCA behavior in individual experiments. 
26890672	High-fat diet (HFD) consumption causes obesity, which is associated with well-known increased health risks. Moreover, obesity has been associated with altered sensorimotor and emotional behaviors of humans and mice. This study attempted to dissociate the influence of HFD-induced obesity on behaviors from the influence of HFD consumption itself.C57BL male mice were randomly allocated to a low-fat diet (LFD) group, an HFD-induced obesity (DIO) group, or a pair-fed HFD-feeding nonobese (HFD) group. A comprehensive behavioral test battery was performed on all three groups to assess sensorimotor functions, anxiety- and depression-like behaviors, reward-related behaviors, social behaviors, and learning/memory functions.	Both the DIO and HFD groups exhibited disturbed olfaction, blunted ethanol preference, and enhanced social interactions. The DIO group exhibited blunted sucrose preference, shorter latency before falling off during the rotarod test, and a lower response to mechanical stimuli.	The HFD-fed nonobese mice showed altered behaviors related to olfaction, social interactions, and rewards that were similar to those of the DIO mice. This finding suggests that HFD consumption alters a variety of behaviors independent of obesity.	
26890248	Oxytocin (OT) has been implicated in a variety of mammalian reproductive and social behaviors, and the use of intranasal OT for clinical purposes is on the rise. However, basic actions of OT, including the rewarding or reinforcing properties of the drug, are currently not fully understood. In this study, the authors investigated whether intranasally administered OT has different reinforcing properties for social and nonsocial stimuli and whether such effects are variable between male and female subjects. Conditioned social preference (CSP) and conditioned place preference (CPP) paradigms were used to examine social and nonsocial reinforcing properties of OT. In CSP, the presence of a same-sex unfamiliar conspecific was repeatedly paired with intranasal OT, while a different conspecific was associated with saline. The reinforcing effect of OT was assessed in a postconditioning choice test under a drug-free condition. In CPP, the 2 conspecifics were replaced with nonsocial black and white compartments. The authors found that intranasal OT (12 μg) in females supported the formation of CSP (Experiment 1) but not CPP (Experiment 3). Neither CSP (Experiment 2) nor CPP (Experiment 4) was formed in males. Extended conditioning with higher dose OT (36 μg), however, abolished the initial CSP in females and produced an aversion to the OT-paired stimulus mouse. Experiment 5 indicated that it was the repeated administrations rather than the higher dose that produced the abolition of the original preference. Overall, the current results demonstrate for the first time a sex- and stimulus-dependent reinforcing property of intranasal OT in mice. (PsycINFO Database Record 
26888930	Initiating a reward-seeking behavior involves deciding on an action, how fast to initiate the action (initiation vigor), as well as how much effort to exert. These processes are thought to involve the mesolimbic dopamine system. Dopamine levels in the ventral striatum rise before initiating a reliably reinforced behavior. However, it is unknown whether dopamine is similarly involved with unreinforced actions (inactive lever presses, premature food port entries, insufficient number of active lever presses). Furthermore, does the dopamine response when initiating an action reflect specific aspects of motivated behavior, such as initiation vigor and exerted effort? Here, we analyzed voltammetry recordings of dopamine levels in the nucleus accumbens (NAcc) core and shell in rats working for food under a progressive ratio reinforcement schedule. We examined dopamine levels when rats initiated distinct actions (active lever presses, inactive lever presses, food port entries) that were temporally separated from cue- and reward-evoked dopamine release. Active lever pressing bouts were preceded by elevated dopamine release in the NAcc shell, as well as in the NAcc core, although only when rats exhibited high initiation vigor. Dopamine levels were transiently reduced in the NAcc core following an unreinforced food port entry and were unchanged throughout the NAcc when initiating inactive lever presses. The effort exerted and vigor to initiate a bout of active lever presses were signaled by dopamine transmission in the NAcc core, but not in the NAcc shell. These results demonstrate that the dopamine response when initiating a behavior is both region- and action-specific.Exogenous activation of the mesolimbic dopamine system facilitates motivated behavior. However, a direct relationship has not been established between endogenous phasic dopamine transmission and measures of motivation, such as the vigor to initiate an action and the effort exerted in a bout of activity. The present work demonstrates that the dopamine response when initiating an action depends both upon where dopamine is released and what action is performed. Furthermore, dopamine reflects measures of motivated behavior selectively within the nucleus accumbens core.	

26888174	A recurrent spiking neural network is proposed that implements planning as probabilistic inference for finite and infinite horizon tasks. The architecture splits this problem into two parts: The stochastic transient firing of the network embodies the dynamics of the planning task. With appropriate injected input this dynamics is shaped to generate high-reward state trajectories. A general class of reward-modulated plasticity rules for these afferent synapses is presented. The updates optimize the likelihood of getting a reward through a variant of an Expectation Maximization algorithm and learning is guaranteed to convergence to a local maximum. We find that the network dynamics are qualitatively similar to transient firing patterns during planning and foraging in the hippocampus of awake behaving rats. The model extends classical attractor models and provides a testable prediction on identifying modulating contextual information. In a real robot arm reaching and obstacle avoidance task the ability to represent multiple task solutions is investigated. The neural planning method with its local update rules provides the basis for future neuromorphic hardware implementations with promising potentials like large data processing abilities and early initiation of strategies to avoid dangerous situations in robot co-worker scenarios. 
26887589	Phentermine is structurally similar to methamphetamine and is widely used as an anti-obesity drug in the USA and many other countries. The potential for reward of phentermine has been noted; however, the mechanisms of phentermine dependence have not been established.Here, we investigated the rewarding and dopaminergic behavioral responses to phentermine in mice and found that phentermine produced conditioned rewarding effects through the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in the nucleus accumbens (NAc).	The impact of phentermine was assessed using conditioned place preference (CPP) test, climbing behavior test, and western blot analysis.	Phentermine 1 and 3 mg/kg (i.p.) significantly increased CPP. Phentermine, a known dopamine releaser, boosted apomorphine-induced climbing behavior in mice, and methamphetamine (i.p.) also increased apomorphine-induced dopaminergic behavior. Phentermine and methamphetamine increased the level of expression of the dopamine transporter (DAT) and phospho-Akt proteins to a similar degree in the NAc of CPP mice. To determine whether the conditioned rewarding effects of phentermine were mediated through the PI3K/Akt pathway, we assessed the effects of the Akt inhibitor LY294002 on phentermine-induced place preference and climbing behavior. LY294002 (1 and 3 μg/site, i.c.v.) reduced phentermine-induced CPP and phentermine-increased climbing behavior. However, LY294002 did not change CPP and climbing behavior itself and also did not decrease apomorphine-induced climbing behavior in mice. Further, LY294002 decreased the phentermine-increased levels of DAT protein and phosphorylation of Akt in the NAc of CPP mice.	Thus, these findings suggest that phentermine induces conditioned rewarding effects via activation of the PI3K/Akt signaling pathway in the NAc.	
26887303	To explore the influence of occupational stress and related factors on depression symptoms in train drives.In March 2012, by using cluster sampling method, a cross-sectional epidemiological study was conducted in 1 402 train drivers in China. Questionnaires was investigation was conducted by face to face interview. Sample with missing variables on demographic characteristics questionnaire with missed survey variables, and occupational stress related factors and with over 3 item missing in depression symptoms self-rating scale were exclued. Depression symptoms were measured by Center for Epidemiological Survey Depression Scale. The occupational stress related actors were measured by the revised effort-reward imbalance (ERI) model questionnaires and occupational stress measurement scale. Chi-square test was carried out to analyze the differences of the incidence of depressive symptoms among different general characteristics groups, and multivariate logistic regression analysis was conducted to analyze the influence of occupational stress and related factors on depression symptoms in train drivers.	The study showed that the average age of 1 402 subjects was (34.95±9.20) years, the length of service were (13.28±9.78) years, the score of depressive symptoms was (24.14±5.98) scores. 902 subjects (64.3%,902/1 402) were classified as people with depressive symptoms, the incidence of depressive symptoms in EMU or high-speed train drivers were the highest (68.0%,51/75); Incidence of depressive symptoms showed that were statistically significant differences in two groups of technical secondary school and college, and incidence of depressive symptoms in the junior college and above group (68.1%,352/517) was higher than that in the senior high school and below group (62.1%, 550/885) (χ(2)=5.02, P=0.025). The results of the multiple logistic regression analysis revealed that high levels of education (OR=1.63, 95%CI: 1.12-2.19), role conflict (OR=1.65, 95% CI: 1.21-2.24), role ambiguity (OR=1.99, 95% CI: 1.45-2.73), negative emotion(OR=2.87, 95%CI: 2.15-3.82), daily tension(OR=2.86, 95%CI: 2.11-3.86), poor colleagues and family support (OR=1.55, 95% CI: 1.11-2.16 and OR=1.75, 95% CI: 1.27-2.41) were risk factors of depressive symptoms, but positive emotion (OR=0.72, 95% CI: 0.53-0.96), self-esteem (OR=0.22, 95% CI: 0.16-0.30), and job itself satisfaction (OR=0.48, 95%CI: 0.35-0.65) were protective factors of depressive symptoms in train drivers.	Train drivers, in particular EMU or high-speed train drivers who were prone to depressive symptoms. To arrange reasonably job roles and tasks, increase support from superiors, colleagues, and family, bring up healthy and coordinated personality, keep a good mood, promote job satisfaction, reduce the daily tension have positive effects on reducing the occurrence of depressive symptoms for train drivers.	
26884545	The habenula has been implicated in predicting negative events and in responding to unexpected negative outcomes. Animal models of depression have supported the hypothesis that perturbations in habenula activity contribute to the pathophysiology of Major Depressive Disorder (MDD), a psychiatric illness characterized by abnormalities in responding to negative feedback and by pessimism in evaluating the likelihood of future events. No research to date, however, has examined human habenula responses to potential and experienced negative outcomes in MDD. In this study, depressed and healthy control participants performed a probabilistic guessing task for monetary rewards and penalties during high-resolution functional magnetic resonance imaging of the habenula. In healthy adults, we observed a pattern of habenula activation consistent with its hypothesized role in predicting future losses and responding to suboptimal outcomes. In contrast, in depressed participants the left habenula was not activated significantly during the prediction or experience of monetary penalty. Complementing this group difference, attenuated habenula activation to negative feedback in control participants was associated with levels of shame and rumination. The results of this study suggest that depressed individuals are characterized by dysfunction in a neural system involved in generating expectations and comparing expectations with objective outcomes.

26883210	Understanding the perceptions and attitudes of physicians is important. This knowledge assists in the efforts to reduce the impact of their interactions with the pharmaceutical industry on clinical practice. It appears that most studies on such perceptions and attitudes have been conducted in high-income countries. The objective was to systematically review the knowledge, beliefs and attitudes of physicians in low and middle-income countries regarding interactions with pharmaceutical companies.Eligible studies addressed any type of interaction between physicians and pharmaceutical companies. The outcomes of interest included knowledge, beliefs and attitudes of practicing physicians. The search strategy covered MEDLINE and EMBASE databases. Two reviewers completed in duplicate and independently study selection, data abstraction, and assessment of methodological features. The data synthesis consisted of a narrative summary of the findings stratified by knowledge, beliefs and attitudes.	We included ten reports from nine eligible studies, each of which had a number of methodological limitations. Four studies found that the top perceived benefits of this interaction were receiving information and rewards. In five out of eight studies assessing the perception regarding the impact of the interaction on the behavior of physician prescription, the majority of participants believed it to be minor. In one of these studies, participants perceived that impact to be lesser when asked about their own behavior. The attitudes of physicians towards information and rewards provided by pharmaceutical company representatives (PCRs) (assessed in 5 and 2 studies respectively) varied across studies. In the only study assessing their attitudes towards pharmaceutical-sponsored Continuing Medical Education, physicians considered local conferences to have higher impact. Their attitudes towards developing policies restricting physicians' interactions with PCRs were positive in two studies. In one study, the majority of participants did not mind the public knowing that physicians were receiving gifts and awards from drug companies.	This review identified few studies conducted in low and middle-income countries. While physicians generally perceived the impact of interactions on their behavior to be minor, their attitudes toward receiving information and rewards varied across studies.	
26881942	Social stimuli can have rewarding properties and promote learning. In birds, conspecific vocalizations like song can act as a reinforcer, and specific song variants can acquire particular rewarding values during early life exposure. Here we ask if, during adulthood, an acoustic signal simpler and shorter than song can become a reward for a female songbird because of its particular social value. Using an operant choice apparatus, we showed that female zebra finches display a preferential response toward their mate's calls. This reinforcing value of mate's calls could be involved in the maintenance of the monogamous pair-bond of the zebra finch.
26881941	Long-term memory can be critical to a species' survival in environments with seasonal and even longer-term cycles of resource availability. The present, longitudinal study investigated whether complex tool behaviors used to gain an out-of-reach reward, following a hiatus of about 3 years and 7 months since initial experiences with a tool use task, were retained and subsequently executed more quickly by experienced than by naïve chimpanzees. Ten of the 11 retested chimpanzees displayed impressive long-term procedural memory, creating elongated tools using the same methods employed years previously, either combining 2 tools or extending a single tool. The complex tool behaviors were also transferred to a different task context, showing behavioral flexibility. This represents some of the first evidence for appreciable long-term procedural memory, and improvements in the utility of complex tool manufacture in chimpanzees. Such long-term procedural memory and behavioral flexibility have important implications for the longevity and transmission of behavioral traditions.
26881417	Financial incentive designs to increase physical activity have not been well-examined.To test the effectiveness of 3 methods to frame financial incentives to increase physical activity among overweight and obese adults.	University of Pennsylvania.	281 adult employees (body mass index ≥27 kg/m2).	13-week intervention. Participants had a goal of 7000 steps per day and were randomly assigned to a control group with daily feedback or 1 of 3 financial incentive programs with daily feedback: a gain incentive ($1.40 given each day the goal was achieved), lottery incentive (daily eligibility [expected value approximately $1.40] if goal was achieved), or loss incentive ($42 allocated monthly upfront and $1.40 removed each day the goal was not achieved). Participants were followed for another 13 weeks with daily performance feedback but no incentives.	Primary outcome was the mean proportion of participant-days that the 7000-step goal was achieved during the intervention. Secondary outcomes included the mean proportion of participant-days achieving the goal during follow-up and the mean daily steps during intervention and follow-up.	The mean proportion of participant-days achieving the goal was 0.30 (95% CI, 0.22 to 0.37) in the control group, 0.35 (CI, 0.28 to 0.42) in the gain-incentive group, 0.36 (CI, 0.29 to 0.43) in the lottery-incentive group, and 0.45 (CI, 0.38 to 0.52) in the loss-incentive group. In adjusted analyses, only the loss-incentive group had a significantly greater mean proportion of participant-days achieving the goal than control (adjusted difference, 0.16 [CI, 0.06 to 0.26]; P = 0.001), but the adjusted difference in mean daily steps was not significant (861 [CI, 24 to 1746]; P = 0.056). During follow-up, daily steps decreased for all incentive groups and were not different from control.	Single employer.	Financial incentives framed as a loss were most effective for achieving physical activity goals.	National Institute on Aging.	
26881125	Adolescent exposure to cannabinoids enhances the behavioural effects of cocaine, and high novelty-seeking trait predicts greater sensitivity to the conditioned place preference (CPP) induced by this drug. Our aim was to evaluate the influence of novelty-seeking on the effects of adolescent cannabinoid exposure. Adolescent male mice were classified as high or low novelty seekers (HNS and LNS) in the hole-board test. First, we evaluated the CPP induced by the cannabinoid agonist WIN 55212-2 (0.05 and 0.075 mg/kg, i.p.) in HNS and LNS mice. Then, HNS and LNS mice were pretreated i.p. with vehicle, WIN 55212-2 (0.1 mg/kg), or cannabinoid antagonist rimonabant (1 mg/kg) and were subsequently conditioned with WIN 55212-2 (0.05 mg/kg, i.p.) or cocaine (1 or 6 mg/kg, i.p.). Only HNS mice conditioned with the 0.075 mg/kg dose acquired CPP with WIN 55212-2. Adolescent exposure to this cannabinoid agonist increased the rewarding effects of 1 mg/kg of cocaine in both HNS and LNS mice, and in HNS mice it also increased the reinstating effect of a low dose of cocaine. Our results endorse a role for individual differences such as a higher propensity for sensation-seeking in the development of addiction.
26879947	Several studies examining the relationship of affective decision-making and delay discounting in disordered gambling demonstrated that adult pathological gamblers differ from healthy controls on both reward-related decision tasks. To date no study analyzed the relative contribution of these variables in adolescent gambling. This study was designed to compare affective decision-making and delay discounting in gamblers and nongamblers Italian adolescents, controlling for alcohol consumption. A total of 138 adolescents took part in the research. Two equal-number groups, defined according to the scoring rules for the South Oaks Gambling Screen-Revised for Adolescents, were administered the Iowa Gambling Task (IGT), the Monetary Choice Questionnaire (MCQ), and the Alcohol Use Disorders Identification Test (AUDIT). Zero-order correlations among all variables revealed a moderate negative association between IGT and MCQ scores only in nongamblers group. Results of mixed-model ANOVAs indicated that, compared with nongamblers, adolescent gamblers performed worse on the IGT, showed steeper delay discounting, and scored significantly higher on the AUDIT. Results of logistic regression analysis indicated that IGT, MCQ, and AUDIT scores are all significant predictors of gambling status. This novel finding provides the first evidence of an association among problematic gambling, maladaptive decision-making, and steep delay discounting among adolescents, as already observed in adults.
26879253	The placebo effect is an excellent model for understanding the mechanisms underlying the interaction between a subjective and complex mental activity (beliefs, expectations, hopes, learning, patient-physician relationship, socio-cultural context .) with different neural and biological systems. Initially, research on the placebo effect has focused on the mechanisms of pain and analgesia. The cognitive processes of conditioning and reward anticipation (hope of a relief) were highlighted. The involvement of different neurobiological pathways has been clearly shown: endogenous opioids, CCK, dopaminergic pathways, endocannabinoids, immunological factors... More recently, the field has open towards new perspectives: depression and anxiety, motor disorders, immune system, endocrine system. Intensive research in the field emerges because of its fundamental implications in neuroscience research but also because of the ethical, clinical and therapeutical issues. Moreover, the placebo effect is considered as a main methodological mean issue in clinical trials that allows the demonstration of the efficacy and tolerance of new drugs. In the field of psychiatry, depression is a placebo highly-sensitive disorder: placebo response rates in clinical trials are of the order of 30 % to 40 %. The identification of biological markers of placebo response, such as neuroimaging and quantitative electroencephalography may lead to develop more efficient models in clinical research.
26879210	Scientific interest in "food addiction" is growing, but the topic remains controversial. One critique of "food addiction" is its high degree of phenotypic overlap with binge eating disorder (BED). In order to examine associations between problematic eating behaviors, such as binge eating and "food addiction," we propose the need to move past examining similarities and differences in symptomology. Instead, focusing on relevant mechanisms may more effectively determine whether "food addiction" contributes to disordered eating behavior for some individuals. This paper reviews the evidence for mechanisms that are shared (i.e., reward dysfunction, impulsivity) and unique for addiction (i.e., withdrawal, tolerance) and eating disorder (i.e., dietary restraint, shape/weight concern) frameworks. This review will provide a guiding framework to outline future areas of research needed to evaluate the validity of the "food addiction" model and to understand its potential contribution to disordered eating. 
26878746	Predictive learning is known to influence instrumental responding for reward. Cues associated with an instrumental outcome can influence performance in two ways: (a) by selectively promoting actions associated with the outcome predicted by the cue (specific transfer), and (b) by increasing motivation and the vigour of instrumental responding (general transfer). To examine these two distinct processes in humans we developed a novel behavioural task in which participants were able to liberate junk-food snacks from a virtual vending machine. Additionally, the relationship between stress and cue-driven reward seeking was examined using participant scores on the Depression Anxiety and Stress Scale (DASS). Reward-paired cues were found to separately bias action selection and influence the rate of responding for rewards. Furthermore, the effects of reward-paired cues on the rate of responding for reward was influenced by increased stress and anxiety. Increased levels of stress and anxiety were associated particularly with changes in cue-driven response vigour; whereas high levels of stress and anxiety were associated with elevated responding above baseline in the presence of a cue associated with a non-rewarding outcome, participants with low levels of anxiety and stress showed appropriate suppression of responding during this cue. These differences in performance between high and low anxiety and stress participants provides initial evidence that, as has been demonstrated in rodents, stress affects the influence of cue-driven response vigour in humans.
26877542	The learning capacities of males and females may differ with sex-specific behavioural requirements. Bumblebees provide a useful model system to explore how different lifestyles are reflected in learning abilities, because their (female but sterile) workers and males engage in fundamentally different behaviour routines. Bumblebee males, like workers, embark on active flower foraging but in contrast to workers they have to trade off their feeding with mate search, potentially affecting their abilities to learn and utilize floral cues efficiently during foraging. We used a serial colour-learning task with freely flying males and workers to compare their ability to flexibly learn visual floral cues with reward in a foraging scenario that changed over time. Male bumblebees did not differ from workers in both their learning speed and their ability to overcome previously acquired associations, when these ceased to predict reward. In all foraging tasks we found a significant improvement in choice accuracy in both sexes over the course of the training. In both sexes, the characteristics of the foraging performance depended largely on the colour difference of the two presented feeder types. Large colour distances entailed fast and reliable learning of the rewarding feeders whereas choice accuracy on highly similar colours improved significantly more slowly. Conversely, switching from a learned feeder type to a novel one was fastest for similar feeder colours and slow for highly different ones. Overall, we show that behavioural sex dimorphism in bumblebees did not affect their learning abilities beyond the mating context. We discuss the possible drivers and limitations shaping the foraging abilities of males and workers and implications for pollination ecology. We also suggest stingless male bumblebees as an advantageous alternative model system for the study of pollinator cognition.
26877129	The error-related negativity (ERN) currently appears as a physiological measure in relation to three Research Domain Criteria (RDoC) constructs: Cognitive Control, Sustained Threat, and Reward Learning. We propose a conceptual model in which variance in the ERN reflects individual differences in the degree to which errors are evaluated as threatening. We also discuss evidence for the placement of the ERN in the "Sustained Threat" construct, as well as evidence that the ERN may more specifically reflect sensitivity to endogenous threat. Following this, we present data from a sample of 515 adolescent females demonstrating a larger ERN in relation to self-reported checking behaviors, but only in older adolescents, suggesting that sensitivity to internal threat and the ERN-checking relationship may follow a developmental course as adolescents develop behavioral control. In contrast, depressive symptoms were linked to a smaller ERN, and this association was invariant with respect to age. Collectively, these data suggest that the magnitude of the ERN is sensitive both to specific anxiety-related processes and depression, in opposing directions that may reflect variation in internal threat sensitivity. We discuss directions for future research, as well as ways in which findings for the ERN complement and challenge aspects of the current RDoC matrix. 
26877086	Dopaminergic neurons serve multiple functions, including reinforcement processing during associative learning [1-12]. It is thus warranted to understand which dopaminergic neurons mediate which function. We study larval Drosophila, in which only approximately 120 of a total of 10,000 neurons are dopaminergic, as judged by the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine biosynthesis [5, 13]. Dopaminergic neurons mediating reinforcement in insect olfactory learning target the mushroom bodies, a higher-order "cortical" brain region [1-5, 11, 12, 14, 15]. We discover four previously undescribed paired neurons, the primary protocerebral anterior medial (pPAM) neurons. These neurons are TH positive and subdivide the medial lobe of the mushroom body into four distinct subunits. These pPAM neurons are acutely necessary for odor-sugar reward learning and require intact TH function in this process. However, they are dispensable for aversive learning and innate behavior toward the odors and sugars employed. Optogenetical activation of pPAM neurons is sufficient as a reward. Thus, the pPAM neurons convey a likely dopaminergic reward signal. In contrast, DL1 cluster neurons convey a corresponding punishment signal [5], suggesting a cellular division of labor to convey dopaminergic reward and punishment signals. On the level of individually identified neurons, this uncovers an organizational principle shared with adult Drosophila and mammals [1-4, 7, 9, 10] (but see [6]). The numerical simplicity and connectomic tractability of the larval nervous system [16-19] now offers a prospect for studying circuit principles of dopamine function at unprecedented resolution. 
26877079	Reward learning gives rise to strong attentional biases. Stimuli previously associated with reward automatically capture visual attention regardless of intention. Dopamine signaling within the ventral striatum plays an important role in reward learning, representing the expected reward initiated by a cue. How dopamine and the striatum may be involved in maintaining behaviors that have been shaped by reward learning, even after reward expectancies have changed, is less well understood. Nonspecific measures of brain activity have implicated the striatum in value-based attention. However, the neurochemical mechanisms underlying the attentional priority of learned reward cues remain unexplored. Here, we investigated the contribution of dopamine to value-based attention using positron emission tomography (PET) with [(11)C]raclopride. We show that, in the explicit absence of reward, the magnitude of attentional capture by previously reward-associated but currently task-irrelevant distractors is correlated across individuals with changes in available D2/D3 dopamine receptors (presumably due to intrasynaptic dopamine) linked to distractor processing within the right caudate and posterior putamen. Our findings provide direct evidence linking dopamine signaling within the striatum to the involuntary orienting of attention, and specifically to the attention-grabbing quality of learned reward cues. These findings also shed light on the neurochemical basis of individual susceptibility to value-driven attentional capture, which is known to play a role in addiction. More broadly, the present study highlights the value and feasibility of using PET to relate changes in the release of a neurotransmitter to learning-dependent changes in healthy adults.
26876975	Stress exposure (SE) during adolescence is associated with an increased risk for the development of alcohol use disorders (AUDs). Past research has shown that SE during adolescence increases voluntary alcohol consumption in mice during adulthood; however, little is known about the positive or negative motivational aspects of this relationship.High-alcohol preferring (HAP2) and low-alcohol preferring (LAP2) male mice were exposed to stress during adolescence, stress during adulthood, or no stress. After a 30-day interim, subjects were exposed to alcohol-induced place and footshock-induced fear conditioning procedures to measure stress-induced behavioral alterations during adulthood.	SE during adolescence did not increase the magnitude of alcohol-induced conditioned place preference (CPP), as hypothesized, but increased the magnitude of conditioned fear, as measured by fear-potentiated startle (FPS), in HAP2 subjects only. Regardless of stress treatment group, LAP2 subjects showed greater alcohol-induced CPP expression than HAP2 mice. HAP2 mice also showed greater FPS than LAP2 mice, as previously shown.	These results in mice, taken together with past research, suggest that mice exposed to stress during adolescence do not increase alcohol consumption during adulthood because of a greater sensitivity to the rewarding effects of alcohol, as measured via place conditioning. These results in mice also suggest that humans exposed to stress during adolescence may be more susceptible to developing anxiety during adulthood. The findings may be particularly relevant for humans with a familial history of AUDs.	
26876919	Evidence suggests that factors associated with obtaining a reward, such as the probability of receiving it, or temporal delays, could influence the reward's subjective value. Several studies have suggested that increasing the effort required decreases the subjective value of a reward. Nevertheless, the nature of effort that results in discounting, discounting in a loss situation, and individual consistency in effort aversion across different types of effort have all remained unclear. Therefore, the present study examined whether physical, emotional, and cognitive efforts induce discounting of subjective reward value under two hypothetical situations. In the gain situation, participants made a choice about engaging in effortful work to obtain a reward, whereas in the loss situation they paid a reward to another person to do the work. The results demonstrated that increasing physical, emotional, and cognitive effort caused discounting of the subjective reward value in both situations. Additionally, the results suggested a relatively high degree of individual consistency in effort aversion in each situation, and a moderate degree of consistency across the two situations. 
26876779	The lateral habenula (LHb) is known to play an important role in signaling aversive or adverse events that have happened or are predicted by cues under Pavlovian conditions. In rodents, it is also required for behavioral flexibility when changes in reward outcomes signal that strategies should be changed. It is not known whether the LHb also controls appetitive behaviors when an animal is able to utilize external cues proactively to guide upcoming decisions. In order to test this, male Long-Evans rats were trained to switch between two arms of a figure eight maze based on the tone presented prior to the choice. Importantly, the tones were switched every three to six trials so rats were able establish a response pattern before being required to switch. This caused rats to rely on both proactive (tones) and retroactive information (reward feedback) to guide behavior. Inactivation of the LHb with the GABA agonists baclofen and muscimol impaired overall performance by increasing both errors when the tones are switched (switch errors) as well as on subsequent trials (perseverative errors) indicating that both proactive and retroactive information are utilized by the LHb to guide behavioral flexibility. Once a correct choice was made in a given block, LHb inactivated rats did not make more errors than controls. A control study revealed that the LHb is not required for tone or reward magnitude discrimination per se. These results demonstrate for the first time that the LHb contributes to behavioral flexibility through utilizing both proactive and retroactive information when performing appetitive tasks.
26875624	Reward motivation is known to modulate memory encoding, and this effect depends on interactions between the substantia nigra/ventral tegmental area complex (SN/VTA) and the hippocampus. It is unknown, however, whether these interactions influence offline neural activity in the human brain that is thought to promote memory consolidation. Here we used fMRI to test the effect of reward motivation on post-learning neural dynamics and subsequent memory for objects that were learned in high- and low-reward motivation contexts. We found that post-learning increases in resting-state functional connectivity between the SN/VTA and hippocampus predicted preferential retention of objects that were learned in high-reward contexts. In addition, multivariate pattern classification revealed that hippocampal representations of high-reward contexts were preferentially reactivated during post-learning rest, and the number of hippocampal reactivations was predictive of preferential retention of items learned in high-reward contexts. These findings indicate that reward motivation alters offline post-learning dynamics between the SN/VTA and hippocampus, providing novel evidence for a potential mechanism by which reward could influence memory consolidation.
26874940	Although medial frontal brain regions are implicated in valuation of rewards, evidence from focal lesions to these areas is scant, with many conflicting results regarding motivation and affect, and no human studies specifically examining incentivisation by reward. Here, 19 patients with isolated, focal damage in ventral and medial prefrontal cortex were selected from a database of 453 individuals with subarachnoid haemorrhage. Using a speeded saccadic task based on the oculomotor capture paradigm, we manipulated the maximum reward available on each trial using an auditory incentive cue. Modulation of behaviour by motivation permitted quantification of reward sensitivity. At the group level, medial frontal damage was overall associated with significantly reduced effects of reward on invigorating saccadic velocity and autonomic (pupil) responses compared to age-matched, healthy controls. Crucially, however, some individuals instead showed abnormally strong incentivisation effects for vigour. Increased sensitivity to rewards within the lesion group correlated with damage in subgenual ventromedial prefrontal cortex (vmPFC) areas, which have recently become the target for deep brain stimulation (DBS) in depression. Lesion correlations with clinical apathy suggested that the apathy associated with prefrontal damage is in fact reduced by damage at those coordinates. Reduced reward sensitivity showed a trend to correlate with damage near nucleus accumbens. Lesions did not, on the other hand, influence reward sensitivity of cognitive control, as measured by distractibility. Thus, although medial frontal lesions may generally reduce reward sensitivity, damage to key subregions paradoxically protect from this effect. 
26874071	Prefrontal cortex (PFC) has been documented to play critical roles in goal-directed behaviors, like representing goal-relevant events and working memory (WM). However, neurophysiological evidence for such roles of PFC has been obtained mainly with visual tasks but rarely with auditory tasks. In the present study, we tested roles of PFC in auditory goal-directed behaviors by recording local field potentials in the auditory region of left ventrolateral PFC while a monkey performed auditory WM tasks. The tasks consisted of multiple events and required the monkey to change its mental states to achieve the reward. The events were auditory and visual stimuli, as well as specific actions. Mental states were engaging in the tasks and holding task-relevant information in auditory WM. We found that, although based on recordings from one hemisphere in one monkey only, PFC represented multiple events that were important for achieving reward, including auditory and visual stimuli like turning on and off an LED, as well as bar touch. The responses to auditory events depended on the tasks and on the context of the tasks. This provides support for the idea that neuronal representations in PFC are flexible and can be related to the behavioral meaning of stimuli. We also found that engaging in the tasks and holding information in auditory WM were associated with persistent changes of slow potentials, both of which are essential for auditory goal-directed behaviors. Our study, on a single hemisphere in a single monkey, reveals roles of PFC in auditory goal-directed behaviors similar to those in visual goal-directed behaviors, suggesting that functions of PFC in goal-directed behaviors are probably common across the auditory and visual modality. This article is part of a Special Issue entitled SI: Auditory working memory. 
26873082	The endocannabinoid system is an important modulator of brain reward signaling. Investigations have focused on cannabinoid (CB1) receptors, because dissection of specific contributions of individual endocannabinoids has been limited by the available toolset. While we recently described an important role for the endocannabinoid anandamide in the regulation of social reward, it remains to be determined whether the other major endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), serves a similar or different function.To study the role of 2-AG in natural reward, we used a transgenic mouse model (MGL-Tg mice) in which forebrain 2-AG levels are selectively reduced. We complemented behavioral analysis with measurements of brain 2-AG levels.	We tested male MGL-Tg mice in conditioned place preference (CPP) tasks for high-fat food, social contact, and cocaine. We measured 2-AG content in the brain regions of interest by liquid chromatography/mass spectrometry.	Male MGL-Tg mice are impaired in developing CPP for high-fat food and social interaction, but do develop CPP for cocaine. Furthermore, compared to isolated mice, levels of 2-AG in socially stimulated wild-type mice are higher in the nucleus accumbens and ventral hippocampus (183 and 140 % of controls, respectively), but unchanged in the medial prefrontal cortex.	The results suggest that reducing 2-AG-mediated endocannabinoid signaling impairs social and high-fat food reward in male mice, and that social stimulation mobilizes 2-AG in key brain regions implicated in the control of motivated behavior. The time course of this response differentiates 2-AG from anandamide, whose role in mediating social reward was previously documented.	
26873017	Deficits in reward and motivation are common symptoms characterizing several psychiatric and neurological disorders. Such deficits may include anhedonia, defined as loss of pleasure, as well as impairments in anticipatory pleasure, reward valuation, motivation/effort, and reward learning. This chapter describes recent advances in the development of behavioral tasks used to assess different aspects of reward processing in both humans and non-human animals. While earlier tasks were generally developed independently with limited cross-species correspondence, a newer generation of translational tasks has emerged that are theoretically and procedurally analogous across species and allow parallel testing, data analyses, and interpretation between human and rodent behaviors. Such enhanced conformity between cross-species tasks will facilitate investigation of the neurobiological mechanisms underlying discrete reward and motivated behaviors and is expected to improve our understanding and treatment of neuropsychiatric disorders characterized by reward and motivation deficits. 
26871628	The motivation to seek social contact may arise from either positive or negative emotional states, as social interaction can be rewarding and social isolation can be aversive. While ventral tegmental area (VTA) dopamine (DA) neurons may mediate social reward, a cellular substrate for the negative affective state of loneliness has remained elusive. Here, we identify a functional role for DA neurons in the dorsal raphe nucleus (DRN), in which we observe synaptic changes following acute social isolation. DRN DA neurons show increased activity upon social contact following isolation, revealed by in vivo calcium imaging. Optogenetic activation of DRN DA neurons increases social preference but causes place avoidance. Furthermore, these neurons are necessary for promoting rebound sociability following an acute period of isolation. Finally, the degree to which these neurons modulate behavior is predicted by social rank, together supporting a role for DRN dopamine neurons in mediating a loneliness-like state. PAPERCLIP.
26871590	Obesity is often accompanied by weight stigmatization; subsequently, individuals with obesity frequently face social rejection. It has been shown that recurrent negative social experiences can alter the perception of social cues. However, the way individuals with obesity process social stimuli is not well understood. This study aims to investigate obesity-related alterations in social compared to nonsocial information processing. Women with obesity (n = 14) and without obesity (n = 14) participated in a social and a monetary incentive delay task in which they anticipated and received positive, negative, and neutral outcomes in the form of faces or money. During the experiment, phasic heart rate changes and reaction times were measured. Women with obesity, compared to lean women, exhibited a stronger differentiation during the anticipation of monetary and social reinforcement, showing slower reaction times to social cues compared to monetary cues. During the outcome processing phase, women with obesity relative to controls demonstrated diminished heart rate responses particularly to negative social outcomes. Interestingly, differences in cardiac responses in participants with obesity were moderated by weight-related teasing experiences. In women with obesity, a higher BMI was associated with blunted cardiac responses to social cues relative to monetary cues only if they reported more emotional pain after weight-related teasing. Our results contribute to a better understanding of social information processing in obesity and give first evidence for the role of negative social experiences in reinforcement processing. 
26869978	Based on numerous studies showing that testing studied material can improve long-term retention more than restudying the same material, it is often suggested that the number of tests in education should be increased to enhance knowledge acquisition. However, testing in real-life educational settings often entails a high degree of extrinsic motivation of learners due to the common practice of placing important consequences on the outcome of a test. Such an effect on the motivation of learners may undermine the beneficial effects of testing on long-term memory because it has been shown that extrinsic motivation can reduce the quality of learning. To examine this issue, participants learned foreign language vocabulary words, followed by an immediate test in which one-third of the words were tested and one-third restudied. To manipulate extrinsic motivation during immediate testing, participants received either monetary reward contingent on test performance or no reward. After 1 week, memory for all words was tested. In the immediate test, reward reduced correct recall and increased commission errors, indicating that reward reduced the number of items that can benefit from successful retrieval. The results in the delayed test revealed that reward additionally reduced the gain received from successful retrieval because memory for initially successfully retrieved words was lower in the reward condition. However, testing was still more effective than restudying under reward conditions because reward undermined long-term memory for concurrently restudied material as well. These findings indicate that providing performance-contingent reward in a test can undermine long-term knowledge acquisition. 
26869263	Motivated reward-seeking behaviours are governed by dopaminergic ventral tegmental area projections to the nucleus accumbens. In addition to dopamine, these mesoaccumbal terminals co-release other neurotransmitters including glutamate and GABA, whose roles in regulating motivated behaviours are currently being investigated. Here we demonstrate that loss of the E3-ubiquitin ligase, UBE3A, from tyrosine hydroxylase-expressing neurons impairs mesoaccumbal, non-canonical GABA co-release and enhances reward-seeking behaviour measured by optical self-stimulation. 
26869075	Prolonged mesolimbic dopamine concentration changes have been detected during spatial navigation, but little is known about the conditions that engender this signaling profile or how it develops with learning. To address this, we monitored dopamine concentration changes in the nucleus accumbens core of rats throughout acquisition and performance of an instrumental action sequence task. Prolonged dopamine concentration changes were detected that ramped up as rats executed each action sequence and declined after earned reward collection. With learning, dopamine concentration began to rise increasingly earlier in the execution of the sequence and ultimately backpropagated away from stereotyped sequence actions, becoming only transiently elevated by the most distal and unexpected reward predictor. Action sequence-related dopamine signaling was reactivated in well-trained rats if they became disengaged in the task and in response to an unexpected change in the value, but not identity of the earned reward. Throughout training and test, dopamine signaling correlated with sequence performance. These results suggest that action sequences can engender a prolonged mode of dopamine signaling in the nucleus accumbens core and that such signaling relates to elements of the motivation underlying sequence execution and is dynamic with learning, overtraining and violations in reward expectation. 
26868969	Rewarding memories induced by addictive drugs may contribute to persistent drug-seeking behaviors, which is an important contributing factor to drug addiction. However, the biological mechanisms underlying drug-associated rewarding memories have not yet been fully understood, especially the new synthetic drugs, such as amphetamine-type stimulants (ATS). In this study, using the rat-conditioned place preference (CPP) model, a classic animal model for the reward-associated effects of addictive drugs, we found that the expression level of GABAA α1 subunits was significantly decreased in the dorsal striatum (Dstr) after conditioned methamphetamine (METH) pairing, and no significant differences were observed in the other four rewarding memory-associated areas (medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala (Amy), and dorsal hippocampus (DH)). Intra-Dstr injection of either the GABAA receptor agonist muscimol or the specific α1GABAA receptor-preferring benzodiazepine (BDZ) agonist zolpidem significantly abolished METH CPP formation. Thus, this study extends previous findings by showing that GABAA receptors, particularly the α1-containing GABAA receptors, may be strongly implicated in METH-associated rewarding memories. This work provides us with a new perspective on the goal of treating ATS addiction. 

26867471	The aims of this study were to investigate the associations between work stress defined by the effort-reward imbalance (ERI) model and diet quality and to examine the potential role of over-commitment (OC) personality in ERI-diet relationships. A cross-sectional study was conducted in random population samples of 6340 men and 5792 women (age 45-69 years) from the Czech Republic, Russia and Poland. Dietary data were collected using FFQ. The healthy diet indicator (HDI) was constructed using eight nutrient/food intakes (HDI components) to reflect the adherence to WHO dietary guideline. The extent of imbalance between effort and reward was measured by the effort:reward (ER) ratio; the effort score was the numerator and the reward score was multiplied by a factor adjusting for unequal number of items in the denominator. Logistic regression and linear regression were used to assess the associations between exposures (ER ratio and OC) and outcomes (HDI components and HDI) after adjustment for confounders and mediators. The results showed that high ER ratio and high OC were significantly associated with unhealthy diet quality. For a 1-SD increase in the ER ratio, HDI was reduced by 0·030 and 0·033 sd in men and women, and for a 1-SD increase in OC, HDI was decreased by 0·036 and 0·032 sd in men and women, respectively. The modifying role of OC in ERI-diet relationships was non-significant. To improve diet quality at workplace, a multiple-level approach combining organisational intervention for work stress and individual intervention for vulnerable personality is recommended.
26866057	Corticostriatal signaling participates in sensitized responses to drugs of abuse, where short-term increases in dopamine availability provoke persistent, yet reversible, changes in glutamate release. Prior studies in mice show that amphetamine withdrawal promotes a chronic presynaptic depression in glutamate release, whereas an amphetamine challenge reverses this depression by potentiating corticostriatal activity in direct pathway medium spiny neurons. This synaptic plasticity promotes corticostriatal activity and locomotor sensitization through upstream changes in the activity of tonically active cholinergic interneurons (ChIs). We used a model of operant drug-taking behaviors, in which mice self-administered amphetamine through an in-dwelling catheter. Mice acquired amphetamine self-administration under fixed and increasing schedules of reinforcement. Following a period of abstinence, we determined whether nicotinic acetylcholine receptors modified drug-seeking behavior and associated alterations in ChI firing and corticostriatal activity. Mice responding to conditioned reinforcement showed reduced ChI and corticostriatal activity ex vivo, which paradoxically increased following an amphetamine challenge. Nicotine, in a concentration that increases Ca(2+) influx and desensitizes α4β2*-type nicotinic receptors, reduced amphetamine-seeking behaviors following abstinence and amphetamine-induced locomotor sensitization. Nicotine blocked the depression of ChI firing and corticostriatal activity and the potentiating response to an amphetamine challenge. Together, these results demonstrate that nicotine reduces reward-associated behaviors following repeated amphetamine and modifies the changes in ChIs firing and corticostriatal activity. By returning glutamatergic activity in amphetamine self-administering mice to a more stable and normalized state, nicotine limits the depression of striatal activity in withdrawal and the increase in activity following abstinence and a subsequent drug challenge. 
26865622	Different subregions of the prefrontal cortex (PFC) contribute to the ability to respond flexibly to changes in reward contingencies, with the medial versus orbitofrontal cortex (OFC) subregions contributing differentially to processes such as set-shifting and reversal learning. To date, the manner in which these regions may facilitate reversal learning in situations involving reward uncertainty remains relatively unexplored. We investigated the involvement of five distinct regions of the rat OFC (lateral and medial) and medial PFC (prelimbic, infralimbic, and anterior cingulate) on probabilistic reversal learning wherein "correct" versus "incorrect" responses were rewarded on 80% and 20% of trials, respectively. Contingencies were reversed repeatedly within a session. In well trained rats, inactivation of the medial or lateral OFC induced dissociable impairments in performance (indexed by fewer reversals completed) when outcomes were probabilistic, but not when they were assured. Medial OFC inactivation impaired probabilistic learning during the first discrimination, increased perseverative responding and reduced sensitivity to positive and negative feedback, suggestive of a deficit in incorporating information about previous action outcomes to guide subsequent behavior. Lateral OFC inactivation preferentially impaired performance during reversal phases. In contrast, prelimbic inactivation caused an apparent improvement in performance by increasing the number of reversals completed. This was associated with enhanced sensitivity to recently rewarded actions and reduced sensitivity to negative feedback. Infralimbic inactivation had no effect, whereas the anterior cingulate appeared to play a permissive role in this form of reversal learning. These results clarify the dissociable contributions of different regions of the frontal lobes to probabilistic learning.The ability to adjust behavior in response to changes involving uncertain or probabilistic reward contingencies is an essential survival skill that is impaired in a variety of psychiatric disorders. It is well established that different forms of cognitive flexibility are mediated by anatomically distinct regions of the frontal lobes when reinforcement contingencies are assured, however, less is known about the contribution of these regions to probabilistic reinforcement learning. Here we show that different regions of the orbitofrontal and medial prefrontal cortex make distinct contributions to probabilistic reversal learning. These findings provide novel information about the complex interplay between frontal lobe regions in mediating these processes and accordingly provide insight into possible pathophysiology that underlies impairments in cognitive flexibility observed in mental illnesses.	
26865618	The ability to delay gratification increases considerably across development. Here, we test the hypothesis that this impulse control capacity is driven by increased maturation of frontostriatal circuitry using a fiber-tracking approach combined with longitudinal imaging. In total, 192 healthy volunteers between 8 and 26 years underwent diffusion tensor imaging scanning and completed a delay-discounting task twice, separated by a 2-year interval. We investigated dynamic associations between frontostriatal white matter (WM) integrity and delay of gratification skills. Moreover, we examined the predictive value of frontostriatal WM integrity for future delay of gratification skills. Results showed that delay discounting increases with age in a quadratic fashion, with greatest patience during late adolescence. Data also indicated nonlinear development of frontostriatal WM, with relative fast development during childhood and early adulthood and--on average--little change during mid-adolescence. Furthermore, the positive association between age and delay discounting was further increased in individuals with higher WM integrity of the frontostriatal tracts. Predictive analysis showed that frontostriatal WM development explained unique variance in current and future delay of gratification skills. This study adds to a descriptive relation between WM integrity and delay of gratification by showing that maturation of frontostriatal connectivity predicts changes in delay of gratification skills. These findings have implications for studies examining deviances in impulse control by showing that the developmental path between striatum and prefrontal cortex may be an important predictor for when development goes astray.During the transition from childhood to adulthood, individuals generally show increased patience and become better in delaying gratification. The exact neural correlates of delay of gratification, however, remain poorly understood. By measuring both frontostriatal white matter (WM) integrity and delay of gratification skills at two time points, we were able to provide links for our understanding of the neural mechanisms underlying this type of impulse regulation capacity. We demonstrate that the ability to delay gratification improves between childhood and young adulthood and this improvement is predicted by the integrity of frontostriatal WM connections. This study adds to a descriptive relation between WM quality and delay of gratification by showing that maturation of frontostriatal connectivity predicts improvements in delay of gratification skills.	
26865020	Environmental stimuli and objects, including rewards, are often processed sequentially in the brain. Recent work suggests that the phasic dopamine reward prediction-error response follows a similar sequential pattern. An initial brief, unselective and highly sensitive increase in activity unspecifically detects a wide range of environmental stimuli, then quickly evolves into the main response component, which reflects subjective reward value and utility. This temporal evolution allows the dopamine reward prediction-error signal to optimally combine speed and accuracy. 
26864879	Counterfactual information processing refers to the consideration of events that did not occur in comparison to those actually experienced, in order to determine optimal actions, and can be formulated as computational learning signals, referred to as fictive prediction errors. Decision making and the neural circuitry for counterfactual processing are altered in healthy elderly adults. This experiment investigated age differences in neural systems for decision making with knowledge of counterfactual outcomes. Two groups of healthy adult participants, young (N = 30; ages 19-30 years) and elderly (N = 19; ages 65-80 years), were scanned with fMRI during 240 trials of a strategic sequential investment task in which a particular strategy of differentially weighting counterfactual gains and losses during valuation is associated with more optimal performance. Elderly participants earned significantly less than young adults, differently weighted counterfactual consequences and exploited task knowledge, and exhibited altered activity in a fronto-striatal circuit while making choices, compared to young adults. The degree to which task knowledge was exploited was positively correlated with modulation of neural activity by expected value in the vmPFC for young adults, but not in the elderly. These findings demonstrate that elderly participants' poor task performance may be related to different counterfactual processing.
26864474	Associative learning is essential for establishing appropriate responses to cause-effect relationships and effective behavioral adjustments to environmental changes. However, learned associations also promote maladaptive behavior such as uncontrollable drug seeking in addicts exposed to drug-associated stimuli. Here, we sought to identify behavioral characteristics that distinguish reward seeking produced by environmental stimuli conditioned to highly potent but non-addictive conventional reinforcers from reward seeking induced by stimuli conditioned to addictive drugs. Rats were trained to associate discriminative (i.e. contextual) stimuli (S+ ) with availability of cocaine, ethanol, palatable sweet solutions or water during dehydration. Following extinction, response-reinstating effects of re-exposure to these stimuli were established in terms of magnitude and perseveration. Initially, the S+ produced strong reinstatement irrespective of association with conventional or drug reward. However, with repeated testing, S+ -induced reward seeking decreased to extinction levels when motivated by the sweet solutions but perseverated when motivated by cocaine or ethanol. In rats placed on water restriction to induce a motivational constraint, the S+ supported perseverating reinstatement identical to that produced by an S+ conditioned to cocaine. The findings suggest that behavior guided by associations between environmental stimuli and drugs of abuse is characterized by perseverating, apparently highly extinction-resistant reward seeking, whereas behavior controlled by stimuli associated with conventional reward extinguishes rapidly in the absence of primary reinforcement. Reward seeking elicited by stimuli associated with natural reward can, however, become perseverative during physiological deprivation states. Possibly, perseverating drug seeking engages mechanisms overlapping with those that have evolved to promote alleviation of physiological deprivation to secure survival.
26861797	We investigated anticipatory and consummatory reward processing in cocaine addiction. In addition, we set out to assess whether task-monitoring systems were appropriately recalibrated in light of variable reward schedules. We also examined neural measures of task-monitoring and reward processing as a function of hedonic tone, since anhedonia is a vulnerability marker for addiction that is obviously germane in the context of reward processing.High-density event-related potentials were recorded while participants performed a speeded response task that systematically varied anticipated probabilities of reward receipt. The paradigm dissociated feedback regarding task success (or failure) from feedback regarding the value of reward (or loss), so that task-monitoring and reward processing could be examined in partial isolation. Twenty-three active cocaine abusers and 23 age-matched healthy controls participated.	Cocaine abusers showed amplified anticipatory responses to reward predictive cues, but crucially, these responses were not as strongly modulated by reward probability as in controls. Cocaine users also showed blunted responses to feedback about task success or failure and did not use this information to update predictions about reward. In turn, they showed clearly blunted responses to reward feedback. In controls and users, measures of anhedonia were associated with reward motivation. In cocaine users, anhedonia was also associated with diminished monitoring and reward feedback responses.	Findings imply that reward anticipation and monitoring deficiencies in addiction are associated with increased responsiveness to reward cues but impaired ability to predict reward in light of task contingencies, compounded by deficits in responding to actual reward outcomes.	
26861539	Although previous research found a positive association between sensitivity to reward (SR) and adolescents' unhealthy snacking and drinking behavior, mechanisms explaining these associations remain to be explored. The present study will therefore examine whether the associations between SR and unhealthy snack and/or sugar-sweetened beverage (SSB) intake are mediated by external and/or emotional eating and if this mediation is moderated by availability at home or at school.Cross-sectional data on snacking, availability of snacks at home and at school, SR (BAS drive scale) and external and emotional eating (Dutch eating behavior questionnaire) of Flemish adolescents (n = 1104, mean age = 14.7 ± 0.8 years; 51 % boys; 18.0% overweight) in 20 schools spread across Flanders were collected. Moderated mediation analyses were conducted using generalized structural equation modeling in three steps: (1) direct association between SR and unhealthy snack or SSB intake, (2) mediation of either external or emotional eating and (3) interaction of home or school availability and emotional or external eating.	Partial mediation of external eating (a*b = 0.69, p < 0.05) and of emotional eating (a*b = 0.92, p < 0.01) in the relation between SR and intake of unhealthy snacks was found (step 2). The relation between SR and SSB intake was not mediated by external or emotional eating (step 2). No moderation effects of home or school availability were found (step 3).	Our findings indicate that the association between SR and the consumption of unhealthy snacks is partially explained by external and emotional eating in a population-based sample of adolescents irrespective of the home or school availability of these foods.	
26861484	Dogs have become the focus of cognitive studies looking at both their physical and social problem-solving abilities (Bensky et al. in Adv Stud Behav, 45:209-387, 2013), but very little is known about the environmental and inherited factors that may affect these abilities. In the current study, we presented a manipulation task (a puzzle box) and a spatial task (the detour) to 128 dogs belonging to four different breed groups: Herding, Mastiff-like, Working and Retrievers (von Holdt et al. in Nature 464:898-902, 2010). Within each group, we tested highly trained and non-trained dogs. Results showed that trained dogs were faster at obtaining the reward in the detour task. In the manipulation task, trained dogs approached the apparatus sooner in the first familiarization trial, but no effect of breed emerged on this variable. Furthermore, regardless of breed, dogs in the trained group spent proportionally more time interacting with the apparatus and were more likely to succeed in the test trial than dogs in the non-trained group, whereas regardless of training, dogs in the working breed group were more likely to succeed than dogs in the retriever and herding breed groups (but not the mastiff-like group). Finally, trained dogs were less likely to look at a person than non-trained dogs during testing, but dogs in the herding group more likely to do so than dogs in the retriever and working but not the mastiff-like breed groups. Overall, results reveal a strong influence of training experience but less consistent differences between breed groups on different components thought to affect problem solving. 
26860055	Neuroimaging studies have demonstrated dysfunction in the brain reward circuit in individuals with online gaming addiction (OGA). We hypothesized that virtual reality therapy (VRT) for OGA would improve the functional connectivity (FC) of the cortico-striatal-limbic circuit by stimulating the limbic system.Twenty-four adults with OGA were randomly assigned to a cognitive behavior therapy (CBT) group or VRT group. Before and after the four-week treatment period, the severity of OGA was evaluated with Young's Internet Addiction Scale (YIAS). Using functional magnetic resonance imaging, the amplitude of low-frequency fluctuation (ALFF) and FC from the posterior cingulate cortex (PCC) seed to other brain areas were evaluated. Twelve casual game users were also recruited and underwent only baseline assessment.	After treatment, both CBT and VRT groups showed reductions in YIAS scores. At baseline, the OGA group showed a smaller ALFF within the right middle frontal gyrus and reduced FC in the cortico-striatal-limbic circuit. In the VRT group, connectivity from the PCC seed to the left middle frontal and bilateral temporal lobe increased after VRT.	VRT seemed to reduce the severity of OGA, showing effects similar to CBT, and enhanced the balance of the cortico-striatal-limbic circuit.	
26859108	Recently, the concept of effort-reward imbalance (ERI) developed by Siegrist had been applied to unpaid household and family work (ERI-HF). Evidence suggests that the imbalance between effort spent and reward received in family and domestic labor is associated with poor mental and physical health. However, so far, the adopted questionnaire ERI-HF was exclusively used among women in childcare responsibility. This paper reports on the application of the model to men in childcare responsibility using data from a clinical sample of fathers in rehabilitation clinics (N=415). Analogous to the original version, ERI-HF is divided into 2 components: (i) dysbalance of effort and reward, and (ii) overcommitment. For both components, confirmatory factor analyses revealed good to satisfactory properties. Overall, 13.4% of men in childcare responsibility showed a dysbalance between high effort and low reward of household and family work. High levels of effort were more frequently reported than high levels of low reward. With percentages ranging between 24.3 and 59.6%, a significant proportion of fathers reported difficulties to withdraw from household and family work obligations. Analyses of construct validity revealed significant associations between ERI and socio-demographic factors (number of children, employment status, single fatherhood, work-family-conflict) as well as subjective health. Taken together, our findings suggest that the instrument is applicable to men in childcare responsibility. 
26858994	Major depressive disorder (MDD) is a highly recurrent condition, and improving our understanding of the abnormalities that persist in remitted MDD (rMDD) may provide insight into mechanisms that contribute to relapse. MDD has been characterized by reward learning deficits linked to dysfunction in frontostriatal regions. Although initial behavioral evidence of reward learning deficits in rMDD has recently emerged, it is unclear whether these reflect impairments in neural reward processing that persist into remission.We examined behavioral reward learning and 128-channel event-related potentials (ERP) during a well-validated probabilistic reward task in 26 rMDD individuals and 34 never-depressed controls. Temporo-spatial principal components analysis (PCA) was used to separate overlapping ERP components, and group differences in neural activity in a priori regions were examined using low-resolution electromagnetic tomography (LORETA).	Individuals with rMDD displayed reduced behavioral reward learning, as well as blunted ERP amplitude to reward feedback. Importantly, the reduction in ERP amplitude occurred at a PCA factor that peaked during the time at which phasic reward feedback-related signaling - hypothesized to originate in the striatum and project to the anterior cingulate cortex (ACC) - are thought to modulate scalp-recorded activity. Consistent with this, LORETA analyses revealed reduced activity in the ACC in the rMDD group, and this blunting correlated with poorer reward learning.	These findings suggest that the reward learning impairment observed in acute MDD persists into full remission and that these impairments may be attributable to abnormalities in the neural processes that support reward feedback monitoring, particularly within the ACC.	
26856319	Novel taste memories, critical for animal survival, are consolidated to form long term memories which are dependent on translation regulation in the gustatory cortex (GC) hours following acquisition. However, the role of transcription regulation in the process is unknown.Here, we report that transcription in the GC is necessary for taste learning in rats, and that drinking and its consequences, as well as the novel taste experience, affect transcription in the GC during taste memory consolidation. We show differential effects of learning on temporal dynamics in set of genes in the GC, including Arc/Arg3.1, known to regulate the homeostasis of excitatory synapses.	We demonstrate that in taste learning, transcription programs were activated following the physiological responses (i.e., fluid consumption following a water restriction regime, reward, arousal of the animal, etc.) and the specific information about a given taste (i.e., taste novelty). Moreover, the cortical differential prolonged kinetics of mRNA following novel versus familiar taste learning may represent additional novelty related molecular response, where not only the total amount, but also the temporal dynamics of transcription is modulated by sensory experience of novel information.	
26854903	Adaptive motivated behavior requires predictive internal representations of the environment, and surprising events are indications for encoding new representations of the environment. The medial temporal lobe memory system, including the hippocampus and surrounding cortex, encodes surprising events and is influenced by motivational state. Because behavior reflects the goals of an individual, we investigated whether motivational valence (i.e., pursuing rewards versus avoiding punishments) also impacts neural and mnemonic encoding of surprising events. During functional magnetic resonance imaging (fMRI), participants encountered perceptually unexpected events either during the pursuit of rewards or avoidance of punishments. Despite similar levels of motivation across groups, reward and punishment facilitated the processing of surprising events in different medial temporal lobe regions. Whereas during reward motivation, perceptual surprises enhanced activation in the hippocampus, during punishment motivation surprises instead enhanced activation in parahippocampal cortex. Further, we found that reward motivation facilitated hippocampal coupling with ventromedial PFC, whereas punishment motivation facilitated parahippocampal cortical coupling with orbitofrontal cortex. Behaviorally, post-scan testing revealed that reward, but not punishment, motivation resulted in greater memory selectivity for surprising events encountered during goal pursuit. Together these findings demonstrate that neuromodulatory systems engaged by anticipation of reward and punishment target separate components of the medial temporal lobe, modulating medial temporal lobe sensitivity and connectivity. Thus, reward and punishment motivation yield distinct neural contexts for learning, with distinct consequences for how surprises are incorporated into predictive mnemonic models of the environment. 
26854803	Dopamine neurons are thought to signal reward prediction error, or the difference between actual and predicted reward. How dopamine neurons jointly encode this information, however, remains unclear. One possibility is that different neurons specialize in different aspects of prediction error; another is that each neuron calculates prediction error in the same way. We recorded from optogenetically identified dopamine neurons in the lateral ventral tegmental area (VTA) while mice performed classical conditioning tasks. Our tasks allowed us to determine the full prediction error functions of dopamine neurons and compare them to each other. We found marked homogeneity among individual dopamine neurons: their responses to both unexpected and expected rewards followed the same function, just scaled up or down. As a result, we were able to describe both individual and population responses using just two parameters. Such uniformity ensures robust information coding, allowing each dopamine neuron to contribute fully to the prediction error signal. 
26854396	Neuroscience research on non-human primates usually requires the animals to sit in a chair. To do this, typically monkeys are fitted with collars and trained to enter the chairs using either a pole, leash and jump cage. Animals may initially show resistance and risk injury. We have developed an automated chair-training method that minimizes restraints to ease the animals into their chairs.We developed a method to automatically train animals to enter a primate chair and stick out their heads for neckplate placement. To do this, we fitted the chairs with Arduino microcontrollers coupled to a water-reward system and touch- and proximity sensors.	We found that the animals responded well to the chair, partially entering the chair within hours, sitting inside the chair within days and allowing us to manually introduce a door and neck plate, all within 14-21 sessions. Although each session could last many hours, automation meant that actual training person-hours could be as little as half an hour per day. The biggest advantage was that animals showed little resistance to entering the chair, compared to monkeys trained by leash pulling.	This automated chair-training method can take longer than the standard collar-and-leash approach, but multiple macaques can be trained in parallel with fewer person-hours. It is also a promising method for animal-use refinement and in our case, it was the only effective training approach for an animal suffering from a behavioral pathology.	
26853737	Investigate impairment of reward anticipation in subjects with schizophrenia (SCZ) and its association with negative symptom dimensions and hedonic experience.Event-related potentials (ERPs) were recorded, in thirty SCZ and twenty-three matched healthy controls (HC), during a "Monetary Incentive Delay" task in which reward and loss cues (incentive cues of positive and negative value) of different magnitude, as well as neutral cues were presented.	anticipatory and consummatory pleasure, trait anhedonia and motivation in all subjects; avolition and expressive deficit in SCZ.	SCZ had lower motivation but comparable hedonic experience with respect to HC. In HC, during reward anticipation, the early P3 was larger for large magnitude incentives, irrespective of their valence, while the late P3 was larger for large reward. In SCZ, early P3 did not discriminate the incentive magnitude and the late P3 was larger for large loss. Early P3 amplitude for large magnitude incentives was inversely related to trait social anhedonia but not to negative symptoms dimensions.	SCZ are unable to integrate the incentive magnitude and reward value of future events in the context of their ongoing task. P3 abnormalities are associated with trait anhedonia, but not with negative symptoms dimensions.	In line with recent studies, our findings indicate that anhedonia and avolition are partially independent constructs.	
26853599	Although eating desires can be easily learned, their extinction appears more difficult. The present two-session study aimed to investigate the role of eating expectancies in the short and longer-term extinction of eating desires. In addition, the relationship between eating desires and conditioned evaluations was examined to test whether they might share a similar mechanism. It was hypothesized that the short-term extinction of eating desires would be more successful after the disconfirmation of eating expectancies (instructed extinction or IE), while resulting in worse longer-term extinction because omission of the food reward during extinction is not surprising. In contrast to the hypotheses, it was found that IE had no effect on the short-term and longer-term extinction of eating desires. Eating desires correlated with conditioned evaluations only to some extent. It is concluded that eating expectancies do not mediate the short-term extinction of conditioned eating desires. In addition, their longer-term extinction does not appear to be facilitated by a greater violation of eating expectancies. This suggests that it might not be necessary to focus on expectancy violation in cue exposure therapy to reduce eating desires. 
26851698	Anhedonia is a significant clinical problem in post-traumatic stress disorder (PTSD). PTSD patients show reduced motivational approach behavior, which may underlie anhedonic symptoms. Oxytocin administration is known to increase reward sensitivity and approach behavior. We therefore investigated whether oxytocin administration affected neural responses during motivational processing in PTSD patients and trauma-exposed controls.35 police officers with PTSD (21 males) and 37 trauma-exposed police officers without PTSD (19 males) were included in a within-subjects, randomized, placebo-controlled fMRI study. Neural responses during anticipation of monetary reward and loss were investigated with a monetary incentive delay task (MID) after placebo and oxytocin (40 IU) administration.	Oxytocin increased neural responses during reward and loss anticipation in PTSD patients and controls in the striatum, dorsal anterior cingulate cortex and insula, key regions in the reward pathway. Although PTSD patients did not differ from controls in motivational processing under placebo, anhedonia severity in PTSD patients was negatively related to reward responsiveness in the ventral striatum. Furthermore, oxytocin effects on reward processing in the ventral striatum were positively associated with anhedonia.	Oxytocin administration increased reward pathway sensitivity during reward and loss anticipation in PTSD patients and trauma-exposed controls. Thus, oxytocin administration may increase motivation for goal-directed approach behavior in PTSD patients and controls, providing evidence for a neurobiological pathway through which oxytocin could potentially increase motivation and reward sensitivity in PTSD patients.	
26851575	Animal research has shown it is possible to want a reward that is not liked once obtained. Although these findings have elicited interest, human experiments have produced contradictory results, raising doubts about the existence of separate wanting and liking influences in human reward processing. This discrepancy could be due to inconsistences in the operationalization of these concepts. We systematically reviewed the methodologies used to assess human wanting and/or liking and found that most studies operationalized these concepts in congruency with the animal literature. Nonetheless, numerous studies operationalized wanting in similar ways to those that operationalized liking. These contradictions might be driven by a major source of confound: expected pleasantness. Expected pleasantness underlies cognitive desires and does not correspond to animal liking, a hedonic experience, or to animal wanting, which relies on affective relevance, consisting of the perception of a cue associated with a relevant reward for the organism's current physiological state. Extending the concept of affective relevance and differentiating it from expected pleasantness might improve measures of human wanting and liking. 

26850629	Faced with the challenge of population aging, a prolonged working life is increasingly important in today's society. Maintaining work ability of employees is one of the effective ways to cope with the challenges to sustainability of the workforce presented by population aging. Researchers have shown ongoing interest in exploring the determinants of restricted work ability. The aim of this study was to evaluate the effects of work stress on work ability among power supply workers in Guangdong, China.A cross-sectional study was conducted among power supply workers during August 2014 to September 2014. A total of 805 subjects were enrolled in the study. Work stress was assessed by the Job Content Questionnaire and the Effort Reward Imbalance Questionnaire. Work ability was assessed by the Work Ability Index (WAI). The structural equation model was applied to test the relationship between different work stress components and work ability simultaneously using the Job Demands-Resources model as a framework.	Job resources (measured by job control, reward and social support) were positively and directly associated with work ability (β = 0.70, P < 0.001). The association between job demands and work ability was also statistically significant (β = -0.09, P = 0.030). In addition, the findings also supported previous studies in that job demands were correlated with job resources (β = -0.26, P < 0.001).	Our findings suggest that decision makers and health care providers should consider increasing job resources available to power supply workers. Consideration of organizational changes related to the design of the job task also would be useful to improve the employees' work ability.	
26850291	In the study of animal emotions, emotional valence has been found to be difficult to measure. Many studies of farm animals' emotions have therefore focussed on the identification of indicators of strong, mainly negative, emotions. However, subtle variations in emotional valence, such as those caused by rather moderate differences in husbandry conditions, may also affect animals' mood and welfare when such variations occur consistently. In this study, we investigated whether repeated moderate aversive or rewarding events could lead to measurable differences in emotional valence in young, weaned pigs. We conditioned 105 female pigs in a test arena to either a repeated startling procedure (sudden noises or appearances of objects) or a repeated rewarding procedure (applesauce, toy and straw) over 11 sessions. Control pigs were also regularly exposed to the same test arena but without conditioning. Before and after conditioning, we measured heart rate and its variability as well as the behavioural reactions of the subjects in the test arena, with a special focus on detailed acoustic analyses of their vocalisations. The behavioural and heart rate measures were analysed as changes compared to the baseline values before conditioning. A limited number of the putative indicators of emotional valence were affected by the conditioning. We found that the negatively conditioned pigs showed changes that were significantly different from those in control pigs, namely a decrease in locomotion and an increase in standing. The positively conditioned pigs, however, showed a stronger increase in heart rate and a smaller decrease in SDNN (a heart rate variability parameter indicating changes in autonomic regulation) compared to the controls. Compared to the negatively conditioned pigs, the positively conditioned pigs produced fewer vocalisations overall as well as fewer low-frequency grunts but more high-frequency grunts. The low-frequency grunts of the negatively conditioned pigs also showed lower frequency parameters (bandwidth, maximum frequency, 25% and 50% quartiles) compared to those of the positively conditioned pigs. In any of the statistically significant results, the conditioning accounted for 1.5-11.9% of variability in the outcome variable. Hence, we conclude that repeated moderate aversive and rewarding events have weak but measurable effects on some aspects of behaviour and physiology in young pigs, possibly indicating changes in emotional valence, which could ultimately affect their welfare. The combination of ethophysiological indicators, i.e., the concurrent examination of heart rate measures, behavioural responses and especially vocalisation patterns, as used in the current study, might be a useful way of examining subtle effects on emotional valence in further studies. 
26850211	Relatively little is known about the neuropathophysiology of binge-eating disorder (BED). Here, the evidence from neuroimaging, neurocognitive, genetics, and animal studies are reviewed to synthesize our current understanding of the pathophysiology of BED. Binge-eating disorder may be conceptualized as an impulsive/compulsive disorder, with altered reward sensitivity and food-related attentional biases. Neuroimaging studies suggest there are corticostriatal circuitry alterations in BED similar to those observed in substance abuse, including altered function of prefrontal, insular, and orbitofrontal cortices and the striatum. Human genetics and animal studies suggest that there are changes in neurotransmitter networks, including dopaminergic and opioidergic systems, associated with binge-eating behaviors. Overall, the current evidence suggests that BED may be related to maladaptation of the corticostriatal circuitry regulating motivation and impulse control similar to that found in other impulsive/compulsive disorders. Further studies are needed to understand the genetics of BED and how neurotransmitter activity and neurocircuitry function are altered in BED and how pharmacotherapies may influence these systems to reduce BED symptoms. 
26848937	In Zambia, only 56% of rural women deliver in a health facility, and improving facility delivery rates is a priority of the Zambian government. 'Mama kit' incentives - small packages of childcare items provided to mothers conditional on delivering their baby in a facility - may encourage facility delivery. This study measured the impact and cost-effectiveness of a US$4 mama kit on rural facility delivery rates in Zambia.A clustered randomised controlled trial was used to measure the impact of mama kits on facility delivery rates in thirty rural health facilities in Serenje and Chadiza districts. Facility-level antenatal care and delivery registers were used to measure the percentage of women attending antenatal care who delivered at a study facility during the intervention period. Results from the trial were then used to model the cost-effectiveness of mama kits at-scale in terms of cost per death averted.	The mama kits intervention resulted in a statistically significant increase in facility delivery rates. The multivariate logistic regression found that the mama kits intervention increased the odds of delivering at a facility by 63% (P-value < 0.01, 95% CI: 29%, 106%), or an increase of 9.9 percentage points, yielding a cost-effectiveness of US$5183 per death averted.	This evaluation confirms that low-cost mama kits can be a cost-effective intervention to increase facility delivery rates in rural Zambia. Mama kits alone are unlikely to completely solve safe delivery challenges but should be embedded in larger maternal and child health programmes.	
26848876	There are established effects of self- and reward-biases even on simple perceptual matching tasks [Sui, J., He, X., & Humphreys, G. W. (2012). Perceptual effects of social salience: Evidence from self-prioritization effects on perceptual matching. Journal of Experimental Psychology, Human Perception and Performance, 38, 1105-1117]; however we know little about whether these biases can be modulated by particular interventions, and whether the biases then change in the same way. Here we assessed how the biases alter under conditions designed to induce negative mood. We had participants read a list of self-related negative or neutral mood statements [Velten, E. (1968). A laboratory task for induction of mood states. Behavior Research and Therapy, 6, 473-482] and also listen for 10 min to a passage of negative or neutral music, prior to carrying out perceptual matching with shapes associated to personal labels (self or stranger) or reward (£12 or £1). Responses to the self- and high-reward-associated shapes were selectively slower and less sensitive (d') following the negative mood induction procedures, and the decrease in mood correlated with decreases in the reaction time bias across "high saliency" (self and high-reward) stimuli. We suggest that negative mood may decrease self- and reward-biases through reducing attention to salient external stimuli.
26846482	Among many personality traits, impulsivity represents one of the most important traits associated with pathological gambling. Empirical research has highlighted the multidimensional nature of impulsivity, which includes different heterogeneous traits and behavioral tendencies. The present study experimentally examined reward preferences of pathological gamblers under conditions of uncertainty using the Balloon Analogue Risk Task (BART). Furthermore it also examined the relationship between impulsivity, time perspective, inability to tolerate delay in gratification, and risk-taking. The present study is the first to simultaneously examine all these variables simultaneously in a sample of pathological gamblers (n = 54) and healthy controls (n = 54) from Italy. All participants participated in the BART and were also administered Italian versions of the South Oaks Gambling Screen, the Barratt Impulsiveness Scale, the Consideration of Future Consequences, and the Monetary Choice Questionnaire. Analyses revealed that compared to HCs, PGs were more risk prone on the BART, and reported elevated levels of impulsivity, steeper discounting rates and a shorter time perspective. All the measures correlated with the gambling severity and strong correlations between the BIS, CFC-14 and BART were observed. Logistic regression analysis demonstrated that impulsivity and risk-taking were strong predictors of pathological gambling.
26846198	Within the field of addiction, as many as four-fifths of individuals in treatment for substance use disorder have co-existing lifetime psychopathology and as high as two-thirds have current psychopathology. Among substance-dependent individuals, excessive delay discounting is pervasive. Despite evidence of excessive discounting across substance use disorders, few studies have investigated the impact of co-occurring psychopathologies and SUD on delay discounting.We compared delay discounting in currently abstaining substance users with (a) SUD (n=166), (b) SUD and managed major depressive disorder (MDD; n=44), (c) SUD and antisocial personality disorder (APD; n=35), (d) SUD and managed MDD and APD (n=22) and (e) no SUD or co-occurring psychopathology (n=60).	All groups with SUD discounted future delayed rewards significantly more than healthy controls (p<0.001 in each case, d=0.686, 0.835, 1.098 and 1.650, respective to groups a-d above). Individuals with both APD and SUD and individuals with MDD, APD, and SUD discounted future rewards significantly more than substance users without comorbid psychopathology (p=0.029, d=0.412 and p<0.001, d=0.964, respectively).	Overall, individuals with multiple psychopathologies in addition to substance use have exacerbated deficits in discounting of the future, above and beyond that observed in substance use alone. Increased discounting in combined substance and psychopathology profiles suggest a greater chance of treatment failure and therefore may necessitate individualized treatment using adjunctive interventions to achieve better treatment outcomes.	
26844834	Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a primary brain reward region, are seen at early versus late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce "metaplasticity" in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner. 
26845506	Research on distributive justice indicates that preschool-age children take issues of equity and merit into account when distributing desirable items, but that they often prefer to see desirable items allocated equally in third-party tasks. By contrast, less is known about the development of retributive justice. In a study with 4- to 10-year-old children (n = 123) and adults (n = 93), we directly compared the development of reasoning about distributive and retributive justice. We measured the amount of rewards or punishments that participants allocated to recipients who differed in the amount of good or bad things they had done. We also measured judgments about collective rewards and punishments. We found that the developmental trajectory of thinking about retributive justice parallels that of distributive justice. The 4- to 5-year-olds were the most likely to prefer equal distributions of both rewarding and aversive consequences; older children and adults preferred deservingness-based allocations. The 4- to 5-year-olds were also most likely to judge collective rewards and punishments as fair; this tendency declined with increasing age. Our results also highlight the extent to which the notion of desert influences thinking about distributive and retributive justice; desert was considered equally when participants allocated reward and punishments, but in judgments about collective discipline, participants focused more on desert in cases of punishment compared with reward. We discuss our results in relation to theories about preferences for equality versus equity, theories about how desert is differentially weighed across distributive and retributive justice, and the literature on moral development and fairness.
26845261	Schizophrenia and bipolar disorder are associated with different clinical profiles of disturbances in motivation, yet few studies have compared the neurophysiological correlates of such disturbances. Outpatients with schizophrenia (n = 34), or bipolar disorder I (n = 33), and healthy controls (n = 31) completed a task in which the late positive potential (LPP), an index of motivated attention, was assessed along motivational gradients determined by apparent distance from potential rewards or punishments. Sequences of cues signaling possible monetary gains or losses appeared to loom progressively closer to the viewer; a reaction time (RT) task after the final cue determined the outcome. Controls showed the expected pattern with LPPs for appetitive and aversive cues that were initially elevated, smaller during intermediate positions, and escalated just prior to the RT task. The clinical groups showed different patterns in the final positions just prior to the RT task: the bipolar group's LPPs to both types of cues peaked relatively early during looming sequences and subsequently decreased, whereas the schizophrenia group showed relatively small LPP escalations, particularly for aversive cues. These distinct patterns suggest that the temporal unfolding of attentional resource allocation for motivationally significant events may qualitatively differ between these disorders. (PsycINFO Database Record
26845257	Schizophrenia is characterized by deficits of context processing, thought to be related to dorsolateral prefrontal cortex (DLPFC) impairment. Despite emerging evidence suggesting a crucial role of the DLPFC in integrating reward and goal information, we do not know whether individuals with schizophrenia can represent and integrate reward-related context information to modulate cognitive control. To address this question, 36 individuals with schizophrenia (n = 29) or schizoaffective disorder (n = 7) and 27 healthy controls performed a variant of a response conflict task (Padmala & Pessoa, 2011) during fMRI scanning, in both baseline and reward conditions, with monetary incentives on some reward trials. We used a mixed state-item design that allowed us to examine both sustained and transient reward effects on cognitive control. Different from predictions about impaired DLPFC function in schizophrenia, we found an intact pattern of increased sustained DLPFC activity during reward versus baseline blocks in individuals with schizophrenia at a group level but blunted sustained activations in the putamen. Contrary to our predictions, individuals with schizophrenia showed blunted cue-related activations in several regions of the basal ganglia responding to reward-predicting cues. Importantly, as predicted, individual differences in anhedonia/amotivation symptoms severity were significantly associated with reduced sustained DLPFC activation in the same region that showed overall increased activity as a function of reward. These results suggest that individual differences in motivational impairments in schizophrenia may be related to dysfunction of the DLPFC and striatum in motivationally salient situations.
26843654	Orexin (Orx) neurons are known to be involved in the promotion and maintenance of waking because they discharge in association with cortical activation and muscle tone during waking and because, in their absence, waking with muscle tone cannot be maintained and narcolepsy with cataplexy ensues. Whether Orx neurons discharge during waking in association with particular conditions, notably with appetitive versus aversive stimuli or positive versus negative emotions, is debated and considered important in understanding their role in supporting particular waking behaviors. Here, we used the technique of juxtacellular recording and labeling in head-fixed rats to characterize the discharge of Orx neurons during the performance of an associative discrimination task with auditory cues for appetitive versus aversive outcomes. Of 57 active, recorded, and neurobiotin-labeled neurons in the lateral hypothalamus, 11 were immunohistochemically identified as Orx-positive (Orx(+)), whereas none were identified as melanin-concentrating hormone-positive. Orx(+) neurons discharged at significantly higher rates during the tone associated with sucrose than during the tone associated with quinine delivered upon licking. They also discharged at high rates after the tone associated with sucrose. Across periods and outcomes, their discharge was positively correlated with EEG gamma activity and EMG activity, which is indicative of cortical activation and behavioral arousal. These results suggest that Orx neurons discharge in a manner characteristic of reward neurons yet also characteristic of arousal neurons. Accordingly, the Orx neurons may respond to and participate in reward processes while modulating cortical activity and muscle tone to promote and maintain arousal along with learned adaptive behavioral responses.Orexin neurons play a critical role in promoting and maintaining a waking state because, in their absence, narcolepsy with cataplexy ensues. Known to discharge during waking and not during sleep, they have also been proposed to be selectively active during appetitive behaviors. Here, we recorded and labeled neurons in rats to determine the discharge of immunohistochemically identified orexin neurons during performance of an associative discrimination task. Orexin neurons responded differentially to auditory cues associated with appetitive sucrose versus aversive quinine, indicating that they behave like reward neurons. However, correlated discharge with cortical and muscle activity indicates that they also behave like arousal neurons and can thus promote cortical activation with behavioral arousal and muscle tone during adaptive waking behaviors.	
26843636	Behavioral and neuroscientific data on reward-based decision making point to a fundamental distinction between habitual and goal-directed action selection. The formation of habits, which requires simple updating of cached values, has been studied in great detail, and the reward prediction error theory of dopamine function has enjoyed prominent success in accounting for its neural bases. In contrast, the neural circuit mechanisms of goal-directed decision making, requiring extended iterative computations to estimate values online, are still unknown. Here we present a spiking neural network that provably solves the difficult online value estimation problem underlying goal-directed decision making in a near-optimal way and reproduces behavioral as well as neurophysiological experimental data on tasks ranging from simple binary choice to sequential decision making. Our model uses local plasticity rules to learn the synaptic weights of a simple neural network to achieve optimal performance and solves one-step decision-making tasks, commonly considered in neuroeconomics, as well as more challenging sequential decision-making tasks within 1 s. These decision times, and their parametric dependence on task parameters, as well as the final choice probabilities match behavioral data, whereas the evolution of neural activities in the network closely mimics neural responses recorded in frontal cortices during the execution of such tasks. Our theory provides a principled framework to understand the neural underpinning of goal-directed decision making and makes novel predictions for sequential decision-making tasks with multiple rewards.Goal-directed actions requiring prospective planning pervade decision making, but their circuit-level mechanisms remain elusive. We show how a model circuit of biologically realistic spiking neurons can solve this computationally challenging problem in a novel way. The synaptic weights of our network can be learned using local plasticity rules such that its dynamics devise a near-optimal plan of action. By systematically comparing our model results to experimental data, we show that it reproduces behavioral decision times and choice probabilities as well as neural responses in a rich set of tasks. Our results thus offer the first biologically realistic account for complex goal-directed decision making at a computational, algorithmic, and implementational level.	
26843555	Large-scale, comparative cognition studies are set to revolutionize the way we investigate and understand the evolution of intelligence. However, the conclusions reached by such work have a key limitation: the cognitive tests themselves. If factors other than cognition can systematically affect the performance of a subset of animals on these tests, we risk drawing the wrong conclusions about how intelligence evolves. Here, we examined whether this is the case for the A-not-B task, recently used by MacLean and co-workers to study self-control among 36 different species. Non-primates performed poorly on this task; possibly because they have difficulty tracking the movements of a human demonstrator, and not because they lack self-control. To test this, we assessed the performance of New Caledonian crows on the A-not-B task before and after two types of training. New Caledonian crows trained to track rewards moved by a human demonstrator were more likely to pass the A-not-B test than birds trained on an unrelated choice task involving inhibitory control. Our findings demonstrate that overlooked task demands can affect performance on a cognitive task, and so bring into question MacLean's conclusion that absolute brain size best predicts self-control.
26842262	Cognitive control deficits, as captured by inhibitory control measures, are indicative of increased impulsivity and are considered a marker for substance use disorder vulnerability. While individuals with alcohol use disorder (AUD) typically exhibit inhibitory control dysfunction, evidence of impaired inhibitory control among harmful drinkers, who are at increased risk of developing an AUD, is mixed. This study examined the response inhibition of binge drinkers using a task that employed neutral, as well as both immediate and delayed reward contingencies, to determine whether reward induced heightened impulsivity in this population.Binge alcohol users (n = 42) and controls (n = 42) were administered a Monetary Incentive Control Task that required participants to successfully inhibit a prepotent motor response to both neutral and immediately rewarding stimuli in order to secure a large delayed reward.	Binge drinkers had significantly worse response inhibition than controls irrespective of trial condition and even after controlling for differences in weekly intake. Although both binge and control participants exhibited significantly worse inhibitory control in the presence of immediate reward, the control group showed a greater reduction in inhibition accuracy compared to the binge group in reward relative to neutral conditions. Both groups demonstrated significantly enhanced control when forewarned there was an increased chance response inhibition would be required. Control participants secured the delayed reward more often than binge participants.	Despite the variability in the literature, this study demonstrated consistent generalized impulse control deficits among binge-drinking individuals that were unrelated to reward manipulations. These findings point to mechanisms that may confer vulnerability for transition from binge drinking to AUD.	
26842253	Prenatal alcohol exposure affects inhibitory control and other aspects of attention and executive function. However, the efficacy of extrinsic reinforcement on these behaviors has not been tested.Alcohol-exposed children (AE; n = 34), children with attention-deficit/hyperactivity disorder (ADHD; n = 23), and controls (CON; n = 31) completed a flanker task with 4 reward conditions (no reward, reward, reward+occasional response cost, equal probability of reward+response cost). Inhibitory control was tested in the no reward conditions using a 3(group) × 2(flanker type) ANCOVA. Response to reinforcement was tested using 3(group) × 4(reward condition) × 4(flanker type) analysis of covariance (ANCOVA). Response time (RT) and accuracy were tested independently.	Groups did not differ on demographic variables. The flanker task was successful in taxing interference control, an aspect of executive attention (i.e., responses to incongruent stimuli were slower than to congruent stimuli) and the AE group demonstrated impaired executive control over the other groups. Overall, the AE group had significantly slower RTs compared to the CON and ADHD groups, which did not differ. However, reinforcement improved RT in all groups. While occasional response cost had the greatest benefit in the CON group, the type of reinforcement did not differentially affect the AE and ADHD groups. Accuracy across reward conditions did not differ by group, but was dependent on flanker type and reward condition.	Alcohol-exposed children, but not children with ADHD, had impaired interference control in comparison with controls, supporting a differential neurobehavioral profile in these 2 groups. Both clinical groups were equally affected by introduction of reinforcement, although the type of reinforcement did not differentially affect performance as it did in the control group, suggesting that reward or response cost could be used interchangeably to result in the same benefit.	
26841552	Article examines the impact of 'energy" drinks that have become so popular in recent decades on people. As a research tool a short structured questionnaire was used. It included questions about whether the respondent used "energy" drinks and, if yes, how often; whether he/she had an experience of using it with alcohol; if one is informed about the affect of substances that are included in the drink on the organism; reason of using; the reason of debut consumption; primary feeling during and after consumption; primary feeling after taking a large dose of "energy" drink. Each respondent also pointed out sex and noted whether he/she wanted to learn more about "energy" drinks and effects of their use on the organism. Within 3 years of study 1377 people (682 men and 695 women) aged 12 to 42 were surveyed. The results showed that 89.0% of respondents consumed energy drinks in some to some degree, and from these 7.4% used it constantly (at least 1 can a day). 24,0% of respondents had an experience of taking "energy" drinks with alcohol. With that, the number of men who used "energy" drinks with alcohol, prevails over the same number of women: 60.3% (n = 199) and 39.7% (n = 131), respectively (p = 0.003). Relationship between age of respondents and features of using as well as effects of "energy drinks" was also statistically proven. The elder the group is the less is the number of responders who drinks energetics constantly (Rs = -0.88, p < 0.001), who knows about the affect of caffeine and other substances on the organism (Rs = -0.93, p < 0.001), who drinks energetics forced by desire to get new feelings (Rs = -0.78, p < 0.001), exams (Rs = -0.73, p < 0.001), who feels fatigue (Rs = -0.79, p < 0.001), and get headache (Rs = -0.8, p < 0.001), the more is the number of responders who noticed that the primal feeling after energetics drinking was rising of working efficiency (Rs = 0.76, p < 0.001) and excessive motional activity (Rs = 0.59, p = 0.01). Basing on the data obtained basic principles of reducing the rate of use of energy drinks program were developed.
26841235	In the last decade dendrites of cortical neurons have been shown to nonlinearly combine synaptic inputs by evoking local dendritic spikes. It has been suggested that these nonlinearities raise the computational power of a single neuron, making it comparable to a 2-layer network of point neurons. But how these nonlinearities can be incorporated into the synaptic plasticity to optimally support learning remains unclear. We present a theoretically derived synaptic plasticity rule for supervised and reinforcement learning that depends on the timing of the presynaptic, the dendritic and the postsynaptic spikes. For supervised learning, the rule can be seen as a biological version of the classical error-backpropagation algorithm applied to the dendritic case. When modulated by a delayed reward signal, the same plasticity is shown to maximize the expected reward in reinforcement learning for various coding scenarios. Our framework makes specific experimental predictions and highlights the unique advantage of active dendrites for implementing powerful synaptic plasticity rules that have access to downstream information via backpropagation of action potentials. 
26840481	Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction. 
26838982	Besides their fundamental movement function evidenced by Parkinsonian deficits, the basal ganglia are involved in processing closely linked non-motor, cognitive and reward information. This review describes the reward functions of three brain structures that are major components of the basal ganglia or are closely associated with the basal ganglia, namely midbrain dopamine neurons, pedunculopontine nucleus, and striatum (caudate nucleus, putamen, nucleus accumbens). Rewards are involved in learning (positive reinforcement), approach behavior, economic choices and positive emotions. The response of dopamine neurons to rewards consists of an early detection component and a subsequent reward component that reflects a prediction error in economic utility, but is unrelated to movement. Dopamine activations to non-rewarded or aversive stimuli reflect physical impact, but not punishment. Neurons in pedunculopontine nucleus project their axons to dopamine neurons and process sensory stimuli, movements and rewards and reward-predicting stimuli without coding outright reward prediction errors. Neurons in striatum, besides their pronounced movement relationships, process rewards irrespective of sensory and motor aspects, integrate reward information into movement activity, code the reward value of individual actions, change their reward-related activity during learning, and code own reward in social situations depending on whose action produces the reward. These data demonstrate a variety of well-characterized reward processes in specific basal ganglia nuclei consistent with an important function in non-motor aspects of motivated behavior. 
26838344	Intelligent animals have a high degree of curiosity--the intrinsic desire to know--but the mechanisms of curiosity are poorly understood. A key open question pertains to the internal valuation systems that drive curiosity. What are the cognitive and emotional factors that motivate animals to seek information when this is not reinforced by instrumental rewards? Using a novel oculomotor paradigm, combined with reinforcement learning (RL) simulations, we show that monkeys are intrinsically motivated to search for and look at reward-predictive cues, and that their intrinsic motivation is shaped by a desire to reduce uncertainty, a desire to obtain conditioned reinforcement from positive cues, and individual variations in decision strategy and the cognitive costs of acquiring information. The results suggest that free-viewing oculomotor behavior reveals cognitive and emotional factors underlying the curiosity driven sampling of information.
26836623	Previous research in patients with anorexia nervosa showed heightened brain response during a taste reward conditioning task and heightened sensitivity to rewarding and punishing stimuli. Here we tested the hypothesis that individuals recovered from anorexia nervosa would also experience greater brain activation during this task as well as higher sensitivity to salient stimuli than controls.Women recovered from restricting-type anorexia nervosa and healthy control women underwent fMRI during application of a prediction error taste reward learning paradigm.	Twenty-four women recovered from anorexia nervosa (mean age 30.3 ± 8.1 yr) and 24 control women (mean age 27.4 ± 6.3 yr) took part in this study. The recovered anorexia nervosa group showed greater left posterior insula activation for the prediction error model analysis than the control group (family-wise error- and small volume-corrected p < 0.05). A group × condition analysis found greater posterior insula response in women recovered from anorexia nervosa than controls for unexpected stimulus omission, but not for unexpected receipt. Sensitivity to punishment was elevated in women recovered from anorexia nervosa.	This was a cross-sectional study, and the sample size was modest.	Anorexia nervosa after recovery is associated with heightened prediction error-related brain response in the posterior insula as well as greater response to unexpected reward stimulus omission. This finding, together with behaviourally increased sensitivity to punishment, could indicate that individuals recovered from anorexia nervosa are particularly responsive to punishment. The posterior insula processes somatosensory stimuli, including unexpected bodily states, and greater response could indicate altered perception or integration of unexpected or maybe unwanted bodily feelings. Whether those findings develop during the ill state or whether they are biological traits requires further study.	
26836514	Choosing between smaller prompt rewards and larger later rewards is a common choice problem, and studies widely agree that frontostriatal circuits heavily innervated by dopamine are centrally involved. Understanding how dopamine modulates intertemporal choice has important implications for neurobiological models and for understanding the mechanisms underlying maladaptive decision-making. However, the specific role of dopamine in intertemporal decisions is not well understood. Dopamine may play a role in multiple aspects of intertemporal choices--the valuation of choice outcomes and sensitivity to reward delays. To assess the role of dopamine in intertemporal decisions, we tested Parkinson disease patients who suffer from dopamine depletion in the striatum, in either high (on medication, PDON) or low (off medication, PDOFF) dopaminergic states. Compared with both PDOFF and healthy controls, PDON made more farsighted choices and reduced their valuations less as a function of increasing time to reward. Furthermore, reduced discounting in the high dopaminergic state was robust across multiple measures, providing new evidence for dopamine's role in making decisions about the future.
26836278	Epidemiological studies have shown an association between vitamin D deficiency and cognitive impairment. However, there is a paucity of preclinical data showing that vitamin D deficiency is a causal factor for impaired cognitive processing. The aim of this study was to assess two cognitive tasks, the 5 choice-serial reaction task and the 5 choice-continuous performance task in adult vitamin D (AVD) deficient BALB/c mice. Ten-week old male and female BALB/c mice were fed a control or vitamin D deficient diet for 10 weeks prior to, and during behavioural testing. We found sex-dependent impairments in attentional processing and showed that male AVD-deficient mice were less accurate, took longer to respond when making a correct choice and were more likely to make an omission, without a change in the motivation to collect reward. By contrast, female AVD-deficient mice had a reduced latency to collect reward, but no changes on any other measures compared to controls. Therefore, we have shown that in otherwise healthy adult mice, vitamin D deficiency led to mild cognitive impairment in male but not female mice and therefore this model will be useful for future investigations into unravelling the mechanism by which vitamin D affects the adult brain and cognitive function.
26834599	Dopamine contributes to the regulation of higher order information processing and executive control. It is important for memory consolidation processes, and for the adaptation of learned responses based on experience. In line with this, under aversive learning conditions, application of dopamine receptor antagonists prior to extinction result in enhanced memory reinstatement. Here, we investigated the contribution of the dopaminergic system to extinction and memory reinstatement (renewal) of an appetitive spatial learning task in rodents. Rats were trained for 3 days in a T-maze (context "A") to associate a goal arm with a food reward, despite low reward probability (acquisition phase). On day 4, extinction learning (unrewarded) occurred, that was reinforced by a context change ("B"). On day 5, re-exposure to the (unrewarded) "A" context took place (renewal of context "A", followed by extinction of context "A"). In control animals, significant extinction occurred on day 4, that was followed by an initial memory reinstatement (renewal) on day 5, that was, in turn, succeeded by extinction of renewal. Intracerebral treatment with a D1/D5-receptor antagonist prior to the extinction trials, elicited a potent enhancement of extinction in context "B". By contrast, a D1/D5-agonist impaired renewal in context "A". Extinction in the "A" context on day 5 was unaffected by the D1/D5-ligands. Treatment with a D2-receptor antagonist prior to extinction had no overall effect on extinction in context "B" or renewal in context "A", although extinction of the renewal effect was impaired on day 5, compared to controls. Taken together, these data suggest that dopamine acting on the D1/D5-receptor modulates both acquisition and consolidation of context-dependent extinction. By contrast, the D2-receptor may contribute to context-independent aspects of this kind of extinction learning. 
26834568	Classical Hebbian learning puts the emphasis on joint pre- and postsynaptic activity, but neglects the potential role of neuromodulators. Since neuromodulators convey information about novelty or reward, the influence of neuromodulators on synaptic plasticity is useful not just for action learning in classical conditioning, but also to decide "when" to create new memories in response to a flow of sensory stimuli. In this review, we focus on timing requirements for pre- and postsynaptic activity in conjunction with one or several phasic neuromodulatory signals. While the emphasis of the text is on conceptual models and mathematical theories, we also discuss some experimental evidence for neuromodulation of Spike-Timing-Dependent Plasticity. We highlight the importance of synaptic mechanisms in bridging the temporal gap between sensory stimulation and neuromodulatory signals, and develop a framework for a class of neo-Hebbian three-factor learning rules that depend on presynaptic activity, postsynaptic variables as well as the influence of neuromodulators. 
26833919	Although behavioral research has shown that positive mood leads to desired outcomes in nearly every major life domain, no studies have directly examined the effects of positive mood on the neural processes underlying reward-related affect and goal-directed behavior. To address this gap, participants in the present fMRI study experienced either a positive (n = 20) or neutral (n = 20) mood induction and subsequently completed a monetary incentive delay task that assessed reward and loss processing. Consistent with prediction, positive mood elevated activity specifically during reward anticipation in corticostriatal neural regions that have been implicated in reward processing and goal-directed behavior, including the nucleus accumbens, caudate, lateral orbitofrontal cortex and putamen, as well as related paralimbic regions, including the anterior insula and ventromedial prefrontal cortex. These effects were not observed during reward outcome, loss anticipation or loss outcome. Critically, this is the first study to report that positive mood enhances reward-related neural activity. Our findings have implications for uncovering the neural mechanisms by which positive mood enhances goal-directed behavior, understanding the malleability of reward-related neural activity, and developing targeted treatments for psychiatric disorders characterized by deficits in reward processing.
26833917	Goal conflict situations, involving the simultaneous presence of reward and punishment, occur commonly in real life, and reflect well-known individual differences in the behavioral tendency to approach or avoid. However, despite accumulating neural depiction of motivational processing, the investigation of naturalistic approach behavior and its interplay with individual tendencies is remarkably lacking. We developed a novel ecological interactive scenario which triggers motivational behavior under high or low goal conflict conditions. Fifty-five healthy subjects played the game during a functional magnetic resonance imaging scan. A machine-learning approach was applied to classify approach/avoidance behaviors during the game. To achieve an independent measure of individual tendencies, an integrative profile was composed from three established theoretical models. Results demonstrated that approach under high relative to low conflict involved increased activity in the ventral tegmental area (VTA), peri-aquaductal gray, ventral striatum (VS) and precuneus. Notably, only VS and VTA activations during high conflict discriminated between approach/avoidance personality profiles, suggesting that the relationship between individual personality and naturalistic motivational tendencies is uniquely associated with the mesostriatal pathway. VTA-VS further demonstrated stronger coupling during high vs low conflict. These findings are the first to unravel the multilevel relationship among personality profile, approach tendencies in naturalistic set-up and their underlying neural manifestation, thus enabling new avenues for investigating approach-related psychopathologies.
26832339	Dopamine (DA) plays a key role in reward-seeking behaviours. Accumulating evidence from animal and human studies suggests that human sexual reward learning may also depend on DA transmission. However, research on the role of DA in human sexual reward learning is completely lacking.To investigate whether DA antagonism attenuates classical conditioning of sexual response in humans.	Healthy women were randomly allocated to one of two treatment conditions: haloperidol (n = 29) or placebo (n = 29). A differential conditioning paradigm was applied with genital vibrostimulation as unconditional stimulus (US) and neutral pictures as conditional stimuli (CSs). Genital arousal was assessed, and ratings of affective value and subjective sexual arousal were obtained.	Haloperidol administration affected unconditional genital responding. However, no significant effects of medication were found for conditioned responding.	No firm conclusions can be drawn about whether female sexual reward learning implicates DA transmission since the results do not lend themselves to unambiguous interpretation.	
26831352	Autism is characterized by impairments of social interaction, but the underlying subpersonal processes are still a matter of controversy. It has been suggested that the autistic spectrum might be characterized by alterations of the brain's inference on the causes of socially relevant signals. However, it is unclear at what level of processing such trait-related alterations may occur.We used a reward-based learning task that requires the integration of nonsocial and social cues in conjunction with computational modeling. Healthy subjects (N = 36) were selected based on their Autism Quotient Spectrum (AQ) score, and AQ scores were assessed for correlations with model parameters and task scores.	Individual differences in AQ were inversely correlated with participants' task scores (r = -.39, 95% confidence interval [CI] [-.68, -.13]). Moreover, AQ scores were significantly correlated with a social weighting parameter that indicated how strongly the decision was influenced by the social cue (r = -.42, 95% CI [-.66, -.19]), but not with other model parameters. Also, more pronounced social weighting was related to higher scores (r = .50, 95% CI [.20, .86]).	Our results demonstrate that higher autistic traits in healthy subjects are related to lower scores in a learning task that requires social cue integration. Computational modeling further demonstrates that these trait-related performance differences are not explained by an inability to process the social stimuli and its causes, but rather by the extent to which participants take into account social information during decision making.	
26831251	We modified functional analysis procedures to include a condition in which we reinforced problem behavior by complying with a child's mands. After identifying compliance with mands as a reinforcer, we evaluated the efficacy of a token system with a response-cost contingency and incorporated discriminative stimuli to signal when mands would be reinforced. The token system with response cost effectively reduced problem behavior. Similar procedures may be beneficial when continuous adult compliance is not possible, when adults want to control when they will comply with the child's mands, or to build a child's tolerance for adult-directed situations.
26831208	The striatum serves as a critical brain region for reward processing. Yet, understanding the link between striatum and reward presents a challenge because rewards are composed of multiple properties. Notably, affective properties modulate emotion while informative properties help obtain future rewards. We approached this problem by emphasizing affective and informative reward properties within two independent guessing games. We found that both reward properties evoked activation within the nucleus accumbens, a subregion of the striatum. Striatal responses to informative, but not affective, reward properties predicted subsequent utilization of information for obtaining monetary reward. We hypothesized that activation of the striatum may be necessary but not sufficient to encode distinct reward properties. To investigate this possibility, we examined whether affective and informative reward properties were differentially encoded in corticostriatal interactions. Strikingly, we found that the striatum exhibited dissociable connectivity patterns with the ventrolateral prefrontal cortex, with increasing connectivity for affective reward properties and decreasing connectivity for informative reward properties. Our results demonstrate that affective and informative reward properties are encoded via corticostriatal interactions. These findings highlight how corticostriatal systems contribute to reward processing, potentially advancing models linking striatal activation to behavior. 
26831116	Phasic dopamine signaling participates in associative learning by reinforcing associations between outcomes (unconditioned stimulus; US) and their predictors (conditioned stimulus; CS). However, prior work has always engendered these associations with innately rewarding stimuli. Thus, whether dopamine neurons can acquire prediction signals in the absence of appetitive experience and update them when the value of the outcome changes remains unknown. Here, we used sodium depletion to reversibly manipulate the appetitive value of a hypertonic sodium solution while measuring phasic dopamine signaling in rat nucleus accumbens. Dopamine responses to the NaCl US following sodium depletion updated independent of prior experience. In contrast, prediction signals were only acquired through extensive experience with a US that had positive affective value. Once learned, dopamine prediction signals were flexibly expressed in a state-dependent manner. Our results reveal striking differences with respect to how physiological state shapes dopamine signals evoked by outcomes and their predictors. 
26831103	The reinforcing and rewarding properties of cocaine are attributed to its ability to increase dopaminergic transmission in nucleus accumbens (NAc). This action reinforces drug taking and seeking and leads to potent and long-lasting associations between the rewarding effects of the drug and the cues associated with its availability. The inability to extinguish these associations is a key factor contributing to relapse. Dopamine produces these effects by controlling the activity of two subpopulations of NAc medium spiny neurons (MSNs) that are defined by their predominant expression of either dopamine D1 or D2 receptors. Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion. However, we still lack a clear understanding of how the endogenous activity of these cell types is affected by cocaine and encodes information that drives drug-associated behaviors. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in NAc that encodes information about drug associations and elucidate the temporal profile with which D1 activity is increased to drive drug seeking in response to contextual cues. Chronic cocaine exposure dysregulates these D1 signals to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Directly manipulating these D1 signals using designer receptors exclusively activated by designer drugs prevents contextual associations. Together, these data elucidate the responses of D1- and D2-type MSNs in NAc to acute cocaine and during the formation of context-reward associations and define how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse. 
26830462	The ability to generalize previously learned information to novel situations is fundamental for adaptive behavior. However, too wide or too narrow generalization is linked to neuropsychiatric disorders. Previous research suggests that interactions between the dopaminergic system and the hippocampus may play a role in generalization, but whether and how the degree of generalization can be modulated via these pathways is currently unknown. Here, we addressed this question in humans using pharmacology, functional magnetic resonance imaging, and computational modeling. Blocking dopamine D2-receptors (D2R) altered generalization behavior as revealed by an increased kurtosis of the generalization gradient, and a decreased width of model-derived generalization parameters. Moreover, D2R-blockade modulated similarity-based responses in the hippocampus and decreased midbrain-hippocampal connectivity, which in turn correlated with individual differences in generalization. These results suggest that dopaminergic activity in the hippocampus may relate to the degree of generalization and highlight a potential target for treatment. 
26830449	Existence of long-term drug-associated memories may be a crucial factor in drug cravings and relapse. RACK1 plays a critical role in morphine-induced reward. In the present study, we used conditioned place preference (CPP) to assess the acquisition and maintenance of morphine conditioned place preference memory. The hippocampal protein level of RACK1 and synaptic quantitation were evaluated by Western blotting, immunohistochemistry and electron microscopy, respectively. Additionally, shRACK1 (shGnb2l1) was used to silence RACK1 in vivo to evaluate the role and the underlying mechanism of RACK1 in maintenance of morphine CPP memory. We found that morphine induced CPP was maintained for at least 7 days after the last morphine treatment, which indicated a positive correlation with hippocampal RACK1 level, and was accompanied simultaneously by increases in the synapse density and hippocampal expression of synaptophysin (SYP), phosphorylation of extracellular signal-regulated kinase1/2 (pERK1/2) and the phosphorylation of cyclic adenosine monophosphate response element-binding (pCREB). ShGnb2l1 icv injection significantly suppressed the expression of all above proteins, decreased the synapse density in the hippocampus and attenuated the acquisition and maintenance of morphine CPP. Our present study highlights that RACK1 plays an important role in the maintenance of morphine CPP, likely via activation of ERK-CREB pathway in hippocampus. 
26829710	Despite the high prevalence of stress exposure healthy adaptation or resilience is a common response. Theoretical work and recent empirical evidence suggest that a robust reward system, in part, supports healthy adaptation by preserving positive emotions even under exceptionally stressful circumstances. We tested this prediction by examining empirical relations among behavioral and self-reported measures of sensitivity to reward, trait resilience, and measures of affect in the context of experimentally induced stress. Using a quasi-experimental design we obtained measures of sensitivity to reward (self-report and behavioral), as well as affective and physiological responses to experimental psychosocial stress in a sample of 140 healthy college-age participants. We used regression-based moderation and mediational models to assess associations among sensitivity to reward, affect in the context of stress, and trait resilience and found that an interaction between exposure to experimental stress and self-reported sensitivity to reward predicted positive affect following experimental procedure. Participants with high sensitivity to reward reported higher positive affect following stress. Moreover, positive affect during or after stress mediated the relation between sensitivity to reward and trait resilience. Consistent with the prediction that a robust reward system serves as a protective factor against stress-related negative outcomes, our results found predictive associations among sensitivity to reward, positive affect, and resilience. 
26829074	Despite aggressive conventional therapy, lasting hemiplegia persists in a large percentage of stroke survivors. The aim of this article is to critically review the rationale behind targeting multiple sites along the motor learning network by combining robotic therapy with pharmacotherapy and virtual reality-based reward learning to alleviate upper extremity impairment in stroke survivors. Methods for personalizing pharmacologic facilitation to each individual's unique biology are also reviewed. At the molecular level, treatment with levodopa was shown to induce long-term potentiation-like and practice-dependent plasticity. Clinically, trials combining conventional therapy with levodopa in stroke survivors yielded statistically significant but clinically unconvincing outcomes because of limited personalization, standardization, and reproducibility. Robotic therapy can induce neuroplasticity by delivering intensive, reproducible, and functionally meaningful interventions that are objective enough for the rigors of research. Robotic therapy also provides an apt platform for virtual reality, which boosts learning by engaging reward circuits. The future of stroke rehabilitation should target distinct molecular, synaptic, and cortical sites through personalized multimodal treatments to maximize motor recovery. 
26827817	The basal ganglia are key neural substrates not only for motor function, but also cognitive functions including reward and aversive learning. Critical for these processes are the functional role played by two projection neurons within nucleus accumbens (NAc); the D1- and D2-expressing neurons. Recently, we have developed a novel reversible neurotransmission blocking technique that specifically blocks neurotransmission from NAc D1- and D2-expressing neurons, allowing for in vivo analysis. In this review, we outline the functional dissociation of NAc D1- and D2-expressing neurons of the basal ganglia in reward and aversive learning, as well as drug addiction. These studies have revealed the importance of activation of NAc D1 receptors for reward learning and drug addiction, and inactivation of NAc D2 receptors for aversive learning and flexibility. Based on these findings, we propose a neural mechanism, in which dopamine neurons in the ventral tegmental area that send inputs to the NAc work as a switch between D1- and D2-expressing neurons. These basal ganglia neural mechanisms will give us new insights into the pathophysiology of neuropsychiatric diseases. 

26826648	The main goal of this study was to provide distributive data for the Palatable Eating Motives Scale (PEMS) on a large (N=1947) ethnically-diverse college student population along with motive scores characteristic of obesity and binge-eating severity. Students completed the PEMS, or a revised version of the PEMS, the Binge Eating Scale, and reported height and weight for a body mass index (BMI). The PEMS identified Coping, Reward Enhancement, Social, and Conformity motives for eating tasty but unhealthy foods for reasons other than hunger. The revised PEMS (included here) had better goodness-of-fit with the motives. Percentile rankings are presented for each of the motive scores. Separate Coping scores are presented for females and males given a modest effect size for females to score higher. Generally, scores on Coping, Reward Enhancement, Conformity, and a total PEMS score in the 70th percentile (those scoring higher than 70% of the sample) were associated with obesity and severe binge-eating. Unlike these motives, Social scores were the highest at each percentile rank but unassociated with BMI or binge-eating, reflecting the culturally-normative intake of these foods for social reasons. These distribution scores on PEMS motives in college students along with scores linked to higher BMI and binge-eating severity represent the first reported data of this type. Knowledge of these scores can be used to individualize and correspondingly improve current strategies aimed at preventing and treating obesity, binge-eating, maladaptive use of food to regulate internal and external pressures, and to improve overall nutritional health.
26826605	Adolescents are the highest consumers of sugar sweetened drinks. Excessive consumption of such drinks is a likely contributor to the development of obesity and may be associated with enduring changes in the systems involved in reward and motivation. We examined the impact of daily sucrose consumption in young male and female rats (N=12 per group) across the adolescent period on the motivation to perform instrumental responses to gain food rewards as adults. Rats were or were not exposed to a sucrose solution for 2 h each day for 28 days across adolescence [postnatal days (P) 28-56]. They were then trained as adults (P70 onward) to lever press for a palatable 15% cherry flavored sucrose reward and tested on a progressive ratio (PR) schedule to assess motivation to respond for reinforcement. Female rats exposed to sucrose had higher breakpoints on the PR schedule than controls, whereas male rats exposed to sucrose had lower breakpoints than controls. These results show that consumption of sucrose during adolescence produced sex-specific behavioral changes in responding for sucrose as adults.
26826400	Through Pavlovian conditioning, reward-associated neutral stimuli can acquire incentive salience and motivate complex behaviors. In smokers, cigarette-associated cues may induce cravings and trigger smoking. Understanding the brain mechanisms underlying conditioned responses to cigarette-associated relative to other inherently pleasant stimuli might contribute to the development of more effective smoking cessation treatments that emphasize the rehabilitation of reward circuitry. Here we measured brain responses to geometric patterns (the conditioned stimuli, CSs) predicting cigarette-related, intrinsically pleasant and neutral images (the unconditioned stimuli, USs) using event-related potentials (ERPs) in 29 never-smokers, 20 nicotine-deprived smokers, and 19 non-deprived smokers. Results showed that during US presentation, cigarette-related and pleasant images prompted higher cortical positivity than neutral images over centro-parietal sensors between 400 and 800ms post-US onset (late positive potential, LPP). The LPP evoked by pleasant images was significantly larger than the LPP evoked by cigarette images. During CS presentation, ERPs evoked by geometric patterns predicting pleasant and cigarette-related images had significantly larger amplitude than ERPs evoked by CSs predicting neutral images. These effects were maximal over right parietal sites between 220 and 240ms post-CS onset and over occipital and frontal sites between 308 and 344ms post-CS onset. Smoking status did not modulate these effects. Our results show that stimuli with no intrinsic reward value (e.g., geometric patterns) may acquire rewarding properties through repeated pairings with established reward cues (i.e., cigarette-related, intrinsically pleasant). 
26822368	Major advances in the neuroscientific understanding of alcohol actions have so far not translated into measurably improved clinical outcomes in alcoholism. Future treatment development should be guided by accumulating insights into a diverse range of biological mechanisms that maintain the pathophysiology of alcoholism in different individuals, but also at different points in time within any given patient. This biological diversity calls for the development and use of biological markers predictive of treatment response in the individual case, at the specific stage of the disease, here called "theragnostics." As novel therapeutic mechanisms and molecules targeting these mechanisms are discovered, the use of theragnostics will be critical for their successful clinical development, as well as their optimal subsequent clinical use. During clinical development, lest theragnostics are utilized, efficacy signals will risk remaining undetected when diluted in study populations that are not appropriately selected. Similarly, for treatments that reach approval, clinical acceptance, and optimal use will require the proper identification of responsive patients. Here, we discuss desirable properties of theragnostic biomarkers in alcohol addiction using two examples: alcohol-induced activation of brain reward circuitry as assessed using positron emission tomography of functional magnetic resonance imaging; and central glutamate tone, as assessed using MR spectroscopy. 
26822364	Effectively treating addiction is a challenge among any population, and treatment for adolescents may be particularly challenging in the context of ongoing neurodevelopment, which may alter the brain's initial response to substances as well as its response to treatment. One way to improve treatment outcomes for youth is to use a translational perspective that explicitly connects cognitive and neurodevelopmental fields with the field of behavioral therapies. This integrative approach is a potential first step to inform the correspondence between the neurocognitive and behavioral fields in youth addiction. This chapter seeks to provide context for neurocognitive treatment studies by first discussing recent structural and functional neuroimaging studies showing associations with substance use or behavioral addictions. Several regions of interest are then proposed that appear to also be associated with addiction treatment across multiple studies, namely, the accumbens/striatum, precuneus, insula, anterior cingulate cortex, and dorsolateral prefrontal cortex. This research suggests that reward, self-reflective, and executive control areas might be especially relevant in youth behavioral treatment response, and preliminary evidence suggests that existing treatments may encourage neurocognitive changes in these areas. 
26822354	In the past decade, electroencephalographic research on addiction has employed passive viewing, oddball, inhibition, prediction, gambling, and reversal learning tasks to study how substance users neurally prioritize drug-related rewards at the expense of nondrug rewards. On the whole, findings across substances (alcohol, cannabis, cocaine, nicotine, opiates, gambling, and gaming) demonstrate impairments in the differentiation of monetary incentives and the inhibition of prepotent responses. Furthermore, exaggerated resources devoted to drug cues and attenuated processing of other types of pleasant emotional stimuli predict greater probability of future drug use. However, drug use recency, frequency, sensitivity, and insight all appear to be moderators of these effects. We argue that more longitudinal studies are warranted to determine the time course of reward processing as a function of development and chronicity. 
26822353	Decision-making tasks that have good ecological validity, such as simulated gambling tasks, are complex, and performance on these tasks represents a synthesis of several different underlying psychological processes, such as learning from experience, and motivational processes such as sensitivity to reward and punishment. Cognitive models can be used to break down performance on these tasks into constituent processes, which can then be assessed and studied in relation to clinical characteristics and neuroimaging outcomes. Whether it will be possible to improve treatment success by targeting these constituent processes more directly remains unexplored. We review the development and testing of the Expectancy-Valence and Prospect-Valence Learning models from the past 10 years or so using simulated gambling tasks, in particular the Iowa and Soochow Gambling Tasks. We highlight the issues of model generalizability and parameter consistency, and we describe findings obtained from these models in clinical populations including substance use disorders. We then suggest future directions for this research that will help to bring its utility to broader research and clinical applications. 
26822352	High rates of relapse to drug use during abstinence is a defining feature of drug addiction. In abstinent drug users, drug relapse is often precipitated by acute exposure to the self-administered drug, drug-associated cues, stress, as well as by short-term and protracted withdrawal symptoms. In this review, we discuss different animal models that have been used to study behavioral and neuropharmacological mechanisms of these relapse-related phenomena. In the first part, we discuss relapse models in which abstinence is achieved through extinction training, including the established reinstatement model, as well as the reacquisition and resurgence models. In the second part, we discuss recent animal models in which drug relapse is assessed after either forced abstinence (e.g., the incubation of drug craving model) or voluntary (self-imposed) abstinence achieved either by introducing adverse consequences to ongoing drug self-administration (e.g., punishment) or by an alternative nondrug reward using a discrete choice (drug vs. palatable food) procedure. We conclude by briefly discussing the potential implications of the recent developments of animal models of drug relapse after voluntary abstinence to the development of medications for relapse prevention. 
26822065	There is preliminary data indicating that patients with generalized anxiety disorder (GAD) show impairment on decision-making tasks requiring the appropriate representation of reinforcement value. The current study aimed to extend this literature using the passive avoidance (PA) learning task, where the participant has to learn to respond to stimuli that engender reward and avoid responding to stimuli that engender punishment. Six stimuli engendering reward and six engendering punishment are presented once per block for 10 blocks of trials. Thirty-nine medication-free patients with GAD and 29 age-, IQ and gender matched healthy comparison individuals performed the task. In addition, indexes of social functioning as assessed by the Global Assessment of Functioning (GAF) scale were obtained to allow for correlational analyzes of potential relations between cognitive and social impairments. The results revealed a Group-by-Error Type-by-Block interaction; patients with GAD committed significantly more commission (passive avoidance) errors than comparison individuals in the later blocks (blocks 7,8, and 9). In addition, the extent of impairment on these blocks was associated with their functional impairment as measured by the GAF scale. These results link GAD with anomalous decision-making and indicate that a potential problem in reinforcement representation may contribute to the severity of expression of their disorder. 
26820558	Being able to recognise when one is being observed by someone else is thought to be adaptive during cooperative or competitive events. In particular for prey species, this ability should be of use in the context of predation. A previous study reported that goats (Capra aegagrus hircus) alter their behaviour according to the body and head orientation of a human experimenter. During a food anticipation task, an experimenter remained in a particular posture for 30 s before delivering a reward, and the goats' active anticipation and standing alert behaviour were analysed. To further evaluate the specific mechanisms at work, we here present two additional test conditions. In particular, we investigated the effects of the eye visibility and head orientation of a human experimenter on the behaviour of the goats (N = 7). We found that the level of the subjects' active anticipatory behaviour was highest in the conditions where the experimenter was directing his head and body towards the goat ('Control' and 'Eyes closed' conditions), but the anticipatory behaviour was significantly decreased when the body ('Head only') or the head and body of the experimenter were directed away from the subject ('Back' condition). For standing alert, we found no significant differences between the three conditions in which the experimenter was directing his head towards the subject ('Control', 'Eyes closed' and 'Head only'). This lack of differences in the expression of standing alert suggests that goats evaluate the direction of a human's head as an important cue in their anticipatory behaviour. However, goats did not respond to the visibility of the experimenter's eyes alone.
26819774	Obesity remains a pervasive global health problem. While there are a number of nonsurgical and surgical options for treatment, the incidence of obesity continues to increase at an alarming rate. The inability to curtail the growing rise of the obesity epidemic may be related to a combination of increased food availability and palatability. Research into feeding behavior has yielded a number of insights into the homeostatic and reward mechanisms that govern feeding. However, there remains a gap between laboratory investigations of feeding physiology in animals and translation into meaningful treatment options for humans. In addition, laboratory investigation may not be able to recapitulate all aspects of human food consumption. In a landmark pilot study of deep brain stimulation (DBS) of the lateral hypothalamic area for obesity, we found that there was an increase in resting metabolic rate as well as a decreased urge to eat. In this review, the authors will review some of the work relating to feeding physiology and research surrounding two nodes involved in feeding homeostasis, nucleus accumbens (NAc) and hypothalamus, and use this to provide a framework for future investigations of DBS as a viable therapeutic modality for obesity. 
26818705	The dorsal raphe nucleus (DRN) is involved in organizing reward-related behaviours; however, it remains unclear how genetically defined neurons in the DRN of a freely behaving animal respond to various natural rewards. Here we addressed this question using fibre photometry and single-unit recording from serotonin (5-HT) neurons and GABA neurons in the DRN of behaving mice. Rewards including sucrose, food, sex and social interaction rapidly activate 5-HT neurons, but aversive stimuli including quinine and footshock do not. Both expected and unexpected rewards activate 5-HT neurons. After mice learn to wait for sucrose delivery, most 5-HT neurons fire tonically during waiting and then phasically on reward acquisition. Finally, GABA neurons are activated by aversive stimuli but inhibited when mice seek rewards. Thus, DRN 5-HT neurons positively encode a wide range of reward signals during anticipatory and consummatory phases of reward responses. Moreover, GABA neurons play a complementary role in reward processing. 
26818510	When informed that A > B and B > C, humans and other animals can easily conclude that A > C. This remarkable trait of advanced animals, which allows them to manipulate knowledge flexibly to infer logical relations, has only recently garnered interest in mainstream neuroscience. How the brain controls these logical processes remains an unanswered question that has been merely superficially addressed in neuroimaging and lesion studies, which are unable to identify the underlying neuronal computations. We observed that the activation pattern of neurons in the prefrontal cortex (PFC) during pair comparisons in a highly demanding transitive inference task fully supports the behavioral performance of the two monkeys that we tested. Our results indicate that the PFC contributes to the construction and use of a mental schema to represent premises. This evidence provides a novel framework for understanding the function of various areas of brain in logic processes and impairments to them in degenerative, traumatic, and psychiatric pathologies.In cognitive neuroscience, it is unknown how information that leads to inferential deductions are encoded and manipulated at the neuronal level. We addressed this question by recording single-unit activity from the dorsolateral prefrontal cortex of monkeys that were performing a transitive inference (TI) task. The TI required one to choose the higher ranked of two items, based on previous, indirect experience. Our results demonstrated that single-neuron activity supports the construction of an abstract, mental schema of ordered items in solving the task and that this representation is independent of the reward value that is experienced for the single items. These findings identify the neural substrates of abstract mental representations that support inferential thinking.	
26818502	Nucleus accumbens (NAc) neurons encode features of stimulus learning and action selection associated with rewards. The NAc is necessary for using information about expected outcome values to guide behavior after reinforcer devaluation. Evidence suggests that core and shell subregions may play dissociable roles in guiding motivated behavior. Here, we recorded neural activity in the NAc core and shell during training and performance of a reinforcer devaluation task. Long-Evans male rats were trained that presses on a lever under an illuminated cue light delivered a flavored sucrose reward. On subsequent test days, each rat was given free access to one of two distinctly flavored foods to consume to satiation and were then immediately tested on the lever pressing task under extinction conditions. Rats decreased pressing on the test day when the reinforcer earned during training was the sated flavor (devalued) compared with the test day when the reinforcer was not the sated flavor (nondevalued), demonstrating evidence of outcome-selective devaluation. Cue-selective encoding during training by NAc core (but not shell) neurons reliably predicted subsequent behavioral performance; that is, the greater the percentage of neurons that responded to the cue, the better the rats suppressed responding after devaluation. In contrast, NAc shell (but not core) neurons significantly decreased cue-selective encoding in the devalued condition compared with the nondevalued condition. These data reveal that NAc core and shell neurons encode information differentially about outcome-specific cues after reinforcer devaluation that are related to behavioral performance and outcome value, respectively.Many neuropsychiatric disorders are marked by impairments in behavioral flexibility. Although the nucleus accumbens (NAc) is required for behavioral flexibility, it is not known how NAc neurons encode this information. Here, we recorded NAc neurons during a training session in which rats learned that a cue predicted a specific reward and during a test session when that reward value was changed. Although encoding in the core during training predicted the ability of rats to change behavior after the reward value was altered, the NAc shell encoded information about the change in reward value during the test session. These findings suggest differential roles of the core and shell in behavioral flexibility.	
26814589	In experiments conducted over 60 years ago, the lateral hypothalamic area (LHA) was identified as a critical neuroanatomical substrate for motivated behavior. Electrical stimulation of the LHA induces voracious feeding even in well-fed animals. In the absence of food, animals will work tirelessly, often lever-pressing thousands of times per hour, for electrical stimulation at the same site that provokes feeding, drinking and other species-typical motivated behaviors. Here we review the classic findings from electrical stimulation studies and integrate them with more recent work that has used contemporary circuit-based approaches to study the LHA. We identify specific anatomically and molecularly defined LHA elements that integrate diverse information arising from cortical, extended amygdala and basal forebrain networks to ultimately generate a highly specified and invigorated behavioral state conveyed via LHA projections to downstream reward and feeding-specific circuits. 
26813728	To explore the influence of occupational stress related factors on depression symptoms among 244 policemen in a city in China.In May 2011, 287 policemen from a city public security bureau were recruited to this survey by cluster sampling method. We deleted questionnaires which include missing variables on demographic characteristics and factors associated with occupational stress questionnaires which include over 3 missing items. 244 policemen were included in this study. Depression symptoms and occupational stressors were measured using Chinese version of depression self-reported questionnaire, job content questionnaire, Chinese version of effort-reward imbalances questionnaire, job hazard scale and occupational stress inventory. Depression symptom scores and the relationship between the variables and occupational stress were analyzed by Spearman correlation analysis and multiple regression analysis.	The Median (P25-P75) of depression symptom scores of all respondents was 16.50 (11.00-25.00). 144 were policemen with no depression symptoms and 100 were with depression symptoms. The median (P25-P75) of depression symptoms scores among policemen with length of serves <10, 10-19, 20-29 and ≥30 was 17.00 (8.00-26.00), 16.00 (11.00-24.50), 19.00 (12.00-27.00), and 12.00 (6.25-15.00), respectively. The difference of scores was significant among length of serves groups (χ2=9.52, P=0.023). The scores of psychological demands, sleep disorder, daily life stress and negative affectivity among policemen with depression symptoms were 17.00 (8.00-26.00), 16.00 (11.00-24.50), 19.00 (12.00-27.00), and 12.00 (6.25-15.00), respectively, which were higher than those with no depression symptoms (24.00 (22.00-25.00), 8.00 (5.00-13.00), 8.00 (6.00-10.00), 1.00 (0-2.75)), and the differences were significant (Z=3.82, 5.39, 5.15, 6.41, P<0.001). Spearman correlation analysis revealed that depression symptoms score was positively related to sleep disorder, commitment effort, psychological demands, daily life stress, negative affectivity and job hazards scores. Correlations coefficient were 0.44, 0.28, 0.28, 0.33, 0.38, 0.44, and 0.38, respectively (P<0.001). Multiple linear regression analysis indicated that self-esteem, daily life stress and negative affectivity had bigger contribution on the depression symptoms scores. The standard regression coefficient was -0.46, 0.19 and 0.13, respectively (P<0.001, P=0.001, P=0.030).	Sleep disorder, commitment effort, psychological demands, daily life stress, negative affectivity and job hazards scores were the inducement of depression symptoms for policemen. To reduce the daily life stress, negative affectivity and improve the quality of sleep, add to self-esteem, reward and social support have positive effects on reducing the occurrence of depressive symptoms for police.	
26812253	Rewards are commonly used in interventions to change behavior, but they can inhibit development of intrinsic motivation, which is associated with long-term behavior maintenance. Gamification is a novel intervention strategy that may target intrinsic motivation through fun and enjoyment. Before the effects of gamified interventions on motivation can be determined, there must be an understanding of how gamified interventions operationalize rewards, such as point systems. The purpose of this review is to determine the prevalence of different reward types, specifically point systems, within gamified interventions. Electronic databases were searched for relevant articles. Data sources included Medline OVID, Medline PubMed, Web of Science, CINAHL, Cochrane Central, and PsycINFO. Out of the 21 articles retrieved, 18 studies described a reward system and were included in this review. Gamified interventions were designed to target a myriad of clinical outcomes across diverse populations. Rewards included points (n = 14), achievements/badges/medals (n = 7), tangible rewards (n = 7), currency (n = 4), other unspecified rewards (n = 3), likes (n = 2), animated feedback (n = 1), and kudos (n = 1). Rewards, and points in particular, appear to be a foundational component of gamified interventions. Despite their prevalence, authors seldom described the use of noncontingent rewards or how the rewards interacted with other game features. The reward systems relying on tangible rewards and currency may have been limited by inhibited intrinsic motivation. As gamification proliferates, future research should explicitly describe how rewards were operationalized in the intervention and evaluate the effects of gamified rewards on motivation across populations and research outcomes. 
26811473	Magnetoreception of the light-dependent magnetic compass in birds is suggested to be mediated by a radical-pair mechanism taking place in the avian retina. Biophysical models on magnetic field effects on radical pairs generally assume that the light activating the magnetoreceptor molecules is nondirectional and unpolarized, and that light absorption is isotropic. However, natural skylight enters the avian retina unidirectionally, through the cornea and the lens, and is often partially polarized. In addition, cryptochromes, the putative magnetoreceptor molecules, absorb light anisotropically, i.e., they preferentially absorb light of a specific direction and polarization, implying that the light-dependent magnetic compass is intrinsically polarization sensitive. To test putative interactions between the avian magnetic compass and polarized light, we developed a spatial orientation assay and trained zebra finches to magnetic and/or overhead polarized light cues in a four-arm "plus" maze. The birds did not use overhead polarized light near the zenith for sky compass orientation. Instead, overhead polarized light modulated light-dependent magnetic compass orientation, i.e., how the birds perceive the magnetic field. Birds were well oriented when tested with the polarized light axis aligned parallel to the magnetic field. When the polarized light axis was aligned perpendicular to the magnetic field, the birds became disoriented. These findings are the first behavioral evidence to our knowledge for a direct interaction between polarized light and the light-dependent magnetic compass in an animal. They reveal a fundamentally new property of the radical pair-based magnetoreceptor with key implications for how birds and other animals perceive the Earth's magnetic field. 
26811252	The orbitofrontal cortex is known to carry information regarding expected reward, risk and experienced outcome. Yet, due to inherent limitations in lesion and neuroimaging methods, the neural dynamics of these computations has remained elusive in humans. Here, taking advantage of the high temporal definition of intracranial recordings, we characterize the neurophysiological signatures of the intact orbitofrontal cortex in processing information relevant for risky decisions. Local field potentials were recorded from the intact orbitofrontal cortex of patients suffering from drug-refractory partial epilepsy with implanted depth electrodes as they performed a probabilistic reward learning task that required them to associate visual cues with distinct reward probabilities. We observed three successive signals: (i) around 400 ms after cue presentation, the amplitudes of the local field potentials increased with reward probability; (ii) a risk signal emerged during the late phase of reward anticipation and during the outcome phase; and (iii) an experienced value signal appeared at the time of reward delivery. Both the medial and lateral orbitofrontal cortex encoded risk and reward probability while the lateral orbitofrontal cortex played a dominant role in coding experienced value. The present study provides the first evidence from intracranial recordings that the human orbitofrontal cortex codes reward risk both during late reward anticipation and during the outcome phase at a time scale of milliseconds. Our findings offer insights into the rapid mechanisms underlying the ability to learn structural relationships from the environment.
26809268	There is some evidence that cocaine addiction manifests as more severe in women than men. Here, we examined whether these sex-specific differences in the clinical setting parallel differential neurobehavioral sensitivity to rewards in the laboratory setting. Twenty-eight (14 females/14 males) cocaine-dependent and 25 (11 females/14 males) healthy individuals completed a monetary reward task during fMRI. Results showed that the effects of cocaine dependence and sex overlapped in regions traditionally considered part of the mesocorticolimbic brain circuits including the hippocampus and posterior cingulate cortex (PCC), as well as those outside of this circuit (e.g., the middle temporal gyrus). The nature of this 'overlap' was such that both illness and female sex were associated with lower activations in these regions in response to money. Diagnosis-by-sex interactions instead emerged in the frontal cortex, such that cocaine-dependent females exhibited lower precentral gyrus and greater inferior frontal gyrus (IFG) activations relative to cocaine-dependent males and healthy females. Within these regions modulated both by diagnosis and sex, lower activation in the hippocampus and PCC, and higher IFG activations, correlated with increased subjective craving during the task. Results suggest sex-specific differences in addiction extend to monetary rewards and may contribute to core symptoms linked to relapse. 
26808920	This study investigated whether dopaminergic systems are involved in the motivation to engage in behaviours associated with anorexia nervosa (AN), specifically, the drive to exercise. Women recovered from AN (AN REC, n = 17) and healthy controls (HC, n = 15) were recruited. The acute phenylalanine/tyrosine depletion (APTD) method was used to transiently decrease dopamine synthesis and transmission. The effect of dopamine precursor depletion on drive to exercise was measured using a progressive ratio (PR) exercise breakpoint task. Both groups worked for the opportunity to exercise, and, at baseline, PR breakpoint scores were higher in AN REC than HC. Compared to values on the experimental control session, APTD did not decrease PR breakpoint scores in AN REC, but significantly decreased scores in HC. These data show that women recovered from AN are more motivated to exercise than HC, although in both groups, activity is more reinforcing than inactivity. Importantly, decreasing dopamine does not reduce the motivation to exercise in people recovered from AN, but in contrast, does so in HC. It is proposed that in AN, drive to exercise develops into a behaviour that is largely independent of dopamine mediated reward processes and becomes dependent on cortico-striatal neurocircuitry that regulates automated, habit- or compulsive-like behaviours. These data strengthen the case for the involvement of reward, learning, habit, and dopaminergic systems in the aetiology of AN. 
26808148	At around 7 months of age, human infants begin to reliably produce well-formed syllables containing both consonants and vowels, a behavior called canonical babbling. Over subsequent months, the frequency of canonical babbling continues to increase. How the infant's nervous system supports the acquisition of this ability is unknown. Here we present a computational model that combines a spiking neural network, reinforcement-modulated spike-timing-dependent plasticity, and a human-like vocal tract to simulate the acquisition of canonical babbling. Like human infants, the model's frequency of canonical babbling gradually increases. The model is rewarded when it produces a sound that is more auditorily salient than sounds it has previously produced. This is consistent with data from human infants indicating that contingent adult responses shape infant behavior and with data from deaf and tracheostomized infants indicating that hearing, including hearing one's own vocalizations, is critical for canonical babbling development. Reward receipt increases the level of dopamine in the neural network. The neural network contains a reservoir with recurrent connections and two motor neuron groups, one agonist and one antagonist, which control the masseter and orbicularis oris muscles, promoting or inhibiting mouth closure. The model learns to increase the number of salient, syllabic sounds it produces by adjusting the base level of muscle activation and increasing their range of activity. Our results support the possibility that through dopamine-modulated spike-timing-dependent plasticity, the motor cortex learns to harness its natural oscillations in activity in order to produce syllabic sounds. It thus suggests that learning to produce rhythmic mouth movements for speech production may be supported by general cortical learning mechanisms. The model makes several testable predictions and has implications for our understanding not only of how syllabic vocalizations develop in infancy but also for our understanding of how they may have evolved. 
26807797	Both reward based operant conditioning (OC) and reflex-based prepulse inhibition (PPI) procedures are used in sound localisation studies in mice. Since the results of both procedures are compared in the literature, it is important to assess whether they provide similar results if the same stimulus paradigm is applied. Here, we compare the sensitivity of C57BL/6 mice in OC and PPI procedures for detecting a switch in speaker location using broadband and narrowband noise stimuli and determined their minimum audible angle (MAA). In the OC procedure, we calculated d' values from the hit and false alarm rates. In the PPI procedure, we calculated the area under ROC curves from the startle response amplitudes and derived da values to obtain a sensitivity measure that corresponds to d'. For both procedures, the mean sensitivity to the speaker switch increased with an increase in angular separation. For broadband noise stimuli, a d' of up to 3.3 (OC) and a da of up to 1.1 (PPI) were observed at large speaker separations. Narrowband noise stimuli resulted in lower sensitivities in both procedures, resulting in a maximum d' of 2.0 (OC) and a maximum da of 0.3 (PPI). Using a sensitivity of 1.0 as the threshold criterion, broadband noise MAAs in the range from 32° to 46° were observed in the OC procedure whereas a broadband noise MAAs of 108° or higher were observed in the PPI procedure. In the OC procedure, narrowband noise MAAs in the range from 37° to 62° were observed. In the PPI procedure, no narrowband noise MAA could be determined since none of the subjects reached the threshold. Thus, OC procedures result in a better performance of the subjects in the sound localization task than PPI procedures, challenging the view that both procedures can be used interchangeably. 
26806872	Appetite and weight changes are common but variable diagnostic markers in major depressive disorder: some depressed individuals manifest increased appetite, while others lose their appetite. Many of the brain regions implicated in appetitive responses to food have also been implicated in depression. It is thus remarkable that there exists no published research comparing the neural responses to food stimuli of depressed patients with increased versus decreased appetites.Using functional MRI, brain activity was compared in unmedicated depressed patients with increased or decreased appetite and healthy control subjects while viewing photographs of food and nonfood objects. The authors also measured how resting-state functional connectivity related to subjects' food pleasantness ratings.	Within putative reward regions, depressed participants with increased appetites exhibited greater hemodynamic activity to food stimuli than both those reporting appetite decreases and healthy control subjects. In contrast, depressed subjects experiencing appetite loss exhibited hypoactivation within a region of the mid-insula implicated in interoception, with no difference observed in this region between healthy subjects and those with depression-related appetite increases. Mid-insula activity was negatively correlated with food pleasantness ratings of depressed participants with increased appetites, and its functional connectivity to reward circuitry was positively correlated with food pleasantness ratings.	Depression-related increases in appetite are associated with hyperactivation of putative mesocorticolimbic reward circuitry, while depression-related appetite loss is associated with hypoactivation of insular regions that support monitoring the body's physiological state. Importantly, the interactions among these regions also contribute to individual differences in the depression-related appetite changes.	
26806862	Blue wavelength light has been used as an effective treatment for some types of mood disorders and circadian rhythm related sleep problems. We hypothesized that acute exposure to blue wavelength light would directly affect the functioning of neurocircuity implicated in emotion regulation (i.e., ventromedial prefrontal cortex, amygdala, insula, and anterior cingulate cortex [ACC]) during 'certain' and 'uncertain' anticipation of negative and positive stimuli. Thirty-five healthy adults were randomized to receive a thirty-minute exposure to either blue (active) or amber (placebo) light, immediately followed by an emotional anticipation task during functional magnetic resonance imaging (fMRI). In contrast to placebo, participants in the blue light group showed significantly reduced activation within the rostral ACC during 'uncertain' anticipation (i.e., uncertainty regarding whether a positive or negative stimulus would be shown) in comparison to 'certain' anticipation of a positive stimulus. These findings may be explicable in terms of interactions between blue light exposure and the influence of specific neuromodulators on ACC-mediated decision-making mechanisms.
26806784	Contributing factors to obesity have been identified, yet prevention and treatment efforts have had limited long-term success. It has recently been suggested that some individuals may experience an addictive-like response to certain foods, such as losing control over consumption and continued consumption despite negative consequences. In support, shared biological and behavioral features seem to exist between "food addiction" and traditional substance-use disorders. "Food addiction" may be another important contributor to obesity. The current chapter reviews existing literature regarding neural systems implicated similarly in obesity and addiction, discusses unique considerations for addictive-like eating, and proposes directions for future research regarding "food addiction" as an emerging construct for addiction medicine. 
26806780	Alcohol addiction is one of the most common and devastating diseases in the world. Given the tremendous heterogeneity of alcohol-addicted individuals, it is unlikely that one medication will help nearly all patients. Thus, there is a clear need to develop predictors of response to existing medications. Naltrexone is a mu opioid receptor antagonist which has been approved in the United States for treatment of alcohol addiction since 1994. It has limited efficacy, in part due to noncompliance, but many patients do not respond despite high levels of compliance. There are reports that a mis-sense single-nucleotide polymorphism (rs179919 or A118G) in the mu opioid receptor gene predicts a favorable response to naltrexone if an individual carries a "G" allele. This chapter will review the evidence for this hypothesis. The data suggest that the "G" allele has a complex role in alcohol addiction, increasing the rewarding valence of alcohol. Whether the G allele increases risk for alcoholism and whether it predisposes to a beneficial naltrexone response among alcohol-addicted persons must await additional research with large sample sizes of multiple ethnicities in prospective clinical trials. 
26806778	Structural and functional neuroimaging studies indicate that heavy alcohol use during adolescence may be neurotoxic to the brain. This chapter reviews the neuroimaging findings in cross-sectional and longitudinal studies of adolescent heavy alcohol users. These youth exhibit reductions in prefrontal, hippocampal, and cerebellar brain volume, decreased frontoparietal, and increased frontolimbic white matter integrity, as well as alterations in blood oxygen level-dependent response during working memory, inhibitory control, verbal encoding, decision making, and reward processing-some of which appear to differ between males and females. Although some exist, additional longitudinal studies will significantly advance addiction medicine by aiding prevention scientists and treatment providers to develop neurobiologically informed ways of strengthening neural networks prior to and after the onset of heavy alcohol use, thereby promoting healthy cognitive functioning across the adolescent period. 
26806771	The transition from recreational drug use to addiction can be conceptualized as a pathological timeline whereby the psychological mechanisms responsible for disordered drug use evolve from positive reinforcement to favor elements of negative reinforcement. Abused substances (ranging from alcohol to psychostimulants) are initially ingested at regular occasions according to their positive reinforcing properties. Importantly, repeated exposure to rewarding substances sets off a chain of secondary reinforcing events, whereby cues and contexts associated with drug use may themselves become reinforcing and thereby contribute to the continued use and possible abuse of the substance(s) of choice. Indeed, the powerful reinforcing efficacy of certain drugs may eclipse that of competing social rewards (such as career and family) and lead to an aberrant narrowing of behavioral repertoire. In certain vulnerable individuals, escalation of drug use over time is thought to drive specific molecular neuroadaptations that foster the development of addiction. Research has identified neurobiological elements of altered reinforcement following excessive drug use that comprise within-circuit and between-circuit neuroadaptations, both of which contribute to addiction. Central to this process is the eventual potentiation of negative reinforcement mechanisms that may represent the final definitive criterion locking vulnerable individuals into a persistent state of addiction. Targeting the neural substrates of reinforcement likely represents our best chances for therapeutic intervention for this devastating disease. 
26806770	In this chapter, we briefly review the basic biology of psychological stress and the stress response. We propose that psychological stress and the neurobiology of the stress response play in substance use initiation, maintenance, and relapse. The proposed mechanisms for this include, on the one hand, the complex interactions between biological mediators of the stress response and the dopaminergic reward system and, on the other hand, mediators of the stress response and other systems crucial in moderating key addiction-related behaviors such as endogenous opioids, the sympathetic-adrenal-medullary system, and endocannabinoids. Exciting new avenues of study including genomics, sex as a moderator of the stress response, and behavioral addictions (gambling, hypersexuality, dysfunctional internet use, and food as an addictive substance) are also briefly presented within the context of stress as a moderator of the addictive process. 
26805766	Nutritional deficiencies during neural development may lead to irreversible changes, even after nutritional rehabilitation, promoting morphological and functional adaptations of structures involved with various behaviours including feeding behaviour. However, the ability of the exposure low protein diet during gestation and lactation to affect the hedonic component of food intake is still poorly understood, especially in females.Wistar rats were divided into two groups according to the diet offered to the dams during pregnancy and lactation: control female (CF; diet with 17% protein, n=7) and low protein female (LPF; diet with 8% protein, n=7). The following parameters were evaluated: (a) body weight during weaning, 30, 45, 60, 75, 90 days of life; (b) standard diet intake from 110 to 132 days of life; (c) fat diet and consumption of simple carbohydrates (HFHS) for 1h at 145 days of life; (d) incentive runway task 60 days after 82 days of life; (e) taste reactivity at 90 days of life; and (f) neuronal activation in the caudate putamen, amygdala, paraventricular nucleus of the hypothalamus under stimulus HFHS at 145 days of life.	The exposure, a low protein diet during gestation and lactation, decreased the body weight throughout the study period from weaning to 90 days of life. However, there was no significant change in the body weight of low protein females from 110 to 132 days of life compared with the control females. There was an increase in the rate of the search for reward and reduced the latency of the perception of bitter taste. The exposure, a low protein diet during gestation and lactation, also promoted hypophagy in adult females compared with control animals. The low protein female had increased HFHS diet consumption compared with the control. Undernutrition increased neuronal activation in response to HFHS diet consumption compared with female controls in the amygdala and in the caudate putamen.	Females subjected to the exposure, a low protein diet during gestation and lactation, exhibit hypophagy on a standard diet but a higher consumption of a diet rich in lipids and simple carbohydrates. And also were more motivated by the pursuit of reward and reduced latency of the bitter taste reactivity, and increased the number of immunoreactive cells c-fos protein activated in the caudate putamen, amygdala and paraventricular nucleus.	
26804993	Dopamine (DA) type 1 receptor (D1R) signaling in the striatum presumably regulates neuronal excitability and reward-related behaviors through PKA. However, whether and how D1Rs and PKA regulate neuronal excitability and behavior remain largely unknown. Here, we developed a phosphoproteomic analysis method to identify known and novel PKA substrates downstream of the D1R and obtained more than 100 candidate substrates, including Rap1 GEF (Rasgrp2). We found that PKA phosphorylation of Rasgrp2 activated its guanine nucleotide-exchange activity on Rap1. Cocaine exposure activated Rap1 in the nucleus accumbens in mice. The expression of constitutively active PKA or Rap1 in accumbal D1R-expressing medium spiny neurons (D1R-MSNs) enhanced neuronal firing rates and behavioral responses to cocaine exposure through MAPK. Knockout of Rap1 in the accumbal D1R-MSNs was sufficient to decrease these phenotypes. These findings demonstrate a novel DA-PKA-Rap1-MAPK intracellular signaling mechanism in D1R-MSNs that increases neuronal excitability to enhance reward-related behaviors.
26803802	How do people solve the explore-exploit trade-off in a changing environment? In this paper we present experimental evidence from an "observe or bet" task, in which people have to determine when to engage in information-seeking behavior and when to switch to reward-taking actions. In particular we focus on the comparison between people's behavior in a changing environment and their behavior in an unchanging one. Our experimental work is motivated by rational analysis of the problem that makes strong predictions about information search and reward seeking in static and changeable environments. Our results show a striking agreement between human behavior and the optimal policy, but also highlight a number of systematic differences. In particular, we find that while people often employ suboptimal strategies the first time they encounter the learning problem, most people are able to approximate the correct strategy after minimal experience. In order to describe both the manner in which people's choices are similar to but slightly different from an optimal standard, we introduce four process models for the observe or bet task and evaluate them as potential theories of human behavior. 
26803528	Given the association between maternal caregiving behavior and heightened neural reward activity in experimental animal studies, the present study examined whether motherhood in humans positively modulates reward-processing neural circuits, even among mothers exposed to various life stressors and depression.Subjects were 77 first-time mothers and 126 nulliparous young women from the Pittsburgh Girls Study, a longitudinal study beginning in childhood. Subjects underwent a monetary reward task during functional magnetic resonance imaging in addition to assessment of current depressive symptoms. Life stress was measured by averaging data collected between ages 8-15 years. Using a region-of-interest approach, we conducted hierarchical regression to examine the relationship of psychosocial factors (life stress and current depression) and motherhood with extracted ventral striatal (VST) response to reward anticipation. Whole-brain regression analyses were performed post-hoc to explore non-striatal regions associated with reward anticipation in mothers vs nulliparous women.	Anticipation of monetary reward was associated with increased neural activity in expected regions including caudate, orbitofrontal, occipital, superior and middle frontal cortices. There was no main effect of motherhood nor motherhood-by-psychosocial factor interaction effect on VST response during reward anticipation. Depressive symptoms were associated with increased VST activity across the entire sample. In exploratory whole brain analysis, motherhood was associated with increased somatosensory cortex activity to reward (FWE cluster forming threshold p<0.001).	These findings indicate that motherhood is not associated with reward anticipation-related VST activity nor does motherhood modulate the impact of depression or life stress on VST activity. Future studies are needed to evaluate whether earlier postpartum assessment of reward function, inclusion of mothers with more severe depressive symptoms, and use of reward tasks specific for social reward might reveal an impact of motherhood on reward system activity.	
26803499	N-(4-hydroxyphenyl)-arachidonamide (AM404) is an anandamide transport inhibitor shown to reduce rewarding and relapse-inducing effects of nicotine in several animal models of tobacco dependence. However, the reinforcing/rewarding effects of AM404 are not clear.We investigated whether AM404 maintains self-administration behavior or reinstates extinguished drug seeking in squirrel monkeys.	In monkeys with a history of anandamide or cocaine self-administration, we substituted injections of AM404 (1-100 μg/kg/injection). Using a 10-response, fixed-ratio schedule, self-administration behavior was maintained by AM404. Dose-response curves had inverted U shapes, with peak response rates occurring at a dose of 10 μg/kg/injection. In anandamide-experienced monkeys, we also demonstrated self-administration of another anandamide transport inhibitor VDM11. In addition to supporting self-administration, priming injections of AM404 (0.03-0.3 mg/kg) reinstated drug-seeking behavior previously reinforced by cannabinoids (∆(9)-tetrahydrocannabinol (THC) or anandamide) or cocaine. Both AM404 self-administration behavior and reinstatement of drug seeking by AM404 were reduced by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist rimonabant (0.3 mg/kg). Moreover, the reinforcing effects of AM404 were potentiated by the treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg) suggesting a major role of anandamide in these effects. Finally, AM404 (0.3 mg/kg) potentiated the reinforcing effects of anandamide but not those of cocaine.	In non-human primates, AM404 effectively reinforced self-administration behavior and induced reinstatement of drug-seeking behavior in abstinent monkeys. These effects appeared to be mediated by cannabinoid CB1 receptors. Therefore, compounds that promote actions of endocannabinoids throughout the brain by inhibiting their membrane transport may have a potential for abuse.	
26803060	One type of Internet addiction is excessive pornography consumption, also referred to as cybersex or Internet pornography addiction. Neuroimaging studies found ventral striatum activity when participants watched explicit sexual stimuli compared to non-explicit sexual/erotic material. We now hypothesized that the ventral striatum should respond to preferred pornographic compared to non-preferred pornographic pictures and that the ventral striatum activity in this contrast should be correlated with subjective symptoms of Internet pornography addiction. We studied 19 heterosexual male participants with a picture paradigm including preferred and non-preferred pornographic materials. Subjects had to evaluate each picture with respect to arousal, unpleasantness, and closeness to ideal. Pictures from the preferred category were rated as more arousing, less unpleasant, and closer to ideal. Ventral striatum response was stronger for the preferred condition compared to non-preferred pictures. Ventral striatum activity in this contrast was correlated with the self-reported symptoms of Internet pornography addiction. The subjective symptom severity was also the only significant predictor in a regression analysis with ventral striatum response as dependent variable and subjective symptoms of Internet pornography addiction, general sexual excitability, hypersexual behavior, depression, interpersonal sensitivity, and sexual behavior in the last days as predictors. The results support the role for the ventral striatum in processing reward anticipation and gratification linked to subjectively preferred pornographic material. Mechanisms for reward anticipation in ventral striatum may contribute to a neural explanation of why individuals with certain preferences and sexual fantasies are at-risk for losing their control over Internet pornography consumption. 
26802874	The majority of studies which have aimed to identify cognitive and motivational factors at play in ADHD have investigated cognitive-control processes and reinforcement effects in isolation. Notably, in recent years, the interaction between these two processes has been increasingly examined. Here, we aimed to provide a comprehensive and critical review of the behavioral and functional neuroimaging studies that have investigated reinforcement effects on inhibitory control in ADHD. The findings of our meta-analyses show that reinforcement can normalize inhibitory control in children and adolescents with ADHD to the baseline level of controls. Furthermore, the data suggests that inhibitory control may improve to a larger extent in youth with ADHD compared with controls, as a function of reinforcement. Based on (1) this review and meta-analyses, (2) functional neuroimaging studies in healthy populations, and (3) existing ADHD and neurobiological models of dual processes, we propose specific guidelines for future research, which are anticipated to further elucidate processes underlying impulsive behavior associated with ADHD. 
26802728	The rapid increase in obesity may be partly mediated by an increase in the exposure to cues for food. Food-paired cues play a role in food procurement and intake under conditions of satiety. The mechanism by which this occurs requires characterization, but may involve ghrelin. This orexigenic peptide alters the response to food-paired conditioned stimuli, and neural responses to food images in reward nuclei. Therefore, we tested whether a ghrelin receptor antagonist alters the influence of food-paired cues on the performance of instrumental responses that earn food and the consumption of food itself using tests of Pavlovian-to-instrumental transfer (PIT) and cue potentiated feeding (CPF), respectively. Food-deprived rats received Pavlovian conditioning where an auditory cue was paired with delivery of sucrose solution followed by instrumental conditioning to lever press for sucrose. Following training, rats were given ad libitum access to chow. On test day, rats were injected with the ghrelin receptor antagonist GHRP-6 [D-Lys3] and then tested for PIT or CPF. Disrupting ghrelin signaling enhanced expression of PIT. In addition, GHRP-6 [D-Lys3] impaired the initiation of feeding behavior in CPF without influencing overall intake of sucrose. Finally, in PIT tested rats, enhanced FOS immunoreactivity was revealed following the antagonist in regions thought to underlie PIT; however, the antagonist had no effect on FOS immunoreactivity in CPF tested rats. 
26801495	Inhibition (i.e. the ability to restrain ineffective responses to a given stimulus) is a good indicator of complex cognitive abilities in animals. Inhibition has been demonstrated in a broad range of mammals with foraging style and social group size identified as potential influences of this ability. Whether these ecological factors also apply to birds has not been well studied. Corvids, a family of birds well known for being able to accomplish difficult cognitive tasks often requiring inhibition, are a good model for studying inhibitory control. During this study, we measured the ability of Clark's nutcrackers (Nucifraga columbiana), a relatively non-social, food specialist corvid to exercise inhibitory control during a detour-reaching test. Individuals had to retrieve a pine nut inserted into a transparent tube through one of the side openings without pecking directly at the nut from the front of the tube. Overall, nutcrackers were able to inhibit pecking directly at the food (i.e. prepotent response), instead detouring to the side to retrieve the reward. However, the nutcrackers first required a learning period before showing inhibitory control. The nutcrackers' ability to inhibit was lower than other corvids studied to date, and we discuss the implications of this result for the role of sociality and dietary breadth for the evolution of inhibitory control. 
26799161	Past work has demonstrated that the reward positivity (RewP) indexes a performance-monitoring system sensitive to positive outcomes. However, studies have not investigated how approach-motivated states occurring in goal pursuit influence performance monitoring. Using a modified monetary incentive delay task, participants played a reaction time game evoking approach-motivated pregoal (reward trials) or neutral (no-reward trials) states. Then, they received trial feedback resulting in monetary gain or no gain. Results revealed that the RewP was larger to win feedback on reward trials than win or no-win feedback after neutral trials. P3 amplitudes were larger to infrequent feedback than frequent feedback, regardless of trial type or outcome. Furthermore, faster reaction times on reward trials related to larger RewP amplitudes after approach-motivated pregoal states. Approach-motivated pregoal states enhance RewP amplitudes for both successful and unsuccessful goal outcomes. Enhanced performance, as measured by faster reaction times, in approach-motivated pregoal states relates to enhanced performance monitoring. 
26797805	Although valuable objects are attractive in nature, people often encounter situations where they would prefer to avoid such distraction while focusing on the task goal. Contrary to the typical effect of attentional capture by a reward-associated item, we provide evidence for a facilitation effect derived from the active suppression of a high reward-associated stimulus when cuing its identity as distractor before the display of search arrays. Selection of the target is shown to be significantly faster when the distractors were in high reward-associated colour than those in low reward-associated or non-rewarded colours. This behavioural reward effect was associated with two neural signatures before the onset of the search display: the increased frontal theta oscillation and the strengthened top-down modulation from frontal to anterior temporal regions. The former suggests an enhanced working memory representation for the reward-associated stimulus and the increased need for cognitive control to override Pavlovian bias, whereas the latter indicates that the boost of inhibitory control is realized through a frontal top-down mechanism. These results suggest a mechanism in which the enhanced working memory representation of a reward-associated feature is integrated with task demands to modify attentional priority during active distractor suppression and benefit behavioural performance. 

26796789	Animals learn to prefer and increase consumption of flavors paired with postingestive nutrient sensing. Analogous effects have been difficult to observe in human studies. One possibility is experience with the modern, processed diet impairs learning. Food processing manipulates flavor, texture, sweetness, and nutrition, obscuring ordinary correspondences between sensory cues and postingestive consequences. Over time, a diet of these processed 'junk' foods may impair flavor-nutrient learning. This 'flavor-confusion' hypothesis was tested by providing rats long-term exposure to cafeteria diets of unusual breadth (2 or 3 foods per day, 96 different foods over 3 months, plus ad libitum chow). One group was fed processed foods (PF) with added sugars/fats and manipulated flavors, to mimic the sensory-nutrient properties of the modern processed diet. Another group was fed only 'natural' foods (NF) meaning minimally-processed foods without manipulated flavors or added sugars/fats (e.g., fresh fruits, vegetables, whole grains) ostensibly preserving the ordinary correspondence between flavors and nutrition. A CON group was fed chow only. In subsequent tests of flavor-nutrient learning, PF and NF rats consistently acquired strong preferences for novel nutrient-paired flavors and PF rats exhibited enhanced learned acceptance, contradicting the 'flavor-confusion' hypothesis. An unexpected finding was PF and NF diets both caused lasting reduction in ad lib sweet solution intake. Groups did not differ in reinforcing value of sugar in a progressive ratio task. In lick microstructure analysis the NF group paradoxically showed increased sucrose palatability relative to PF and CON, suggesting the diets have different effects on sweet taste evaluation.
26796614	Positive mood can affect a person's tendency to gamble, possibly because positive mood fosters unrealistic optimism. At the same time, unexpected positive outcomes, often called prediction errors, influence mood. However, a linkage between positive prediction errors-the difference between expected and obtained outcomes-and consequent risk taking has yet to be demonstrated. Using a large data set of New York City lottery gambling and a model inspired by computational accounts of reward learning, we found that people gamble more when incidental outcomes in the environment (e.g., local sporting events and sunshine) are better than expected. When local sports teams performed better than expected, or a sunny day followed a streak of cloudy days, residents gambled more. The observed relationship between prediction errors and gambling was ubiquitous across the city's socioeconomically diverse neighborhoods and was specific to sports and weather events occurring locally in New York City. Our results suggest that unexpected but incidental positive outcomes influence risk taking. 
26796595	3,4-Methylenedioxymethamphetamine (MDMA), a methamphetamine (METH) derivative, exhibits METH-like actions at monoamine transporters and positive reinforcing effects in rodents and primates. The purposes of the present study were to determine whether cross-reinstatement would be observed between MDMA and METH and if the cannabinoid receptor, a receptor known to play critical roles in the brain reward system, could modulate MDMA craving.Rats were trained to press a lever for intravenous MDMA (0.3mg/infusion) or METH (0.02mg/infusion) infusions under a fixed ratio 1 schedule paired with drug-associated cues (light and tone). Following drug self-administration acquisition training, rats underwent extinction training (an infusion of saline). Reinstatement tests were performed once the extinction criteria were achieved.	In MDMA-trained rats, the MDMA-priming injection (3.2mg/kg, i.p.) or re-exposure to MDMA-associated cues reinstated MDMA-seeking behavior. Additionally, a priming injection of METH (1.0mg/kg, i.p.) also reinstated MDMA-seeking behavior. In contrast, none of the MDMA doses reinstated METH-seeking behavior in the METH-trained rats. The CB1 cannabinoid receptor antagonist AM251 markedly attenuated the MDMA-seeking behaviors induced by MDMA-priming injection or re-exposure to MDMA-associated cues in a dose-dependent manner.	These findings show that MDMA has obvious addictive potential for reinstating drug-seeking behavior and that METH can be an effective stimulus for reinstating MDMA-seeking behaviors. Furthermore, based on the attenuating effect of AM251 in the reinstatement of MDMA-seeking behaviors, drugs that suppress CB1 receptors may be used in treatment of MDMA dependence.	
26796027	Neuroimaging studies have started to explore the role of food characteristics (e.g., calorie-content) and psychological factors (e.g., restrained eating, craving) for the human appetitive system, motivated by the significant health implications of food-choice, overeating and overweight/obesity. However, one key aspect of modern food environments, food availability, especially of high energy foods, has not been adequately modeled in experimental research. Food that is immediately available for consumption could elicit stronger reward system activity and associated cognitive control than food that is not currently available for consumption and this could vary as a function of energy density. To examine this question, 32 healthy participants (16 women) underwent functional magnetic resonance imaging while passively viewing available foods - i.e. foods that could be eaten during and after the experiment - and unavailable foods of either high or low-caloric density in a 2 × 2 design. Available compared to unavailable foods elicited higher palatability ratings as well as stronger neural activation in the orbitofrontal cortex (OFC), amygdala, and left caudate nucleus as well as in the anterior cingulate cortex (ACC) - and thus structures implicated in reward and appetitive motivation as well as cognitive control, respectively. Availability effects in the caudate were mainly attributable to the high calorie condition (availability × calorie density interaction). These neuroimaging results support the contention that foods are particularly rewarding when immediately available and particularly so when high in caloric density. Thus, our results are consistent with health promoting interventions utilizing a nudging approach, i.e. aiming at decreasing accessibility of high calorie and increasing accessibility of low calorie foods in daily life. Results also imply that controlling/manipulating food availability may be an important methodological aspect in neuroscientific eating research. 
26795580	Reinforcement learning (RL) is a powerful concept underlying forms of associative learning governed by the use of a scalar reward signal, with learning taking place if expectations are violated. RL may be assessed using model-based and model-free approaches. Model-based reinforcement learning involves the amygdala, the hippocampus, and the orbitofrontal cortex (OFC). The model-free system involves the pedunculopontine-tegmental nucleus (PPTgN), the ventral tegmental area (VTA) and the ventral striatum (VS). Based on the functional connectivity of VS, model-free and model based RL systems center on the VS that by integrating model-free signals (received as reward prediction error) and model-based reward related input computes value. Using the concept of reinforcement learning agent we propose that the VS serves as the value function component of the RL agent. Regarding the model utilized for model-based computations we turned to the proactive brain concept, which offers an ubiquitous function for the default network based on its great functional overlap with contextual associative areas. Hence, by means of the default network the brain continuously organizes its environment into context frames enabling the formulation of analogy-based association that are turned into predictions of what to expect. The OFC integrates reward-related information into context frames upon computing reward expectation by compiling stimulus-reward and context-reward information offered by the amygdala and hippocampus, respectively. Furthermore we suggest that the integration of model-based expectations regarding reward into the value signal is further supported by the efferent of the OFC that reach structures canonical for model-free learning (e.g., the PPTgN, VTA, and VS).
26795233	Serious games are becoming popular in various healthcare domains. However, they should be designed to cater toward learners' perspectives, needs, and specifications in order to be used to their full potential in education. This study investigated the gaming experiences, motivations, and preferences of pharmacy students.An anonymous self-administered survey obtained participant demographics, gaming experiences (enjoyment level of different game genres, years of experience, gaming frequency and duration, and motivations), and gaming preferences (on in-game rewards, settings, storylines, perspectives, and styles). Descriptive statistics, t tests, analysis of variance, chi-squared tests, and Fisher's exact tests were used for analysis.	The response rate was 69.1 percent (465/673 undergraduates). Role-playing games (RPGs) (4.12 ± 1.07) and massively multiplayer online RPGs (MMORPGs) (3.81 ± 1.26) had the highest enjoyment ratings. Males enjoyed imagination games (e.g., RPGs, MMORPGs) more than females, whereas females enjoyed simulation games more. Top motivating factors for respondents were progressing to the next level (3.63 ± 1.19), excitement (3.33 ± 1.33), and a feeling of efficacy when playing (3.02 ± 1.16). Unlocking mechanisms (25.2 percent) and experience points (17.6 percent) were the most popular in-game reward systems. Most respondents preferred a fantasy/medieval/mythic setting (59.8 percent) and an adventurer storyline (41.3 percent), with similar proportions preferring competitive (35.3 percent), cooperative (33.3 percent), and collaborative (30.8 percent) game styles.	Different groups of pharmacy students differ in their gaming experiences, motivating factors, and preferences. There is no "one size fits all" game that is suitable for all pharmacy education. Such differences should be considered when developing a pharmacy game in order to cater to the diverse student population.	
26793069	Central thalamic deep brain stimulation (CT-DBS) has been proposed as an experimental therapeutic approach to produce consistent sustained regulation of forebrain arousal for several neurological diseases. We investigated local field potentials (LFPs) induced by CT-DBS from the thalamic central lateral nuclei (CL) and the striatum as potential biomarkers for the enhancement of lever-pressing skill learning. LFPs were simultaneously recorded from multiple sites in the CL, ventral striatum (Vstr), and dorsal striatum (Dstr). LFP oscillation power and functional connectivity were assessed and compared between the CT-DBS and sham control groups. The theta and alpha LFP oscillations were significantly increased in the CL and striatum in the CT-DBS group. Furthermore, interhemispheric coherences between bilateral CL and striatum were increased in the theta band. Additionally, enhancement of c-Fos activity, dopamine D2 receptor (Drd2), and α4-nicotinic acetylcholine receptor (α4-nAChR) occurred after CT-DBS treatment in the striatum and hippocampus. CT-DBS strengthened thalamic-striatal functional connectivity, which demonstrates that the inter-regional connectivity enhancement might contribute to synaptic plasticity in the striatum. Altered dopaminergic and cholinergic receptors resulted in modulation of striatal synaptic plasticity's ability to regulate downstream signaling cascades for higher brain functions of lever-pressing skill learning. 
26792770	Toddlers often go through a picky eating phase, which can make it difficult to introduce new foods into the diet. A better understanding of how parents' prompts to eat fruits and vegetables are related to children's intake of these foods will help promote healthy eating habits. 60 families recorded all toddler meals over one day, plus a meal in which parents introduced a novel fruit/vegetable to the child. Videos were coded for parent and child behaviors. Parents completed a feeding style questionnaire and three 24-h dietary recalls about their children's intake. Parents made, on average, 48 prompts for their children to eat more during the main meals in a typical day, mostly of the neutral type. Authoritarian parents made the most prompts, and used pressure the most often. In the novel food situation, it took an average of 2.5 prompts before the child tasted the new food. The most immediately successful prompt for regular meals across food types was modeling. There was a trend for using another food as a reward to work less well than a neutral prompt for encouraging children to try a novel fruit or vegetable. More frequent prompts to eat fruits and vegetables during typical meals were associated with higher overall intake of these food groups. More prompts for children to try a novel vegetable was associated with higher overall vegetable intake, but this pattern was not seen for fruits, suggesting that vegetable variety may be more strongly associated with intake. Children who ate the most vegetables had parents who used more "reasoning" prompts, which may have become an internalized motivation to eat these foods, but this needs to be tested explicitly using longer-term longitudinal studies. 
26791822	Adolescents make more reckless decisions when with peers than when alone, which poses a challenge for organizations that place adolescents in situations in which risky and myopic decision making is problematic. We asked whether the effect of peers on adolescents' decision making is mitigated by the presence of a slightly older adult. We examined whether target subjects' risk taking was greater when they were in groups of 4 late-adolescent males (ages 18-22) than when they were in groups that mixed 3 late-adolescent males with 1 slightly older adult (age 25-30); risk taking in both of these conditions was compared with that of adolescents tested alone. We found that adolescents took more risks and expressed stronger preference for immediate rewards when they were grouped with 3 same-age peers than when they were alone. When 1 adolescent was replaced by someone slightly older, however, adolescents' decision making and reward processing resembled that seen when adolescents were tested alone. Adding a young adult to a work team of adolescents may improve group decision making. 
26791209	Similar to other addiction disorders, the cues inherent in many gambling procedures are thought to play an important role in mediating their addictive nature. Animal models of gambling-related behavior, while capturing dimensions of economic decision making, have yet to address the impact that these salient cues may have in promoting maladaptive choice. Here, we determined whether adding win-associated audiovisual cues to a rat gambling task (rGT) would influence decision making. Thirty-two male Long-Evans rats were tested on either the cued or uncued rGT. In these tasks, animals chose between four options associated with different magnitudes and frequencies of reward and punishing time-out periods. As in the Iowa Gambling Task, favoring options associated with smaller per-trial rewards but smaller losses and avoiding the tempting "high-risk, high-reward" decks maximized profits. Although the reinforcement contingencies were identical in both task versions, rats' choice of the disadvantageous risky options was significantly greater on the cued task. Furthermore, a D3 receptor agonist increased choice of the disadvantageous options, whereas a D3 antagonist had the opposite effects, only on the cued task. These findings are consistent with the reported role of D3 receptors in mediating the facilitatory effects of cues in addiction. Collectively, these results indicate that the cued rGT is a valuable model with which to study the mechanism by which salient cues can invigorate maladaptive decision making, an important and understudied component of both gambling and substance use disorders. Significance statement: We used a rodent analog of the Iowa Gambling Task to determine whether the addition of audiovisual cues would affect choice preferences. Adding reward-concurrent cues significantly increased risky choice. This is the first clear demonstration that reward-paired cues can bias cost/benefit decision making against a subject's best interests in a manner concordant with elevated addiction susceptibility. Choice on the cued task was uniquely sensitive to modulation by D3 receptor ligands, yet these drugs did not alter decision making on the uncued task. The relatively unprecedented sensitivity of choice on the cued task to D3-receptor-mediated neurotransmission data suggest that similar neurobiological processes underlie the ability of cues to both bias animals toward risky options and facilitate drug addiction.
26788861	Reward-dependent instrumental behavior must continuously be re-adjusted according to environmental conditions. Failure to adapt to changes in reward contingencies may incur psychiatric disorders like anxiety and depression. When an expected reward is omitted, behavior undergoes extinction. While extinction involves active re-learning, it is also accompanied by emotional behaviors indicative of frustration, anxiety, and despair (extinction-induced depression). Here, we report evidence for a sphingolipid mechanism in the extinction of behavior. Rapid extinction, indicating efficient re-learning, coincided with a decrease in the activity of the enzyme acid sphingomyelinase (ASM), which catalyzes turnover of sphingomyelin to ceramide, in the dorsal hippocampus of rats. The stronger the decline in ASM activity, the more rapid was the extinction. Sphingolipid-focused lipidomic analysis showed that this results in a decline of local ceramide species in the dorsal hippocampus. Ceramides shape the fluidity of lipid rafts in synaptic membranes and by that way can control neural plasticity. We also found that aging modifies activity of enzymes and ceramide levels in selective brain regions. Aging also changed how the chronic treatment with corticosterone (stress) or intranasal dopamine modified regional enzyme activity and ceramide levels, coinciding with rate of extinction. These data provide first evidence for a functional ASM-ceramide pathway in the brain involved in the extinction of learned behavior. This finding extends the known cellular mechanisms underlying behavioral plasticity to a new class of membrane-located molecules, the sphingolipids, and their regulatory enzymes, and may offer new treatment targets for extinction- and learning-related psychopathological conditions. Sphingolipids are common lipids in the brain which form lipid domains at pre- and postsynaptic membrane compartments. Here we show a decline in dorsal hippocampus ceramide species together with a reduction of acid sphingomyelinase activity during extinction of conditioned behavior in rats. This reduction was associated with expression of re-learning-related behavior, but not with emotional behaviors. Read the Editorial Highlight for this article on page 485. 
26788716	Chronic pain is an important public health problem that negatively impacts the quality of life of affected individuals and exacts enormous socioeconomic costs. Chronic pain is often accompanied by comorbid emotional disorders including anxiety, depression, and possibly anhedonia. The neural circuits underlying the intersection of pain and pleasure are not well understood. We summarize recent human and animal investigations and demonstrate that aversive aspects of pain are encoded in brain regions overlapping with areas processing reward and motivation. We highlight findings revealing anatomical and functional alterations of reward/motivation circuits in chronic pain. Finally, we review supporting evidence for the concept that pain relief is rewarding and activates brain reward/motivation circuits. Adaptations in brain reward circuits may be fundamental to the pathology of chronic pain. Knowledge of brain reward processing in the context of pain could lead to the development of new therapeutics for the treatment of emotional aspects of pain and comorbid conditions.
26786746	Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take the drug, loss of control in limiting intake and, eventually, the emergence of a negative emotional state when access to the drug is prevented. Both dopamine and corticotropin-releasing factor (CRF)-mediated systems seem to play important roles in the modulation of alcohol abuse and dependence. The present study investigated the effects of alcohol consumption on anxiety and locomotor parameters and on the activation of dopamine and CRF-innervated brain regions. Male Wistar rats were given a choice of two bottles for 31 days, one containing water and the other a solution of saccharin + alcohol. Control animals only received water and a solution of 0.2% saccharin. On the 31st day, animals were tested in the elevated plus-maze and open field, and euthanized immediately after the behavioral tests. An independent group of animals was treated with ethanol and used to measure blood ethanol concentration. Results showed that alcohol intake did not alter behavioral measurements in the plus-maze, but increased the number of crossings in the open field, an index of locomotor activity. Additionally, alcohol intake increased Fos-immunoreactivity (Fos-ir) in the prefrontal cortex, in the shell region of the nucleus accumbens, in the medial and central amygdala, in the bed nucleus of the stria terminalis, in the septal region, and in the paraventricular and dorsomedial hypothalamus, structures that have been linked to reward and to approach/withdrawal behavior. These observations might be relevant to a better understanding of the behavioral and physiological alterations that follow alcohol consumption.
26786412	The psychostimulant properties of caffeine are reviewed and compared with those of prototypical psychostimulants able to cause substance use disorders (SUD). Caffeine produces psychomotor-activating, reinforcing, and arousing effects, which depend on its ability to disinhibit the brake that endogenous adenosine imposes on the ascending dopamine and arousal systems.A model that considers the striatal adenosine A2A-dopamine D2 receptor heteromer as a key modulator of dopamine-dependent striatal functions (reward-oriented behavior and learning of stimulus-reward and reward-response associations) is introduced, which should explain most of the psychomotor and reinforcing effects of caffeine.	The model can explain the caffeine-induced rotational behavior in rats with unilateral striatal dopamine denervation and the ability of caffeine to reverse the adipsic-aphagic syndrome in dopamine-deficient rodents. The model can also explain the weaker reinforcing effects and low abuse liability of caffeine, compared with prototypical psychostimulants. Finally, the model can explain the actual major societal dangers of caffeine: the ability of caffeine to potentiate the addictive and toxic effects of drugs of abuse, with the particularly alarming associations of caffeine (as adulterant) with cocaine, amphetamine derivatives, synthetic cathinones, and energy drinks with alcohol, and the higher sensitivity of children and adolescents to the psychostimulant effects of caffeine and its potential to increase vulnerability to SUD.	The striatal A2A-D2 receptor heteromer constitutes an unequivocal main pharmacological target of caffeine and provides the main mechanisms by which caffeine potentiates the acute and long-term effects of prototypical psychostimulants.	
26786151	The results of research about the influences of impulsivity on decision-making in situations of risk have been inconsistent. In this study, we used functional magnetic resonance imaging to examine the neural correlates of decision-making under risk in 12 impulsive, as defined by the Barratt Impulsiveness Scale-11, and 13 normal men. Although both groups showed similar decision-making behavior, neural activation regarding decision-making processes differed significantly. Impulsive persons revealed stronger activation in the (ventro-) medial prefrontal cortex and less deactivation of the orbitofrontal cortex while playing for potential gains. These brain regions might be associated with the emotional components of decision-making processes. Significant differences in brain areas linked to cognitive decision-making components were not found. This activation pattern might be seen as an indication for a hypersensitivity to rewarding cues in impulsive persons and might be linked to the propensity for inappropriate risk-taking behavior in persons with more extreme impulsivity levels, especially in situations in which they have a strong emotional involvement in the decision process. 
26785520	The basal ganglia are key neural substrates that control not only motor balance but also emotion, motivation, cognition, learning, and decision-making. Dysfunction of the basal ganglia leads to neurodegenerative diseases (e.g. Parkinson's disease and Huntington's disease) and psychiatric disorders (e.g. drug addiction, schizophrenia, and depression). In the basal ganglia circuit, there are two important pathways: the direct and indirect striatal pathways. Recently, new molecular techniques that activate or inactive selectively the direct or indirect pathway neurons have revealed the function of each pathway. Here we review the distinct roles of the direct and indirect striatal pathways in brain function and drug addiction. We have developed a reversible neurotransmission blocking technique, in which transmission of each pathway is selectively blocked by specific expression of transmission-blocking tetanus toxin, and revealed that the activation of D1 receptors in the direct pathway is critical for reward learning/cocaine addiction, and that the inactivation of D2 receptors is critical for aversive learning/learning flexibility. We propose a new circuit mechanism by which the dopaminergic input from the ventral tegmental area can switch the direct and indirect pathways in the nucleus accumbens. These basal ganglia circuit mechanisms will give us insights into the pathophysiology of mental diseases.
26783880	Curiosity drives many of our daily pursuits and interactions; yet, we know surprisingly little about how it works. Here, we harness an idea implied in many conceptualizations of curiosity: that information has value in and of itself. Reframing curiosity as the motivation to obtain reward-where the reward is information-allows one to leverage major advances in theoretical and computational mechanisms of reward-motivated learning. We provide new evidence supporting 2 predictions that emerge from this framework. First, we find an asymmetric effect of positive versus negative information, with positive information enhancing both curiosity and long-term memory for information. Second, we find that it is not the absolute value of information that drives learning but, rather, the gap between the reward expected and reward received, an "information prediction error." These results support the idea that information functions as a reward, much like money or food, guiding choices and driving learning in systematic ways.
26783525	Individuals typically evaluate whether their performance and the obtained feedback match. Previous research has shown that feedback negativity (FN) depends on outcome probability and feedback valence. It is, however, less clear to what extent previous effects of outcome probability on FN depend on self-evaluations of response correctness. Therefore, we investigated the effects of outcome probability on FN amplitude in a simple go/no-go task that allowed for the self-evaluation of response correctness. We also investigated effects of performance incompatibility and feedback valence. In a sample of N = 22 participants, outcome probability was manipulated by means of precues, feedback valence by means of monetary feedback, and performance incompatibility by means of feedback that induced a match versus mismatch with individuals' performance. We found that the 100% outcome probability condition induced a more negative FN following no-loss than the 50% outcome probability condition. The FN following loss was more negative in the 50% compared to the 100% outcome probability condition. Performance-incompatible loss resulted in a more negative FN than performance-compatible loss. Our results indicate that the self-evaluation of the correctness of responses should be taken into account when the effects of outcome probability and expectation mismatch on FN are investigated. 
26781058	We tested two pigeons in a continuously streaming digital environment. Using animation software that constantly presented a dynamic, three-dimensional (3D) environment, the animals were tested with a conditional object identification task. The correct object at a given time depended on the virtual context currently streaming in front of the pigeon. Pigeons were required to accurately peck correct target objects in the environment for food reward, while suppressing any pecks to intermixed distractor objects which delayed the next object's presentation. Experiment 1 established that the pigeons' discrimination of two objects could be controlled by the surface material of the digital terrain. Experiment 2 established that the pigeons' discrimination of four objects could be conjunctively controlled by both the surface material and topography of the streaming environment. These experiments indicate that pigeons can simultaneously process and use at least two context cues from a streaming environment to control their identification behavior of passing objects. These results add to the promise of testing interactive digital environments with animals to advance our understanding of cognition and behavior.
26781055	It is well known that when humans are given a choice between two options, their preference is affected by the presence of a third. Generally, there is an increase in preference for the option closer to the third. We show that a shift in preference in the direction away from the third option can occur in animals. We gave pigeons a choice between A, reinforcement following 10 pecks and a 0.5-s delay, and B, reinforcement following 5 pecks and a 1.5-s delay. Once stable preferences were established, we introduced a third stimulus, less preferred than the other two: C, reinforcement following 20 pecks and a 0.5-s delay or D, reinforcement following 5 pecks and a 4.5-s delay. We found that pigeons presented with C showed an increased preference for B, whereas pigeons presented with D showed an increased preference for A. Our results were consistent with the similarity or attentional hypothesis, which suggests that the third option should interfere with the option more similar to it or would draw attention to the less preferred component of the third option and generalize to the option more similar to it. Possible accounts for the differences in outcomes are suggested.
26781050	Pigeons and other animals sometimes deviate from optimal choice behavior when given informative signals for delayed outcomes. For example, when pigeons are given a choice between an alternative that always leads to food after a delay and an alternative that leads to food only half of the time after a delay, preference changes dramatically depending on whether the stimuli during the delays are correlated with (signal) the outcomes or not. With signaled outcomes, pigeons show a much greater preference for the suboptimal alternative than with unsignaled outcomes. Key variables and research findings related to this phenomenon are reviewed, including the effects of durations of the choice and delay periods, probability of reinforcement, and gaps in the signal. We interpret the available evidence as reflecting a preference induced by signals for good news in a context of uncertainty. Other explanations are briefly summarized and compared.
26780509	Cholinergic neurotransmission affects decision-making, notably through the modulation of perceptual processing in the cortex. In addition, acetylcholine acts on value-based decisions through as yet unknown mechanisms. We found that nicotinic acetylcholine receptors (nAChRs) expressed in the ventral tegmental area (VTA) are involved in the translation of expected uncertainty into motivational value. We developed a multi-armed bandit task for mice with three locations, each associated with a different reward probability. We found that mice lacking the nAChR β2 subunit showed less uncertainty-seeking than their wild-type counterparts. Using model-based analysis, we found that reward uncertainty motivated wild-type mice, but not mice lacking the nAChR β2 subunit. Selective re-expression of the β2 subunit in the VTA was sufficient to restore spontaneous bursting activity in dopamine neurons and uncertainty-seeking. Our results reveal an unanticipated role for subcortical nAChRs in motivation induced by expected uncertainty and provide a parsimonious account for a wealth of behaviors related to nAChRs in the VTA expressing the β2 subunit. 
26779747	Delay discounting refers to a decline in the value of a reward when it is delayed relative to when it is immediately available. Delay discounting tasks are used to identify indifference points, which reflect equal preference for two dichotomous reward alternatives differing in both delay and magnitude. Indifference points are key to assessing the shape of a delay-discounting gradient because they allow us to isolate the effect of delay on value. For example, if at a 1 week delay and a maximum of $1,000, the indifference point is at $700 we know that, for that participant, a 1-week delay corresponds to a 30% reduction in value. This video outlines an adjusting amount delay-discounting task that identifies indifference points relatively quickly and is inexpensive and easy to administer. Once data have been collected, non-linear regression techniques are typically used to generate discounting curves. The steepness of the discounting curve reflects the degree of impulsive choice of a group or individual. These techniques have been used with a wide range of commodities and have identified populations that are relatively impulsive. For example, people with substance abuse problems discount delayed rewards more steeply than control participants. Although degree of discounting varies as a function of the commodity examined, discounting of one commodity correlates with discounting of other commodities, which suggests that discounting may be a persistent pattern of behavior(1). 
26779054	We hypothesized that embedding educational learning in a game would improve learning outcomes, with increased engagement and recruitment of cognitive resources evidenced by increased activation of working memory network (WMN) and deactivation of default mode network (DMN) regions. In an fMRI study, we compared activity during periods of learning in three conditions that were increasingly game-like: Study-only (when periods of learning were followed by an exemplar question together with its correct answer), Self-quizzing (when periods of learning were followed by a multiple choice question in return for a fixed number of points) and Game-based (when, following each period of learning, participants competed with a peer to answer the question for escalating, uncertain rewards). DMN hubs deactivated as conditions became more game-like, alongside greater self-reported engagement and, in the Game-based condition, higher learning scores. These changes did not occur with any detectable increase in WMN activity. Additionally, ventral striatal activation was associated with responding to questions and receiving positive question feedback. Results support the significance of DMN deactivation for educational learning, and are aligned with recent evidence suggesting DMN and WMN activity may not always be anti-correlated. 
26778996	Emotion-related areas of the brain, such as the medial frontal cortices, amygdala, and striatum, are activated during listening to sad or happy music as well as during listening to pleasurable music. Indeed, in music, like in other arts, sad and happy emotions might co-exist and be distinct from emotions of pleasure or enjoyment. Here we aimed at discerning the neural correlates of sadness or happiness in music as opposed those related to musical enjoyment. We further investigated whether musical expertise modulates the neural activity during affective listening of music. To these aims, 13 musicians and 16 non-musicians brought to the lab their most liked and disliked musical pieces with a happy and sad connotation. Based on a listening test, we selected the most representative 18 sec excerpts of the emotions of interest for each individual participant. Functional magnetic resonance imaging (fMRI) recordings were obtained while subjects listened to and rated the excerpts. The cortico-thalamo-striatal reward circuit and motor areas were more active during liked than disliked music, whereas only the auditory cortex and the right amygdala were more active for disliked over liked music. These results discern the brain structures responsible for the perception of sad and happy emotions in music from those related to musical enjoyment. We also obtained novel evidence for functional differences in the limbic system associated with musical expertise, by showing enhanced liking-related activity in fronto-insular and cingulate areas in musicians. 
26774978	Activation of the immune system due to infection or aging is increasingly linked to impaired neuropsychological function. Toll-like receptors 2 and 4 (TLR2, TLR4) are well-characterised for their role in inflammatory events, and their combined activation has been implicated in neurological diseases. We therefore determined whether TLR2 and TLR4 double gene knockout (GKO) mice showed modified behaviour and cognitive function during a 16-day test sequence that employed the automated IntelliCage test system. The IntelliCage features a home cage environment in which groups of mice live and where water reward is gained through performing various tasks centred on drinking stations in each corner of the apparatus. All mice were tested twice, one month apart (the first sequence termed "R1"and the second "R2"). There were fewer corner visits and nosepokes in TLR2/4 GKO compared to wild-type mice during early exploration in R1, suggesting elevated neophobia in GKO mice. Reduced exploration persisted over subsequent test modules during the dark phase. TLR2/4 GKO mice also displayed increased corner visits during drinking sessions compared to non-drinking sessions, but this was not associated with increased drinking. In subsequent, more complex test modules, TLR2/4 GKO mice had unimpaired spatial learning, but showed markedly poorer performance in a visual discrimination reversal task compared to wild-type mice. These results indicated subtle impairments in behaviour and cognitive functions due to double deficiency in TLR2 and TLR4. These finding are highly relevant to understanding the combined actions of TLR2 and TLR4 on neurological status in a range of different disease conditions. 
26774464	Decision making under risk involves balancing the potential of gaining rewards with the possibility of loss and/or punishment. Tolerance to risk varies between individuals. Understanding the biological basis of risk tolerance is pertinent because excessive tolerance contributes to adverse health and safety outcomes. Yet, not much is known about biological factors mediating inter-individual variability in this regard. We investigate if latent Toxoplasma gondii infection can cause risk tolerance. Using a rodent model of the balloon analogous risk task, we show that latent T. gondii infection leads to a greater tolerance of reward forfeiture. Furthermore, effects of the infection on risk can be recapitulated with testosterone supplementation alone, demonstrating that greater testosterone synthesis by the host post-infection is sufficient to change risk tolerance. T. gondii is a frequent parasite of humans and animals. Thus, the infection status can potentially explain some of the inter-individual variability in the risky decision making. 
26774291	According to the dual systems perspective, risk taking peaks during adolescence because activation of an early-maturing socioemotional-incentive processing system amplifies adolescents' affinity for exciting, pleasurable, and novel activities at a time when a still immature cognitive control system is not yet strong enough to consistently restrain potentially hazardous impulses. We review evidence from both the psychological and neuroimaging literatures that has emerged since 2008, when this perspective was originally articulated. Although there are occasional exceptions to the general trends, studies show that, as predicted, psychological and neural manifestations of reward sensitivity increase between childhood and adolescence, peak sometime during the late teen years, and decline thereafter, whereas psychological and neural reflections of better cognitive control increase gradually and linearly throughout adolescence and into the early 20s. While some forms of real-world risky behavior peak at a later age than predicted, this likely reflects differential opportunities for risk-taking in late adolescence and young adulthood, rather than neurobiological differences that make this age group more reckless. Although it is admittedly an oversimplification, as a heuristic device, the dual systems model provides a far more accurate account of adolescent risk taking than prior models that have attributed adolescent recklessness to cognitive deficiencies. 
26774181	Recent work has suggested separate developmental periods within the broader framework of adolescence, with data suggesting distinct alterations and vulnerabilities within these intervals. While previous research has suggested reduced sensitivity to the aversive effects of alcohol in adolescence relative to adults, a more detailed ontogeny of this effect has yet to be conducted. The adolescent brain undergoes significant transitions throughout adolescence, including in regions linked with drug reward and aversion. The current study aimed to determine the ontogeny of ethanol aversion by utilizing a conditioned taste aversion procedure at six different ages to test the hypothesis that the transitions into, through, and out of adolescence are associated with ontogenetic alterations in sensitivity to the aversive properties of ethanol. Non-deprived animals given Boost® as the conditioned stimulus (CS) were used in Experiment 1, whereas Experiment 2 used water-restricted animals provided with a saccharin/sucrose solution as the CS. In both experiments, an attenuated sensitivity to the aversive properties of ethanol was evident in adolescents compared to adults, although more age differences were apparent in water deprived animals than when a highly palatable CS was given to ad libitum animals. Overall, the data suggest an attenuated sensitivity to the aversive properties of ethanol that is most pronounced during pre- and early adolescence, declining thereafter to reach the enhanced aversive sensitivity of adults. 
26772873	High reward sensitivity has been linked with motivational and cognitive disorders related with prefrontal and striatal brain function during inhibitory control. However, few studies have analyzed the interaction among reward sensitivity, task performance and neural activity. Participants (N=57) underwent fMRI while performing a Go/No-go task with Frequent-go (77.5%), Infrequent-go (11.25%) and No-go (11.25%) stimuli. Task-associated activity was found in inhibition-related brain regions, with different activity patterns for right and left inferior frontal gyri (IFG): right IFG responded more strongly to No-go stimuli, while left IFG responded similarly to all infrequent stimuli. Reward sensitivity correlated with omission errors in Go trials and reaction time (RT) variability, and with increased activity in right and left IFG for No-go and Infrequent-go stimuli compared with Frequent-go. Bilateral IFG activity was associated with RT variability, with reward sensitivity mediating this association. These results suggest that reward sensitivity modulates behavior and brain function during executive control. 
26772761	There is growing appreciation that various aspects of learning and memory are strongly influenced by dopamine neurotransmission, and that zebrafish hold particular promise in the study of neurotransmitter systems. In this study, we sought to investigate the effect of dopamine receptors on acquisition and consolidation of memory in zebrafish using a latent learning paradigm. To this end, fish were subjected to a 30 min training trial each day for 16 days during which fish were allowed to freely explore a complex maze with the left or right path blocked and without the presence of a reward. During 16 days fish were treated with dopaminergic agonists (apomorphine, SKF-38393, and quinpirole) and antagonists (SCH-23390 and eticlopride) before or after training trials. To assess cognitive performance of fish, a subsequent probe trial was performed on day 17 while all paths leading to a reward chamber were open and the maze now contained stimulus fish as a reward. Pre- and post-training exposure to apomorphine, SKF-38393, and quinpirole significantly impaired learning and memory in fish. In contrast, fish exposed to eticlopride before and after training exhibited improved performance in a latent learning task. Administration of SCH-23390 before training did not affect zebrafish learning ability, but produced significant memory enhancement when given after training trials. Taken together, these findings are the first indications that D1 and D2 receptors are critically involved in acquisition and consolidation of latent learning in zebrafish, with a more prominent role for D2 receptors. The current study opens the door to future studies to investigate the involvement of dopamine receptors in various aspects of cognitive processes.
26772145	Developmental studies indicate that children rely more on external feedback than adults. Some of these studies claim that they additionally show higher sensitivity toward positive feedback, while others find they preferably use negative feedback for learning. However, these studies typically did not disentangle feedback valence and expectancy, which might contribute to the controversial results. The present study aimed at examining the neurophysiological correlates of feedback processing in children (8-10 years) and adolescents (12-14 years) in a time estimation paradigm that allows separating the contribution of valence and expectancy. Our results show that in the feedback-related negativity (FRN), an event-related potential (ERP) reflecting the fast initial processing of feedback stimuli, children and adolescents did not differentiate between unexpected positive and negative feedback. Thus, they did not show higher sensitivity to positive feedback. The FRN did also not differentiate between expected and unexpected feedback, as found for adults. In contrast, in a later processing stage mirrored in the P300 component of the ERP, children and adolescents processed the feedback's unexpectedness. Interestingly, adolescents with better behavioral adaptation (high-performers) also had a more frontal P300 expectancy effect. Thus, the recruitment of additional frontal brain regions might lead to better learning from feedback in adolescents. 
26771832	Reward-processing abnormalities are thought to be a key feature of various psychiatric disorders and may also play a role in disruptive mood dysregulation disorder (DMDD), a new diagnosis in DSM-5. In the current study, we used event-related potentials (ERP) sensitive to monetary gains (i.e., the reward positivity [RewP]) and losses (i.e., the N200) to examine associations between symptoms of DMDD during early childhood and later reward processing during preadolescence.To assess early emerging DMDD symptoms in a large longitudinal community sample (n=373) of 3-year old children, we administered a diagnostic interview, Preschool Age Psychiatric Assessment (PAPA) with parents. At a later assessment, ∼6 years later, children completed a monetary reward task while an electroencephalogram (EEG) was recorded. Children's lifetime history of psychopathology was also assessed at that time using Kiddie-Schedule of Affective Disorders and Schizophrenia (K-SADS) with the child and parent.	Multiple regression analyses revealed that age 3 DMDD symptoms predicted an enhanced RewP to monetary rewards in preadolescence. This association is independent of demographics and lifetime history of symptoms of depression, any anxiety disorder, attention-deficit disorder, oppositional defiant disorder, or conduct disorder Conclusions: Early manifestations of DMDD in children as young as 3 years old predicted enhanced reward processing later in development. These findings add to the growing corpus of literature on the pathophysiology of DMDD, and underscore the predictive validity of preschool DMDD on a neural level.	
26771250	During adolescence there is a normative increase in risk-taking behavior, which is reflected in, for example, increases in alcohol consumption. Prior research has demonstrated a link between testosterone and alcohol consumption, and between testosterone and neural responses to rewards. Yet, no study to date tested how testosterone levels and neural responses to rewards relate to and predict individual differences in alcohol use. The current study aimed to investigate this by assessing alcohol use, testosterone levels and neural responses to rewards in adolescents (12-17 years old) and young adults (18-26 years old). Participants were measured twice with a two-year interval between testing sessions. Cross-sectional analysis showed that at the second time point higher neural activity to rewards, but not testosterone levels, explained significant variance above age in reported alcohol use. Predictive analyses showed that, higher testosterone level at the first time point, but not neural activity to rewards at the first time point, was predictive of more alcohol use at the second time point. These results suggest that neural responses to rewards are correlated with current alcohol consumption, and that testosterone level is predictive of future alcohol consumption. These results are interpreted in the context of trajectory models of adolescent development. 
26768421	Assessment of consulting skills using simulated patients is widespread in medical education. Most research into such assessment is sited in a statistical paradigm that focuses on psychometric properties or replicability of such tests. Equally important, but less researched, is the question of how far consultations with simulated patients reflect real clinical encounters--for which sociolinguistics, defined as the study of language in its socio-cultural context, provides a helpful analytic lens.In this debate article, we draw on a detailed empirical study of assessed role-plays, involving sociolinguistic analysis of talk in OSCE interactions. We consider critically the evidence for the simulated consultation (a) as a proxy for the real; (b) as performance; (c) as a context for assessing talk; and (d) as potentially disadvantaging candidates trained overseas. Talk is always a performance in context, especially in professional situations (such as the consultation) and institutional ones (the assessment of professional skills and competence). Candidates who can handle the social and linguistic complexities of the artificial context of assessed role-plays score highly--yet what is being assessed is not real professional communication, but the ability to voice a credible appearance of such communication. Fidelity may not be the primary objective of simulation for medical training, where it enables the practising of skills. However the linguistic problems and differences that arise from interacting in artificial settings are of considerable importance in assessment, where we must be sure that the exam construct adequately embodies the skills expected for real-life practice. The reproducibility of assessed simulations should not be confused with their validity. Sociolinguistic analysis of simulations in various professional contexts has identified evidence for the gap between real interactions and assessed role-plays. The contextual conditions of the simulated consultation both expect and reward a particular interactional style. Whilst simulation undoubtedly has a place in formative learning for professional communication, the simulated consultation may distort assessment of professional communication These sociolinguistic findings contribute to the on-going critique of simulations in high-stakes assessments and indicate that further research, which steps outside psychometric approaches, is necessary.	
26768226	The neural mechanisms whereby a reward-associated stimulus gains reinforcing properties and comes to function as a conditioned reward (CR) are not understood. We propose that muscarinic acetylcholine (mACh) receptor stimulation is necessary for this type of learning. Here we tested the hypothesis that mACh receptor antagonism, with scopolamine, would attenuate the acquisition by a food-related stimulus of the capacity to function as a CR. Rats were exposed to 5 pre-exposure sessions during which two levers were present, one producing a light and the other a tone when pressed. This was followed by 3 conditioning sessions in which the levers were absent and the rats were presented with 30 light-food pairings delivered randomly. In the test session, the levers were present and presses on both levers were recorded. Different groups of rats received intraperitoneal injections of scopolamine (0, 0.375, 0.75 and 1mg/kg) either prior to each conditioning session or prior to the test session. All groups showed significantly greater responding on the light lever in the test compared to the pre-exposure sessions, demonstrating the CR effect. In animals treated prior to conditioning the scopolamine groups pressed significantly less on the light lever than the vehicle group. In animals treated prior to the test the increased lever pressing for light was similar for all groups. These data suggest that scopolamine impaired the acquisition of CR but not its expression. The results support the hypothesis that mACh receptor stimulation is important for the acquisition by reward-associated stimuli of the ability to function as CRs. 
26765948	Previous studies on the neurophysiological underpinnings of feedback processing almost exclusively used low-ambiguity feedback, which does not fully address the diversity of situations in everyday life. We therefore used a pseudo trial-and-error learning task to investigate ERPs of low- versus high-ambiguity feedback. Twenty-eight participants tried to deduce the rule governing visual feedback to their button presses in response to visual stimuli. In the blocked condition, the same two feedback words were presented across several consecutive trials, whereas in the random condition feedback was randomly drawn on each trial from sets of five positive and five negative words. The feedback-related negativity (FRN-D), a frontocentral ERP difference between negative and positive feedback, was significantly larger in the blocked condition, whereas the centroparietal late positive complex indicating controlled attention was enhanced for negative feedback irrespective of condition. Moreover, FRN-D in the blocked condition was due to increased reward positivity (Rew-P) for positive feedback, rather than increased (raw) FRN for negative feedback. Our findings strongly support recent lines of evidence that the FRN-D, one of the most widely studied signatures of reinforcement learning in the human brain, critically depends on feedback discriminability and is primarily driven by the Rew-P. A novel finding concerned larger frontocentral P2 for negative feedback in the random but not the blocked condition. Although Rew-P points to a positivity bias in feedback processing under conditions of low feedback ambiguity, P2 suggests a specific adaptation of information processing in case of highly ambiguous feedback, involving an early negativity bias. Generalizability of the P2 findings was demonstrated in a second experiment using explicit valence categorization of highly emotional positive and negative adjectives.
26763779	As the major input to the basal ganglia, the striatum is innervated by a wide range of other areas. Overlapping input from these regions is speculated to influence temporal correlations among striatal ensembles. However, the network dynamics among behaviorally related neural populations in the striatum has not been extensively studied. We used large-scale neural recordings to monitor activity from striatal ensembles in mice undergoing Pavlovian reward conditioning. A subpopulation of putative medium spiny projection neurons (MSNs) was found to discriminate between cues that predicted the delivery of a reward and cues that predicted no specific outcome. These cells were preferentially located in lateral subregions of the striatum. Discriminating MSNs were more spontaneously active and more correlated than their nondiscriminating counterparts. Furthermore, discriminating fast spiking interneurons (FSIs) represented a highly prevalent group in the recordings, which formed a strongly correlated network with discriminating MSNs. Spike time cross-correlation analysis showed the existence of synchronized activity among FSIs and feedforward inhibitory modulation of MSN spiking by FSIs. These findings suggest that populations of functionally specialized (cue-discriminating) striatal neurons have distinct network dynamics that sets them apart from nondiscriminating cells, potentially to facilitate accurate behavioral responding during associative reward learning.
26763695	Time is an extremely valuable resource but little is known about the efficiency of time allocation in decision-making. Empirical evidence suggests that in many ecologically relevant situations, decision difficulty and the relative reward from making a correct choice, compared to an incorrect one, are inversely linked, implying that it is optimal to use relatively less time for difficult choice problems. This applies, in particular, to value-based choices, in which the relative reward from choosing the higher valued item shrinks as the values of the other options get closer to the best option and are thus more difficult to discriminate. Here, we experimentally show that people behave sub-optimally in such contexts. They do not respond to incentives that favour the allocation of time to choice problems in which the relative reward for choosing the best option is high; instead they spend too much time on problems in which the reward difference between the options is low. We demonstrate this by showing that it is possible to improve subjects' time allocation with a simple intervention that cuts them off when their decisions take too long. Thus, we provide a novel form of evidence that organisms systematically spend their valuable time in an inefficient way, and simultaneously offer a potential solution to the problem. 
26763628	Negative symptoms like avolition and anhedonia are thought to involve difficulties with reward processing and motivation. The current study aimed to replicate and extend prior findings that individuals with schizophrenia display reduced willingness to expend effort for rewards and that such reduced effort is associated with negative symptoms, poor functioning, and cognitive impairment. The present study compared the effortful decision making of individuals with schizophrenia (n=48) and healthy controls (n=27) on the Effort Expenditure for Rewards Task (EEfRT). Individuals with schizophrenia chose a smaller proportion of hard tasks than healthy controls across all probability and reward levels with the exception of trials with a 12% probability and low or medium reward magnitude wherein both groups chose similarly few hard tasks. Contrary to expectations, in individuals with schizophrenia, greater negative symptoms were associated with making more effortful choices. Effortful decision making was unrelated to positive symptoms, depression, cognition, and functioning in individuals with schizophrenia. Our results are consistent with prior findings that revealed a pattern of inefficient decision making in individuals with schizophrenia relative to healthy controls. However the results did not support the hypothesized association of negative symptoms and reduced effort in schizophrenia and highlight prior inconsistencies in this literature. Future research is needed to understand what factors may be related to diminished effortful decision making in schizophrenia and the clinical significance of such performance deficits. 
26763483	Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction. 
26763116	The ventral tegmental area (VTA) is an evolutionarily conserved structure that has roles in reward-seeking, safety-seeking, learning, motivation, and neuropsychiatric disorders such as addiction and depression. The involvement of the VTA in these various behaviors and disorders is paralleled by its diverse signaling mechanisms. Here we review recent advances in our understanding of neuronal diversity in the VTA with a focus on cell phenotypes that participate in 'multiplexed' neurotransmission involving distinct signaling mechanisms. First, we describe the cellular diversity within the VTA, including neurons capable of transmitting dopamine, glutamate or GABA as well as neurons capable of multiplexing combinations of these neurotransmitters. Next, we describe the complex synaptic architecture used by VTA neurons in order to accommodate the transmission of multiple transmitters. We specifically cover recent findings showing that VTA multiplexed neurotransmission may be mediated by either the segregation of dopamine and glutamate into distinct microdomains within a single axon or by the integration of glutamate and GABA into a single axon terminal. In addition, we discuss our current understanding of the functional role that these multiplexed signaling pathways have in the lateral habenula and the nucleus accumbens. Finally, we consider the putative roles of VTA multiplexed neurotransmission in synaptic plasticity and discuss how changes in VTA multiplexed neurons may relate to various psychopathologies including drug addiction and depression. 
26762379	Increased activity of prefrontal D1 dopamine receptors (D1R) is involved in reward-related behavior found in bipolar disorder and drug addiction. While the effects of elevated D1R are known, depressive-like behaviors also occur in these disorders after reward-seeking ends.The goal is to characterize how termination of D1R overexpression influences depressive-like behaviors.	An inducible (Tet.On), lentiviral vector was used to manipulate the expression of the DRD1 gene in glutamate neurons within the prefrontal cortex in male, adult rats. Sexual activity and sucrose preference were studied in both D1R elevated ON and relatively reduced OFF states. Following termination of the D1R ON state, depressive-like behavior was determined in the OFF state. Expression of the transcriptional regulator, cyclic AMP-responsive element-binding protein (CREB), was used as an indication of downstream effects in the nucleus accumbens (NA).	ON D1R expression increased sexual activity that returned to baseline in the OFF state. Sucrose preferences increased ~6 % in ON state but fell 11 % below control levels when OFF. Consistent with a depressive-like phenotype, D1R OFF decreased activity by 40 %, impaired the ability to control (43 %) and motivation to escape shock (27 % more impaired) relative to dsRed OFF. CREB increased 29 % in the NA in the D1R OFF state relative to the ON state.	This novel approach demonstrates that elevated D1R expression increased hedonic behavior, whereas the termination of D1R overexpression often resulted in depressive-like behavior. These observations support a role for D1R expression cycling in bipolar-associated behaviors and addiction.	
26762310	Adolescence is a critical period characterized by major neurobiological changes. Chronic stimulation of the reward system might constitute an important factor in vulnerability to pathological development. In spite of the dramatic increase in the consumption of sweet palatable foods during adolescence in our modern societies, the long-term consequences of such exposure on brain reward processing remain poorly understood. Here, we investigated in rats the long-lasting effects of sugar overconsumption during their adolescence on their adult reactivity to the hedonic properties of sweet rewards. Adolescent rats with continuous access to 5% sucrose solution (from postnatal day 30-46) showed escalating intake. At adulthood (post-natal day 70), using two-bottle free choice tests, sucrose-exposed rats showed lower intake than non-exposed rats suggesting decreased sensitivity to the rewarding properties of sucrose. In Experiment 1, we tested their hedonic-related orofacial reactions to intraoral infusion of tasty solutions. We showed that sucrose-exposed rats presented less hedonic reactions in response to sweet tastes leaving the reactivity to water or quinine unaltered. Hence, in Experiment 2, we observed that this hedonic deficit is associated with lower c-Fos expression levels in the nucleus accumbens, a brain region known to play a central role in hedonic processing. These findings demonstrate that a history of high sucrose intake during the critical period of adolescence induces long-lasting deficits in hedonic treatment that may contribute to reward-related disorders. 
26758844	The ventral striatum is critical for evaluating reward information and the initiation of goal-directed behaviors. The many cellular, afferent, and efferent similarities between the ventral striatum's nucleus accumbens and olfactory tubercle (OT) suggests the distributed involvement of neurons within the ventral striatopallidal complex in motivated behaviors. Although the nucleus accumbens has an established role in representing goal-directed actions and their outcomes, it is not known whether this function is localized within the nucleus accumbens or distributed also within the OT. Answering such a fundamental question will expand our understanding of the neural mechanisms underlying motivated behaviors. Here we address whether the OT encodes natural reinforcers and serves as a substrate for motivational information processing. In recordings from mice engaged in a novel water-motivated instrumental task, we report that OT neurons modulate their firing rate during initiation and progression of the instrumental licking behavior, with some activity being internally generated and preceding the first lick. We further found that as motivational drive decreases throughout a session, the activity of OT neurons is enhanced earlier relative to the behavioral action. Additionally, OT neurons discriminate the types and magnitudes of fluid reinforcers. Together, these data suggest that the processing of reward information and the orchestration of goal-directed behaviors is a global principle of the ventral striatum and have important implications for understanding the neural systems subserving addiction and mood disorders.Goal-directed behaviors are widespread among animals and underlie complex behaviors ranging from food intake, social behavior, and even pathological conditions, such as gambling and drug addiction. The ventral striatum is a neural system critical for evaluating reward information and the initiation of goal-directed behaviors. Here we show that neurons in the olfactory tubercle subregion of the ventral striatum robustly encode the onset and progression of motivated behaviors, and discriminate the type and magnitude of a reward. Our findings are novel in showing that olfactory tubercle neurons participate in such coding schemes and are in accordance with the principle that ventral striatum substructures may cooperate to guide motivated behaviors.	
26758824	The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate the consumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloric intake and produced weight gain in mice that had access to a high-fat diet, while not altering general locomotor activity. Anterior LHA glutamatergic neurons send a functional glutamatergic projection to the LHb, a brain region involved in processing aversive stimuli and negative reward prediction outcomes. Pathway-specific, optogenetic stimulation of glutamatergic LHA-LHb circuit resulted in detectable glutamate-mediated EPSCs as well as GABA-mediated IPSCs, although the net effect of neurotransmitter release was to increase the firing of most LHb neurons. In vivo optogenetic inhibition of LHA-LHb glutamatergic fibers produced a real-time place preference, whereas optogenetic stimulation of LHA-LHb glutamatergic fibers had the opposite effect. Furthermore, optogenetic inhibition of LHA-LHb glutamatergic fibers acutely increased the consumption of a palatable liquid caloric reward. Collectively, these results demonstrate that LHA glutamatergic neurons are well situated to bidirectionally regulate feeding and potentially other behavioral states via their functional circuit connectivity with the LHb and potentially other brain regions.In this study, we show that the genetic ablation of LHA glutamatergic neurons enhances caloric intake. Some of these LHA glutamatergic neurons project to the lateral habenula, a brain area important for generating behavioral avoidance. Optogenetic stimulation of this circuit has net excitatory effects on postsynaptic LHb neurons. This is the first study to characterize the functional connectivity and behavioral relevance of this circuit within the context of feeding and reward-related behavior.	
26758721	Could a pat on the back affect motor adaptation? Recent studies indeed suggest that rewards can boost motor adaptation. However, the rewards used were typically reward gradients that carried quite detailed information about performance. We investigated whether simple binary rewards affected how participants learned to correct for a visual rotation of performance feedback in a 3D pointing task. To do so, we asked participants to align their unseen hand with virtual target cubes in alternating blocks with and without spatial performance feedback. Forty participants were assigned to one of two groups: a 'spatial only' group, in which the feedback consisted of showing the (perturbed) endpoint of the hand, or to a 'spatial & reward' group, in which a reward could be received in addition to the spatial feedback. In addition, six participants were tested in a 'reward only' group. Binary reward was given when the participants' hand landed in a virtual 'hit area' that was adapted to individual performance to reward about half the trials. The results show a typical pattern of adaptation in both the 'spatial only' and the 'spatial & reward' groups, whereas the 'reward only' group was unable to adapt. The rewards did not affect the overall pattern of adaptation in the 'spatial & reward' group. However, on a trial-by-trial basis, the rewards reduced adaptive changes to spatial errors. 
26756995	In this study on skill acquisition in a computerized throwing task, we examined the effect of graded correct-related performance feedback on the reward positivity of the event-related brain potential (ERP). Theories of reinforcement learning predict effects of reward magnitude and expectancy on the reward prediction error. The later is supposed to be reflected in reward positivity, a fronto-central ERP component. A sample of 68 participants learned to throw at a beamer-projected target disk while performance accuracy, displayed as the place of impact of the projectile on the target, served as graded feedback. Effects of performance accuracy in successful trials, hit frequency, and preceding trial performance on reward positivity were analyzed simultaneously on a trial-by-trial basis by means of linear mixed models. In accord with previous findings, reward positivity increased with feedback about more accurate performance. This relationship was not linear, but cubic, with larger impact of feedback towards the end of the accuracy distribution. In line with being a measure of expectancy, the reward positivity decreased with increasing hit frequency and was larger after unsuccessful trials. The effect of hit frequency was more pronounced following successful trials. These results indicate a fast trial-by-trial adaptation of expectation. The results confirm predictions of reinforcement learning theory and extend previous findings on reward magnitude to the area of complex, goal directed skill acquisition. 
26756798	Emerging evidence suggests that the endocannabinoid system (ECS) is involved in modulating the rewarding effects of abused drugs. Recently, the cannabinoid receptor 2 (CB2R) was shown to be expressed in brain reward circuitry and is implicated in modulating the rewarding effects of alcohol.CB2 ligands and CB2R knockout (KO) mice were used to assess CB2R involvement in alcohol reward-related behavior in 2 well-established behavioral models: limited-access 2-bottle choice drinking and conditioned place preference (CPP). For the pharmacological studies, mice received pretreatments of either vehicle, the CB2R agonist JWH-133 (10 and 20 mg/kg) or the CB2R antagonist AM630 (10 and 20 mg/kg) 30 minutes before behavioral testing. For the genetic studies, CB2R KO mice were compared to wild-type (WT) littermate controls.	CB2R KO mice displayed increased magnitude of alcohol-induced CPP compared to WT mice. Neither agonism nor antagonism of CB2R affected alcohol intake or the expression of CPP, and antagonism of CB2R during CPP acquisition trials also did not affect CPP.	The CB2R KO CPP data provide partial support for the hypothesis that CB2Rs are involved in the modulation of alcohol reward-related behaviors. However, pharmacological manipulation of CB2Rs did not alter alcohol's rewarding effects in the alcohol-seeking models used here. These results highlight the importance of pharmacological validation of effects seen with lifetime KO models. Given the ongoing efforts toward medications development, future studies should continue to explore the role of the CB2R as a potential neurobiological target for the treatment of alcohol use disorders.	
26755548	Neurotensin is a tridecapeptide originally identified in extracts of bovine hypothalamus. This peptide has a close anatomical and functional relationship with the mesocorticolimbic and nigrostriatal dopamine system. Neural circuits containing neurotensin were originally proposed to play a role in the mechanism of action of antipsychotic agents. Additionally, neurotensin-containing pathways were demonstrated to mediate some of the rewarding and/or sensitizing properties of drugs of abuse.This review attempts to contribute to the understanding of the role of neurotensin and its receptors in drug abuse. In particular, we will summarize the potential relevance of neurotensin, its related compounds and neurotensin receptors in substance use disorders, with a focus on the preclinical research. 
26755093	Emotion regulation research has shown successful altering of unwanted aversive emotional reactions. Cognitive strategies can also downregulate expectations of reward arising from conditioned stimuli, including sexual stimuli. However, little is known about whether such strategies can also efficiently upregulate expectations of sexual reward arising from conditioned stimuli, and possible gender differences therein.The present study examined whether a cognitive upregulatory strategy could successfully upregulate sexual arousal elicited by sexual reward-conditioned cues in men and women.	Men (n = 40) and women (n = 53) participated in a study using a differential conditioning paradigm, with genital vibrostimulation as unconditioned stimulus (US) and sexually relevant pictures as conditional stimuli.	Penile circumference and vaginal pulse amplitude were assessed and ratings of US expectancy, affective value, and sexual arousal value were obtained. Also a stimulus response compatibility task was included to assess automatic approach and avoidance tendencies.	Evidence was found for emotion upregulation to increase genital arousal response in the acquisition phase in both sexes, and to enhance resistance to extinction of conditioned genital responding in women. In men, the emotion upregulatory strategy resulted in increased conditioned positive affect.	The findings support that top-down modulation may indeed influence conditioned sexual responses. This knowledge may have implications for treating disturbances in sexual appetitive responses, such as low sexual arousal and desire.	
26754292	The current study aimed to determine whether reversal learning impairments and feedback-related negativity (FRN), reflecting reward prediction error signals generated by negative feedback during the reversal learning tasks, were associated with social disinhibition in a group of participants with traumatic brain injury (TBI).Number of reversal errors on a social and a non-social reversal learning task and FRN were examined for 21 participants with TBI and 21 control participants matched for age. Participants with TBI were also divided into low and high disinhibition groups based on rated videotaped interviews.	Participants with TBI made more reversal errors and produced smaller amplitude FRNs than controls. Furthermore, participants with TBI high on social disinhibition made more reversal errors on the social reversal learning task than did those low on social disinhibition. FRN amplitude was not related to disinhibition.	These results suggest that impairment in the ability to update behavior when social reinforcement contingencies change plays a role in social disinhibition after TBI. Furthermore, the social reversal learning task used in this study may be a useful neuropsychological tool for detecting susceptibility to acquired social disinhibition following TBI. Finally, that the FRN amplitude was not associated with social disinhibition suggests that reward prediction error signals are not critical for behavioral adaptation in the social domain.	
26751780	Hippocampal oscillations are dynamic, with unique oscillatory frequencies present during different behavioral states. To examine the extent to which these oscillations reflect neuron engagement in distinct local circuit processes that are important for memory, we recorded single cell and local field potential activity from the CA1 region of the hippocampus as rats performed a context-guided odor-reward association task. We found that theta (4-12 Hz), beta (15-35 Hz), low gamma (35-55 Hz), and high gamma (65-90 Hz) frequencies exhibited dynamic amplitude profiles as rats sampled odor cues. Interneurons and principal cells exhibited unique engagement in each of the four rhythmic circuits in a manner that related to successful performance of the task. Moreover, principal cells coherent to each rhythm differentially represented task dimensions. These results demonstrate that distinct processing states arise from the engagement of rhythmically identifiable circuits, which have unique roles in organizing task-relevant processing in the hippocampus. 
26751363	Research has shown trait self-control, neuroticism, and coping and enhancement drinking motives to be predictors of alcohol consumption among college students. Recent research also provides evidence for the effects of role investment and role-based alcohol consumption-decision making (i.e., partying decisions). The goal of the present study was to clarify the organization and contributions of these multifarious influences on college student drinking.College students (N = 355; 51.8% female) with a heterogeneous prevalence of alcohol dependence completed measures of trait self-control; neuroticism; coping and enhancement drinking motives; subjective college student role investment, satisfaction, and stress; role-based partying scenarios; and a typical weekly alcohol consumption interview. Internal and comparative fit indices for alternative path models were evaluated and bootstrapping procedures were used to examine indirect effects.	Modeling results favored a more stratified organization, where (a) the association between trait self-control and consumption was mediated by drinking motives and partying decisions, (b) the association between neuroticism and consumption was mediated by coping motives, and (c) the association between role investment and consumption was mediated by partying decisions. The associations between motives and consumption were not mediated by partying decisions.	The results provide support for disinhibitory and distress pathways to college student drinking, where impulsive and anxious students are more likely to drink excessively because of more frequent mood-affecting drinking goals, less academic involvement, and/or more frequent decisions to attend parties where negative academic consequences are likely but where perceived rewarding alcohol-related and social features are present.	
26750264	Orexin (ORX) (also known as hypocretin) neurons are located exclusively in the posterior hypothalamus, and are involved in a wide range of behaviours, including motivation for drugs of abuse such as alcohol. Hypothalamic subregions contain functionally distinct populations of ORX neurons that may play different roles in regulating drug-motivated and alcohol-motivated behaviours. To investigate the role of ORX neurons in ethanol (EtOH) seeking, we measured Fos activation of ORX neurons in rats following three different measures of EtOH seeking and preference: (i) context-induced reinstatement, or ABA renewal; (ii) cue-induced reinstatement of extinguished responding for EtOH; and (iii) a home cage task in which preference for EtOH (vs. water) was measured in the absence of either reinforcer. We found significant activation of ORX neurons in multiple subregions across all three behavioural tests. Notably, ORX neuron activation in the lateral hypothalamus correlated with the degree of seeking in context reinstatement and the degree of preference in home cage preference testing. In addition, Fos activation in ORX neurons in the dorsomedial hypothalamic and perifornical areas was correlated with context and home cage seeking/preference, respectively. Surprisingly, we found no relationship between the degree of cue-induced reinstatement and ORX neuron activation in any region, despite robust activation overall during reinstatement. These results demonstrate a strong relationship between ORX neuron activation and EtOH seeking/preference, but one that is differentially expressed across ORX field subregions, depending on reinstatement modality. 
26748873	Taxi drivers play an important role in providing safe and professional public transport services. However, they tend to be more involved than other professional driver groups in accidents caused by deliberate recklessness. This study used an event-related potential (ERP) experiment to examine risk-taking behavior arising from impulsivity by comparing the underlying neural processes of taxi drivers with and without traffic offence records in Hong Kong. A sample of 15 traffic offenders and 15 nonoffenders, matched by sociodemographic characteristics, was recruited. The results show that the offender group demonstrated significantly less negative-going (less negative) feedback-related negativity but more positive-going (more positive) feedback-related P300 when than with their nonoffending counterparts. These findings show that taxi drivers with traffic offence records were less sensitive to the consequences of behavior and more attuned to the magnitude of potential reward. In addition, behavioral data revealed that they were more willing to make risky decisions. All these characteristics pertain to impulsive personality traits. Based on these findings, we can conclude that the offenders in this sample were more impulsive than their nonoffending counterparts. 
26748378	Many clinicians who provide mental health treatment find developmental neuroscience discoveries to be exciting. However, the utility of these findings often seem far removed from everyday clinical care. Thus, the goal of this article is to offer a bridge to connect the fields of applied adolescent treatment and developmental neuroscience investigation. An overview of the relevance of developmental neuroscience in adolescent direct practice and a rationale for how and why this integration could benefit adolescent treatment outcomes is provided. Finally, a series of practical suggestions is generated for enhancing collaborative, interdisciplinary work that ultimately advances treatment response for this important clinical population. 
26748087	While chronic pain is considered by some to be a CNS disease, little is understood about underlying neurobiological mechanisms. Addiction models have heuristic value in this regard, because both pain and addictive disorders are characterized by impaired hedonic capacity, compulsive drug seeking, and high stress. In drug addiction such symptomatology has been attributed to reward deficiency, impaired inhibitory control, incentive sensitization, aberrant learning, and anti-reward allostatic neuroadaptations. Here we propose that similar neuroadaptations exist in chronic pain patients. 
26747414	Affect and motivation influence the error-related negativity (ERN) elicited by full errors; however, it is unknown whether they also influence ERNs to correct responses accompanied by covert incorrect response activation (partial errors). Here we compared a neutral condition with conditions, where correct responses were rewarded or where incorrect responses were punished with gains and losses of small amounts of money, respectively. Data analysis distinguished ERNs elicited by full and partial errors. In the reward and punishment conditions, ERN amplitudes to both full and partial errors were larger than in the neutral condition, confirming participants' sensitivity to the significance of errors. We also investigated the relationships between ERN amplitudes and the behavioral inhibition and activation systems (BIS/BAS). Regardless of reward/punishment condition, participants scoring higher on BAS showed smaller ERN amplitudes in full error trials. These findings provide further evidence that the ERN is related to motivational valence and that similar relationships hold for both full and partial errors. 
26747088	Weight gain is a common and serious adverse effect of antipsychotic treatment. A variable individual predisposition to development of metabolic disturbances calls for predictive biological markers.To investigate whether attenuated striatal activity during reward anticipation is associated with amisulpride-induced weight change in antipsychotic-naive patients with schizophrenia undergoing initial treatment and to examine the association between weight change and changes in reward anticipation activity after treatment.	Sixty-nine antipsychotic-naive inpatients and outpatients with schizophrenia were included in a multimodal longitudinal cohort study from December 16, 2008, to December 11, 2013. Fifty-eight patients underwent functional magnetic resonance imaging (fMRI) while performing a monetary reward task. After 6 weeks of treatment with amisulpride, a relatively selective dopamine D2 antagonist, 39 patients underwent a second fMRI scan and measurement of change in body weight. Final follow-up was completed on January 14, 2014, and data were analyzed from October 25, 2014, to June 15, 2015 and August 31 to September 19, 2015.	Six weeks of individually dosed amisulpride treatment.	Reward-anticipation activity in the striatum before and after treatment and weight change.	Of the 69 patients who consented to the study, 39 underwent the follow-up fMRI and weight measurement (age range, 18-45 years; 17 women and 22 men). The mean (SD) daily dose of amisulpride was 272 (168; range, 50-800) mg, and patients gained a mean (SD) of 2.3 (2.8; range, -4 to 8) kg in body weight. Improvement from baseline to follow-up was found on the mean (SD) positive (19.9 [4.1] to 14.3 [3.8]), general (39.7 [7.7] to 30.5 [7.7]), and total (78.5 [15.3] to 63.2 [13.9]) scores on the Positive and Negative Syndrome Scale (P < .001). Weight gain was predicted by low mean (SD) baseline reward-related activity in the right-sided putamen (0.20 [0.93]; F35,3 = 5.64; P = .003). After 6 weeks, weight gain was associated with an increase in mean (SD) reward activity in the same region during treatment (0.28 [0.74]; F37,1 = 4.48; P = .04).	Activity in striatal regions of the reward system appears to be associated with the individual variability in the predisposition for antipsychotic-associated weight gain. Moreover, pharmacologic modulation of the reward system may play a role in antipsychotic-associated weight gain.	

26746312	Although emotion is known to reciprocally interact with cognitive and motor performance, contemporary theories of motor learning do not specifically consider how dynamic variations in a learner's affective state may influence motor performance during motor learning. Using a prism adaptation paradigm, we assessed emotion during motor learning on a trial-by-trial basis. We designed two dart-throwing experiments to dissociate motor performance and reward outcomes by giving participants maximum points for accurate throws and reduced points for throws that hit zones away from the target (i.e., "accidental points"). Experiment 1 dissociated motor performance from emotional responses and found that affective ratings tracked points earned more closely than error magnitude. Further, both reward and error uniquely contributed to motor learning, as indexed by the change in error from one trial to the next. Experiment 2 manipulated accidental point locations vertically, whereas prism displacement remained horizontal. Results demonstrated that reward could bias motor performance even when concurrent sensorimotor adaptation was taking place in a perpendicular direction. Thus, these experiments demonstrate that affective states were dissociable from error magnitude during motor learning and that affect more closely tracked points earned. Our findings further implicate reward as another factor, other than error, that contributes to motor learning, suggesting the importance of incorporating affective states into models of motor learning. 
26744037	Which stimuli we pay attention to is strongly influenced by learning. Stimuli previously associated with reward outcomes, such as money and food, and stimuli previously associated with aversive outcomes, such as monetary loss and electric shock, automatically capture attention. Social reward (happy expressions) can bias attention towards associated stimuli, but the role of negative social feedback in biasing attentional selection remains unexplored. On the one hand, negative social feedback often serves to discourage particular behaviours. If attentional selection can be curbed much like any other behavioural preference, we might expect stimuli associated with negative social feedback to be more readily ignored. On the other hand, if negative social feedback influences attention in the same way that other aversive outcomes do, such feedback might ironically bias attention towards the stimuli it is intended to discourage selection of. In the present study, participants first completed a training phase in which colour targets were associated with negative social feedback. Then, in a subsequent test phase, these same colour stimuli served as task-irrelevant distractors during a visual search task. The results strongly support the latter interpretation in that stimuli previously associated with negative social feedback impaired search performance.
26744024	The present study was designed to investigate the effect of a methanolic extract of Morinda citrifolia Linn. fruit (MMC) on the rewarding effect of heroin in the rat conditioned place preference (CPP) paradigm and naloxone-precipitated withdrawal in mice. In the first experiment, following a baseline preference test (preconditioning score), the rats were subjected to conditioning trials with five counterbalanced escalating doses of heroin versus saline followed by a preference test conducted under drug-free conditions (post-conditioning score) using the CPP test. Meanwhile, in the second experiment, withdrawal jumping was precipitated by naloxone administration after heroin dependence was induced by escalating doses for 6 days (3×/ day). The CPP test results revealed that acute administration of MMC (1, 3, and 5 g/kg body weight (bw), p.o.), 1 h prior to the CPP test on the 12th day significantly reversed the heroin-seeking behavior in a dose-dependent manner, which was similar to the results observed with a reference drug, methadone (3 mg/kg bw, p.o.). On the other hand, MMC (0.5, 1, and 3 g/kg bw, p.o.) did not attenuate the heroin withdrawal jumps precipitated by naloxone. These findings suggest that the mechanism by which MMC inhibits the rewarding effect of heroin is distinct from naloxone-precipitated heroin withdrawal. 
26743954	Following adverse work conditions, health consequences can be explained by an imbalance between the effort made and the reward received. We investigated the association between extra effort, perceived reward, and post-traumatic stress disorder (PTSD). The Effort-Reward Imbalance Model was used to examine whether extra effort at work in the aftermath of a workplace-related terrorist attack affected the risk of PTSD and the effects of reward for extra effort from a leader or colleagues.Cross-sectional data were collected 10 months after a terrorist attack in Norway in 2011. Out of 3520 Ministry employees invited, 1927 agreed to participate. Employees reported any extra effort performed as a result of the bomb explosion and any reward received from a leader or colleagues. PTSD was assessed with the PTSD Checklist.	Employees who reported extra effort displayed increased risk for PTSD (odds ratio [OR]=1.71, 95% confidence interval [CI]: 1.15-2.55, P=0.008). Perceived reward for extra effort from a leader was associated with lower risk for PTSD (OR=0.39, 95% CI: 0.23-0.64, P<0.001) but not perceived reward from colleagues.	Extra effort may increase the risk of PTSD, but reward from a leader may mitigate this effect. The Effort-Reward Imbalance Model appears to be an appropriate approach that may contribute to understanding of the etiology of work-related PTSD.	
26743042	Prenatal morphine (PM) affects the development of brain reward system and cognitive function. The present study aimed to determine whether PM exposure increases the vulnerability to MA addiction. Pregnant Sprague-Dawley rats were administered saline or morphine during embryonic days 3-20. The acquisition, extinction and reinstatement of methamphetamine (MA) conditioned place preference (CPP) and intravenous self-administration (SA) paradigms were assessed in the male adult offspring. There was no difference in the acquisition and expression of MA CPP between saline- and PM-exposed rats, whereas PM-exposed rats exhibited slower extinction and greater MA priming-induced reinstatement of drug-seeking behavior than controls. Similarly, MA SA under progressive ratio and fixed ratio schedules was not affected by PM exposure, but PM-exposed rats required more extinction sessions to reach the extinction criteria and displayed more severe MA priming-, but not cue-induced, reinstatement. Such alterations in extinction and reinstatement were not present when PM-exposed rats were tested in an equivalent paradigm assessing operant responding for food pellets. Our results demonstrate that PM exposure did not affect the association memory formation during acquisition of MA CPP or SA, but impaired extinction learning and increased MA-primed reinstatement in both tasks. These findings suggest that the offspring of women using morphine or heroin during pregnancy might predict persistent MA seeking during extinction and enhanced propensity to MA relapse although they might not be more susceptible to the reinforcing effect of MA during initiation of drug use. 
26742929	When an anticipated food reward is unexpectedly reduced in quality or quantity, many mammals show a successive negative contrast (SNC) effect, i.e. a reduction in instrumental or consummatory responses below the level shown by control animals that have only ever received the lower-value reward. SNC effects are believed to reflect an aversive emotional state, caused by the discrepancy between the expected and the actual reward. Furthermore, how animals respond to such discrepancy has been suggested to be a sign of animals' background mood state. However, the occurrence and interpretation of SNC effects are not unequivocal, and there is a relative lack of studies conducted outside of laboratory conditions. Here, we tested two populations of domestic dogs (24 owned pet dogs and 21 dogs from rescue kennels) in a SNC paradigm following the methodology by Bentosela et al. (J Comp Psychol 123:125-130, 2009), using a design that allowed a within-, as well as a between-, subjects analysis. We found no evidence of a SNC effect in either population using a within- or between-subjects design. Indeed, the within-subjects analysis revealed a reverse SNC effect, with subjects in the shifted condition showing a significantly higher level of response, even after they received an unexpected reduction in reward quality. Using a within-, rather than a between-, subjects design may be beneficial in studies of SNC due to higher sensitivity and statistical power; however, order effects on subject performance need to be considered. These results suggest that this particular SNC paradigm may not be sufficiently robust to replicate easily in a range of environmental contexts and populations. 
26742068	Increasing either protein or fiber at mealtimes has relatively modest effects on ingestive behavior. Whether protein and fiber have additive or interactive effects on ingestive behavior is not known. Fifteen overweight adults (5 female, 10 male; BMI: 27.1 ± 0.2 kg/m²; aged 26 ± 1 year) consumed four breakfast meals in a randomized crossover manner (normal protein (12 g) + normal fiber (2 g), normal protein (12 g) + high fiber (8 g), high protein (25 g) + normal fiber (2 g), high protein (25 g) + high fiber (8 g)). The amount of protein and fiber consumed at breakfast did not influence postprandial appetite or ad libitum energy intake at lunch. In the fasting-state, visual food stimuli elicited significant responses in the bilateral insula and amygdala and left orbitofrontal cortex. Contrary to our hypotheses, postprandial right insula responses were lower after consuming normal protein vs. high protein breakfasts. Postprandial responses in other a priori brain regions were not significantly influenced by protein or fiber intake at breakfast. In conclusion, these data do not support increasing dietary protein and fiber at breakfast as effective strategies for modulating neural reward processing and acute ingestive behavior in overweight adults. 
26741800	When a stimulus is associated with a reward, it becomes prioritized, and the allocation of attention to that stimulus increases. For low-level features, such as color, this reward-based allocation of attention can manifest early in time and as a faster and stronger shift of attention to targets with that color, as reflected by the N2pc (a parieto-occipital electrophysiological component peaking at ∼250 msec). It is unknown, however, if reward associations can similarly modulate attentional shifts to complex objects or object categories, or if reward-related modulation of attentional allocation to such stimuli would occur later in time or through a different mechanism. Here, we used magnetoencephalographic recordings in 24 participants to investigate how object categories with a reward association would modulate the shift of attention. On each trial, two colored squares were presented, one in a target color and the other in a distractor color, each with an embedded object. Participants searched for the target-colored square and performed a corner discrimination task. The embedded objects were from either a rewarded or non-rewarded category, and if a rewarded-category object were present within the target-colored square, participants could earn extra money for correct performance. We observed that when the target color contained an object from a rewarded versus a non-rewarded category, the neural shift of attention to the target was faster and of greater magnitude, although the rewarded objects were not relevant for correct task performance. These results suggest that reward associations of complex objects can rapidly modulate attentional allocation to a target.
26740664	Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse.Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence, particularly its role in behavior in nondrug situations. Here, rats learned about food-paired stimuli after prolonged abstinence from cocaine self-administration. Using voltammetry, we found that real-time DA signals in cocaine-experienced rats were strikingly altered relative to controls. Further, cocaine-experienced animals found reward-predictive stimuli abnormally salient and spent more time interacting with cues. Therefore, cocaine induces neuroplastic changes in the DA system that biases animals toward salient stimuli (including reward-associated cues), putting addicts at increasing risk to relapse as addiction increases in severity.	
26740653	Dynamic signaling of mesolimbic dopamine (DA) neurons has been implicated in reward learning, drug abuse, and motivation. However, this system is complex because firing patterns of these neurons are heterogeneous; subpopulations receive distinct synaptic inputs, and project to anatomically and functionally distinct downstream targets, including the nucleus accumbens (NAc) shell and core. The functional roles of these cell populations and their real-time signaling properties in freely moving animals are unknown. Resolving the real-time DA signal requires simultaneous knowledge of the synchronized activity of DA cell subpopulations and assessment of the down-stream functional effect of DA release. Because this is not yet possible solely by experimentation in vivo, we combine computational modeling and fast-scan cyclic voltammetry data to reconstruct the functionally relevant DA signal in DA neuron subpopulations projecting to the NAc core and shell in freely moving rats. The approach provides a novel perspective on real-time DA neuron firing and concurrent activation of presynaptic autoreceptors and postsynaptic targets. We first show that individual differences in DA release arise from differences in autoreceptor feedback. The model predicts that extracellular DA concentrations in NAc core result from constant baseline DA firing, whereas DA concentrations in NAc shell reflect highly dynamic firing patters, including synchronized burst firing and pauses. Our models also predict that this anatomical difference in DA signaling is exaggerated by intravenous infusion of cocaine.Orchestrated signaling from mesolimbic dopamine (DA) neurons is important for initiating appropriate behavior in response to salient stimuli. Thus, subpopulations of mesolimbic DA neurons show different in vitro properties and synaptic inputs depending on their specific projections to the core and shell subterritories of the nucleus accumbens (NAc). However, the functional consequence of these differences is unknown. Here we analyze and model DA dynamics in different areas of the NAc to establish the real-time DA signal. In freely behaving animals, we find that the DA signal from mesencephalic neurons projecting to the NAc shell is dominated by synchronized bursts and pauses, whereas signaling is uniform for core-projecting neurons; this difference is amplified by cocaine.	

26740533	Evaluating outcomes of behavior is a central function of the striatum. In circuits engaging the dorsomedial striatum, sensitivity to goal value is accentuated during learning, whereas outcome sensitivity is thought to be minimal in the dorsolateral striatum and its habit-related corticostriatal circuits. However, a distinct population of projection neurons in the dorsolateral striatum exhibits selective sensitivity to rewards. Here, we evaluated the outcome-related signaling in such neurons as rats performed an instructional T-maze task for two rewards. As the rats formed maze-running habits and then changed behavior after reward devaluation, we detected outcome-related spike activity in 116 units out of 1,479 recorded units. During initial training, nearly equal numbers of these units fired preferentially either after rewarded runs or after unrewarded runs, and the majority were responsive at only one of two reward locations. With overtraining, as habits formed, firing in nonrewarded trials almost disappeared, and reward-specific firing declined. Thus error-related signaling was lost, and reward signaling became generalized. Following reward devaluation, in an extinction test, postgoal activity was nearly undetectable, despite accurate running. Strikingly, when rewards were then returned, postgoal activity reappeared and recapitulated the original early response pattern, with nearly equal numbers responding to rewarded and unrewarded runs and to single rewards. These findings demonstrate that outcome evaluation in the dorsolateral striatum is highly plastic and tracks stages of behavioral exploration and exploitation. These signals could be a new target for understanding compulsive behaviors that involve changes to dorsal striatum function.
26740530	Functional magnetic resonance imaging (fMRI) is a noninvasive tool used to probe cognitive and affective processes. Although fMRI provides indirect measures of neural activity, the advent of fMRI has allowed for1) the corroboration of significant animal findings in the human brain, and2) the expansion of models to include more common human attributes that inform behavior. In this review, we briefly consider the neural basis of the blood oxygenation level dependent signal to set up a discussion of how fMRI studies have applied it in examining cognitive models in humans and the promise of using fMRI to advance such models. Specifically, we illustrate the contribution that fMRI has made to the study of reward processing, focusing on the role of the striatum in encoding reward-related learning signals that drive anticipatory and consummatory behaviors. For instance, we discuss how fMRI can be used to link neural signals (e.g., striatal responses to rewards) to individual differences in behavior and traits. While this functional segregation approach has been constructive to our understanding of reward-related functions, many fMRI studies have also benefitted from a functional integration approach that takes into account how interconnected regions (e.g., corticostriatal circuits) contribute to reward processing. We contend that future work using fMRI will profit from using a multimodal approach, such as combining fMRI with noninvasive brain stimulation tools (e.g., transcranial electrical stimulation), that can identify causal mechanisms underlying reward processing. Consequently, advancements in implementing fMRI will promise new translational opportunities to inform our understanding of psychopathologies.
26740161	The basolateral amygdala (BLA) and the gustatory region of the insular cortex (IC) are required for the encoding and retrieval of outcome value. Here, we examined if these regions are also necessary to learn associations between actions and their outcomes. Hungry rats were first trained to press two levers for a common outcome. Next, specific response-outcome (R-O) associations were introduced such that each response now earned a distinct food outcome. Prior to each specific R-O training session, rats received a bilateral infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-APV, into either the BLA or the IC. One of the two outcomes was then devalued immediately prior to a choice test. Inhibition of NMDA receptor activity in the BLA, but not the IC, during the acquisition of specific R-O associations abolished selective devaluation. These results indicate that the BLA is critical for learning the association between actions and their specific consequences.
26739226	By saying "Anyone who has never made a mistake has never tried anything new", Albert Einstein himself allegedly implied that the making and processing of errors are essential for behavioral adaption to a new or changing environment. These essential error-related cognitive and neural processes are likely influenced by reward value. However, previous studies have not dissociated accuracy and value and so the distinct effect of reward on error processing in the brain remained unknown. Therefore, we set out to investigate this at various points in decision-making. We used functional magnetic resonance imaging to scan participants while they completed a random dot motion discrimination task where reward and non-reward were associated with stimuli via classical conditioning. Pre-error activity was found in the medial frontal cortex prior to response but this was not related to reward value. At response time, error-related activity was found to be significantly greater in reward than non-reward trials in the midcingulate cortex. Finally at outcome time, error-related activity was found in the anterior cingulate cortex in non-reward trials. These results show that reward value enhances post-decision but not pre-decision error-related activities and these results therefore have implications for theories of error correction and confidence. 
26738968	Calcium sensors detect intracellular calcium changes and interact with downstream targets to regulate many functions. Neuronal Calcium Sensor-1 (NCS-1) or Frequenin is widely expressed in the nervous system, and involved in neurotransmission, synaptic plasticity and learning. NCS-1 interacts with and regulates dopamine D2 receptor (D2R) internalization and is implicated in disorders like schizophrenia and substance abuse. However, the role of NCS-1 in behaviors dependent on dopamine signaling in the striatum, where D2R is most highly expressed, is unknown. We show that Ncs-1 deletion in the mouse decreases willingness to work for food. Moreover, Ncs-1 knockout mice have significantly lower activity-dependent dopamine release in the nucleus accumbens core in acute slice recordings. In contrast, food preference, responding for conditioned reinforcement, ability to represent changes in reward value, and locomotor response to amphetamine are not impaired. These studies identify novel roles for NCS-1 in regulating activity-dependent striatal dopamine release and aspects of motivated behavior.
26737783	Basal Ganglia (BG) are implied in many motor and cognitive tasks, such as action selection, and have a central role in many pathologies, primarily Parkinson Disease. In the present work, we use a recently developed biologically inspired BG model to analyze how the dopamine (DA) level can affect the temporal response during action selection, and the capacity to learn new actions following rewards and punishments. The model incorporates the 3 main pathways (direct, indirect and hyperdirect) working in BG functioning. The behavior of 2 alternative networks (the first with normal DA levels, the second with reduced DA) is analyzed both in untrained conditions, and during training performed in different epochs. The results show that reduced DA causes delayed temporal responses in the untrained network, and difficult of learning during training, characterized by the necessity of much more epochs. The results provide interesting hints to understand the behavior of healthy and dopamine depleted subjects, such as parkinsonian patients. 
26736244	It is commonly acknowledged that movement performance is determined by a trade-off between accuracy requirements and energetic expenditure. However, their relative weights are subjective and depend on the perceived benefit (or cost) associated to successful movement completion. A deeper knowledge on how this trade-off affects motor behavior may suggest ways to manipulate it in pathologies, like Parkinson's disease, in which the mechanisms underlying the selection of motor response are believed to be defective. In this preliminary study, we associate a monetary incentive to successful completion of a full-body reaching task and look at the determinants of motor performance. Our preliminary results suggest that motor performance (measured as the absolute average acceleration of hand movements) increases with movement amplitude/target elevation. Overall, performance also increases with the amount of monetary incentive and with the average reward experienced in previous trials. In addition, subjects with a greater sensitivity to incentive exhibit a low sensitivity to the average reward. In contrast, subjects with a negative sensitivity to incentive exhibit a smaller sensitivity to the average reward. These results suggest that motor performance has a complex relation with its perceived benefits, and this relation is probably subject-dependent. 
26735742	We consider the learning problem under an online Markov decision process (MDP) aimed at learning the time-dependent decision-making policy of an agent that minimizes the regret-the difference from the best fixed policy. The difficulty of online MDP learning is that the reward function changes over time. In this letter, we show that a simple online policy gradient algorithm achieves regret O(√T) for T steps under a certain concavity assumption and O(log T) under a strong concavity assumption. To the best of our knowledge, this is the first work to present an online MDP algorithm that can handle continuous state, action, and parameter spaces with guarantee. We also illustrate the behavior of the proposed online policy gradient method through experiments.
26734022	Non-medical applications of computed tomography (CT) scanning have flourished in recent years, including in Plant Science. This Perspective article on CT scanning of root systems and leaf canopies is intended to be of interest to three categories of readers: those who have not yet tried plant CT scanning, and should find inspiration for new research objectives; readers who are on the learning curve with applications-here is helpful advice for them; and researchers with greater experience-the field is evolving quickly and it is easy to miss aspects. Our conclusion is that CT scanning of roots and canopies is highly demanding in terms of technology, multidisciplinarity and big-data analysis, to name a few areas of expertise, but eventually, the reward for researchers is directly proportional! 
26733906	Understanding how humans weigh long-term and short-term goals is important for both basic cognitive science and clinical neuroscience, as substance users need to balance the appeal of an immediate high vs. the long-term goal of sobriety. We use a computational model to identify learning and decision-making abnormalities in methamphetamine-dependent individuals (MDI, n = 16) vs. healthy control subjects (HCS, n = 16), in a two-armed bandit task. In this task, subjects repeatedly choose between two arms with fixed but unknown reward rates. Each choice not only yields potential immediate reward but also information useful for long-term reward accumulation, thus pitting exploration against exploitation. We formalize the task as comprising a learning component, the updating of estimated reward rates based on ongoing observations, and a decision-making component, the choice among options based on current beliefs and uncertainties about reward rates. We model the learning component as iterative Bayesian inference (the Dynamic Belief Model), and the decision component using five competing decision policies: Win-stay/Lose-shift (WSLS), ε-Greedy, τ-Switch, Softmax, Knowledge Gradient. HCS and MDI significantly differ in how they learn about reward rates and use them to make decisions. HCS learn from past observations but weigh recent data more, and their decision policy is best fit as Softmax. MDI are more likely to follow the simple learning-independent policy of WSLS, and among MDI best fit by Softmax, they have more pessimistic prior beliefs about reward rates and are less likely to choose the option estimated to be most rewarding. Neurally, MDI's tendency to avoid the most rewarding option is associated with a lower gray matter volume of the thalamic dorsal lateral nucleus. More broadly, our work illustrates the ability of our computational framework to help reveal subtle learning and decision-making abnormalities in substance use. 
26733838	Fear inhibition learning induces plasticity and remodeling of circuits within the amygdala. Most studies examine these changes in nondiscriminative fear conditioning paradigms. Using a discriminative fear, safety, and reward conditioning task, Sangha et al. (2013) have previously reported several neural microcircuits within the basal amygdala (BA) which discriminate among these cues, including a subpopulation of neurons responding selectively to a safety cue and not a fear cue. Here, the hypothesis that these "safety" neurons isolated during discriminative conditioning are biased to become fear cue responsive as a result of extinction, when fear behavior diminishes, was tested. Although 41% of "safety" neurons became fear cue responsive as a result of extinction, the data revealed that there was no bias for these neurons to become preferentially responsive during fear extinction compared to the other identified subgroups. In addition to the plasticity seen in the "safety" neurons, 44% of neurons unresponsive to either the fear cue or safety cue during discriminative conditioning became fear cue responsive during extinction. Together these emergent responses to the fear cue as a result of extinction support the hypothesis that new learning underlies extinction. In contrast, 47% of neurons responsive to the fear cue during discriminative conditioning became unresponsive to the fear cue during extinction. These findings are consistent with a suppression of neural responding mediated by inhibitory learning, or, potentially, by direct unlearning. Together, the data support extinction as an active process involving both gains and losses of responses to the fear cue and suggests the final output of the integrated BA circuit in influencing fear behavior is a balance of excitation and inhibition, and perhaps reversal of learning-induced changes. 
26733674	Animals can shape their timed behaviors based on experienced probabilistic relations in a nearly optimal fashion. On the other hand, it is not clear if they adopt these timed decisions by making computations based on previously learnt task parameters (time intervals, locations, and probabilities) or if they gradually develop their decisions based on trial and error. To address this question, we tested mice in the timed-switching task, which required them to anticipate when (after a short or long delay) and at which of the two delay locations a reward would be presented. The probability of short trials differed between test groups in two experiments. Critically, we first trained mice on relevant task parameters by signaling the active trial with a discriminative stimulus and delivered the corresponding reward after the associated delay without any response requirement (without inducing switching behavior). During the test phase, both options were presented simultaneously to characterize the emergence and temporal characteristics of the switching behavior. Mice exhibited timed-switching behavior starting from the first few test trials, and their performance remained stable throughout testing in the majority of the conditions. Furthermore, as the probability of the short trial increased, mice waited longer before switching from the short to long location (experiment 1). These behavioral adjustments were in directions predicted by reward maximization. These results suggest that rather than gradually adjusting their time-dependent choice behavior, mice abruptly adopted temporal decision strategies by directly integrating their previous knowledge of task parameters into their timed behavior, supporting the model-based representational account of temporal risk assessment. 
26731530	Hallucinations and delusions are the most prominent symptoms of schizophrenia and characterized by impaired reality testing. Representation-mediated taste aversion (RMTA) has been proposed as a potential behavioral assessment of reality testing and has been applied to a neurodevelopmental rat model of schizophrenia. However, the theory underlying this approach has not been generalized yet with any demonstration of impaired reality testing in other animal models of schizophrenia, such as genetically-modified mice. We devised a RMTA procedure for mice that combines a Pavlovian association protocol pairing odor conditioned stimulus (CS) with sugar reward unconditioned stimulus (US), and a conditioned taste aversion (CTA) method. In this RMTA paradigm, we compared performances of wild-type (PLCβ1+/+) mice and phospholipase C β1 knock-out (PLCβ1-/-) mice which are known as one of the genetic models for schizophrenia. With a minimal amount of initial odor-sugar associative training, both PLCβ1+/+ and PLCβ1-/- mice were able to form an aversion to the sugar reward when the odor CS predicting sugar was paired with nausea. With an extended initial training, however, only PLCβ1-/- mice could form a RMTA. This persistent RMTA displayed by PLCβ1-/- mice shows their inability to distinguish real sugar from the CS-evoked representation of sugar at a stage in associative learning where wild-type mice normally could differentiate the two. These results demonstrate an impaired reality testing first observed in a genetic mouse model of schizophrenia, and suggest that RMTA paradigm may, with general applicability, allow diverse biological approaches to impaired reality testing. 
26731403	High comorbidity among pediatric disorders characterized by behavioral and emotional dysregulation poses problems for diagnosis and treatment, and suggests that these disorders may be better conceptualized as dimensions of abnormal behaviors. Furthermore, identifying neuroimaging biomarkers related to dimensional measures of behavior may provide targets to guide individualized treatment. We aimed to use functional neuroimaging and pattern regression techniques to determine whether patterns of brain activity could accurately decode individual-level severity on a dimensional scale measuring behavioural and emotional dysregulation at two different time points.A sample of fifty-seven youth (mean age: 14.5 years; 32 males) was selected from a multi-site study of youth with parent-reported behavioral and emotional dysregulation. Participants performed a block-design reward paradigm during functional Magnetic Resonance Imaging (fMRI). Pattern regression analyses consisted of Relevance Vector Regression (RVR) and two cross-validation strategies implemented in the Pattern Recognition for Neuroimaging toolbox (PRoNTo). Medication was treated as a binary confounding variable. Decoded and actual clinical scores were compared using Pearson's correlation coefficient (r) and mean squared error (MSE) to evaluate the models. Permutation test was applied to estimate significance levels.	Relevance Vector Regression identified patterns of neural activity associated with symptoms of behavioral and emotional dysregulation at the initial study screen and close to the fMRI scanning session. The correlation and the mean squared error between actual and decoded symptoms were significant at the initial study screen and close to the fMRI scanning session. However, after controlling for potential medication effects, results remained significant only for decoding symptoms at the initial study screen. Neural regions with the highest contribution to the pattern regression model included cerebellum, sensory-motor and fronto-limbic areas.	The combination of pattern regression models and neuroimaging can help to determine the severity of behavioral and emotional dysregulation in youth at different time points.	
26730406	Decision-making studies have implicated the ventromedial prefrontal cortex (vmPFC) in tracking the value of rewards and punishments. At the same time, fear-learning studies have pointed to a role of the same area in updating previously learned cue-outcome associations. To disentangle these accounts, we used a reward reversal-learning paradigm in a functional magnetic resonance imaging study in 18 human participants. Participants first learned that one of two colored squares (color A) was associated with monetary reward, whereas the other (color B) was not, and then had to learn that these contingencies reversed. Consistent with value representation, activity of a dorsal region of vmPFC was positively correlated with reward magnitude. Conversely, a more ventral region of vmPFC responded more to color A than to color B after contingency reversal, compatible with a role of inhibiting the previously learned response that was no longer appropriate. Moreover, the response strength was correlated with subjects' behavioral learning strength. Our findings provide direct evidence for the spatial dissociation of value representation and affective response inhibition in the vmPFC. 
26729938	Humans cooperate in large groups of unrelated individuals, and many authors have argued that such cooperation is sustained by contingent reward and punishment. However, such sanctioning systems can also stabilize a wide range of behaviours, including mutually deleterious behaviours. Moreover, it is very likely that large-scale cooperation is derived in the human lineage. Thus, understanding the evolution of mutually beneficial cooperative behaviour requires knowledge of when strategies that support such behaviour can increase when rare. Here, we derive a simple formula that gives the relatedness necessary for contingent cooperation in n-person iterated games to increase when rare. This rule applies to a wide range of pay-off functions and assumes that the strategies supporting cooperation are based on the presence of a threshold fraction of cooperators. This rule suggests that modest levels of relatedness are sufficient for invasion by strategies that make cooperation contingent on previous cooperation by a small fraction of group members. In contrast, only high levels of relatedness allow the invasion by strategies that require near universal cooperation. In order to derive this formula, we introduce a novel methodology for studying evolution in group structured populations including local and global group-size regulation and fluctuations in group size. 
26729033	This unit is designed to facilitate implementation of the fixed and progressive ratio paradigms and the effort-related choice task in the rodent touchscreen apparatus to permit direct measurement of motivation and reward-related decision making in this equipment. These protocols have been optimized for use in the mouse and reliably yield stable performance levels that can be enhanced or suppressed by systemic pharmacological manipulation. Instructions are also provided for the adjustment of task parameters to permit use in mouse models of neurodegenerative disease. These tasks expand the utility of the rodent touchscreen apparatus beyond the currently available battery of cognitive assessment paradigms.
26728894	Several lines of evidence suggest that endocannabinoid and nicotinic cholinergic systems are implicated in the regulation of different physiological processes, including reward, and in the neuropathological mechanisms of psychiatric diseases, such as addiction. A crosstalk between these two systems is substantiated by the overlapping distribution of cannabinoid and nicotinic acetylcholine receptors in many brain structures.We will review recent preclinical data showing how the endocannabinoid and nicotinic cholinergic systems interact bidirectionally at the level of the brain reward pathways, and how this interaction plays a key role in modulating nicotine and cannabinoid intake and dependence.	Many behavioral and neurochemical effects of nicotine that are related to its addictive potential are reduced by pharmacological blockade or genetic deletion of type-1 cannabinoid receptors, inhibition of endocannabinoid uptake or metabolic degradation, and activation of peroxisome proliferator-activated-receptor-α. On the other hand, cholinergic antagonists at α7 nicotinic acetylcholine receptors as well as endogenous negative allosteric modulators of these receptors are effective in blocking dependence-related effects of cannabinoids.	Pharmacological manipulation of the endocannabinoid system and endocannabinoid-like neuromodulators shows promise in the treatment of nicotine dependence and in relapse prevention. Likewise, drugs acting at nicotinic acetylcholine receptors might prove useful in the therapy of cannabinoid dependence. Research by Steven R. Goldberg has significantly contributed to the progress in this research field.	
26724460	Data collected over the last decade has begun to implicate behavioural impulsivity in overeating behaviour. However, recent work has suggested that the reinforcing value of food may be associated with impulsive choice (a sub-type of impulsivity), but to date no study has examined how the reinforcing value of food relates to other aspects of impulsivity. To examine these inter-relationships, 80 women completed measures of eating (a snack intake test and the Three-Factor Eating Questionnaire and then in a separate test session an inhibitory control task, a delay discounting task, a reflection impulsivity task, and a measure of the reinforcing value of their chosen snack foods. Participants also completed the Behavioural Inhibition System/Behavioural Activation System (BIS/BAS) questionnaire to examine self-report and behavioural parallels between measures. In regression models, only Behavioural Inhibition System subscales of the BIS/BAS predicted increased responding on the reinforcing value of food task. The reinforcing value of food task predicted and trended to predict calorie and grams intake of snack foods in regression models, supporting RRV as a predictive measure of short-term snack intake. Likewise, impulsive choice and inhibitory control was not related to eating measures. Methodological implications are discussed. 
26724386	Midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta and ventral tegmental area regulate extrapyramidal movement and important cognitive functions, including motivation, reward associations, and habit learning. Dysfunctions in DA neuron circuitry have been implicated in several neuropsychiatric disorders, including addiction and schizophrenia, whereas selective degeneration of DA neurons in substantia nigra pars compacta is a key neuropathological feature in Parkinson disease. Efforts to understand these disorders have focused on dissecting the underlying causes, as well as developing therapeutic strategies to replenish dopamine deficiency. In particular, the promise of cell replacement therapies for clinical intervention has led to extensive research in the identification of mechanisms involved in DA neuron development. It is hoped that a comprehensive understanding of these mechanisms will lead to therapeutic strategies that improve the efficiency of DA neuron production, engraftment, and function. This review provides a comprehensive discussion on how Wnt/β-catenin and sonic hedgehog-Smoothened signaling mechanisms control the specification and expansion of DA progenitors and the differentiation of DA neurons. We also discuss how mechanisms involving transforming growth factor-β and transcriptional cofactor homeodomain interacting protein kinase 2 regulate the survival and maturation of DA neurons in early postnatal life. These results not only reveal fundamental mechanisms regulating DA neuron development, but also provide important insights to their potential contributions to neuropsychiatric and neurodegenerative diseases. 
26723281	Instrumental renewal, the return of extinguished instrumental responding after removal from the extinction context, is an important model of behavioral relapse that is poorly understood at the neural level. In two experiments, we examined the role of the dorsomedial prefrontal cortex (dmPFC) and the ventromedial prefrontal cortex (vmPFC) in extinction and ABA renewal of instrumental responding for a sucrose reinforcer. Previous work, exclusively using drug reinforcers, has suggested that the roles of the dmPFC and vmPFC in expression of extinction and ABA renewal may depend at least in part on the type of drug reinforcer used. The current experiments used a food reinforcer because the behavioral mechanisms underlying the extinction and renewal of instrumental responding are especially well worked out in this paradigm. After instrumental conditioning in context A and extinction in context B, we inactivated dmPFC, vmPFC, or a more ventral medial prefrontal cortex region by infusing baclofen/muscimol (B/M) just prior to testing in both contexts. In rats with inactivated dmPFC, ABA renewal was still present (i.e., responding increased when returned to context A); however responding was lower (less renewal) than controls. Inactivation of vmPFC increased responding in context B (the extinction context) and decreased responding in context A, indicating no renewal in these animals. There was no effect of B/M infusion on rats with cannula placements ventral to the vmPFC. Fluorophore-conjugated muscimol was infused in a subset of rats following test to visualize infusion spread. Imaging suggested that the infusion spread was minimal and mainly constrained to the targeted area. Together, these experiments suggest that there is a region of medial prefrontal cortex encompassing both dmPFC and vmPFC that is important for ABA renewal of extinguished instrumental responding for a food reinforcer. In addition, vmPFC, but not dmPFC, is important for expression of extinction of responding for a food reinforcer. The role of the medial prefrontal cortex in renewal in the original conditioning context may depend in part on control over excitatory context-response or context-(response-outcome) relations that might be learned in acquisition. The role of the vmPFC in expression of extinction may depend on its control over inhibitory context-response or context-(response-outcome) relations that are learned in extinction. 
26722992	Heavy drinking patterns during marriage can be problematic for both spouses and the relationship. Moreover, spouses use different strategies in an attempt to change their partner's drinking behavior, which can impact the relationship in different ways. The current research examined whether associations between heavy drinking and marital adjustment are mediated by partner regulation strategies (i.e., punishment and reward). Married couples (N=123 dyads) with at least one spouse who consumed alcohol regularly and at least one undergraduate spouse completed web-based assessments at baseline and three and six months later. Mediation hypotheses were tested using a repeated-measures version of the Actor-Partner Interdependence Model. As predicted, a significant partner effect emerged suggesting that heavy drinking was associated with greater use of punishment strategies, which were in turn associated with diminished satisfaction. Another significant partner effect revealed that heavy drinking also predicted greater use of reward strategies, which were positively associated with satisfaction. However, the magnitude of the indirect effects via punishment was more than twice as large as the mediated effect via reward. Results underscore the importance of an interdependent, dyadic perspective in understanding associations between heavy drinking and marital outcomes as well as differences between punishing and rewarding regulation strategies in these associations. 
26722017	The hypothalamic peptide oxytocin (OXT) has been identified as a key modulator of pair-bonding in men, but its effects in women are still elusive. Moreover, there is substantial evidence that hormonal contraception (HC) influences partner preferences and sexual satisfaction, which constitute core domains of OXT function. We thus hypothesized that OXT effects on partner-related behavioral and neural responses could be significantly altered in women using HC. In this functional magnetic resonance imaging study involving 40 pair-bonded women, 21 of whom were using HC, we investigated whether a 24-IU nasal dose of OXT would modulate brain reward responses evoked by the romantic partner's face relative to the faces of familiar and unfamiliar people. Treatment with OXT increased the perceived attractiveness of the partner relative to other men, which was paralleled by elevated responses in reward-associated regions, including the nucleus accumbens. These effects of OXT were absent in women using HC. Our results confirm and extend previous findings in men that OXT interacts with the brain reward system to reinforce partner value representations, indicating a common OXT-dependent mechanism underlying partner attraction in both sexes. This mechanism may be disturbed in women using HC, suggesting that gonadal steroids could alter partner-specific OXT effects.
26722001	Motivation for reward drives adaptive behaviors, whereas impairment of reward perception and experience (anhedonia) can contribute to psychiatric diseases, including depression and schizophrenia. We sought to test the hypothesis that the medial prefrontal cortex (mPFC) controls interactions among specific subcortical regions that govern hedonic responses. By using optogenetic functional magnetic resonance imaging to locally manipulate but globally visualize neural activity in rats, we found that dopamine neuron stimulation drives striatal activity, whereas locally increased mPFC excitability reduces this striatal response and inhibits the behavioral drive for dopaminergic stimulation. This chronic mPFC overactivity also stably suppresses natural reward-motivated behaviors and induces specific new brainwide functional interactions, which predict the degree of anhedonia in individuals. These findings describe a mechanism by which mPFC modulates expression of reward-seeking behavior, by regulating the dynamical interactions between specific distant subcortical regions. 

26721172	In operant conditioning, rats pressing levers and pigeons pecking keys depend on contingent food reinforcement. Food reward agrees with Skinner's behaviorism, undergraduate textbooks, and folk psychology. However, nearly a century of experimental evidence shows, instead, that food in an operant conditioning chamber acts forward to evoke species-specific feeding behavior rather than backward to reinforce experimenter-defined responses. Furthermore, recent findings in neuroscience show consistently that intracranial stimulation to reward centers and dopamine release, the proposed reward molecule, also act forward to evoke inborn species-specific behavior. These results challenge longstanding views of hedonic learning and must be incorporated into contemporary learning theory.
26718607	The ability of neurons to change the amount or type of neurotransmitter they use, or 'neurotransmitter plasticity', is an emerging new form of adult brain plasticity. For example, it has recently been shown that neurons in the adult rat hypothalamus up- or down-regulate dopamine (DA) neurotransmission in response to the amount of light the animal receives (photoperiod), and that this in turn affects anxiety- and depressive-like behaviors (Dulcis et al., 2013). In this Chapter I consolidate recent evidence from my laboratory suggesting neurons in the adult mouse substantia nigra pars compacta (SNc) also undergo DA neurotransmitter plasticity in response to persistent changes in their electrical activity, including that driven by the mouse's environment or behavior. Specifically, we have shown that the amounts of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) gene promoter activity, TH mRNA and TH protein in SNc neurons increases or decreases after ∼20h of altered electrical activity. Also, infusion of ion-channel agonists or antagonists into the midbrain for 2 weeks results in ∼10% (∼500 neurons) more or fewer TH immunoreactive (TH+) SNc neurons, with no change in the total number of SNc neurons (TH+ and TH-). Targeting ion-channels mediating cell-autonomous pacemaker activity in, or synaptic input and afferent pathways to, SNc neurons are equally effective in this regard. In addition, exposing mice to different environments (sex pairing or environment enrichment) for 1-2 weeks induces ∼10% more or fewer TH+ SNc (and ventral tegmental area or VTA) neurons and this is abolished by concurrent blockade of synaptic transmission in midbrain. Although further research is required to establish SNc (and VTA) DA neurotransmitter plasticity, and to determine whether it alters brain function and behavior, it is an exciting prospect because: (1) It may play important roles in movement, motor learning, reward, motivation, memory and cognition; and (2) Imbalances in midbrain DA cause symptoms associated with several prominent brain and behavioral disorders such as schizophrenia, addiction, obsessive-compulsive disorder, depression, Parkinson's disease and attention-deficit and hyperactivity disorder. Midbrain DA neurotransmitter plasticity may therefore play a role in the etiology of these symptoms, and might also offer new treatment options. 
28163893	Background: Potassium channels have been shown to be involved in neural plasticity and learning. Kv4.2 is a subunit of the A-type potassium channel. Kv4.2 channels modulate excitability in the dendrites of pyramidal neurons in the cortex and hippocampus. Deletion of Kv4.2 results in spatial learning and conditioned fear deficits; however, previous studies have only examined deletion of Kv4.2 in aversive learning tests. Methods: For the current study, we used the Lashley maze as an appetitive learning test. We examined Kv4.2 wildtype (WT) and knockout (KO) mice in the Lashley maze over 4 days during adulthood. The first day consisted of habituating the mice to the maze. The mice then received five trials per day for the next 3 days. The number of errors and the time to the goal box was recorded for each trial. The goal box contained a weigh boat with an appetitive reward (gelatin with sugar). There was an intertrial interval of 15 minutes. Results: We found that Kv4.2 KO mice committed more errors across the trials compared to the WT mice p<0.001. There was no difference in the latency to find the goal box over the period. Discussion: Our finding that deletion of Kv4.2 resulted in more errors in the Lashley maze across 15 trials contribute to a growing body of evidence that Kv4.2 channels are significantly involved in learning and memory.
26716004	In many species, males tend to have lower parental investment than females and greater variance in their reproductive success. Males might therefore be expected to adopt more high-risk, high-return behaviours than females. Next to risk-taking behaviour itself, sexes might also differ in how they respond to information and learn new associations owing to the fundamental link of these cognitive processes with the risk-reward axis. Here we investigated sex differences in both risk-taking and learned responses to risk by measuring male and female rats' (Rattus norvegicus) behaviour across three contexts in an open field test containing cover. We found that when the environment was novel, males spent more time out of cover than females. Males also hid less when exposed to the test arena containing predator odour. By contrast, females explored more than males when the predator odour was removed (associatively learned risk). These results suggest that males are more risk-prone but behave more in line with previous experiences, while females are more risk-averse and more responsive to changes in their current environment. Our results suggest that male and female rats differ in how they cope with risk and highlight that a general link may exist between risk-taking behaviour and learning style. 
26715366	Environmental reward-predictive stimuli provide a major source of motivation for instrumental reward-seeking activity and this has been linked to dopamine signaling in the nucleus accumbens (NAc) core. This cue-induced incentive motivation can be quite general, not restricted to instrumental actions that earn the same unique reward, and is also typically regulated by one's current need state, such that cues only motivate actions when this is adaptive. But it remains unknown whether cue-evoked dopamine signaling is similarly regulated by need state. Here, we used fast-scan cyclic voltammetry to monitor dopamine concentration changes in the NAc core of rats during a Pavlovian-to-instrumental transfer task in which the motivating influence of two cues, each signaling a distinct food reward (sucrose or food pellets), over an action earning a third unique food reward (polycose) was assessed in a state of hunger and of satiety. Both cues elicited a robust NAc dopamine response when hungry. The magnitude of the sucrose cue-evoked dopamine response correlated with the Pavlovian-to-instrumental transfer effect that was selectively induced by this stimulus. Satiety attenuated these cue-evoked dopamine responses and behavioral responding, even though rats had never experienced the specific food rewards in this state. These data demonstrate that cue-evoked NAc core responses are sensitive to current need state, one critical variable that determines the current adaptive utility of cue-motivated behavior. Food-predictive stimuli motivate food-seeking behavior. Here, we show that food cues evoke a robust nucleus accumbens core dopamine response when hungry that correlates with the cue's ability to invigorate general food seeking. This response is attenuated when sated, demonstrating that food cue-evoked accumbens dopamine responses are sensitive to the need state information that determines the current adaptive utility of cue-motivated action. 
26713775	Successful adjustment to dynamic environments requires the simultaneous pursuit of multiple goals. However, the pursuit of multiple goals may bring about goal conflict. Despite evidence indicating that goal conflict can have a detrimental effect on subjective well-being, little is known about the effects of goal competition in the context of pain. This experiment investigated whether different types of goal competition increase pain-related fear and slow pain-related decision-making. Forty-six participants completed a cross-directional movement task in which they learned to associate movements in 1 direction (eg, left) with pain, and movements in the opposite direction (eg, right) with safety; and that movements in other directions (eg, up and down) were associated with reward and loss of reward, respectively. In the test phase, both phases were combined, creating different types of goal competition. The results showed that participants were most afraid of movements associated with 2 concurrent avoidance goals, and the least afraid of movements associated with approach-approach competition. Additionally, participants were slower in making a choice when presented with an avoidance-avoidance competition compared with approach-approach and avoidance-approach competition. These findings suggest that avoidance-avoidance competition increased fear and slowed decision-making compared with other types of competition.This study provides experimental evidence for the differential effects of various goal conflicts on pain-related fear and decision-making. This knowledge may improve our understanding of patients' behavior when experiencing goal conflict and may contribute to improving treatments by addressing multiple goals patients are pursuing, and not just pain avoidance/reduction.	

26711909	Somatosensory learning and memory studies in rodents have primarily focused on the role of whiskers and the barrel structure of the sensory cortex, characteristics unique to rodents. In contrast, whether associative learning can occur in animals (and humans) via foot stimulation remains unclear. The sensory cortex corresponding to the plantar foot surface is localized in the centroparietal area, providing relatively easy access for studying somatosensory learning and memory. To assess the contribution of sole stimulation to somatosensory learning and memory, we developed a novel operant-lever-pressing task. In Experiment 1, head-fixed mice were trained to press a lever to receive a water reward upon presentation of an associated stimulus (S+). Following training, they were administered a reversal-learning protocol, in which "S+ " and "S-" (a stimulus not associated with reward) were switched. Mice were then submitted to training with a progressively extended delay period between stimulation and lever presentation. In Experiment 2, the delayed discrimination training was replicated with longer delay periods and restricted training days, to further explore the results of Experiment 1. When the stimuli were presented to a single left hind paw, we found that male C57BL/6J mice were capable of learning to discriminate between different foot stimuli (electrical or mechanical), and of retaining this information for 10s. This novel task has potential applications for electrophysiological and optogenetic studies to clarify the neural circuits underlying somatosensory learning and behavior.
26710978	Pharmacotherapeutic agents that could facilitate extinction of cocaine cues would be useful in the treatment of cocaine addiction. We tested whether SR 21502, a selective dopamine (DA) D3 receptor antagonist, can facilitate extinction of cocaine conditioned place preference (CPP) in rats.In experiment 1, cocaine (10mg/kg) CPP was first established and then extinguished. During the extinction phase the rats were injected with SR 21502 and placed in the previously cocaine-paired compartment for four sessions and vehicle in the other compartment on four alternating sessions. The rats were then tested again for cocaine CPP. In experiment 2, different groups of rats were trained to associate SR 21502 with one compartment and saline with the other.	In experiment 1, the animals spent significantly more time in the cocaine-paired compartment after cocaine conditioning than they did before conditioning. Subsequently, the animals treated with SR 21502 during the extinction phase spent significantly less time in the cocaine-paired compartment than the vehicle group. In experiment 2, animals conditioned with SR 21502 preferred neither side of the CPP apparatus, indicating that SR 21502 produced no effects of its own.	These findings suggest that treatment with SR 21502, a DA D3 receptor antagonist, in the presence of cocaine cues can facilitate extinction of cocaine CPP and further suggest that this compound might be an effective cocaine addiction treatment.	
26709497	Recent findings indicate that monetary rewards have a powerful effect on cognitive performance. In order to maximize overall gain, the prospect of earning reward biases visual attention to specific locations or stimulus features improving perceptual sensitivity and processing. The question we addressed in this study is whether the prospect of reward also affects the subjective perception of time. Here, participants performed a prospective timing task using temporal oddballs. The results show that temporal oddballs, displayed for varying durations, presented in a sequence of standard stimuli were perceived to last longer when they signaled a relatively high reward compared to when they signaled no or low reward. When instead of the oddball the standards signaled reward, the perception of the temporal oddball remained unaffected. We argue that by signaling reward, a stimulus becomes subjectively more salient thereby modulating its attentional deployment and distorting how it is perceived in time. 
26708774	The prevailing view in the field of adolescent brain development is that heightened activity in the mesolimbic dopaminergic reward system serves as a liability, orienting adolescents toward risky behaviors, increasing their sensitivity to social evaluation and loss, and resulting in compromised well-being. Several findings inconsistent with this deficit view challenge the perspective that adolescent reward sensitivity largely serves as a liability and highlights the potential adaptive function that heightened striatal reactivity can serve. The goal of this review is to refine our understanding of dopaminergic reward sensitivity in adolescence. I review several studies showing that ventral striatum activation serves an adaptive function for adolescents' health and well being relating to declines in both risk taking and depression and increases in cognitive persistence and achievement. 
26708331	The seminal Marshmallow Test (Mischel & Ebbesen, 1970) has reliably demonstrated that children who can delay gratification are more likely to be emotionally stable and successful later in life. However, this is not good news for those children who can't delay. Therefore, this study aimed to explore whether a metacognitive therapy technique, Attention Training (ATT: Wells, 1990) can improve young children's ability to delay gratification. One hundred children participated. Classes of 5-6 year olds were randomly allocated to either the ATT or a no-intervention condition and were tested pre and post-intervention on ability to delay gratification, verbal inhibition (executive control), and measures of mood. The ATT intervention significantly increased (2.64 times) delay of gratification compared to the no-intervention condition. After controlling for age and months in school, the ATT intervention and verbal inhibition task performance were significant independent predictors of delay of gratification. These results provide evidence that ATT can improve children's self-regulatory abilities with the implication that this might reduce psychological vulnerability later in life. The findings highlight the potential contribution that the Self-Regulatory Executive Function (S-REF) model could make to designing techniques to enhance children's self-regulatory processes. 
26708084	Huntington's disease (HD) is a neurodegenerative disorder that produces a bias toward risky, reward-driven decisions in situations where the outcomes of decisions are uncertain and must be discovered. However, it is unclear whether HD patients show similar biases in decision-making when learning demands are minimized and prospective risks and outcomes are known explicitly. We investigated how risk decision-making strategies and adjustments are altered in HD patients when reward contingencies are explicit.HD (N=18) and healthy control (HC; N=17) participants completed a risk-taking task in which they made a series of independent choices between a low-risk/low reward and high-risk/high reward risk options.	Computational modeling showed that compared to HC, who showed a clear preference for low-risk compared to high-risk decisions, the HD group valued high-risks more than low-risk decisions, especially when high-risks were rewarded. The strategy analysis indicated that when high-risk options were rewarded, HC adopted a conservative risk strategy on the next trial by preferring the low-risk option (i.e., they counted their blessings and then played the surer bet). In contrast, following a rewarded high-risk choice, HD patients showed a clear preference for repeating the high-risk choice.	These results indicate a pattern of high-risk/high-reward decision bias in HD that persists when outcomes and risks are certain. The allure of high-risk/high-reward decisions in situations of risk certainty and uncertainty expands our insight into the dynamic decision-making deficits that create considerable clinical burden in HD.	
26707890	Decision theories mandate that organisms should adjust their behaviour in the light of the contextual reward statistics. We tested this notion using a gambling choice task involving distinct contexts with different reward distributions. The best fitting model of subjects' behaviour indicated that the subjective values of options depended on several factors, including a baseline gambling propensity, a gambling preference dependent on reward amount, and a contextual reward adaptation factor. Combining this behavioural model with simultaneous functional magnetic resonance imaging we probed neural responses in three key regions linked to reward and value, namely ventral tegmental area/substantia nigra (VTA/SN), ventromedial prefrontal cortex (vmPFC) and ventral striatum (VST). We show that activity in the VTA/SN reflected contextual reward statistics to the extent that context affected behaviour, activity in the vmPFC represented a value difference between chosen and unchosen options while VST responses reflected a non-linear mapping between the actual objective rewards and their subjective value. The findings highlight a multifaceted basis for choice behaviour with distinct mappings between components of this behaviour and value sensitive brain regions.
26706667	Disproportionately high rates of alcohol use disorders are present in many American Indian/Alaska Native (AI/AN) communities, yet little information exists regarding the effectiveness of alcohol treatments in AI/AN populations. Contingency management is an intervention for illicit drug use in which tangible reinforcers (rewards) are provided when patients demonstrate abstinence as assessed by urine drug tests. Contingency management has not been widely studied as an intervention for alcohol problems because until recently, no alcohol biomarker has been available to adequately verify abstinence.The HONOR Study is designed to determine whether a culturally-tailored contingency management intervention is an effective intervention for AI/AN adults who suffer from alcohol use disorders.	Participants include 400 AI/AN alcohol-dependent adults residing in one rural reservation, one urban community, as well as a third site to be decided, in the Western U.S. Participants complete a 4-week lead-in phase prior to randomization, then 12 weeks of either a contingency management intervention for alcohol abstinence, or a control condition where participants receive reinforcers for attending study visits regardless of alcohol use. Participants are then followed for 3-more months post-intervention. The primary study outcome is urinary ethyl glucuronide-confirmed alcohol abstinence; secondary outcomes include self-reported alcohol and drug use, HIV risk behaviors, and self-reported cigarette smoking.	This will be the largest randomized, controlled trial of any alcohol for AI/ANs and the largest contingency management study targeting alcohol use disorders, thus providing important information to AI/AN communities and the alcohol treatment field in general.	
26705698	Convergent evidence suggests that the basal ganglia support reinforcement learning by adjusting action values according to reward prediction errors. However, adaptive behavior in stochastic environments requires the consideration of uncertainty to dynamically adjust the learning rate. We consider how cholinergic tonically active interneurons (TANs) may endow the striatum with such a mechanism in computational models spanning three Marr's levels of analysis. In the neural model, TANs modulate the excitability of spiny neurons, their population response to reinforcement, and hence the effective learning rate. Long TAN pauses facilitated robustness to spurious outcomes by increasing divergence in synaptic weights between neurons coding for alternative action values, whereas short TAN pauses facilitated stochastic behavior but increased responsiveness to change-points in outcome contingencies. A feedback control system allowed TAN pauses to be dynamically modulated by uncertainty across the spiny neuron population, allowing the system to self-tune and optimize performance across stochastic environments. 
26704813	Orexinergic neurons originate from the hypothalamic nuclei, sending projections toward mesolimbic regions such as the nucleus accumbens (NAc). In this study, an attempt was made to determine the effects of intra-accumbal administration of SB334867 as an orexin-1 receptor (OX1R) antagonist and TCS OX2 29 as an orexin-2 receptor (OX2R) antagonist in the expression and maintenance of morphine-induced conditioned place preference (CPP) in rats. One hundred and five adult Wistar rats weighing 200-280g were bilaterally implanted with cannulae into the NAc. During the 3-day conditioning phase, animals received daily subcutaneous administration of morphine (5mg/kg). CPP score and locomotor activity of animals were recorded by Ethovision software. Different doses of bilateral injections of the OX1R and OX2R antagonists (3, 30 and 300μg/0.5μl DMSO) were administered just before the conditioning test or daily injection during extinction phase. Our finding revealed that intra-accumbal administration of OX1R not OX2R antagonist just before the CPP test attenuated the expression of the morphine-induced CPP. However, the blockade of these two kinds of receptors shortened the extinction phase in the rats. This effect was more significant in intra-NAc OX1R antagonist-treated animals. The results suggested that OX1R within the NAc may be necessary for the morphine-induced expression. Additionally, it seems that the existence of the orexin receptors in the NAc was important for the maintenance of morphine rewarding properties during the extinction phase. Therefore, orexins may be considered as a promising therapeutic agent in preventing the expression and maintenance of morphine rewarding effects on dependent individuals. 
26703459	Workplace health promotion (WHP) has been proposed as a preventive intervention for job stress, possibly operating by promoting positive organizational culture or via programs promoting healthy lifestyles. The aim of this study was to investigate whether job stress changed over time in association with the availability of, and/or participation in a comprehensive WHP program (Healthy@Work).This observational study was conducted in a diverse public sector organization (~28,000 employees). Using a repeated cross-sectional design with models corroborated using a cohort of repeat responders, self-report survey data were collected via a 40 % employee population random sample in 2010 (N = 3406) and 2013 (N = 3228). Outcomes assessed were effort and reward (self-esteem) components of the effort-reward imbalance (ERI) measure of job stress. Exposures were availability of, and participation in, comprehensive WHP. Linear mixed models and Poisson regression were used, with analyses stratified by sex and weighted for non-response.	Higher WHP availability was positively associated with higher perceived self-esteem among women. Women's mean reward scores increased over time but were not statistically different (p > 0.05) after 3 years. For men, higher WHP participation was associated with lower perceived effort. Men's mean ERI increased over time. Results were supported in the cohort group.	For women, comprehensive WHP availability contributed to a sense of organizational support, potentially impacting the esteem component of reward. Men with higher WHP participation also benefitted but gains were modest over time and may have been hindered by other work environment factors.	
26702397	Previous receptor binding studies suggest dopamine function is altered in the basal ganglia circuitry in task-specific dystonia, a condition characterized by contraction of agonist and antagonist muscles while performing specific tasks. Dopamine plays a role in reward-based learning. Using fMRI, this study compared 31 right-handed writer's cramp patients to 35 controls in reward-based learning of a probabilistic reversal-learning task. All subjects chose between two stimuli and indicated their response with their left or right index finger. One stimulus response was rewarded 80%, the other 20%. After contingencies reversal, the second stimulus response was rewarded in 80%. We further linked the DRD2/ANKK1-TaqIa polymorphism, which is associated with 30% reduction of the striatal dopamine receptor density with reward-based learning and assumed impaired reversal learning in A + subjects. Feedback learning in patients was normal. Blood-oxygen level dependent (BOLD) signal in controls increased with negative feedback in the insula, rostral cingulate cortex, middle frontal gyrus and parietal cortex (pFWE < 0.05). In comparison to controls, patients showed greater increase in BOLD activity following negative feedback in the dorsal anterior cingulate cortex (BA32). The genetic status was not correlated with the BOLD activity. The Brodmann area 32 (BA32) is part of the dorsal anterior cingulate cortex (dACC) that plays an important role in coordinating and integrating information to guide behavior and in reward-based learning. The dACC is connected with the basal ganglia-thalamo-loop modulated by dopaminergic signaling. This finding suggests disturbed integration of reinforcement history in decision making and implicate that the reward system might contribute to the pathogenesis in writer's cramp. 
26701649	The current study examined whether effort-cost computation was associated with negative symptoms of schizophrenia (SZ). Participants included outpatients diagnosed with SZ (n=27) and demographically matched healthy controls (n=32) who completed a Progressive Ratio task that required incrementally greater amounts of physical effort to obtain monetary reward. Breakpoint, the point at which participants was no longer willing to exert effort for a certain reward value, was examined as an index of effort-cost computation. There were no group differences in breakpoint for low, medium, or high value rewards on the Progressive Ratio task. However, lower breakpoint scores were associated with greater severity of avolition and anhedonia symptoms in SZ patients. Findings provide further evidence that impaired effort-cost computation is linked to motivational abnormalities in SZ. 
26700246	Prescription opiate use and abuse has increased dramatically over the past two decades, including increased use in adolescent populations. Recently, it has been proposed that use during this critical period may affect future offspring even when use is discontinued prior to conception. Here, we utilize a rodent model to examine the effects of adolescent morphine exposure on the reward functioning of the offspring. Female Sprague Dawley rats were administered morphine for 10 days during early adolescence (post-natal day 30-39) using an escalating dosing regimen. Animals then remained drug free until adulthood at which point they were mated with naïve males. Adult offspring (F1 animals) were tested for their response to morphine-induced (0, 1, 2.5, 5, and 10 mg/kg, s.c.) conditioned place preference (CPP) and context-independent morphine-induced sensitization. Naïve littermates were used to examine mu opiate receptor expression in the nucleus accumbens and ventral tegmental area. Results indicate that F1 females whose mothers were exposed to morphine during adolescence (Mor-F1) demonstrate significantly enhanced CPP to the lowest doses of morphine compared with Sal-F1 females. There were no differences in context-independent sensitization between maternal treatment groups. Protein expression analysis showed significantly increased levels of accumbal mu opiate receptor in Mor-F1 offspring and decreased levels in the VTA. Taken together, these findings demonstrate a shift in the dose response curve with regard to the rewarding effects of morphine in Mor-F1 females which may in part be due to altered mu opiate receptor expression in the nucleus accumbens and VTA.
26699940	Substantial evidence suggests that the phasic activity of dopamine neurons represents reinforcement learning's temporal difference prediction error. However, recent reports of ramp-like increases in dopamine concentration in the striatum when animals are about to act, or are about to reach rewards, appear to pose a challenge to established thinking. This is because the implied activity is persistently predictable by preceding stimuli, and so cannot arise as this sort of prediction error. Here, we explore three possible accounts of such ramping signals: (a) the resolution of uncertainty about the timing of action; (b) the direct influence of dopamine over mechanisms associated with making choices; and (c) a new model of discounted vigour. Collectively, these suggest that dopamine ramps may be explained, with only minor disturbance, by standard theoretical ideas, though urgent questions remain regarding their proximal cause. We suggest experimental approaches to disentangling which of the proposed mechanisms are responsible for dopamine ramps. 

26698397	Although gambling disorder is a serious social problem in modern societies, information about the behavioral traits that could determine vulnerability to this psychopathology is still scarce. In this study, we used a recently developed ambiguous-cue interpretation ​(ACI)​ paradigm to investigate whether 'optimism' and 'pessimism' as behavioral traits may determine the gambling-like behavior of rodents. In a series of ACI tests (cognitive bias screening), we identified rats that displayed 'pessimistic' and 'optimistic' traits. Subsequently, using the rat slot machine task (rSMT), we investigated if the 'optimistic'/'pessimistic' traits could determine the crucial feature of gambling-like behavior that has been investigated in rats and humans: the ​interpretation of 'near-miss' outcomes as a positive (i.e., win) situation. We found that 'optimists' did not interpret 'near-miss', 'near loss', or 'clear win' as win trials more often than ​their 'pessimistic' ​conspecifics; however, the 'optimists' were statistically more likely to reach for a reward in the hopeless 'clear loss' situation. This agrees with human studies and provides a platform for modeling interactions between behavioral traits and gambling in animals. 
26698021	Eating disorders (EDs) and overweight/obesity (OW/OB) are serious public health concerns that share common neuropsychological features and patterns of disturbed eating. Reward-related decision making as a basic neurocognitive function may trans-diagnostically underlie both pathological overeating and restricted eating. The present meta-analysis synthesizes the evidence from N=82 neuropsychological studies for altered reward-related decision making in all ED subtypes, OW and OB. The overall effect sizes for the differences between currently-ill ED patients and OW/OB people and controls were Hedge's g=-0.49 [CI: -0.63; -0.35], and Hedge's g=-0.39 [CI: -0.53; -0.25], respectively. Decision making was found to be altered to similar degrees in all ED subtypes and OB. Effect sizes, however, diverged for the different measures of decision making. Adolescents appear to be less affected than adults. When foods were used as rewarding stimuli, decision making was found to be intact in OB. The findings support that altered general reward-related decision making is a salient neuropsychological factor across eating and weight disorders in adulthood. 
26698020	Less than two decades after its inception, the burgeoning field of neuroaesthetics continues to grow in interest and momentum. Despite the biological and social importance of the human body and the attention people pay to its appearance in daily life, only recently has neuroaesthetic inquiry turned its attention to questions concerning the aesthetic appraisal of the human body. We review evidence illustrating that the complexity of aesthetic experience is reflected by dynamic interplay between brain systems involved in reward, perceptual and motor processing, with a focus on aesthetic perception involving the human body. We then evaluate work demonstrating how these systems are modulated by beholders' expertise or familiarity. Finally, we discuss seminal studies revealing the plasticity of behavioural and neural responses to beauty after perceptual and motor training. This research highlights the rich potential for neuroaesthetic inquiry to extend beyond its typical realm of the fine arts to address important questions regarding the relationship between embodiment, aesthetics and performing arts. We conclude by considering some of the criticisms and limitations of neuroaesthetics, and highlight several outstanding issues for future inquiry. 
26695169	Pavlovian stimuli exert a range of effects on behavior from simple conditioned reflexes, such as salivation, to altering the vigor and direction of instrumental actions. It is currently accepted that these distinct behavioral effects stem from two sources (i) the various associative connections between predictive stimuli and the component features of the events that these stimuli predict and (ii) the distinct motivational and cognitive functions served by cues, particularly their arousing and informational effects on the selection and performance of specific actions. Here, we describe studies that have assessed these latter phenomena using a paradigm that has come to be called Pavlovian-instrumental transfer. We focus first on behavioral experiments that have described distinct sources of stimulus control derived from the general affective and outcome-specific predictions of conditioned stimuli, referred to as general transfer and specific transfer, respectively. Subsequently, we describe research efforts attempting to establish the neural bases of these transfer effects, largely in the afferent and efferent connections of the nucleus accumbens (NAc) core and shell. Finally, we examine the role of predictive cues in examples of aberrant stimulus control associated with psychiatric disorders and addiction. 
26694811	Effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue, are an important aspect of depression and other disorders. Motivational symptoms are resistant to some treatments, including serotonin transport (SERT) inhibitors.Tests of effort-based choice using operant behavior tasks (e.g., concurrent lever pressing/ chow feeding tasks) can be used as animal models of motivational symptoms. Tests of effort-related choice allow animals to choose between high-effort actions that lead to more highly valued rewards vs. low-effort alternatives that lead to less valued rewards (i.e., less preferred or lower magnitude). Rats treated with the vesicular monoamine transport inhibitor tetrabenazine, or the cytokine interleukin-1β (IL-1β), which are associated with depressive symptoms in humans, can alter effort-related choice, reducing selection of the high effort alternative (lever pressing) while increasing intake of freely available chow.	The present studies focused upon the ability of lisdexamfetamine (LDX) to increase exertion of effort in rats responding on effort-based choice tasks under several different conditions.	LDX attenuated the shift from fixed ratio 5 lever pressing to chow intake induced by tetrabenazine and IL-1β. In contrast, the SERT inhibitor s-citalopram failed to reverse the effects of tetrabenazine. When given in combination with tetrabenazine+s-citalopram, LDX significantly increased lever pressing output compared to tetrabenaine+citalopram alone. LDX also increased work output in rats responding on a progressive ratio/chow feeding choice task.	LDX can increase work output in rats responding on effort-based choice tasks, which may have implications for understanding the neurochemistry of motivational symptoms in humans.	
26692452	Orexins are hypothalamic peptides involved in the modulation of the feeding, arousal, reward function, learning, and memory; nevertheless, the role of orexins in stress and relapse are largely unclear. Therefore, in the present study, the reinstatement model were used to examine the effects of intradentate gyrus (DG) administration of SB334867 as an orexin-1 receptor antagonist and TCS OX2 29, as an orexin-2 receptor antagonist on drug priming- and forced swim stress (FSS)-induced reinstatement of morphine. One-hundred and 44 adult male albino Wistar rats weighing 200 g-280 g were bilaterally implanted by cannulas into the DG. For induction of conditioned place preference (CPP), subcutaneous (sc) injection of morphine (5 mg/kg) was used daily during a 3-day conditioning phase. Then, the conditioning score (conditional stimulus [CS]) was calculated. After a 24 hr "off" period following achievement of extinction criterion, rats were tested for drug priming-induced reinstatement by priming dose of morphine (1 mg/kg, sc) and for FSS-induced reinstatement 10 min after FSS. In the next experiments, animals received different doses of intra-DG administration of SB334867 and TCS OX2 29 (3, 10, and 30 μg/0.5 μl 12% DMSO per side), bilaterally and were subsequently tested for morphine priming- and FSS-induced reinstatement. Our findings indicated that the FSS-induced the reinstatement of seeking behaviors. Furthermore, intra-DG administration of orexin-1 and orexin-2 receptor antagonists attenuated drug priming-induced reinstatement dose-dependently. However, they have trivial role in FSS-induced reinstatement. It is concluded that drug priming-induced reinstatement may be mediated, at least in part, by stimulation of orexin receptors in the DG.
26692448	Previous studies showed that the anterior cingulate cortex (ACC) plays a role in selective visual attention. The current study further examined the role of the ACC in attention using a visual cuing task with task-relevant and task-irrelevant stimuli. On every trial, 2 stimuli were presented on the touchscreen; 1 was task-relevant and the other was task-irrelevant. Rats were trained to attend to the task-relevant stimulus over the task-irrelevant stimulus to determine which side of the touchscreen should be selected for reward. After the rats were well-trained, cannulas targeting the ACC were implanted bilaterally for infusions of PBS or muscimol. When the ACC was functionally intact, high task performance was correlated with the anticipatory touches toward the reward; rats touched the stimulus proximal to the correct side more often, regardless of its task-relevancy. Analysis of the presurgery training data showed that rats developed anticipatory touches during training. Linear discriminant analyses of the touches also showed that the touches predict rats' choices in trials. With muscimol infusions, choice accuracy was impaired and the anticipatory touches toward the correct response location were less frequent. A control experiment, in which there were no irrelevant stimuli, showed no effects of ACC inactivation on choice accuracy or anticipatory touches. These results indicate that the rat ACC plays a critical role in reducing distraction from irrelevant stimuli as well as in guiding attention toward the goal locations.
26691848	In delay discounting, temporally remote outcomes have less value. Cigarette smoking is associated with steeper discounting of money and consumable outcomes. It is presently unclear whether smokers discount health outcomes more than nonsmokers. We sought to establish the generality of steep discounting for different types of health outcomes in cigarette smokers. Seventy participants (38 smokers and 32 nonsmokers) completed 4 hypothetical outcome delay-discounting tasks: a gain of $500, a loss of $500, a temporary boost in health, and temporary cure from a debilitating disease. Participants reported the duration of each health outcome that would be equivalent to $500; these durations were then used in the respective discounting tasks. Delays ranged from 1 week to 25 years. Smokers' indifference points for monetary gains, boosts in health, and temporary cures were lower than indifference points from nonsmokers. Indifference points of 1 outcome were correlated with indifference points of other outcomes. Smokers demonstrate steeper discounting across a range of delayed outcomes. How a person discounts 1 outcome predicts how they will discount other outcomes. These 2 findings support our assertion that delay discounting is in part a trait. 
26690807	Social rewards are processed by the same dopaminergic-mediated brain networks as non-social rewards, suggesting a common representation of subjective value. Individual differences in personality and motivation influence the reinforcing value of social incentives, but it remains open whether the pursuit of social incentives is analogously supported by the neural reward system when positive social stimuli are connected to approach behavior. To test for a modulation of neural activation by approach motivation, individuals with high and low approach motivation (BAS) completed implicit and explicit social approach-avoidance paradigms during fMRI. High approach motivation was associated with faster implicit approach reactions as well as a trend for higher approach ratings, indicating increased approach tendencies. Implicit and explicit positive social approach was accompanied by stronger recruitment of the nucleus accumbens, middle cingulate cortex, and (pre-)cuneus for individuals with high compared to low approach motivation. These results support and extend prior research on social reward processing, self-other distinctions and affective judgments by linking approach motivation to the engagement of reward-related circuits during motivational reactions to social incentives. This interplay between motivational preferences and motivational contexts might underlie the rewarding experience during social interactions. 
26690806	Adolescence is a particularly vulnerable period for the onset of substance use disorders and other psychopathology. Individual variability in motivational tendencies and temperament and significant changes in functional brain organization during adolescence are important factors to consider in the development of substance use and dependence. Recent conceptualizations suggest that sensitivity to reward is heightened in adolescence and that this motivation tendency may precipitate subsequent substance abuse. The present study examined the role of personality traits in mesolimbic neurobehavioral response on a monetary incentive delay (MID) task in young adolescents (11-14 years) and emerging adults (18-25 years) using functional magnetic resonance imaging. As a group, adolescents were not more sensitive to gains than losses compared to adults during either anticipatory and feedback phases; instead, compared to adults they showed less sensitivity to incentive magnitude in mesolimbic circuitry during anticipation and feedback stages. However, personality modulated this response such that adolescents high in impulsivity or low in avoidance tendencies showed greater gain sensitivity and adolescents high in avoidance showed greater loss sensitivity during cue anticipation. In adults, mesolimbic response was modulated by the impulsivity construct such that high-impulsive adults showed reduced magnitude sensitivity during both anticipation and feedback compared to low impulsive adults. The present findings suggest that impulsive personality significantly modulates mesolimbic reward response during both adolescence and adulthood but avoidance and approach tendencies also modulate this response in adolescents. Moreover, personality modulated incentive valence in adolescents but incentive magnitude in adults. Collectively, these findings suggest that mesolimbic reward circuitry function is modulated by somewhat different parameters in adolescence than in adulthood.
26690805	Older and younger adults performed a state-based decision-making task while undergoing functional MRI (fMRI). We proposed that younger adults would be more prone to base their decisions on expected value comparisons, but that older adults would be more reactive decision-makers who would act in response to recent changes in rewards or states, rather than on a comparison of expected values. To test this we regressed BOLD activation on two measures from a sophisticated reinforcement learning (RL) model. A value-based regressor was computed by subtracting the immediate value of the selected alternative from its long-term value. The other regressor was a state-change uncertainty signal that served as a proxy for whether the participant's state improved or declined, relative to the previous trial. Younger adults' activation was modulated by the value-based regressor in ventral striatal and medial PFC regions implicated in reinforcement learning. Older adults' activation was modulated by state-change uncertainty signals in right dorsolateral PFC, and activation in this region was associated with improved performance in the task. This suggests that older adults may depart from standard expected-value based strategies and recruit lateral PFC regions to engage in reactive decision-making strategies. 
26690621	Recent studies have challenged the anxiety-avoidance model of obsessive-compulsive disorder (OCD), linking OCD to impulsivity, risky-decision-making and reward-system dysfunction, which can also be found in addiction and might support the conceptualization of OCD as a behavioral addiction. Here, we conducted an exploratory investigation of the behavioral addiction model of OCD by assessing whether OCD patients are more impulsive, have impaired decision-making, and biased probabilistic reasoning, three core dimensions of addiction, in a sample of OCD patients and healthy controls.We assessed these dimensions on 38 OCD patients and 39 healthy controls with the Barratt Impulsiveness Scale (BIS-11), the Iowa Gambling Task (IGT) and the Beads Task.	OCD patients had significantly higher BIS-11 scores than controls, in particular on the cognitive subscales. They performed significantly worse than controls on the IGT preferring immediate reward despite negative future consequences, and did not learn from losses. Finally, OCD patients demonstrated biased probabilistic reasoning as reflected by significantly fewer draws to decision than controls on the Beads Task.	OCD patients are more impulsive than controls and demonstrate risky decision-making and biased probabilistic reasoning. These results might suggest that other conceptualizations of OCD, such as the behavioral addiction model, may be more suitable than the anxiety-avoidance one. However, further studies directly comparing OCD and behavioral addiction patients are needed in order to scrutinize this model.	
26690620	Excoriation (skin-picking) disorder (SPD) is often conceptualized as a behavioral addiction in which aberrant reward processing may play an important role. The current study sought to develop a self-report instrument--the Skin Picking Reward Scale (SPRS)--that measures how strongly skin picking is 'liked' (i.e., the degree of pleasurable feelings while receiving the reward) and 'wanted' (i.e., the degree of the motivation to seek the reward).We administered the SPRS to individuals who endorsed excessive skin picking in online surveys and examined the scale's factor structure (Studies 1 and 2). We then asked individuals with documented pathological skin picking to complete the SPRS and other relevant questionnaires on two occasions one week apart (Study 3).	Exploratory (Study 1; n = 330) and confirmatory (Study 2; n = 144) factor analyses consistently supported a two-factor structure reflecting the 'liking' and 'wanting' constructs. Results from Study 3 (N = 36) indicated that the Wanting and the Liking scales had adequate internal consistency and test-retest reliability. Additionally, consistent with predictions, the Wanting scale, but not the Liking scale, was associated with picking urges the following week, greater cue-reactivity, and more picking-related routines/habits.	These initial findings suggest that SPRS is a psychometrically sound measure of 'wanting' and 'liking' in pathological skin picking. The SPRS may facilitate research on reward processing anomalies in SPD and serve as a useful clinical instrument (e.g., to identify those at risk for cue-induced relapse).	
26690588	Environmental factors influence the etiology of many psychiatric disorders. Likewise, environmental factors can alter processes central to motivation. Therefore, motivational deficits present in many disorders may be influenced by early life environmental conditions.We examined whether housing animals in different environmental conditions influenced the ability of sensory stimuli to acquire incentive value and whether elevated monoamine activity altered responsing for these stimuli.	Isolation-housed (IH), pair-housed (PH), and environmentally enriched (EE) male C57BL/6N mice were examined in tests of responding for a conditioned reinforcer (CRf) or an unconditioned sensory reinforcer (USRf). The CRf was previously paired with saccharin delivery through Pavlovian conditioning, while the USRf was not conditioned with a reward. Following baseline tests of responding for the CRf or USRf, the effects of elevated monoamine activity were examined.	At baseline, PH and EE mice responded similarly for the CRf or USRf. IH mice responded more for the CRf but exhibited slower acquisition of responding for the USRf. Administration of citalopram, a serotonin transporter blocker, or atomoxetine, a norepinephrine transporter blocker, decreased responding for the CRf and USRf in all groups. The dopamine transporter blocker GBR 12909 generally increased responding for the CRf and USRf, but further analysis revealed enhanced responding for both reinforcers only in EE mice.	Baseline incentive motivation is strongly influenced by the social component of housing conditions. Furthermore, environmental enrichment increased the sensitivity to elevated dopamine activity, while acute elevations in serotonin and norepinephrine inhibit incentive motivation irrespective of housing condition.	
26689711	Despite improvements in treatment, acute coronary syndrome remains a substantial cause for prolonged sick absences and premature retirement. Knowledge regarding what benefits return to work is limited, especially the effect of psychological processes and psychosocial work factors. The purposes of this cross-sectional study were two-fold: to examine associations between adverse psychosocial job conditions and fear-avoidance beliefs towards work, and to determine whether such beliefs mediated the relationship between work conditions and expected return to work in acute coronary syndrome survivors.Study inclusion criteria: acute myocardial infarction or unstable angina diagnosis, below 65 years of age, being a resident in the West county of Sweden and currently working. In all, 509 individuals (21.8 % women) accepted study participation and for whom all data of study interest were available for analysis. Psychosocial work variables; job demand-control and effort-reward imbalance, were assessed with standard questionnaire batteries. Linear regression models were used to investigate relationships between psychosocial factors and fear-avoidance, and to evaluate mediator effects for fear-avoidance. Both total sample and gender stratified analyses were calculated.	Fear-avoidance beliefs about work were associated to psychosocial job environments characterized by high strain (β 1.4; CI 1.2-1.6), active and passive work and high effort-reward imbalance (β 0.6; CI 0.5-0.7). Further, such beliefs also mediated the relationship between adverse work conditions and expected time for return to work. However, these results were only observed in total sample analyses or among or male participants. For women only high strain was linked to fear-avoidance, and these relationships became non-significant when entering chosen confounders.	This cross-sectional study showed that acute coronary syndrome survivors, who laboured under adverse psychosocial work conditions, held fear-avoidance beliefs towards their workplace. Furthermore, these beliefs mediated the relationships between - high strained or high effort-reward imbalanced work - and expected return to work. However, mentioned results were primarily found among men, which could results from few female study participants or gender differences in return to work mechanisms. Still, an earlier return to work might be promoted by interventions focusing on improved psychosocial work conditions and cognitive behavioural therapy targeting fear-avoidance beliefs.	
26687216	State representation is fundamental to behavior. However, identifying the true state of the world is challenging when explicit cues are ambiguous. Here, Bradfield and colleagues show that the medial OFC is critical for using associative information to discriminate ambiguous states. 
26686767	Studies in humans and experimental animals have demonstrated the vulnerability of the adolescent brain to actions of ethanol and the long-term consequences of binge drinking, including the behavioral and cognitive deficits that result from alcohol neurotoxicity, and increased risk to alcohol abuse and dependence. Although the mechanisms that participate in these effects are largely unknown, we have shown that ethanol by activating innate immune receptors, toll-like receptor 4 (TLR4), induces neuroinflammation, impairs myelin proteins and causes cognitive dysfunctions in adolescent mice. Since neuroimmune signaling is also involved in alcohol abuse, the aim of this study was to assess whether ethanol treatment in adolescence promotes the long-term synaptic and molecular events associated with alcohol abuse and addiction. Using wild-type (WT) and TLR4-deficient (TLR4-KO) adolescent mice treated intermittently with ethanol (3g/kg) for 2 weeks, we showed that binge-like ethanol treatment in adolescent mice promotes short- and long-term alterations in synaptic plasticity and epigenetic changes in the promoter region of bdnf and fosb, which increased their expression in the mPFC of young adult animals. These molecular events were associated with long-term rewarding and anxiogenic-related behavioral effects, along with increased alcohol preference. Our results further showed the participation of neuroimmune system activation and the TLR4 signaling response since deficient mice in TLR4 (TLR4-KO) are protected against molecular and behavioral alterations of ethanol in the adolescent brain. Our results highlight a new role of the neuroimmune function and open up new avenues to develop pharmacological treatments that can normalize the immune signaling responsible for long-term effects in adolescence, including alcohol abuse and related disorders.
26685155	Patients with loss of dopamine due to Parkinson's disease are impaired at learning from reward. However, it remains unknown precisely which aspect of learning is impaired. In particular, learning from reward, or reinforcement learning, can be driven by two distinct computational processes. One involves habitual stamping-in of stimulus-response associations, hypothesized to arise computationally from 'model-free' learning. The other, 'model-based' learning, involves learning a model of the world that is believed to support goal-directed behaviour. Much work has pointed to a role for dopamine in model-free learning. But recent work suggests model-based learning may also involve dopamine modulation, raising the possibility that model-based learning may contribute to the learning impairment in Parkinson's disease. To directly test this, we used a two-step reward-learning task which dissociates model-free versus model-based learning. We evaluated learning in patients with Parkinson's disease tested ON versus OFF their dopamine replacement medication and in healthy controls. Surprisingly, we found no effect of disease or medication on model-free learning. Instead, we found that patients tested OFF medication showed a marked impairment in model-based learning, and that this impairment was remediated by dopaminergic medication. Moreover, model-based learning was positively correlated with a separate measure of working memory performance, raising the possibility of common neural substrates. Our results suggest that some learning deficits in Parkinson's disease may be related to an inability to pursue reward based on complete representations of the environment. 
26683066	Converging evidence links individual differences in mesolimbic and mesocortical dopamine (DA) to variation in the tendency to choose immediate rewards ("Now") over larger, delayed rewards ("Later"), or "Now bias." However, to date, no study of healthy young adults has evaluated the relationship between Now bias and DA with positron emission tomography (PET). Sixteen healthy adults (ages 24-34 yr; 50% women) completed a delay-discounting task that quantified aspects of intertemporal reward choice, including Now bias and reward magnitude sensitivity. Participants also underwent PET scanning with 6-[(18)F]fluoro-l-m-tyrosine (FMT), a radiotracer that measures DA synthesis capacity. Lower putamen FMT signal predicted elevated Now bias, a more rapidly declining discount rate with increasing delay time, and reduced willingness to accept low-interest-rate delayed rewards. In contrast, lower FMT signal in the midbrain predicted greater sensitivity to increasing magnitude of the Later reward. These data demonstrate that intertemporal reward choice in healthy humans varies with region-specific measures of DA processing, with regionally distinct associations with sensitivity to delay and to reward magnitude.
26679531	Many everyday choices are associated with both delayed and probabilistic outcomes. The temporal attention hypothesis suggests that individuals' decision making can be improved by focusing attention on temporally distal events and implies that environmental manipulations that bring temporally distal outcomes into focus may alter an individual's degree of discounting. One such manipulation, episodic future thinking, has shown to lower discount rates; however, several questions remain about the applicability of episodic future thinking to domains other than delay discounting. The present experiments examine the effects of a modified episodic-future-thinking procedure in which participants viewed age-progressed computer-generated images of themselves and answered questions related to their future, on probability discounting in the context of both a delayed health gain and loss. Results indicate that modified episodic future thinking effectively altered individuals' degree of discounting in the predicted directions and demonstrate the applicability of episodic future thinking to decision making of socially significant outcomes. 
26679226	The composition of the N-methyl-d-aspartate receptor receptor in GluN2A/GluN2B subunits is important in determining its characteristics and its role in plasticity, a property of the brain which is known to be critically affected by early experiences. In the present work we employed an early experience model involving either receipt (RER) or denial (DER) of the expected reward of maternal contact within the context of learning by the pups of a T-maze on postnatal days (PND) 10-13. We investigated the effects of the RER and DER early experiences on GluN1, GluN2A and GluN2B levels in the prefrontal cortex (PFC), hippocampus and amygdala of the rat. We show that on PND13 the DER animals had lower GluN2A levels in the PFC. In adulthood DER males had higher GluN2A levels in the hippocampus, both under basal conditions and after exposure to a novel environment. The early experiences did not affect the response to the novelty. After exposure to a novel environment animals of all three groups (DER, RER, Control) responded with an increase in GluN2A levels in the brain areas examined. We did not detect any effects on GluN1 or GluN2B levels. The alterations in GluN2A levels observed in the DER animals could in part be responsible for their behavioral phenotype, described previously, which includes an increased susceptibility for the expression of depressive-like behavior.

26676982	N-acetylcysteine can increase extrasynaptic glutamate and reduce nicotine self-administration in rats and smoking rates in humans.The aim of this study was to determine if N-acetylcysteine modulates the development of nicotine place conditioning and withdrawal in mice.	N-acetylcysteine was given to nicotine-treated male ICR mice. Experiment 1: reward-like behavior. N-acetylcysteine (0, 5, 15, 30, or 60 mg/kg, i.p.) was given 15 min before nicotine (0.5 mg/kg, s.c.) or saline (10 ml/kg, s.c.) in an unbiased conditioned place preference (CPP) paradigm. Conditioning for highly palatable food served as control. Experiment 2: spontaneous withdrawal. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia was measured 18-24 h after continuous nicotine (24 mg/kg/day, 14 days). Experiment 3: mecamylamine-precipitated, withdrawal-induced aversion. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on mecamylamine (3.5 mg/kg, i.p.)-precipitated withdrawal was determined after continuous nicotine (24 mg/kg, i.p., 28 days) using the conditioned place aversion (CPA) paradigm.	Dose-related reductions in the development of nicotine CPP, somatic withdrawal signs, hyperalgesia, and CPA were observed after N-acetylcysteine pretreatment. No effect of N-acetylcysteine was found on palatable food CPP, anxiety-like behavior, or motoric capacity (crosses between plus maze arms). Finally, N-acetylcysteine did not affect any measure in saline-treated mice at doses effective in nicotine-treated mice.	These are the first data suggesting that N-acetylcysteine blocks specific mouse behaviors associated with nicotine reward and withdrawal, which adds to the growing appreciation that N-acetylcysteine may have high clinical utility in combating nicotine dependence.	
26676872	Recent research reported that task-irrelevant colors captured attention if these colors previously served as search targets and received high monetary reward. We showed that both monetary reward and value-independent mechanisms influenced selective attention. Participants searched for two potential target colors among distractor colors in the training phase. Subsequently, they searched for a shape singleton in a testing phase. Experiment 1 found that participants were slower in the testing phase if a distractor of a previous target color was present rather than absent. Such slowing was observed even when no monetary reward was used during training. Experiment 2 associated monetary rewards with the target colors during the training phase. Participants were faster finding the target associated with higher monetary reward. However, reward training did not yield value-dependent attentional capture in the testing phase. Attentional capture by the previous target colors was not significantly greater for the previously high-reward color than the previously low or no-reward color. These findings revealed both the power and limitations of monetary reward on attention. Although monetary reward can increase attentional priority for the high-reward target during training, subsequent attentional capture effects may not be reward-based, but reflect, in part, attentional capture by previous targets. 
26676183	Pigeons' demand and preference for specific and generalized tokens was examined in a token economy. Pigeons could produce and exchange different colored tokens for food, for water, or for food or water. Token production was measured across three phases, which examined: (1) across-session price increases (typical demand curve method); (2) within-session price increases (progressive-ratio, PR, schedule); and (3) concurrent pairwise choices between the token types. Exponential demand curves were fitted to the response data and accounted for over 90% total variance. Demand curve parameter values, Pmax , Omax and α showed that demand was ordered in the following way: food tokens, generalized tokens, water tokens, both in Phase 1 and in Phase 3. This suggests that the preferences were predictable on the basis of elasticity and response output from the demand analysis. Pmax and Omax values failed to consistently predict breakpoints and peak response rates in the PR schedules in Phase 2, however, suggesting limits on a unitary conception of reinforcer efficacy. The patterns of generalized token production and exchange in Phase 3 suggest that the generalized tokens served as substitutes for the specific food and water tokens. Taken together, the present findings demonstrate the utility of behavioral economic concepts in the analysis of generalized reinforcement. 
26674876	Reciprocal connections between the orbitofrontal cortex (OFC) and the basolateral nucleus of the amygdala (BLA) provide a critical circuit for guiding normal behavior when information about expected outcomes is required. Recently, we reported that outcome signaling by OFC neurons is also necessary for learning in the face of unexpected outcomes during a Pavlovian over-expectation task. Key to learning in this task is the ability to build on prior learning to infer or estimate an amount of reward never previously received. OFC was critical to this process. Notably, in parallel work, we found that BLA was not necessary for learning in this setting. This suggested a dissociation in which the BLA might be critical for acquiring information about the outcomes but not for subsequently using it to make novel predictions. Here we evaluated this hypothesis by recording single-unit activity from BLA in rats during the same Pavlovian over-expectation task used previously. We found that spiking activity recorded in BLA in control rats did reflect novel outcome estimates derived from the integration of prior learning, however consistent with a model in which this process occurs in the OFC, these correlates were entirely abolished by ipsilateral OFC lesions. These data indicate that this information about these novel predictions is represented in the BLA, supported via direct or indirect input from the OFC, even though it does not appear to be necessary for learning.The basolateral nucleus of the amygdala (BLA) and the orbitofrontal cortex (OFC) are involved in behavior that depends on knowledge of impending outcomes. Recently, we found that only the OFC was necessary for using such information for learning in a Pavlovian over-expectation task. The current experiment was designed to search for neural correlates of this process in the BLA and, if present, to ask whether they would still be dependent on OFC input. We found that although spiking activity in BLA in control rats did reflect the novel outcome estimates underlying learning, these correlates were entirely abolished by OFC lesions.	
26674562	Drug addiction is a major psychiatric disorder with a neurobiological basis that is still insufficiently understood. Initially, non-addicted, controlled drug consumption and drug instrumentalization are established. They comprise highly systematic behaviours acquired by learning and the establishment of drug memories. Ca(2+)/calmodulin-dependent protein kinases (CaMKs) are important Ca(2+) sensors translating glutamatergic activation into synaptic plasticity during learning and memory formation. Here we review the role of CaMKs in the establishment of drug-related behaviours in animal models and in humans. Converging evidence now shows that CaMKs are a crucial mechanism of how addictive drugs induce synaptic plasticity and establish various types of drug memories. Thereby, CaMKs are not only molecular relays for glutamatergic activity but they also directly control dopaminergic and serotonergic activity in the mesolimbic reward system. They can now be considered as major molecular pathways translating normal memory formation into establishment of drug memories and possibly transition to drug addiction. 
26674388	Recently, anorexia nervosa (AN) has been conceptualized as a reward-related disorder, and alterations in brain reward processes have been documented in both acute and recovered AN patients. However, the role of endogenous biochemical mediators, such as ghrelin, in the modulation of reward processes has been poorly investigated in this eating disorder. Hedonic eating, that is the consumption of food exclusively for pleasure and not to maintain energy homeostasis, is a useful paradigm to investigate the physiology of food-related reward. Therefore, we assessed the response of peripheral ghrelin to hedonic eating in 7 underweight and 7 recently weight-restored AN patients and compared it to that of previously studied healthy controls. We found that in satiated underweight patients with AN plasma ghrelin levels progressively decreased after the exposure and the consumption of both the favorite and unfavorite food whereas in satiated weight-restored AN patients and satiated healthy controls plasma ghrelin concentrations significantly increased after the exposure to the favorite food and after eating it, but decreased after the unfavorite food. These results suggest a derangement in the ghrelin modulation of food-related pleasurable and rewarding feelings, which might sustain the reduced motivation toward food intake of acute AN patients. 
26674058	Reactivation of consolidated memory initiates a memory reconsolidation process, during which the reactivated memory is susceptible to strengthening, weakening or updating. Therefore, effective interference with the memory reconsolidation process is expected to be an important treatment for drug addiction. The nucleus accumbens (NAc) has been well recognized as a pathway component that can prevent drug relapse, although the mechanism underlying this function is poorly understood. We aimed to clarify the regulatory role of the NAc in the cocaine memory reconsolidation process, by examining the effect of applying different pharmacological interventions to the NAc on Zif 268 and Fos B expression in the entire reward circuit after cocaine memory reactivation. Through the cocaine-induced conditioned place preference (CPP) model, immunohistochemical and immunofluorescence staining for Zif 268 and Fos B were used to explore the functional activated brain nuclei after cocaine memory reactivation. Our results showed that the expression of Zif 268 and Fos B was commonly increased in the medial prefrontal cortex (mPFC), the infralimbic cortex (IL), the NAc-core, the NAc-shell, the hippocampus (CA1, CA2, and CA3 subregions), the amygdala, the ventral tegmental area (VTA), and the supramammillary nucleus (SuM) following memory reconsolidation, and Zif 268/Fos B co-expression was commonly observed (for Zif 268: 51-68%; for Fos B: 52-66%). Further, bilateral NAc-shell infusion of MK 801 and SCH 23390, but not raclopride or propranolol, prior to addictive memory reconsolidation, decreased Zif 268 and Fos B expression in the entire reward circuit, except for the amygdala, and effectively disturbed subsequent CPP-related behavior. In summary, N-methyl-d-aspartate (NMDA) and dopamine D1 receptors, but not dopamine D2 or β adrenergic receptors, within the NAc-shell, may regulate Zif 268 and Fos B expression in most brain nuclei of the reward circuit after cocaine memory reactivation. These findings indicated that the NAc played a key role in regulating addictive memory reconsolidation by influencing the function of the entire addictive memory network. 
26673891	The macaque orbitofrontal cortex (OFC) is essential for selecting goals based on current, updated values of expected reward outcomes. As monkeys consume a given type of reward to satiety, its value diminishes, and OFC damage impairs the ability to shift goal choices away from devalued outcomes. To examine the contributions of OFC's components to goal selection, we reversibly inactivated either its anterior (area 11) or posterior (area 13) parts. We found that neurons in area 13 must be active during the selective satiation procedure to enable the updating of outcome valuations. After this updating has occurred, however, area 13 is not needed to select goals based on this knowledge. In contrast, neurons in area 11 do not need to be active during the value-updating process. Instead, inactivation of this area during choices causes an impairment. These findings demonstrate selective and complementary specializations within the OFC. 
26670544	The lateral orbitofrontal cortex (lOFC) has been described as signaling either outcome expectancies or value. Previously, we used unblocking to show that lOFC neurons respond to a predictive cue signaling a 'valueless' change in outcome features (McDannald, 2014). However, many lOFC neurons also fired to a cue that simply signaled more reward. Here, we recorded lOFC neurons in a variant of this task in which rats learned about cues that signaled either more (upshift), less (downshift) or the same (blocked) amount of reward. We found that neurons acquired responses specifically to one of the three cues and did not fire to the other two. These results show that, at least early in learning, lOFC neurons fire to valued cues in a way that is more consistent with signaling of the predicted outcome's features than with signaling of a general, abstract or cached value that is independent of the outcome. 
26670182	Synapsin is an evolutionarily conserved presynaptic phosphoprotein. It is encoded by only one gene in the Drosophila genome and is expressed throughout the nervous system. It regulates the balance between reserve and releasable vesicles, is required to maintain transmission upon heavy demand, and is essential for proper memory function at the behavioral level. Task-relevant sensorimotor functions, however, remain intact in the absence of Synapsin. Using an odor-sugar reward associative learning paradigm in larval Drosophila, we show that memory scores in mutants lacking Synapsin (syn(97)) are lower than in wild-type animals only when more salient, higher concentrations of odor or of the sugar reward are used. Furthermore, we show that Synapsin is selectively required for larval short-term memory. Thus, without Synapsin Drosophila larvae can learn and remember, but Synapsin is required to form memories that match in strength to event salience-in particular to a high saliency of odors, of rewards, or the salient recency of an event. We further show that the residual memory scores upon a lack of Synapsin are not further decreased by an additional lack of the Sap47 protein. In combination with mass spectrometry data showing an up-regulated phosphorylation of Synapsin in the larval nervous system upon a lack of Sap47, this is suggestive of a functional interdependence of Synapsin and Sap47. 
26669602	Nearly 50 % of patients with chronic medical illness exhibit poor treatment adherence. When making treatment decisions, these patients must balance the probability of current side effects against the probability of long-term benefits. This study examines if the behavioral economic construct of probability discounting can be used to explain treatment decisions in chronic disease.Thirty-eight nonadherent and 39 adherent patients with multiple sclerosis (MS) completed a series of hypothetical treatment scenarios with varied risk and benefit probabilities.	As described by a hyperbolic probability discounting model, all patients reported decreased medication initiation as the probability of treatment efficacy decreased and the probability of treatment side effects increased. When compared to adherent patients, nonadherent patients significantly devalued treatment efficacy and inflated treatment risk.	The methods in this study can be used to identify optimal risk/benefit ratios for treatment development and inform the process by which patients make treatment decisions.	

26668400	Social decisions require evaluation of costs and benefits to oneself and others. Long associated with emotion and vigilance, the amygdala has recently been implicated in both decision-making and social behavior. The amygdala signals reward and punishment, as well as facial expressions and the gaze of others. Amygdala damage impairs social interactions, and the social neuropeptide oxytocin (OT) influences human social decisions, in part, by altering amygdala function. Here we show in monkeys playing a modified dictator game, in which one individual can donate or withhold rewards from another, that basolateral amygdala (BLA) neurons signaled social preferences both across trials and across days. BLA neurons mirrored the value of rewards delivered to self and others when monkeys were free to choose but not when the computer made choices for them. We also found that focal infusion of OT unilaterally into BLA weakly but significantly increased both the frequency of prosocial decisions and attention to recipients for context-specific prosocial decisions, endorsing the hypothesis that OT regulates social behavior, in part, via amygdala neuromodulation. Our findings demonstrate both neurophysiological and neuroendocrinological connections between primate amygdala and social decisions. 
26667478	Addiction is a disorder of motivational learning and memory. Maladaptive motivational memories linking drug-associated stimuli to drug seeking are formed over hundreds of reinforcement trials and accompanied by aberrant neuroadaptation in the mesocorticolimbic reward system. Such memories are resistant to extinction. However, the discovery of retrieval-dependent memory plasticity has opened up the possibility of permanent modification of established (long-term) memories during 'reconsolidation'.Here, we investigate whether reappraisal of maladaptive alcohol cognitions performed after procedures designed to destabilize alcohol memory networks affected subsequent alcohol memory, craving, drinking and attentional bias.	Forty-seven at-risk drinkers attended two sessions. On the first lab session, participants underwent one of two prediction error-generating procedures in which outcome expectancies were violated while retrieving alcohol memories (omission and value prediction error groups). Participants in a control group retrieved non-alcohol memories. Participants then reappraised personally relevant maladaptive alcohol memories and completed measures of reappraisal recall, alcohol verbal fluency and craving. Seven days later, they repeated these measures along with attentional bias assessment.	Omission prediction error (being unexpectedly prevented from drinking beer), but not a value prediction error (drinking unexpectedly bitter-tasting beer) or control procedure (drinking unexpectedly bitter orange juice), was associated with significant reductions in verbal fluency for positive alcohol-related words. No other statistically robust outcomes were detected.	This study provides partial preliminary support for the idea that a common psychotherapeutic strategy used in the context of putative memory retrieval-destabilization can alter accessibility of alcohol semantic networks. Further research delineating the necessary and sufficient requirements for producing alterations in alcohol memory performance based on memory destabilization is still required.	
26667365	Loss aversion is a defining characteristic of prospect theory, whereby responses are stronger to losses than to equivalently sized gains (Kahneman & Tversky Econometrica, 47, 263-291, 1979). By monitoring electrodermal activity (EDA) during a gambling task, in this study we examined physiological activity during risky decisions, as well as to both obtained (e.g., gains and losses) and counterfactual (e.g., narrowly missed gains and losses) outcomes. During the bet selection phase, EDA increased linearly with bet size, highlighting the role of somatic signals in decision-making under uncertainty in a task without any learning requirement. Outcome-related EDA scaled with the magnitudes of monetary wins and losses, and losses had a stronger impact on EDA than did equivalently sized wins. Narrowly missed wins (i.e., near-wins) and narrowly missed losses (i.e., near-losses) also evoked EDA responses, and the change of EDA as a function of the size of the missed outcome was modestly greater for near-losses than for near-wins, suggesting that near-losses have more impact on subjective value than do near-wins. Across individuals, the slope for choice-related EDA (as a function of bet size) correlated with the slope for outcome-related EDA as a function of both the obtained and counterfactual outcome magnitudes, and these correlations were stronger for loss and near-loss conditions than for win and near-win conditions. Taken together, these asymmetrical EDA patterns to objective wins and losses, as well as to near-wins and near-losses, provide a psychophysiological instantiation of the value function curve in prospect theory, which is steeper in the negative than in the positive domain. 
26664702	When faced with a choice, humans and animals commonly distribute their behavior in proportion to the frequency of payoff of each option. Such behavior is referred to as matching and has been captured by the matching law. However, matching is not a general law of economic choice. Matching in its strict sense seems to be specifically observed in tasks whose properties make matching an optimal or a near-optimal strategy. We engaged monkeys in a foraging task in which matching was not the optimal strategy. Over-matching the proportions of the mean offered reward magnitudes would yield more reward than matching, yet, surprisingly, the animals almost exactly matched them. To gain insight into this phenomenon, we modeled the animals' decision-making using a mechanistic model. The model accounted for the animals' macroscopic and microscopic choice behavior. When the models' three parameters were not constrained to mimic the monkeys' behavior, the model over-matched the reward proportions and in doing so, harvested substantially more reward than the monkeys. This optimized model revealed a marked bottleneck in the monkeys' choice function that compares the value of the two options. The model featured a very steep value comparison function relative to that of the monkeys. The steepness of the value comparison function had a profound effect on the earned reward and on the level of matching. We implemented this value comparison function through responses of simulated biological neurons. We found that due to the presence of neural noise, steepening the value comparison requires an exponential increase in the number of value-coding neurons. Matching may be a compromise between harvesting satisfactory reward and the high demands placed by neural noise on optimal neural computation. 
26661229	Several human functional magnetic resonance imaging studies point to an activation of the mesolimbic dopamine system during reward, addiction and learning. We previously found activation of the mesolimbic system in response to continuous but not to discontinuous perforant pathway stimulation in an experimental model that we now used to investigate the role of dopamine release for the formation of functional magnetic resonance imaging responses. The two stimulation protocols elicited blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Inhibition of dopamine D1/5 receptors abolished the formation of functional magnetic resonance imaging responses in the medial prefrontal/anterior cingulate cortex during continuous but not during discontinuous pulse stimulations, i.e. only when the mesolimbic system was activated. Direct electrical or optogenetic stimulation of the ventral tegmental area caused strong dopamine release but only electrical stimulation triggered significant blood-oxygen level-dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. These functional magnetic resonance imaging responses were not affected by the D1/5 receptor antagonist SCH23390 but reduced by the N-methyl-D-aspartate receptor antagonist MK801. Therefore, glutamatergic ventral tegmental area neurons are already sufficient to trigger blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Although dopamine release alone does not affect blood-oxygen-level dependent responses it can act as a switch, permitting the formation of blood-oxygen-level dependent responses.
26660448	Tobacco smoking is associated with dysregulated reward processing within the striatum, characterized by hypersensitivity to smoking rewards and hyposensitivity to non-smoking rewards. This bias toward smoking reward at the expense of alternative rewards is further exacerbated by deprivation from smoking, which may contribute to difficulty maintaining abstinence during a quit attempt.We examined whether abstinence-induced changes in striatal processing of rewards predicted lapse likelihood during a quit attempt supported by contingency management (CM), in which abstinence from smoking was reinforced with money.	Thirty-six non-treatment-seeking smokers participated in two functional MRI (fMRI) sessions, one following 24-h abstinence and one following smoking as usual. During each scan, participants completed a rewarded guessing task designed to elicit striatal activation in which they could earn smoking and monetary rewards delivered after the scan. Participants then engaged in a 3-week CM-supported quit attempt.	As previously reported, 24-h abstinence was associated with increased striatal activation in anticipation of smoking reward and decreased activation in anticipation of monetary reward. Individuals exhibiting greater decrements in right striatal activation to monetary reward during abstinence (controlling for activation during non-abstinence) were more likely to lapse during CM (p < 0.025), even when controlling for other predictors of lapse outcome (e.g., craving); no association was seen for smoking reward.	These results are consistent with a growing number of studies indicating the specific importance of disrupted striatal processing of non-drug reward in nicotine dependence and highlight the importance of individual differences in abstinence-induced deficits in striatal function for smoking cessation.	
26657967	Motivational relevance can prioritize information for memory encoding and consolidation based on reward value. In this review, we pinpoint the possible psychological and neural mechanisms by which reward promotes learning, from guiding attention to enhancing memory consolidation. We then discuss how reward value can spill-over from one conditioned stimulus to a non-conditioned stimulus. Such generalization can occur across perceptually similar items or through more complex relations, such as associative or logical inferences. Existing evidence suggests that the neurotransmitter dopamine boosts the formation of declarative memory for rewarded information and may also control the generalization of reward values. In particular, temporally-correlated activity in the hippocampus and in regions of the dopaminergic circuit may mediate value-based decisions and facilitate cross-item integration. Given the importance of generalization in learning, our review points to the need to study not only how reward affects later memory but how learned reward values may generalize to related representations and ultimately alter memory structure. 
26656672	The personality traits of harm avoidance (HA), novelty seeking (NS), and reward dependence (RD), as measured by the Tridimensional Personality Questionnaire (TPQ), have been linked to smoking behavior. The extent to which these traits are associated with smoking withdrawal and cessation outcome is unclear. We sought to address this question among 131 treatment-seeking smokers who were randomly assigned to either a smoking cessation treatment (four 30-min behavioral counseling sessions) or a control condition. We found that HA was positively associated with baseline depressive symptoms, baseline negative affect, and post-quit withdrawal, and negatively associated with positive affect at both baseline and post-quit. Additionally, we found that smokers with higher HA scores were more likely to be abstinent. NS was negatively associated with post-quit positive affect and positively associated with post-quit negative affect and withdrawal. RD was not found to be related to any outcome measures. Our findings suggest that, despite experiencing greater baseline and post-quit negative affect, smokers higher in trait harm avoidance are more likely to quit smoking. The treatment and theoretical ramifications of these findings are discussed. 
26656645	To study how the interaction between orbitofrontal (OFC) and rhinal (Rh) cortices influences the judgment of reward size, we reversibly disconnected these regions using hM4Di-DREADD (designer receptor exclusively activated by designer drug). Repeated inactivation reduced sensitivity to differences in reward size in two monkeys. These results suggest that retrieval of relative stimulus values from memory depends on the interaction between Rh and OFC. 
26656274	Intracranial self-stimulation (ICSS) of the lateral hypothalamus (LH) is involved in the activation of neuroanatomical systems that are also associated with the processing of natural and other artificial rewarding stimuli. Specific components of this behavior (hedonic impact, learning, and motor behavior) may involve changes in different neurotransmitters, such as dopamine and opioids. In this study, quantitative autoradiography was used to examine changes in mu-opioid and D1/D2-dopamine receptor expression in various anatomical regions related to the motor and mesolimbic reward systems after intracranial self-stimulation of the LH. Results of the behavioral procedure and subsequent radiochemical assays show selective changes in D1 but not D2 or mu receptors in Accumbens-Shell, Ventral Pallidum, Caudate-Putamen, and Medial Globus Pallidus. These findings are discussed in relation to the different psychobiological components of the appetitive motivational system, identifying some dissociation among them, particularly with respect to the involvement of the D1-dopamine subsystem (but not D2 or mu receptors) in goal-directed behaviors. 
26655783	Changes to typical procedures in animal husbandry are often necessary to accommodate the needs of behavioral experiments. Two common changes in husbandry for rodents are light chronic food restriction (to motivate animals in reward-association tasks) and social isolation (to accommodate individual feeding schedules or need to reduce interactions because of implants for example). Each of these intervention individually has been shown to modulate behavioral state and with it performance in behavioral tasks. We here systematically test how social isolation and light chronic food restriction modulate olfactory memory in rats. Our results show a strong modulation of olfactory memory after both types of husbandry interventions. These results suggest that common changes in animal husbandry promote distinct and relevant changes in animal behavior. 
26655599	Approximately one third of all major depression patients fail to respond to conventional pharmacological antidepressants, and brain stimulation methods pose a promising alternative for this population. Recently, based on repeated multifactorial selective inbreeding of rats for depressive-like behaviors, we introduced a novel animal model for MDD. Rats from this Depressive Rat Line (DRL) exhibit inherent depressive-like behaviors, which are correlated with lower levels of brain-derived neurotrophic factor (BDNF) in specific brain regions. In addition, DRL rats do not respond to antidepressant medication but respond to electroconvulsive treatment, and they can thus be utilized to test the effectiveness of brain stimulation on hereditary, medication-resistant depressive-like behaviors.To test the effect of sub-convulsive electrical stimulation (SCES) of the prelimbic cortex, using TMS-like temporal pattern of stimulation, on depressive-like behaviors and regional BDNF levels in DRL rats.	SCES sessions were administered daily for 10 days through chronically implanted electrodes. Temporal stimulation parameters were similar to those used in TMS for major depression in human patients. Depressive-like behaviors were assayed after treatment, followed by brain extraction and regional BDNF measurements.	SCES normalized both the depressive-like behaviors and the reduced BDNF levels observed in DRL rats. Correlation analyses suggest that changes in specific behaviors are mediated, at least in part, by BDNF expression in reward-related brain regions.	Brain stimulation is effective in a drug-resistant, inherited animal model for depression. BDNF alterations in specific regions may mediate different antidepressant effects.	
26655337	A central question in artificial intelligence is how to design agents capable of switching between different behaviors in response to environmental changes. Taking inspiration from neuroscience, we address this problem by utilizing artificial neural networks (NNs) as agent controllers, and mechanisms such as neuromodulation and synaptic gating. The novel aspect of this work is the introduction of a type of artificial neuron we call "switch neuron". A switch neuron regulates the flow of information in NNs by selectively gating all but one of its incoming synaptic connections, effectively allowing only one signal to propagate forward. The allowed connection is determined by the switch neuron's level of modulatory activation which is affected by modulatory signals, such as signals that encode some information about the reward received by the agent. An important aspect of the switch neuron is that it can be used in appropriate "switch modules" in order to modulate other switch neurons. As we show, the introduction of the switch modules enables the creation of sequences of gating events. This is achieved through the design of a modulatory pathway capable of exploring in a principled manner all permutations of the connections arriving on the switch neurons. We test the model by presenting appropriate architectures in nonstationary binary association problems and T-maze tasks. The results show that for all tasks, the switch neuron architectures generate optimal adaptive behaviors, providing evidence that the switch neuron model could be a valuable tool in simulations where behavioral plasticity is required. 
26653714	Rats suppress intake of a palatable taste cue when paired with a rewarding or an aversive stimulus in appetitive or aversive conditioning, respectively. A similar phenomenon occurs with drugs of abuse, but the nature of this conditioning has been subject for debate. While relatively little is known about the underlying neural circuitry, we recently reported bilateral lesions of the thalamic trigeminal orosensory area isolate drug-induced suppression of intake of a taste cue. The lesion blocks avoidance of the taste cue when paired with experimenter delivered drugs of abuse, yet has no effect on avoidance of the same cue when paired with an aversive agent or when it predicts access to a highly palatable sucrose solution. We hypothesize the lesion may blunt the rewarding properties of the drug. To test this, we used a runway apparatus, as running speed has been shown to increase with increasing reward value. Our hypothesis was supported by failure of the lesioned rats to increase running speed for morphine. Interestingly, lesioned rats did avoid intake of the drug-paired cue when presented in the runway apparatus and displayed naloxone-precipitated withdrawal. Using a partial crossover design, the lesion prevented avoidance of a cocaine-paired cue when presented in the home cage. We conclude that the lesion disrupts avoidance of a taste cue in anticipation of the rewarding properties of a drug but, at least in the presence of contextual cues, allows for avoidance of a taste cue as it elicits the onset of an aversive conditioned state of withdrawal.
26653713	Many debilitating psychiatric conditions, including drug addiction, are characterized by poor decision making and maladaptive risk-taking. Recent research has begun to probe this relationship to determine how brain mechanisms mediating risk-taking become compromised after chronic drug use. Currently, however, the majority of work in this field has used male subjects. Given the well-established sex differences in drug addiction, it is conceivable that such differences are also evident in risk-based decision making. To test this possibility, male and female adult rats were trained in a risky decision making task (RDT), in which they chose between a small, "safe" food reward and a large, "risky" food reward accompanied by an increasing probability of mild footshock punishment. Consistent with findings in human subjects, females were more risk averse, choosing the large, risky reward significantly less than males. This effect was not due to differences in shock reactivity or body weight, and risk-taking in females was not modulated by estrous phase. Systemic amphetamine administration decreased risk-taking in both males and females; however, females exhibited greater sensitivity to amphetamine, suggesting that dopaminergic signaling may partially account for sex differences in risk-taking. Finally, although males displayed greater instrumental responding for food reward, reward choice in the RDT was not affected by satiation, indicating that differences in motivation to obtain food reward cannot fully account for sex differences in risk-taking. These results should prove useful for developing targeted treatments for psychiatric conditions in which risk-taking is altered and that are known to differentially affect males and females.
26653393	Usage-Based Insurances (UBI) enable policyholders to actively reduce the impact of vehicle insurance costs by adopting a safer and more eco-friendly driving style. UBI is especially relevant for younger drivers, who are a high-risk population. The effectiveness of UBI should be enhanced by providing in-car feedback optimised for individual drivers. Thirty young novice drivers were therefore invited to complete six experimental drives with an in-car interface that provided real-time information on rewards gained, their driving behaviour and the speed limit. Reward size was either displayed directly in euro, indirectly as a relatively large amount of credits, or as a percentage of the maximum available bonus. Also, interfaces were investigated that provided partial information to reduce the potential for driver distraction. Compared to a control no-UBI condition, behaviour improved similarly across interfaces, suggesting that interface personalisation after an initial familiarisation period could be feasible without compromising feedback effectiveness. Practitioner Summary: User experiences and effects on driving behaviour of six in-car interfaces were compared. The interface provided information on driving behaviour and rewards in a UBI setting. Results suggest that some personalisation of interfaces may be an option after an initial familiarisation period as driving behaviour improved similarly across interfaces. 
26651939	In this issue of Cell Host & Microbe, Tripathi et al. (2015) report an in-depth meta-analysis of eight influenza virus siRNA screens combined with viral-host protein interactome data. The integration of the different omics datasets highlights candidate genes and pathways for further investigation and potential therapeutic targeting in the future.
26650254	In recent years, studies with animal models of reward, such as the intracranial self-stimulation, self-administration, and conditioned place preference paradigms, have increased our knowledge on the neurochemical substrates of the rewarding effects of 3,4-methylenedioxymetamphetamine (MDMA) in rodents. However, pharmacological and neuroimaging studies with human participants are scarce. Serotonin [5-hydroxytryptamine (5-HT)], dopamine (DA), endocannabinoids, and endogenous opiates are the main neurotransmitter systems involved in the rewarding effects of MDMA in rodents, but other neurotransmitters such as glutamate, acetylcholine, adenosine, and neurotensin are also involved. The most important finding of recent research is the demonstration of differential involvement of specific neurotransmitter receptor subtypes (5-HT2, 5-HT3, DA D1, DA D2, CB1, μ and δ opioid, etc.) and extracellular proteins (DA and 5-HT transporters) in the acquisition, expression, extinction, and reinstatement of MDMA self-administration and conditioned place preference. It is important to extend the research on the effects of different compounds acting on these receptors/transporters in animal models of reward, especially in priming-induced, cue-induced, and stress-induced reinstatement. Increase in knowledge of the neurochemical substrates of the rewarding effects of MDMA may contribute to the design of new pharmacological treatments for individuals who develop MDMA dependence. 
26647004	There is a growing body of research into the development of prospective memory (PM) in typically developing children but research is limited in autistic children (Aut) and rarely includes children with more severe symptoms.This study is the first to specifically compare event-based PM in severely autistic children to mildly autistic and typically developing children.	Fourteen mildly autistic children and 14 severely autistic children, aged 5-13 years, were matched for educational attainment with 26 typically developing children aged 5-6 years. Three PM tasks and a retrospective memory task were administered.	Results showed that severely autistic children performed less well than typically developing children on two PM tasks but mildly autistic children did not differ from either group. No group differences were found on the most motivating (a toy reward) task.	The findings suggest naturalistic tasks and motivation are important factors in PM success in severely autistic children and highlights the need to consider the heterogeneity of autism and symptom severity in relation to performance on event-based PM tasks.	
26645625	Discordant associations between monoamine oxidase A (MAOA) genotype and high alcohol drinking have been reported in human and non-human primates. Environmental influences likely moderate genetic susceptibility. The biological basis for this interplay remains elusive, and inconsistencies call for translational studies in which conditions can be controlled and brain tissue is accessible. The present study investigated whether early life stress and subsequent adult episodic alcohol consumption affect Maoa expression in stress- and reward-related brain regions in the rat. Outbred Wistar rats were exposed to rearing conditions associated with stress (prolonged maternal separation) or no stress during early life, and given free choice between alcohol and/or water in adulthood. Transcript levels of Maoa were assessed in the ventral tegmental area, nucleus accumbens (NAc), medial prefrontal cortex, cingulate cortex, amygdala and dorsal striatum (DS). Blood was collected to assess corticosterone levels. After alcohol consumption, lower blood corticosterone and Maoa expression in the NAc and DS were found in rats exposed to early life stress compared with control rats. An interaction between early life stress and voluntary alcohol intake was found in the NAc. Alcohol intake before death correlated negatively with Maoa expression in DS in high alcohol-drinking rats exposed to early life stress. Maoa expression is sensitive to adulthood voluntary alcohol consumption in the presence of early life stress in outbred rats. These findings add knowledge of the molecular basis of the previously reported associations between early life stress, MAOA and susceptibility to alcohol misuse. 
26644599	Psychiatric disorders can affect our ability to successfully and enjoyably interact with others. Conversely, having difficulties in social relations is known to increase the risk of developing a psychiatric disorder. In this article, the assumption that psychiatric disorders can be construed as disorders of social interaction is reviewed from a clinical point of view. Furthermore, it is argued that a psychiatrically motivated focus on the dynamics of social interaction may help to provide new perspectives for the field of social neuroscience. Such progress may be crucial to realize social neuroscience's translational potential and to advance the transdiagnostic investigation of the neurobiology of psychiatric disorders. 
26644268	A 59-year-old Caucasian man with a past history of Parkinson's disease (PD) status post-bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), who also had treatment-resistant (TR) obsessive-compulsive disorder (OCD), and treatment-resistant depression (TRD), presented for further evaluation and management of his TR OCD. After an unsuccessful attempt to treat his OCD by reprogramming his existing STN DBS, he was offered bilateral ventral capsule/ventral striatum (VC/VS) DBS surgery. In addition to the expected improvement in OCD symptoms, he experienced significant improvement in both PD-related apathy and depression along with resolution of suicidal ideation. Furthermore, the patient's festinating gait dramatically improved. This case demonstrates that DBS of both the STN and VC/VS appears to have an initial signal of safety and tolerability. This is the first instance where both the STN and the VC/VS DBS targets have been implanted in an individual and the first case where a patient with PD has received additional DBS in mood-regulatory circuitry. 
26642092	Correlative studies have strongly linked phasic changes in dopamine activity with reward prediction error signaling. But causal evidence that these brief changes in firing actually serve as error signals to drive associative learning is more tenuous. Although there is direct evidence that brief increases can substitute for positive prediction errors, there is no comparable evidence that similarly brief pauses can substitute for negative prediction errors. In the absence of such evidence, the effect of increases in firing could reflect novelty or salience, variables also correlated with dopamine activity. Here we provide evidence in support of the proposed linkage, showing in a modified Pavlovian over-expectation task that brief pauses in the firing of dopamine neurons in rat ventral tegmental area at the time of reward are sufficient to mimic the effects of endogenous negative prediction errors. These results support the proposal that brief changes in the firing of dopamine neurons serve as full-fledged bidirectional prediction error signals. 
26642087	It is widely held that dopamine signaling encodes predictions of future rewards and such predictions are regularly used to drive behavior, but the relationship between these two is poorly defined. We found in rats that nucleus accumbens dopamine following a reward-predicting cue was attenuated unless movement was correctly initiated. Our results indicate that dopamine release in this region is contingent on correct action initiation and not just reward prediction. 
26641854	Research supports the effectiveness of a dissonance-based eating disorder prevention program wherein high-risk young women with body dissatisfaction critique the thin ideal, which reduces pursuit of this ideal, and the theory that dissonance induction contributes to these effects. Based on evidence that dissonance produces attitudinal change by altering neural representation of valuation, we tested whether completing the Body Project would reduce response of brain regions implicated in reward valuation to thin models. Young women with body dissatisfaction were randomized to this intervention or an educational control condition, completing assessments and fMRI scans while viewing images of thin versus average-weight female models at pre and post. Whole brain analyses indicated that, compared to controls, Body Project participants showed greater reductions in caudate response to images of thin versus average-weight models, though participants in the two conditions showed pretest differences in responsivity of other brain regions that might have contributed to this effect. Greater pre-post reductions in caudate and putamen response to thin models correlated with greater reductions in body dissatisfaction. The finding that the Body Project reduces caudate response to thin models provides novel preliminary evidence that this intervention reduces valuation of media images thought to contribute to body dissatisfaction and eating disorders, providing support for the intervention theory by documenting that this intervention alters an objective biological outcome. 
26640481	The basal ganglia (BG) are a subcortical structure implicated in action selection. The aim of this work is to present a new cognitive neuroscience model of the BG, which aspires to represent a parsimonious balance between simplicity and completeness. The model includes the 3 main pathways operating in the BG circuitry, that is, the direct (Go), indirect (NoGo), and hyperdirect pathways. The main original aspects, compared with previous models, are the use of a two-term Hebb rule to train synapses in the striatum, based exclusively on neuronal activity changes caused by dopamine peaks or dips, and the role of the cholinergic interneurons (affected by dopamine themselves) during learning. Some examples are displayed, concerning a few paradigmatic cases: action selection in basal conditions, action selection in the presence of a strong conflict (where the role of the hyperdirect pathway emerges), synapse changes induced by phasic dopamine, and learning new actions based on a previous history of rewards and punishments. Finally, some simulations show model working in conditions of altered dopamine levels, to illustrate pathological cases (dopamine depletion in parkinsonian subjects or dopamine hypermedication). Due to its parsimonious approach, the model may represent a straightforward tool to analyze BG functionality in behavioral experiments. 
26639718	Alzheimer's disease (AD) is the major age-related progressive neurodegenerative disorder. The brain of AD patients suffers from loss of cholinergic neurons and decreased number of synapses [1]. AD is caused by an imbalance between Aβ production and clearance, resulting in increased amount of Aβ in various forms [2]. Reduction of Aβ production and increasing clearance of Aβ pathogenic forms are key targets in the development of potential therapeutic agents for AD treatment. Unfortunately, only nosotropic approaches for treatment of AD are currently effective in humans. These approaches mainly focus on the inhibition of brain acetyl-cholinesterase (AChE) to increase lifetime of cerebral acetylcholine [3]. It is important to emphasize that AChE itself promotes the formation of Aβ fibrils in vitro and Aβ plaques in the cerebral cortex of transgenic mouse models of AD [4]. This property of AChE results from interaction between Aβ and the peripheral anionic site of the enzyme (PAS) [5]. Dual binding site inhibitors of both catalytic active site (CAS) and PAS can simultaneously improve cognition and slow down the rate of Aβ-induced neural degeneration. Unfortunately, the assortment of AChE PAS ligands is still extremely limited.To study putative advantages of AChE non-charged PAS inhibitors based on 6-methyluracil derivatives for the treatment of Alzheimer's disease.	In vitro studies. Concentration of drug producing 50% of AChE/BuChE activity inhibition (IC50) was measured using the method of Ellman et al. [6]. Toxicological experiments were performed using IP injection of the different compounds in mice. LD50, dose (in mg/kg) causing lethal effects in 50% of animals was taken as a criterion of toxicity [7]. The ability of compound to block in vitro AChE-induced Aβ1-40 aggregation was studied using a thioflavin T (ThT) fluorescent probe [8].In vivo biological assays. For in vivo blood-brain barrier permeation assay brains were removed 30 min after IP injection of LD50 dose of tested compound injection. The inhibitory potency was measured using the method of Ellman.Scopolamine and transgenic models of AD were used to evaluate the influence of compound 35 on spatial memory performance.Water solution of scopolamine was injected to mice (ip) 20 minutes before starting memory test during 14 days [9]. Mice were assigned to 7 groups, including 4 groups receiving injection (ip) of compound in different dosages, donepezil-treated mice (donepezil is conventionally used to treat Alzheimer's disease), positive and negative control groups. Double transgenic (APP/PS1) mice expressing a chimeric mouse/human amyloid precursor protein and a mutant of human presenilin-1 [10] were assigned to 4 groups, including transgenic animals injected (ip) with compound 35 or donepezil solution, positive (transgenes injected with water) and negative (wild-type mice) controls.To evaluate spatial memory performance, mice were trained on a reward alternation task using a conventional T-maze [11]. The criterion for a mouse having learned the rewarded alternation task was 3 consecutive days of at least 5 correct responses out of the 6 free trials.For β-amyloid peptide load was evaluated quantitatively as a number and summary area of Thioflavine S fluorescent spots in cerebral cortex and hippocampal images using Image J program. Statistical analyses were performed using the Mann-Whitney test.	We evaluated the acute toxicity of the most active compounds. The most potent AChE inhibitor compound 35 (IC50 (AChE) = 5 ± 0.5 nM) exhibited the lowest LD50 values (51 mg/kg) and inhibited brain AChE by more than 71 ± 1%. Compound 35 at 10 nM, exhibited a significant (35 ± 9%) inhibitory activity toward human AChE-induced Aβ aggregation.Scopolamine injection induced significant decrease in correct choice percentage in T-maze, as well as decrease in percentage of mice reaching criterion for learning the task by day 14. This memory deficit was relieved to some extent either by compound 35 (5 mg/kg) or donepezil (reference compound) treatment (0.75 mg/kg). Interestingly, higher doses of compound 35 (10 and 15 mg/kg) produced less therapeutic effect on spatial memory deficit.Group of APP/PS1 mice showed 3 times lower percentage of reaching behavioral criterion and lower percentage of correct choice in T-maze alternation task comparing to WT mice, whereas compound 35 (5 mg/kg) or Donepezil treatment effectively improved these parameters in APP/PS1 mice.Compound 35 treatment (5 mg/kg) during 14 days significantly reduced percentage of summary area and number of β-amyloid peptide (βAP) deposits visualized in sections of cerebral cortex, dentate gyrus, and hippocampal CA3 area in APP/PS1 mice. The most prominent reduction of βAP load by compound 35 treatment was found in CA3 area and cerebral cortex. Meanwhile, Donepezil treatment (1 mg/kg) during 14 days significantly reduced βAP load in cerebral cortex but not in dentate gyrus and CA3 area.	Experiments showed that the most potent AChE inhibitor compound 35 (6-methyluracil derivative) permeated the blood-brain barrier, improved working memory in the APP/PS1 transgenic mice and significantly reduced the number and area of Aβ plaques in the brain. Thus, compound 35 is a promising candidate as a bi-functional inhibitor of AChE for treatment of AD.	
26639316	Environmental enrichment has multiple effects on behaviour, including modification of responses to psychostimulant drugs mediated by striatal neurons. However, the underlying molecular and cellular mechanisms are not known. Here we show that DARPP-32, a hub signalling protein in striatal neurons, interacts with adducins, which are cytoskeletal proteins that cap actin filaments' fast-growing ends and regulate synaptic stability. DARPP-32 binds to adducin MARCKS domain and this interaction is modulated by DARPP-32 Ser97 phosphorylation. Phospho-Thr75-DARPP-32 facilitates β-adducin Ser713 phosphorylation through inhibition of a cAMP-dependent protein kinase/phosphatase-2A cascade. Caffeine or 24-h exposure to a novel enriched environment increases adducin phosphorylation in WT, but not T75A mutant mice. This cascade is implicated in the effects of brief exposure to novel enriched environment on dendritic spines in nucleus accumbens and cocaine locomotor response. Our results suggest a molecular pathway by which environmental changes may rapidly alter responsiveness of striatal neurons involved in the reward system. 
26638769	Evidence suggests that the endocannabinoid system has been conserved in the animal kingdom for 500 million years, and this system influences many critical behavioral processes including associative learning, reward signaling, goal-directed behavior, motor skill learning, and action-habit transformation. Additionally, the neurotransmitter dopamine has long been recognized to play a critical role in the processing of natural rewards, as well as of motivation that regulates approach and avoidance behavior. This motivational role of dopamine neurons is also based upon the evidence provided by several studies investigating disorders of dopamine pathways such as drug addiction and Parkinson's disease. From an evolutionary point of view, individuals engage in behaviors aimed at maximizing and minimizing positive and aversive consequences, respectively. Accordingly, those with the greatest fitness have a better potential to survival. Hence, deviations from fitness can be viewed as a part of the evolutionary process by means of natural selection. Given the long evolutionary history of both the endocannabinoid and dopaminergic systems, it is plausible that they must serve as fundamental and basic modulators of physiological functions and needs. Notably, endocannabinoids regulate dopamine neuronal activity and its influence on behavioral output. The goal of this chapter is to examine the endocannabinoid influence on dopamine signaling specifically related to (i) those behavioral processes that allow us to successfully adapt to ever-changing environments (i.e., reward signaling and motivational processes) and (ii) derangements from behavioral flexibility that underpin drug addiction. 
26635564	Previous research indicates that extinction of rodent maze behavior may occur without explicit performance of the previously acquired response. In latent extinction, confining an animal to a previously rewarded goal location without reinforcement is typically sufficient to produce extinction of maze learning. However, previous studies have not determined whether latent extinction may be successfully employed to extinguish all types of memory acquired in the maze, or whether only specific types of memory may be vulnerable to latent extinction. The present study examined whether latent extinction may be effective across two plus-maze tasks that depend on anatomically distinct neural systems. Adult male Long-Evans rats were trained in a hippocampus-dependent place learning task (Experiment 1), in which animals were trained to approach a consistent spatial location for food reward. A separate group of rats were trained in a dorsolateral striatum-dependent response learning task (Experiment 2), in which animals were trained to make a consistent egocentric body-turn response for food reward. Following training, animals received response extinction or latent extinction. For response extinction, animals were given the opportunity to execute the original running approach response toward the empty food cup. For latent extinction, animals were confined to the original goal locations with the empty food cup, thus preventing them from making the original running approach response. Results indicate that, relative to no extinction, latent extinction was effective at extinguishing memory in the place learning task, but remained ineffective in the response learning task. In contrast, typical response extinction remained very effective at extinguishing memory in both place and response learning tasks. The present findings confirm that extinction of maze learning may occur with or without overt performance of the previously acquired response, but that the effectiveness of latent extinction may depend on the type of memory being extinguished. The findings suggest that behavioral treatments modeled after response extinction protocols may be especially useful in alleviating human psychopathologies involving striatum-dependent memory processes (e.g., drug addiction and relapse). 
26634907	Collective punishment and reward are usually regarded as two potential mechanisms to explain the evolution of cooperation. Both scenarios, however, seem problematic to understand cooperative behavior, because they can raise the second-order free-rider problem and many organisms are not able to discriminate less cooperating individuals. Even though they have been proved to increase cooperation, there has been a debate about which one being more effective. To address this issue, we resort to the N-player evolutionary snowdrift game (NESG), where a collective punishment/reward mechanism is added by allowing some players to display punishment/reward towards all remaining players. By means of numerous simulations and analyses, we find that collective punishment is more effective in promoting cooperation for a relatively high initial frequency of cooperation or for a relatively small group. When the intensity of punishment exceeds a certain threshold, a stable state of full cooperation emerges for both small and large groups. In contrast, such state does not appear for large groups playing a NESG with reward mechanism. In the case of mutualistic interactions, finally, our results show the new payoff with collective punishment/reward can lead to the coexistence of cooperators and defectors when discrimination between these two is not possible. 
26633264	The ability to learn is assumed to support successful recovery and rehabilitation therapy after stroke. Hence, learning impairments may reduce the recovery potential. Here, the hypothesis is tested that stroke survivors have deficits in feedback-driven implicit learning. Stroke survivors (n=30) and healthy age-matched control subjects (n=21) learned a probabilistic classification task with brain activation measured using functional magnetic resonance imaging in a subset of these individuals (17 stroke and 10 controls). Stroke subjects learned slower than controls to classify cues. After being rewarded with a smiley face, they were less likely to give the same response when the cue was repeated. Stroke subjects showed reduced brain activation in putamen, pallidum, thalamus, frontal and prefrontal cortices and cerebellum when compared with controls. Lesion analysis identified those stroke survivors as learning-impaired who had lesions in frontal areas, putamen, thalamus, caudate and insula. Lesion laterality had no effect on learning efficacy or brain activation. These findings suggest that stroke survivors have deficits in reinforcement learning that may be related to dysfunctional processing of feedback-based decision-making, reward signals and working memory. 
26632336	Pavlovian conditioning is an elementary form of reward-related behavioral adaptation. The mesolimbic dopamine system is widely considered to mediate critical aspects of reward-related learning. For example, initial acquisition of positively-reinforced operant behavior requires dopamine (DA) D1 receptor (D1R) activation in the basolateral amygdala (BLA), central nucleus of the amygdala (CeA), and the ventral subiculum (vSUB). However, the role of D1R activation in these areas on appetitive, non-drug-related, Pavlovian learning is not currently known. In separate experiments, microinfusions of the D1-like receptor antagonist SCH-23390 (3.0 nmol/0.5 μL per side) into the amygdala and subiculum preceded discriminated Pavlovian conditioned approach (dPCA) training sessions. D1-like antagonism in all three structures impaired the acquisition of discriminated approach, but had no effect on performance after conditioning was asymptotic. Moreover, dissociable effects of D1-like antagonism in the three structures on components of discriminated responding were obtained. Lastly, the lack of latent inhibition in drug-treated groups may elucidate the role of D1-like in reward-related Pavlovian conditioning. The present data suggest a role for the D1 receptors in the amygdala and hippocampus in learning the significance of conditional stimuli, but not in the expression of conditional responses.
26631475	Ventral tegmental area (VTA) neurons play roles in reward and aversion. The VTA has three major neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. VTA glutamatergic neurons--expressing vesicular glutamate transporter-2 (VGluT2)--project to limbic and cortical regions, but also excite neighboring dopaminergic neurons. Here, we test whether local photoactivation of VTA VGluT2 neurons expressing Channelrhodopsin-2 (ChR2) under the VGluT2 promoter causes place preference and supports operant responding for the stimulation. By using a Cre-dependent viral vector, ChR2 (tethered to mCherry) was expressed in VTA glutamatergic neurons of VGluT2::Cre mice. The mCherry distribution was evaluated by immunolabeling. By confocal microscopy, we detected expression of mCherry in VTA cell bodies and local processes. In contrast, VGluT2 expression was restricted to varicosities, some of them coexpressing mCherry. By electron microscopy, we determined that mCherry-VGluT2 varicosities correspond to axon terminals, forming asymmetric synapses on neighboring dopaminergic neurons. These findings indicate that ChR2 was present in terminals containing glutamatergic synaptic vesicles and involved in local synaptic connections. Photoactivation of VTA slices from ChR2-expressing mice induced AMPA/NMDA receptor-dependent firing of dopaminergic neurons projecting to the nucleus accumbens. VTA photoactivation of ChR2-expressing mice reinforced instrumental behavior and established place preferences. VTA injections of AMPA or NMDA receptor antagonists blocked optical self-stimulation and place preference. These findings suggest a role in reward function for VTA glutamatergic neurons through local excitatory synapses on mesoaccumbens dopaminergic neurons.
26631365	Schizophrenia is a severe psychiatric disorder associated with impaired fronto-striatal functioning. Similar deficits are observed in unaffected siblings of patients, indicating that these deficits are linked to a familial risk for the disorder. Fronto-striatal deficits may arise during adolescence and precede clinical manifestation of the disorder. However, the development of the fronto-striatal network in adolescents at increased familial risk for schizophrenia is still poorly understood. In this cross-sectional study, we investigate the impact of familial risk on fronto-striatal functioning across age related to reward anticipation and receipt in 25 adolescent offspring of schizophrenia patients (SZ offspring) and 36 age-matched healthy controls (range 10-19years). Subjects performed a reward task while being scanned with functional MRI. Overall response times and the amount of money won did not differ between the groups. Striatal activation during reward anticipation decreased across age in the SZ offspring, while it did not in the healthy controls. Activation in the orbitofrontal cortex during reward receipt did not differ between the groups. These results, taken together with data from adult schizophrenia patients and their siblings, indicate that the diminishing striatal activation across adolescence may signify a familial vulnerability for schizophrenia. 
26631146	When we evaluate an option, how is the neural representation of its value linked to information that identifies it, such as its position in space? We hypothesized that value information and identity cues are not bound together at a particular point but are represented together at the single unit level throughout the entirety of the choice process. We examined neuronal responses in two-option gambling tasks with lateralized and asynchronous presentation of offers in five reward regions: orbitofrontal cortex (OFC, area 13), ventromedial prefrontal cortex (vmPFC, area 14), ventral striatum (VS), dorsal anterior cingulate cortex (dACC), and subgenual anterior cingulate cortex (sgACC, area 25). Neuronal responses in all areas are sensitive to the positions of both offers and of choices. This selectivity is strongest in reward-sensitive neurons, indicating that it is not a property of a specialized subpopulation of cells. We did not find consistent contralateral or any other organization to these responses, indicating that they may be difficult to detect with aggregate measures like neuroimaging or studies of lesion effects. These results suggest that value coding is wed to factors that identify the object throughout the reward system and suggest a possible solution to the binding problem raised by abstract value encoding schemes.
26630955	Anhedonia, the inability to feel pleasure, and amotivation, the lack of motivation, are two prominent negative symptoms of schizophrenia, which contribute to the poor social and occupational behaviors in the patients. Recently growing evidence shows that anhedonia and amotivation are tied together, but have distinct neural correlates. It is important to note that both of these symptoms may derive from deficient functioning of the reward network. A further analysis into the neuroimaging findings of schizophrenia shows that the neural correlates overlap in the reward network including the ventral striatum, anterior cingulate cortex and orbitofrontal cortex. Other neuroimaging studies have demonstrated the involvement of the default mode network in anhedonia. The identification of aspecific deficit in hedonic and motivational capacity may help to elucidate the mechanisms behind social functioning deficits in schizophrenia, and may also lead to more targeted treatment of negative symptoms.
26630279	Avoidance behavior is a critical component of many psychiatric disorders, and as such, it is important to understand how avoidance behavior arises, and whether it can be modified. In this study, we used empirical and computational methods to assess the role of informational feedback and ambiguous outcome in avoidance behavior. We adapted a computer-based probabilistic classification learning task, which includes positive, negative and no-feedback outcomes; the latter outcome is ambiguous as it might signal either a successful outcome (missed punishment) or a failure (missed reward). Prior work with this task suggested that most healthy subjects viewed the no-feedback outcome as strongly positive. Interestingly, in a later version of the classification task, when healthy subjects were allowed to opt out of (i.e. avoid) responding, some subjects ("avoiders") reliably avoided trials where there was a risk of punishment, but other subjects ("non-avoiders") never made any avoidance responses at all. One possible interpretation is that the "non-avoiders" valued the no-feedback outcome so positively on punishment-based trials that they had little incentive to avoid. Another possible interpretation is that the outcome of an avoided trial is unspecified and that lack of information is aversive, decreasing subjects' tendency to avoid. To examine these ideas, we here tested healthy young adults on versions of the task where avoidance responses either did or did not generate informational feedback about the optimal response. Results showed that provision of informational feedback decreased avoidance responses and also decreased categorization performance, without significantly affecting the percentage of subjects classified as "avoiders." To better understand these results, we used a modified Q-learning model to fit individual subject data. Simulation results suggest that subjects in the feedback condition adjusted their behavior faster following better-than-expected outcomes, compared to subjects in the no-feedback condition. Additionally, in both task conditions, "avoiders" adjusted their behavior faster following worse-than-expected outcomes, and treated the ambiguous no-feedback outcome as less rewarding, compared to non-avoiders. Together, results shed light on the important role of ambiguous and informative feedback in avoidance behavior. 
26627312	Choice between actions often requires the ability to retrieve action consequences in circumstances where they are only partially observable. This capacity has recently been argued to depend on orbitofrontal cortex; however, no direct evidence for this hypothesis has been reported. Here, we examined whether activity in the medial orbitofrontal cortex (mOFC) underlies this critical determinant of decision-making in rats. First, we simulated predictions from this hypothesis for various tests of goal-directed action by removing the assumption that rats could retrieve partially observable outcomes and then tested those predictions experimentally using manipulations of the mOFC. The results closely followed predictions; consistent deficits only emerged when action consequences had to be retrieved. Finally, we put action selection based on observable and unobservable outcomes into conflict and found that whereas intact rats selected actions based on the value of retrieved outcomes, mOFC rats relied solely on the value of observable outcomes.
26626414	Humans tend to be conservative and typically will retain their initial decision even if an option to change is provided. We investigated whether the stimulus-preceding negativity (SPN), an event-related potential associated with the affective-motivational anticipation of feedback in gambling tasks, represents the strong response tendency to retain an initial decision. We compared SPNs in three different card-gambling tasks wherein the participants were given the opportunity to change their initial decision after they chose one of three cards. In two of these tasks, the winning probability was equiprobable (1/3 and 1/2, respectively) whether or not the participants changed their initial decision. However, in the Monty Hall dilemma task, changing the initial decision stochastically doubled the probability of winning (2/3) compared with retaining (1/3). In this counterintuitive probabilistic dilemma task, after the participant chose an option among three cards, a nonreward (losing) option is revealed. Then, the participants are offered a chance to change their mind and asked to make their final decision: to retain their initial choice or change to the alternate option. In all tasks, maintenance of previous behaviors was observed, although the rate of retaining earlier choices tended to be lower in the Monty Hall dilemma task than in the other two tasks. The SPNs were larger on retain trials than on change trials irrespective of task. These results suggest that underlying brain activities associated with the strong tendency to retain the initial decision can be observed by the SPN and thus it reflects expectancy of outcomes in terms of self-chosen behaviors. 
26625969	Substance dependent (SD) relative to non-dependent (ND) individuals exhibit an attenuated reward positivity, an electrophysiological signal believed to index sensitivity of anterior cingulate cortex (ACC) to rewards. Here we asked whether this altered neural response reflects a specific devaluation of monetary rewards relative to drug-related rewards by ACC.We recorded the reward positivity from SD and ND individuals who currently smoke, following an overnight period of abstinence, while they engaged in two feedback tasks. In a money condition the feedback indicated either a monetary reward or no reward, and in a cigarette condition the feedback indicated either a drug-related reward or no reward.	Overall, cigarette relative to monetary rewards elicited a larger reward positivity. Further, for the subjects who engaged in the money condition first, the reward positivity was smaller for the SD compared to the ND participants, but for the subjects who engaged in the cigarette condition first, the reward positivity was larger for the SD compared to the ND participants.	Our results suggest that the initial category of feedback "primed" the response of the ACC to the alternative feedback type on subsequent trials, and that SD and ND individuals responded differently to this priming effect.	We propose that for people who misuse addictive substances, the prospect of obtaining drug-related rewards engages the ACC to exert control over extended behaviors.	

26625423	Reinforcement learning (RL)-based decoders in brain-machine interfaces (BMIs) interpret dynamic neural activity without patients' real limb movements. In conventional RL, the goal state is selected by the user or defined by the physics of the problem, and the decoder finds an optimal policy essentially by assigning credit over time, which is normally very time-consuming. However, BMI tasks require finding a good policy in very few trials, which impose a limit on the complexity of the tasks that can be learned before the animal quits. Therefore, this paper explores the possibility of letting the agent infer potential goals through actions over space with multiple objects, using the instantaneous reward to assign credit spatially. A previous method, attention-gated RL employs a multilayer perceptron trained with backpropagation, but it is prone to local minima entrapment. We propose a quantized attention-gated kernel RL (QAGKRL) to avoid the local minima adaptation in spatial credit assignment and sparsify the network topology. The experimental results show that the QAGKRL achieves higher successful rates and more stable performance, indicating its powerful decoding ability for more sophisticated BMI tasks as required in clinical applications.
26623536	Poor decision-making is a feature of borderline personality disorder (BPD) and bipolar disorder (BD). Twenty women with BPD, 20 women with BD, and 20 healthy females completed a risky choice task. Those with BPD exhibited altered processing of information about potential gains and losses, with a bias toward large compared to small gains, large compared to small losses, and a tendency to choose outcomes with a negative expected value. This failure to use explicit reinforcement signals was not observed in those with BD. Difficulties using reward information to make decisions may impair day-to-day function. Such impairments offer new treatment targets in BPD. 
26623516	A great deal of interest has been focused recently on the habenula and its critical role in aversion, negative-reward and drug dependence. Using a conditional mouse model of the ACh-synthesizing enzyme choline acetyltransferase (Chat), we report that local elimination of acetylcholine (ACh) in medial habenula (MHb) neurons alters glutamate corelease and presynaptic facilitation. Electron microscopy and immuno-isolation analyses revealed colocalization of ACh and glutamate vesicular transporters in synaptic vesicles (SVs) in the central IPN. Glutamate reuptake in SVs prepared from the IPN was increased by ACh, indicating vesicular synergy. Mice lacking CHAT in habenular neurons were insensitive to nicotine-conditioned reward and withdrawal. These data demonstrate that ACh controls the quantal size and release frequency of glutamate at habenular synapses, and suggest that the synergistic functions of ACh and glutamate may be generally important for modulation of cholinergic circuit function and behavior. 
26621112	The number of massively multiplayer online games (MMOs) is on the rise worldwide along with the fascination that they inspire. Problems occur when the use of MMOs becomes excessive at the expense of other life domains. Although not yet formally included as disorder in common diagnostic systems, internet gaming disorder (IGD) is considered a "condition for further study" in section III of the DSM-5. The current review aims to provide an overview of cognitive and neurobiological data currently available on IGD, with a particular focus on impulsivity, compulsivity, and sensitivity to reward and punishment. Additionally, we also compare these findings on IGD with data from studies on pathological gambling (PG)-so far the only condition officially classified as a behavioral addiction in the DSM-5. Multiple similarities have been observed in the neurobiology of IGD and PG, as measured by alterations in brain function and behavior. Both patients with IGD and those with PG exhibited decreased loss sensitivity; enhanced reactivity to gaming and gambling cues, respectively; enhanced impulsive choice behavior; aberrant reward-based learning; and no changes in cognitive flexibility. In conclusion, the evidence base on the neurobiology of gaming and gambling disorders is beginning to illuminate the similarities between the two. However, as only a few studies have addressed the neurobiological basis of IGD, and some of these studies suffer from significant limitations, more research is required before IGD's inclusion as a second behavioral addiction in the next versions of the ICD and DSM can be justified.
26620193	Neonatal handling has an impact on adult behavior of experimental animals and is associated with rapid and increased palatable food ingestion, impaired behavioral flexibility, and fearless behavior to novel environments. These symptoms are characteristic features of impulsive trait, being controlled by the medial prefrontal cortex (mPFC). Impulsive behavior is a key component of many psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), manic behavior, and schizophrenia. Others have reported a methylphenidate (MPH)-induced enhancement of mPFC functioning and improvements in behavioral core symptoms of ADHD patients. The aims of the present study were: (i) to find in vivo evidence for an association between neonatal handling and the development of impulsive behavior in adult Wistar rats and (ii) to test whether neonatal handling could have an impact on monoamine levels in the mPFC and the pharmacological response to MPH in vivo. Therefore, experimental animals (litters) were classified as: "non-handled" and "handled" (10[Formula: see text]min/day, postnatal days 1-10). After puberty, they were exposed to either a larger and delayed or smaller and immediate reward (tolerance to delay of reward task). Acute MPH (3[Formula: see text]mg/Kg. i.p.) was used to suppress and/or regulate impulsive behavior. Our results show that only neonatally handled male adult Wistar rats exhibit impulsive behavior with no significant differences in monoamine levels in the medial prefrontal cortex, together with a decreased response to MPH. On this basis, we postulate that early life interventions may have long-term effects on inhibitory control mechanisms and affect the later response to pharmacological agents during adulthood. 
26619211	Cognitive theories of depression and anxiety have traditionally emphasized the role of attentional biases in the processing of negative information. The dot-probe task has been widely used to study this phenomenon. Recent findings suggest that biased processing of positive information might also be an important aspect of developing psychopathological symptoms. However, despite some evidence suggesting persons with symptoms of depression and anxiety may avoid positive information, many dot-probe studies have produced null findings. The present review used conventional and novel meta-analytic methods to evaluate dot-probe attentional biases away from positive information and, for comparison, toward negative information, in depressed and anxious individuals. Results indicated that avoidance of positive information is a real effect exhibiting substantial evidential value among persons experiencing psychopathology, with individuals evidencing primary symptoms of depression clearly demonstrating this effect. Different theoretical explanations for these findings are evaluated, including those positing threat-processing structures, even-handedness, self-regulation, and reward devaluation, with the novel theory of reward devaluation emphasized and expanded. These novel findings and theory suggest that avoidance of prospective reward helps to explain the cause and sustainability of depressed states. Suggestions for future research and methodological advances are discussed.
26615907	The hedonic value of a sweet food reward, or how much a taste is 'liked', has been suggested to be encoded by neuronal firing in the posterior ventral pallidum (VP). Hedonic impact can be altered by psychological manipulations, such as taste aversion conditioning, which can make an initially pleasant sweet taste become perceived as disgusting. Pairing nausea-inducing LiCl injection as a Pavlovian unconditioned stimulus (UCS) with a novel taste that is normally palatable as the predictive conditioned stimulus (CS+) suffices to induce a learned taste aversion that changes orofacial 'liking' responses to that sweet taste (e.g., lateral tongue protrusions) to 'disgust' reactions (e.g., gapes) in rats. We used two different sweet tastes of similar initial palatability (a sucrose solution and a polycose/saccharin solution, CS ± assignment was counterbalanced across groups) to produce a discriminative conditioned aversion. Only one of those tastes (arbitrarily assigned and designated as CS+) was associatively paired with LiCl injections as UCS to form a conditioned aversion. The other taste (CS-) was paired with mere vehicle injections to remain relatively palatable as a control sweet taste. We recorded the neural activity in VP in response to each taste, before and after aversion training. We found that the safe and positively hedonic taste always elicited excitatory increases in firing rate of VP neurons. By contrast, aversion learning reversed the VP response to the 'disgusting' CS+ taste from initial excitation into a conditioned decrease in neuronal firing rate after training. Such neuronal coding of hedonic impact by VP circuitry may contribute both to normal pleasure and disgust, and disruptions of VP coding could result in affective disorders, addictions and eating disorders.
26615561	In this article we examine the relationship between extent of gambling for U.S. adults and the distance from their residence to the nearest casino or track. We employ data from a telephone survey of U.S. adults conducted in 2011-2013. The chances that the respondents gambled in the past year, were frequent gamblers, or were problem gamblers were greater if they lived close to a casino. The chances that the respondents gambled in the past year or were frequent gamblers were greater if they lived close to a horse or dog track. The effects of closeness to a casino on the likelihood of past-year gambling, frequent gambling, and problem gambling, as well as the effect of closeness to a track on past-year gambling, extended to about 30 miles from the respondent's home. In addition, the concentration of casinos within 30 miles of the respondent's home was positively related to the respondents' chance of being a frequent or problem gambler. If a respondent had no casinos within 30 miles, he or she had a 2.7 % chance of being a problem gambler; if one casino, a 3.9 % chance; if six or more, a 6.2 % chance. The authors estimate that at least part of this effect is causal.
26613565	Financial incentives may have utility in promoting psychotherapy attendance and adherence, leading to improved clinical functioning. This study presents results from a novel application of financial incentives-a progressively lowered pay scale that rewards therapy attendance and adherence.Overall, 110 outpatients participated; 56 patients (51%) were enrolled in the financial incentives condition and received a 5% fee discount-applied iteratively across sessions-if they followed defined criteria (e.g., completed homework).	There were no statistically significant differences between groups in terms of the number of sessions attended, therapy duration, and number of no-shows and cancellations. However, adjusting for Global Assessment of Functioning (GAF) at intake, patients receiving the financial incentives had significantly higher GAF rating at termination compared with those who did not receive the intervention.	Financial incentives that reward therapy attendance and adherence with discounted fees is associated with improved clinical functioning.	
26613374	Cues (conditioned stimuli; CSs) associated with rewards can come to motivate behavior, but there is considerable individual variation in their ability to do so. For example, a lever-CS that predicts food reward becomes attractive and wanted, and elicits reward-seeking behavior, to a greater extent in some rats ('sign-trackers'; STs) than others ('goal-trackers'; GTs). Variation in dopamine (DA) neurotransmission in the nucleus accumbens (NAc) core is thought to contribute to such individual variation. Given that the DA transporter (DAT) exerts powerful regulation over DA signaling, we characterized the expression and function of the DAT in the accumbens of STs and GTs. STs showed greater DAT surface expression in ventral striatal synaptosomes than GTs, and ex vivo fast-scan cyclic voltammetry recordings of electrically evoked DA release confirmed enhanced DAT function in STs, as indicated by faster DA uptake, specifically in the NAc core. Consistent with this, systemic amphetamine (AMPH) produced greater inhibition of DA uptake in STs than in GTs. Furthermore, injection of AMPH directly into the NAc core enhanced lever-directed approach in STs, presumably by amplifying the incentive value of the CS, but had no effect on goal-tracking behavior. On the other hand, there were no differences between STs and GTs in electrically-evoked DA release in slices, or in total ventral striatal DA content. We conclude that greater DAT surface expression may facilitate the attribution of incentive salience to discrete reward cues. Investigating this variability in animal sub-populations may help explain why some people abuse drugs while others do not.
26612627	Previous studies showed that both human and non-human animals can discriminate between different quantities (i.e., time intervals, numerosities) with a limited level of precision due to their endogenous/representational uncertainty. In addition, other studies have shown that subjects can modulate their temporal categorization responses adaptively by incorporating information gathered regarding probabilistic contingencies into their time-based decisions. Despite the psychophysical similarities between the interval timing and nonverbal counting functions, the sensitivity of count-based decisions to probabilistic information remains an unanswered question. In the current study, we investigated whether exogenous probabilistic information can be integrated into numerosity-based judgments by mice. In the task employed in this study, reward was presented either after few (i.e., 10) or many (i.e., 20) lever presses, the last of which had to be emitted on the lever associated with the corresponding trial type. In order to investigate the effect of probabilistic information on performance in this task, we manipulated the relative frequency of different trial types across different experimental conditions. We evaluated the behavioral performance of the animals under models that differed in terms of their assumptions regarding the cost of responding (e.g., logarithmically increasing vs. no response cost). Our results showed for the first time that mice could adaptively modulate their count-based decisions based on the experienced probabilistic contingencies in directions predicted by optimality.
26612620	There is an emerging body of evidence that implicates a crucial role of γ-aminobutyric acid subtype A (GABAA) receptors in modulating the rewarding effects of a number of abused drugs. Modulation of GABAA receptors may therefore represent a novel drug-class independent mechanism for the development of abuse treatment pharmacotherapeutics.We tested the hypothesis that the GABAA receptor benzodiazepine-site (BDZ) negative modulator Ro15-4513 would reduce the reward-related effects of three pharmacologically dissimilar drugs; toluene vapor, d-methamphetamine, and diazepam using intracranial self-stimulation (ICSS) in mice. We also examined whether Ro15-4513 attenuated dopamine release produced by d-methamphetamine in an in vivo microdialysis procedure.	Ro15-4513 abolished ICSS reward facilitation produced by all three abused drugs at Ro15-4513 doses which had no effect on ICSS when administered alone. In contrast, the BDZ antagonist flumazenil only attenuated the ICSS-facilitating effects of diazepam. Administration of the same dose of Ro15-4513 which abolished drug-facilitated ICSS produced a 58 % decrease in d-methamphetamine-stimulated dopamine in the nucleus accumbens of mice relative to d-methamphetamine alone.	These results demonstrate that negative modulation of GABAA receptors can produce profound reductions in reward-related effects of a diverse group of drugs that activate the mesolimbic reward pathway through different mechanisms. These data suggest that pharmacological modulation of GABAA receptors may represent a viable pathway for the development of drug abuse pharmacotherapies.	
26612552	4-Methylethcathinone is a drug that belongs to the second generation of synthetic cathinones, and recently it has been ranked among the most popular "legal highs". Although it has similar in vitro neurochemical actions to other drugs such as cocaine, the behavioral effects of 4-methylethcathinone remain to be determined.The addictive potential and locomotor potentiation by 4-methylethcathinone were investigated in rats using the conditioned place preference and sensitization paradigm. Methamphetamine was used as a positive control. Because synthetic cathinones can have psychological effects, we also examined anxiety-like behavior using the elevated plus maze.	A conditioning dose of 10 mg/kg 4-methylethcathinone was able to induce conditioned place preference and reinstatement (following 2 weeks of withdrawal). Acute or repeated injections of 4-methylethcathinone at 3 or 10mg/kg failed to alter locomotor activity. At 30 mg/kg, however, acute 4-methylethcathinone increased locomotor activity compared with saline, while chronic 4-methylethcathinone induced a delayed and attenuated sensitization compared with methamphetamine. Additionally, repeated daily injections of 4-methylethcathinone (30 mg/kg) reduced, whereas methamphetamine increased time spent by rats in the open arm of an elevated plus maze compared with saline injections. Interestingly, a 2-week withdrawal period following chronic injections of 4-methylethcathinone or methamphetamine increased time spent in the open arm in all rats.	The rewarding properties of 4-methylethcathinone were found to be dissociated from its effects on locomotor activity. Additionally, chronic 4-methylethcathinone use may trigger abnormal anxious behaviors. These behavioral effects caused by 4-methylethcathinone appear to last even after a withdrawal period.	
26612385	Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake.In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2-AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions.	A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks.	Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep.	A commentary on this article appears in this issue on page 495.	
26611719	Late adolescence and emerging adulthood (specifically ages 15-24) represent a period of heightened sexual risk taking resulting in the greatest annual rates of sexually transmitted infections and unplanned pregnancies in the US population. Ongoing efforts to prevent such negative consequences are likely to benefit from a deepening of our understanding of biological mechanisms through which sexual risk taking emerges and biases decision making during this critical window. Here we present a neuroscience framework from which a mechanistic examination of sexual risk taking can be advanced. Specifically, we adapt the neurodevelopmental triadic model, which outlines how motivated behavior is governed by three systems: approach, avoidance, and regulation, to sexual decision making and subsequent risk behavior. We further propose a testable hypothesis of the triadic model, wherein relatively decreased threat-related amygdala reactivity and increased reward-related ventral striatum reactivity leads to sexual risk taking, which is particularly exaggerated during adolescence and young adulthood when there is an overexpression of dopaminergic neurons coupled with immature top-down prefrontal cortex regulation. We conclude by discussing how future research based on our adapted triadic model can inform ongoing efforts to improve intervention and prevention efforts. 
26609118	Microsaccades are small-amplitude (typically <1°), ballistic eye movements that occur when attempting to fixate gaze. Initially thought to be generated randomly, it has recently been established that microsaccades are influenced by sensory stimuli, attentional processes, and certain cognitive states. Whether decision processes influence microsaccades, however, is unknown. Here, we adapted two classic economic tasks to examine whether microsaccades reflect evolving saccade decisions. Volitional saccade choices of monkey and human subjects provided a measure of the subjective value of targets. Importantly, analyses occurred during a period of complete darkness to minimize the known influence of sensory and attentional processes on microsaccades. As the time of saccadic choice approached, microsaccade direction became the following: 1) biased toward targets as a function of their subjective value and 2) predictive of upcoming, voluntary choice. Our results indicate that microsaccade direction is influenced by and is a reliable tell of evolving saccade decisions. Our results are consistent with dynamic decision processes within the midbrain superior colliculus; that is, microsaccade direction is influenced by the transition of activity toward caudal saccade regions associated with high saccade value and/or future saccade choice.
26609106	Aberrant brain reward responses to food-related cues are an implied characteristic of human obesity; yet, findings are inconsistent. To explain these inconsistencies, we aimed to uncover endophenotypes associated with heterogeneity in attributing incentive salience to food cues in the context of other emotionally salient cues; a phenomenon described as sign- vs goal tracking in preclinical models. Data from 64 lean and 88 obese adults who were 35.5 ± 9.4 years old and predominantly women (79%) were analyzed. Participants viewed food-related, pleasant, neutral and unpleasant images while recording electroencephalograph. Late positive potentials were used to assess incentive salience attributed to the visual stimuli. Eating and affective traits were also assessed. Findings demonstrated that obese individuals, in general, do not demonstrate aberrant brain reward responses to food-related cues. As hypothesized, latent profile analysis of the late positive potential uncovered two distinct groups. 'Sign-trackers' showed greater responses to food-related cues (P < 0.001) but lower responses to pleasant stimuli (P < 0.001) compared with 'goal-trackers'. There were proportionally more obese than lean 'sign-trackers' (P = 0.03). Obese 'sign-trackers' reported significantly higher levels of emotional eating and food craving (P < 0.001). By examining the heterogeneity in brain reactivity to various emotional stimuli, this translational study highlights the need to consider important neurobehavioral endophenotypes of obesity.
26608538	Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional enzyme that is required for synaptic plasticity and has been proposed to be a primary molecular component of the etiology of alcohol addiction. Chronic alcohol intake upregulates CaMKIIα protein expression in reward-related brain regions including the amygdala and nucleus accumbens, and CaMKIIα activity in the amygdala is required for the positive reinforcing effects of alcohol, suggesting this system promotes consumption in the early stages of alcohol addiction. Alternatively, the medial prefrontal cortex (mPFC) is known to inhibit limbic activity via CaMKII-dependent excitatory projections and may, therefore, enable top-down regulation of motivation. Here we sought to remove that regulatory control by site-specifically inhibiting CaMKII activity in the mPFC, and measured effects on the positive reinforcing effects of sweetened alcohol in C57BL/6J mice. Infusion of the CAMKII inhibitor KN-93 (0-10.0 μg) in the mPFC primarily increased alcohol+sucrose reinforced response rate in a dose- and time-dependent manner. KN-93 infusion reduced response rate in behavior-matched sucrose-only controls. Importantly, potentiation of operant responding for sweetened alcohol occurred immediately after infusion, at a time during which effects on sucrose responding were not observed, and persisted through the session. These results suggest that endogenous CaMKII activity in the mPFC exerts inhibitory control over the positive reinforcing effects of alcohol. Downregulation of CaMKII signaling in the mPFC might contribute to escalated alcohol use.
26608281	Stress in health care professionals may reflect both the work and appraisal of work and impacts on the individuals, their patients, colleagues and managers.The purpose of the present study is to examine physiological and psychological effects of stressors (tasks) and theory-based perceptions of work stressors within and between nurses in real time.	During two work shifts, 100 nurses rated experienced stress, affect, fatigue, theory-based measures of work stress and nursing tasks on electronic diaries every 90 min, whereas heart rate and activity were measured continuously.	Heart rate was associated with both demand and effort. Experienced stress was related to demand, control, effort and reward. Effort and reward interacted as predicted (but only within people). Results were unchanged when allowance was made for work tasks.	Real-time appraisals were more important than actual tasks in predicting both psychological and physiological correlates of stress. At times when effort was high, perceived reward reduced stress.	
26606725	The Internet provides a large source of novel and rewarding stimuli, particularly with respect to sexually explicit materials. Novelty-seeking and cue-conditioning are fundamental processes underlying preference and approach behaviors implicated in disorders of addiction. Here we examine these processes in individuals with compulsive sexual behaviors (CSB), hypothesizing a greater preference for sexual novelty and stimuli conditioned to sexual rewards relative to healthy volunteers. Twenty-two CSB males and forty age-matched male volunteers were tested in two separate behavioral tasks focusing on preferences for novelty and conditioned stimuli. Twenty subjects from each group were also assessed in a third conditioning and extinction task using functional magnetic resonance imaging. CSB was associated with enhanced novelty preference for sexual, as compared to control images, and a generalized preference for cues conditioned to sexual and monetary versus neutral outcomes compared to healthy volunteers. CSB individuals also had greater dorsal cingulate habituation to repeated sexual versus monetary images with the degree of habituation correlating with enhanced preference for sexual novelty. Approach behaviors to sexually conditioned cues dissociable from novelty preference were associated with an early attentional bias to sexual images. This study shows that CSB individuals have a dysfunctional enhanced preference for sexual novelty possibly mediated by greater cingulate habituation along with a generalized enhancement of conditioning to rewards. We further emphasize a dissociable role for cue-conditioning and novelty preference on the early attentional bias for sexual cues. These findings have wider relevance as the Internet provides a broad range of novel and potentially rewarding stimuli. 
26605053	Insects are widely used as models to study neural mechanisms of learning and memory. Our recent studies on crickets, together with reports on other insect species, suggest that some fundamental differences exist in neural and molecular mechanisms of learning and memory among different species of insects, particularly between crickets and fruit flies. First, we suggested that in crickets octopamine (OA) and dopamine (DA) neurons convey reward and punishment signals, respectively, in associated learning. On the other hand, it has been reported that in fruit flies different sets of DA neurons convey reward or punishment signals. Secondly, we have suggested that in crickets OA and DA neurons participate in the retrieval of appetitive and aversive memories, respectively, while this is not the case in fruit flies. Thirdly, cyclic AMP signaling is critical for short-term memory formation in fruit flies, but not in crickets. Finally, nitric oxide-cyclic GMP signaling and calcium-calmodulin signaling are critical for long-term memory (LTM) formation in crickets, but such roles have not been reported in fruit flies. Not all of these differences can be ascribed to different experimental methods used in studies. We thus suggest that there are unexpected diversities in basic mechanisms of learning and memory among different insect species, especially between crickets and fruit flies. Studies on a larger number of insect species will help clarify the diversity of learning and memory mechanisms in relation to functional adaptation to the environment and evolutionary history. 
26603560	Relief from pain in humans is rewarding and pleasurable. Primary rewards, or reward-predictive cues, are encoded in brain reward/motivational circuits. While considerable advances have been made in our understanding of reward circuits underlying positive reinforcement, less is known about the circuits underlying the hedonic and reinforcing actions of pain relief. We review findings from electrophysiological, neuroimaging, and behavioral studies supporting the concept that the rewarding effect of pain relief requires opioid signaling in the anterior cingulate cortex (ACC), activation of midbrain dopamine neurons, and the release of dopamine in the nucleus accumbens (NAc). Understanding of circuits that govern the reward of pain relief may allow the discovery of more effective and satisfying therapies for patients with acute or chronic pain.
26602173	We suggest a new placebo analgesia animal model and investigated the role of the dopamine and opioid systems in placebo analgesia. Before and after the conditioning, we conducted a conditioned place preference (CPP) test to measure preferences for the cues (Rooms 1 and 2), and a hot plate test (HPT) to measure the pain responses to high level-pain after the cues. In addition, we quantified the expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and c-Fos in the anterior cingulate cortex (ACC) as a response to reward learning and pain response. We found an enhanced preference for the low level-pain paired cue and enhanced TH expression in the VTA of the Placebo and Placebo + Naloxone groups. Haloperidol, a dopamine antagonist, blocked these effects in the Placebo + Haloperidol group. An increased pain threshold to high-heat pain and reduced c-Fos expression in the ACC were observed in the Placebo group only. Haloperidol blocked the place preference effect, and naloxone and haloperidol blocked the placebo analgesia. Cue preference is mediated by reward learning via the dopamine system, whereas the expression of placebo analgesia is mediated by the dopamine and opioid systems.
26601911	The development and expression of the midbrain dopamine system is determined in part by genetic factors that vary across individuals such that dopamine-related genes are partly responsible for addiction vulnerability. However, a complete account of how dopamine-related genes predispose individuals to drug addiction remains to be developed. Adopting an intermediate phenotype approach, we investigated whether reward-related electrophysiological activity of ACC-a cortical region said to utilize dopamine reward signals to learn the value of extended, context-specific sequences of goal-directed behaviors-mediates the influence of multiple dopamine-related functional polymorphisms over substance use. We used structural equation modeling to examine whether two related electrophysiological phenomena associated with the control and reinforcement learning functions of ACC-theta power and the reward positivity-mediated the relationship between the degree of substance misuse and genetic polymorphisms that regulate dopamine processing in frontal cortex. Substance use data were collected from 812 undergraduate students. One hundred ninety-six returned on a subsequent day to participate in an electrophysiological experiment and to provide saliva samples for DNA analysis. We found that these electrophysiological signals mediated a relationship between the DRD4-521T dopamine receptor genotype and substance misuse. Our results provide a theoretical framework that bridges the gap between genes and behavior in drug addiction and illustrate how future interventions might be individually tailored for specific genetic and neurocognitive profiles. 
26599765	The proper functioning of the mesolimbic reward system is largely dependent on the neurotransmitter dopamine. Recent evidence suggests that the hypocretin system has significant projections to this reward system. We examined the distinct effects of reduced dopamine or reduced hypocretin levels on reward activity in patients with Parkinson's disease, dopamine deficient, as well as patients with narcolepsy-cataplexy, hypocretin depleted, and healthy controls. Participants performed a simple game-like task while high-density electroencephalography was recorded. Topography and timing of event-related potentials for both reward cue, and reward feedback was examined across the entire dataset. While response to reward cue was similar in all groups, two distinct time points were found to distinguish patients and controls for reward feedback. Around 160 ms both patient groups had reduced ERP amplitude compared to controls. Later at 250 ms, both patient groups also showed a clear event-related potential (ERP), which was absent in controls. The initial differences show that both patient groups show a similar, blunted response to reward delivery. The second potential corresponds to the classic feedback-related negativity (FRN) potential which relies on dopamine activity and reflects reward prediction-error signaling. In particular the mismatch between predicted reward and reward subsequently received was significantly higher in PD compared to NC, independent of reward magnitude and valence. The intermediate FRN response in NC highlights the contribution of hypocretin in reward processing, yet also shows that this is not as detrimental to the reward system as in Parkinson's. Furthermore, the inability to generate accurate predictions in NC may explain why hypocretin deficiency mediates cataplexy triggered by both positive and negative emotions.
26599542	Reward processing has been implicated in developmental disorders. However, the classic task to probe reward anticipation, the monetary incentive delay task, has an abstract coding of reward and no storyline and may therefore be less appropriate for use with developmental populations. We modified the task to create a version appropriate for use with children. We investigated whether this child-friendly version could elicit ventral striatal activation during reward anticipation in typically developing children and young adolescents (aged 9.5-14.5). In addition, we tested whether our performance-based measure of reward sensitivity was associated with anticipatory activity in ventral striatum. Reward anticipation was related to activity in bilateral ventral striatum. Moreover, we found an association between individual reward sensitivity and activity in ventral striatum. We conclude that this task assesses ventral striatal activity in a child-friendly paradigm. The combination with a performance-based measure of reward sensitivity potentially makes the task a powerful tool for developmental imaging studies of reward processing. 
26599537	Thinking about personal future events is a fundamental cognitive process that helps us make choices in daily life. We investigated how the imagination of episodic future events is influenced by implicit motivational factors known to guide decision making. In a two-day functional magnetic resonance imaging (fMRI) study, we controlled learned reward association and stimulus novelty by pre-familiarizing participants with two sets of words in a reward learning task. Words were repeatedly presented and consistently followed by monetary reward or no monetary outcome. One day later, participants imagined personal future events based on previously rewarded, unrewarded and novel words. Reward association enhanced the perceived vividness of the imagined scenes. Reward and novelty-based construction of future events were associated with higher activation of the motivational system (striatum and substantia nigra/ ventral tegmental area) and hippocampus, and functional connectivity between these areas increased during imagination of events based on reward-associated and novel words. These data indicate that implicit past motivational experience contributes to our expectation of what the future holds in store. 
26598677	In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson's disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson's disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons. 
26596916	In a recent study, we demonstrated that rats prefer mutual rewards in a Prosocial Choice Task. Here, employing the same task, we show that the integrity of basolateral amygdala was necessary for the expression of mutual reward preferences. Actor rats received bilateral excitotoxic (n=12) or sham lesions (n=10) targeting the basolateral amygdala and were subsequently tested in a Prosocial Choice Task where they could decide between rewarding ("Both Reward") or not rewarding a partner rat ("Own Reward"), either choice yielding identical reward to the actors themselves. To manipulate the social context and control for secondary reinforcement sources, actor rats were paired with either a partner rat (partner condition) or with an inanimate rat toy (toy condition). Sham-operated animals revealed a significant preference for the Both-Reward-option in the partner condition, but not in the toy condition. Amygdala-lesioned animals exhibited significantly lower Both-Reward preferences than the sham group in the partner but not in the toy condition, suggesting that basolateral amygdala was required for the expression of mutual reward preferences. Critically, in a reward magnitude discrimination task in the same experimental setup, both sham-operated and amygdala-lesioned animals preferred large over small rewards, suggesting that amygdala lesion effects were restricted to decision making in social contexts, leaving self-oriented behavior unaffected. 
26596700	Primary sensory cortical fields develop highly specific associative representational plasticity, notably enlarged area of representation of reinforced signal stimuli within their topographic maps. However, overtraining subjects after they have solved an instrumental task can reduce or eliminate the expansion while the successful behavior remains. As the development of this plasticity depends on the learning strategy used to solve a task, we asked whether the loss of expansion is due to the strategy used during overtraining. Adult male rats were trained in a three-tone auditory discrimination task to bar-press to the CS+ for water reward and refrain from doing so during the CS- tones and silent intertrial intervals; errors were punished by a flashing light and time-out penalty. Groups acquired this task to a criterion within seven training sessions by relying on a strategy that was "bar-press from tone-onset-to-error signal" ("TOTE"). Three groups then received different levels of overtraining: Group ST, none; Group RT, one week; Group OT, three weeks. Post-training mapping of their primary auditory fields (A1) showed that Groups ST and RT had developed significantly expanded representational areas, specifically restricted to the frequency band of the CS+ tone. In contrast, the A1 of Group OT was no different from naïve controls. Analysis of learning strategy revealed this group had shifted strategy to a refinement of TOTE in which they self-terminated bar-presses before making an error ("iTOTE"). Across all animals, the greater the use of iTOTE, the smaller was the representation of the CS+ in A1. Thus, the loss of cortical expansion is attributable to a shift or refinement in strategy. This reversal of expansion was considered in light of a novel theoretical framework (CONCERTO) highlighting four basic principles of brain function that resolve anomalous findings and explaining why even a minor change in strategy would involve concomitant shifts of involved brain sites, including reversal of cortical expansion. 
26596557	The nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP-dependent protein kinase (PKG) signaling pathway has been reported to play a key role in memory processing. However, little is known about its role in drug-associated reward memory. Here, we report the following. 1) The NO pathway in the CA1 is critical for the retrieval of morphine-associated reward memory. Specifically, the nNOS, sGC and PKG protein levels in the CA1 were increased after the expression of morphine conditioned place preference (CPP). Intra-CA1 injection of an NOS, sGC or PKG inhibitor prevented morphine CPP expression. 2) The involvement of the NO pathway in morphine CPP requires NR2B-containing NMDA receptors (NR2B-NMDARs). NR2B-NMDAR expression was elevated in the CA1 following morphine CPP expression, and intra-CA1 injection of the NR2B-NMDAR antagonist Ro25-6981 not only blocked morphine CPP expression but also inhibited the up-regulation of nNOS, sGC and PKG. Moreover, the Ro25-6981-induced blockade of morphine CPP was abolished by intra-CA1 injection of a NOS substrate or an sGC activator. 3) The NR2B-NMDAR stimulated the NO pathway by up-regulating the phosphorylation of Akt(Ser473). Morphine CPP expression enhanced the pAkt(Ser473) level, which has been corroborated to regulate nNOS activity, and this effect was reversed by intra-CA1 injection of Ro25-6981. 4) GluR1 acted downstream of the NO pathway. The membrane level of GluR1 in the CA1 was increased after morphine CPP expression, and this effect was prevented by pre-injection of a PKG inhibitor into the CA1. Additionally, co-immunoprecipitation revealed an interaction between PKG and GluR1; this result further indicated a role of PKG in regulating GluR1 trafficking. Collectively, the results of our study demonstrated that the activation of the NR2B-NMDAR/NO/sGC/PKG signaling pathway is necessary for the retrieval of morphine-associated reward memory. 
26595894	This study examines the impact of individually oriented, purely altruistic, and a hybrid of competitive and cooperative monetary reward incentives on older adults' completion of cognitive exercises and cognitive function. We find that all three incentive structures approximately double the number of exercises completed during the six-week active experimental period relative to a no incentive control condition. However, the altruistic and cooperative/competitive incentives led to different patterns of participation, with significantly higher inter-partner correlations in utilization of the software, as well as greater persistence once incentives were removed. Provision of all incentives significantly improved performance on the incentivized exercises. However, results of an independent cognitive testing battery suggest no generalizable gains in cognitive function resulted from the training. 
26595840	One of the many proclivities of our species is the drive to share information with others. What drives this unusual proclivity for propagating knowledge? Here, we test a common prediction made by recent theories in this domain: that individuals value opportunities to inform others. Two sets of studies supported this hypothesis. Behaviorally, individuals gave up money to inform others, even in "minimalistic" settings under which informing neither improved participants' reputation nor provided material benefits to information recipients. Neurally, opportunities to inform others engaged brain regions associated with motivation and reward, including the nucleus accumbens and ventromedial prefrontal cortex. Together, these findings suggest that people place intrinsic value on sharing information with others.
26595818	Two experiments examined the role of propositional and automatic (ideomotor) processes in cue-elicited responding for rewarding outcomes (beer and chocolate). In a training phase, participants earned either chocolate or beer points by making one of two button-press responses. Rewards were indicated by the presentation of chocolate and beer pictures. On test, each trial began with a picture of beer or chocolate, or a blank screen, and choice of the beer versus chocolate response was assessed in the presence of these three pictures. Participants tended to choose the beer and chocolate response in the presence of the beer and chocolate pictures, respectively. In Experiment 1, instructions signalling that the pictures did not indicate which response would be rewarded significantly reduced the priming effect. In Experiment 2, instructions indicating that the pictures signified which response would not be rewarded resulted in a reversed priming effect. Finally, in both experiments, the priming effect correlated with self-reported beliefs that the cues signalled which response was more likely to be reinforced. These results suggest that cue-elicited response selection is mediated by a propositional belief regarding the efficacy of the response-outcome relationship, rather than an automatic ideomotor mechanism.
26595651	Dopamine cell firing can encode errors in reward prediction, providing a learning signal to guide future behavior. Yet dopamine is also a key modulator of motivation, invigorating current behavior. Existing theories propose that fast (phasic) dopamine fluctuations support learning, whereas much slower (tonic) dopamine changes are involved in motivation. We examined dopamine release in the nucleus accumbens across multiple time scales, using complementary microdialysis and voltammetric methods during adaptive decision-making. We found that minute-by-minute dopamine levels covaried with reward rate and motivational vigor. Second-by-second dopamine release encoded an estimate of temporally discounted future reward (a value function). Changing dopamine immediately altered willingness to work and reinforced preceding action choices by encoding temporal-difference reward prediction errors. Our results indicate that dopamine conveys a single, rapidly evolving decision variable, the available reward for investment of effort, which is employed for both learning and motivational functions. 
26595474	The social zeitgeber model (Ehlers, Frank, & Kupfer, 1988) suggests that irregular daily schedules or social rhythms provide vulnerability to bipolar spectrum disorders. This study tested whether social rhythm regularity prospectively predicted first lifetime onset of bipolar spectrum disorders in adolescents already at risk for bipolar disorder based on exhibiting reward hypersensitivity. Adolescents (ages 14-19 years) previously screened to have high (n = 138) or moderate (n = 95) reward sensitivity, but no lifetime history of bipolar spectrum disorder, completed measures of depressive and manic symptoms, family history of bipolar disorder, and the Social Rhythm Metric. They were followed prospectively with semistructured diagnostic interviews every 6 months for an average of 31.7 (SD = 20.1) months. Hierarchical logistic regression indicated that low social rhythm regularity at baseline predicted greater likelihood of first onset of bipolar spectrum disorder over follow-up among high-reward-sensitivity adolescents but not moderate-reward-sensitivity adolescents, controlling for follow-up time, gender, age, family history of bipolar disorder, and initial manic and depressive symptoms (β = -.150, Wald = 4.365, p = .037, odds ratio = .861, 95% confidence interval [.748, .991]). Consistent with the social zeitgeber theory, low social rhythm regularity provides vulnerability to first onset of bipolar spectrum disorder among at-risk adolescents. It may be possible to identify adolescents at risk for developing a bipolar spectrum disorder based on exhibiting both reward hypersensitivity and social rhythm irregularity before onset occurs.
26595464	Marijuana is the most commonly used illicit drug in the United States and its use is rising. Nonetheless, scientific efforts to clarify the risk for addiction and other harm associated with marijuana use have been lacking. Maladaptive decision-making is a cardinal feature of addiction that is likely to emerge in heavy users. In particular, distorted subjective reward valuation related to homeostatic or allostatic processes has been implicated for many drugs of abuse. Selective changes in responses to uncertainty have been observed in response to intoxication and deprivation from various drugs of abuse. To assess for these potential neuroadaptive changes in reward valuation associated with marijuana deprivation, we examined the subjective value of uncertain and certain rewards among deprived and nondeprived heavy marijuana users in a behavioral economics decision-making task. Deprived users displayed reduced valuation of uncertain rewards, particularly when these rewards were more objectively valuable. This uncertainty aversion increased with increasing quantity of marijuana use. These results suggest comparable decision-making vulnerability from marijuana use as other drugs of abuse, and highlights targets for intervention.
26595439	Adolescence is characterized by heightened and sometimes impairing reward sensitivity, yet less is known about how adolescents recover from highly arousing positive states. This is particularly important given high onset rates of psychopathology associated with reward sensitivity during late adolescence and early adulthood. The current study thus utilized a novel reward sensitivity task in order to examine potential ways in which older adolescent females (ages 18-21; N = 83) might recover from high arousal positive reward sensitive states. Participants underwent a fixed incentive reward sensitivity task and subsequently watched a neutral, sad, or a low approach-motivated positive emotional film clip during which subjective and physiological recovery was assessed. Results indicated that the positive and negative film conditions were associated with maintained physiological arousal while the neutral condition facilitated faster physiological recovery from the reward sensitivity task. It is interesting to note that individual differences in self-reported positive emotion during the reward task were associated with faster recovery in the neutral condition. Findings suggest elicited emotion (regardless of valence) may serve to maintain reward sensitivity whereas self-reported positive emotional experience may be a key ingredient facilitating physiological recovery or undoing. Understanding the nuances of reward recovery provides a critical step in understanding the etiology and persistence of reward dysregulation more generally.
26595426	Delay discounting (DD) refers to how rapidly an individual devalues goods based on delays to receipt. DD usually is considered a trait variable but can be state dependent, yet few studies have assessed commodity valuation at short, naturalistically relevant time intervals that might enable state-dependent analysis. This study aimed to determine whether drug-use impulsivity and intelligence influence heroin DD at short (ecologically relevant) delays during two pharmacological states (heroin satiation and withdrawal). Out-of-treatment, intensive heroin users (n = 170; 53.5% African American; 66.7% male) provided complete DD data during imagined heroin satiation and withdrawal. Delays were 3, 6, 12, 24, 48, 72, and 96 hours; maximum delayed heroin amount was thirty $10 bags. Indifference points were used to calculate area under the curve (AUC). We also assessed drug-use impulsivity (subscales from the Impulsive Relapse Questionnaire [IRQ]) and estimated intelligence (Shipley IQ) as predictors of DD. Heroin discounting was greater (smaller AUC) during withdrawal than satiation. In regression analyses, lower intelligence and IRQ Capacity for Delay as well as higher IRQ Speed (to return to drug use) predicted greater heroin discounting in the satiation condition. Lower intelligence and higher IRQ Speed predicted greater discounting in the withdrawal condition. Sex, race, substance use variables, and other IRQ subscales were not significantly related to the withdrawal or satiation DD behavior. In summary, heroin discounting was temporally rapid, pharmacologically state dependent, and predicted by drug-use impulsivity and estimated intelligence. These findings highlight a novel and sensitive measure of acute DD that is easy to administer.
26595376	There is growing consensus that reward plays an important role in the control of attention. Until recently, reward was thought to influence attention indirectly by modulating task-specific motivation and its effects on voluntary control over selection. Such an account was consistent with the goal-directed (endogenous) versus stimulus-driven (exogenous) framework that had long dominated the field of attention research. Now, a different perspective is emerging. Demonstrations that previously reward-associated stimuli can automatically capture attention even when physically inconspicuous and task-irrelevant challenge previously held assumptions about attentional control. The idea that attentional selection can be value driven, reflecting a distinct and previously unrecognized control mechanism, has gained traction. Since these early demonstrations, the influence of reward learning on attention has rapidly become an area of intense investigation, sparking many new insights. The result is an emerging picture of how the reward system of the brain automatically biases information processing. Here, I review the progress that has been made in this area, synthesizing a wealth of recent evidence to provide an integrated, up-to-date account of value-driven attention and some of its broader implications. 
26594137	The persistence of associative memories linked to the rewarding properties of drugs of abuse is a core underlying feature of the addiction process. Opiate class drugs in particular, possess potent euphorigenic effects which, when linked to environmental cues, can produce drug-related "trigger" memories that may persist for lengthy periods of time, even during abstinence, in both humans, and other animals. Furthermore, the transitional switch from the drug-naïve, non-dependent state to states of dependence and withdrawal, represents a critical boundary between distinct neuronal and molecular substrates associated with opiate-reward memory formation. Identifying the functional molecular and neuronal mechanisms related to the acquisition, consolidation, recall, and extinction phases of opiate-related reward memories is critical for understanding, and potentially reversing, addiction-related memory plasticity characteristic of compulsive drug-seeking behaviors. The mammalian prefrontal cortex (PFC) and basolateral nucleus of the amygdala (BLA) share important functional and anatomical connections that are involved importantly in the processing of associative memories linked to drug reward. In addition, both regions share interconnections with the mesolimbic pathway's ventral tegmental area (VTA) and nucleus accumbens (NAc) and can modulate dopamine (DA) transmission and neuronal activity associated with drug-related DAergic signaling dynamics. In this review, we will summarize research from both human and animal modeling studies highlighting the importance of neuronal and molecular plasticity mechanisms within this circuitry during critical phases of opiate addiction-related learning and memory processing. Specifically, we will focus on two molecular signaling pathways known to be involved in both drug-related neuroadaptations and in memory-related plasticity mechanisms; the extracellular-signal-regulated kinase system (ERK) and the Ca(2+)/calmodulin-dependent protein kinases (CaMK). Evidence will be reviewed that points to the importance of critical molecular memory switches within the mammalian brain that might mediate the neuropathological adaptations resulting from chronic opiate exposure, dependence, and withdrawal. 
26593091	In reward-based learning, synaptic modifications depend on a brief stimulus and a temporally delayed reward, which poses the question of how synaptic activity patterns associate with a delayed reward. A theoretical solution to this so-called distal reward problem has been the notion of activity-generated "synaptic eligibility traces," silent and transient synaptic tags that can be converted into long-term changes in synaptic strength by reward-linked neuromodulators. Here we report the first experimental demonstration of eligibility traces in cortical synapses. We demonstrate the Hebbian induction of distinct traces for LTP and LTD and their subsequent timing-dependent transformation into lasting changes by specific monoaminergic receptors anchored to postsynaptic proteins. Notably, the temporal properties of these transient traces allow stable learning in a recurrent neural network that accurately predicts the timing of the reward, further validating the induction and transformation of eligibility traces for LTP and LTD as a plausible synaptic substrate for reward-based learning.
26592452	Ghrelin is an orexigenic hormone produced by the stomach that acts on growth hormone secretagogue receptors (GHSRs) both peripherally and centrally. The presence of GHSRs in the ventral tegmental area (VTA) suggests that ghrelin signaling at this level may increase the incentive value of palatable foods as well as other natural and artificial rewards. The present investigation sought to determine if ghrelin plays a role in relapse to such foods following a period of abstinence. To achieve this, thirty-six male Long Evans rats were trained to press a lever to obtain a high fat chocolate food reward on a fixed ratio schedule of 1. Following an extinction period during which lever presses were not reinforced, rats were implanted with a cannula connected to a minipump that continuously delivered ghrelin, a GHSR antagonist ([d-Lys-3]-GHRP-6), or saline in the VTA for 14days. One week later, food reward-associated cues, food reward priming, and an overnight fast were used to induce reinstatement of the lever pressing response. Our results indicate that intra-VTA ghrelin enhances cue-induced reinstatement of responses for palatable food pellets. To the extent that the reinstatement paradigm is considered a valid model of relapse in humans, this suggests that ghrelin signaling facilitates relapse to preferred foods in response to food cues through GHSR signaling in the VTA. 
26590845	Frontal alpha band asymmetry (FAA) is a marker of altered reward processing in major depressive disorder (MDD), associated with reduced approach behavior and withdrawal. However, its association with brain metabolism remains unclear. The aim of this study was to investigate FAA and its correlation with resting-state cerebral blood flow (rCBF). We hypothesized an association of FAA with regional rCBF in brain regions relevant to reward processing and motivated behavior, such as the striatum. We enrolled 20 patients and 19 healthy subjects. FAA scores and rCBF were quantified with the use of EEG and arterial spin labeling. Correlations of the two were evaluated, as well as the association with FAA and psychometric assessments of motivated behavior and anhedonia. Patients showed a left-lateralized pattern of frontal alpha activity and a correlation of FAA lateralization with subscores of Hamilton Depression Rating Scale linked to motivated behavior. An association of rCBF and FAA scores was found in clusters in the dorsolateral prefrontal cortex bilaterally (patients), in the left medial frontal gyrus, in the right caudate head and in the right inferior parietal lobule (whole group). No correlations were found in healthy controls. Higher inhibitory right-lateralized alpha power was associated with lower rCBF values in prefrontal and striatal regions, predominantly in the right hemisphere, which are involved in the processing of motivated behavior and reward. Inhibitory brain activity in the reward system may contribute to some of the motivational problems observed in MDD.
26590512	Bipolar disorders' (BD) onset before age 18 is a potential marker for a more severe illness course. Adolescence is also a period of significant normative maturation of inhibitory control and reward-relevant decision-making processes, such as decreased delay discounting (i.e., decreased preference for smaller, immediate versus larger, delayed rewards). Adults with BD exhibit elevated delay discounting rates. Very little is known about developmental changes in delay discounting in adolescents with BD, or about associations between inhibitory control and delay discounting in BD. The present study addresses these questions.The sample included 78 participants, ages 13 to 23, with BD or without history of mental illness. Group differences and group by age interaction effects on delay discounting (32 BD, 32 controls with valid responses), probability discounting (34 BD, 37 controls) and inhibitory control indices (34 BD, 38 controls) were assessed.	Among healthy controls, less discounting of delayed rewards was associated with older age, whereas adolescents with BD did not show age-related associations. There were no group differences in probability discounting or inhibitory control.	The cross-sectional nature of the study cannot fully rule out the less likely interpretation of group differences in cohort effects.	The lack of age-related improvement in delay tolerance in BD suggests disrupted development of executive control processes within reward contexts, which in turn may contribute to understanding more severe course of pediatric onset BD. Longitudinal studies are needed to examine delay discounting in relation to maturation of neural reward systems among adolescents with BD.	
26590511	Anhedonia is a cardinal feature of major depression and is hypothesized to be driven by low motivation, in particular blunted reward sensitivity. It has been suggested to be a marker that represents a genetic predisposition to this disorder. However, little is known about the mechanisms underlying this heightened risk in unaffected first-degree relatives of patients with major depression. We previously demonstrated abnormal reward biases in acutely depressed patients. The present study aimed to examine the development of reward bias in first-degree relatives of patients with major depression.Forty-seven first-degree relatives of patients with major depression (26 females, age 18-52) and 60 healthy controls with no family history of depression (34 females, age 21-48) were recruited. A probabilistically rewarded difficult visual discrimination task, in which participants were instructed about the contingencies, was used to assess blunted reward sensitivity. A response bias towards the more frequently rewarded stimulus (termed "reward bias") was the primary outcome variable in this study. Participants also completed self-reported measures of anhedonia and depressive symptoms.	Compared with the control group, relatives of patients with major depression with sub-clinical depressive symptoms displayed a blunted reward bias. Relatives without symptoms displayed largely intact motivational processing on both self-report and experimental measures. The degree of anhedonia was associated with attenuated reward bias in first-degree relatives of patients with major depression, especially in those with sub-clinical symptoms.	The study did not include a depressed patient group, which restricted our ability to interpret the observed group differences.	Blunted reward sensitivity may be largely manifested in a subgroup of relatives with high levels of depressive symptoms.	
26590420	Dopamine neurons promote learning by processing recent changes in reward values, such that reward may be maximized. However, such a flexible signal is not suitable for habitual behaviors that are sustained regardless of recent changes in reward outcome. We discovered a type of dopamine neuron in the monkey substantia nigra pars compacta (SNc) that retains past learned reward values stably. After reward values of visual objects are learned, these neurons continue to respond differentially to the objects, even when reward is not expected. Responses are strengthened by repeated learning and are evoked upon presentation of the objects long after learning is completed. These "sustain-type" dopamine neurons are confined to the caudal-lateral SNc and project to the caudate tail, which encodes long-term value memories of visual objects and guides gaze automatically to stably valued objects. This population of dopamine neurons thus selectively promotes learning and retention of habitual behavior. 
26588849	Fifteen triads of unacquainted men conversed for ten minutes while stress was measured in real time by pulse rate and thumb blood volume (TBV). Salivary measures of testosterone (T), cortisol (C), and the stress-related enzyme alpha-amylase (AA) were measured at the beginning and end of the session. Fully or partially transitive status hierarchies formed in 14 triads. (Highest ranked man was scored 1, lowest 3, with ties allowed.) Ten of the triads participated in Study 1, where nothing was at stake in the casual conversation. Five additional triads were run in Study 2, intended to introduce competition by offering a $20 reward to the man afterward chosen as having led the conversation. Most results from the two studies are similar, suggesting that the $20 reward had little effect. Combining studies, pulse and TBV show that conversation is more stressful than watching a video beforehand. Within the conversation, speaking turns are more stressful than listening turns, especially among the lowest ranked men, less so among those higher in rank. This supports a stress-based mechanism for status allocation among humans. Apparently, human speech is a form of status signaling, homologous with nonlinguistic status signals used by other primates, as posited by the "biosocial model." The biosocial model also posits that a physiological substrate (T, C, and AA) is related to dominance or status. Predicted effects are not replicated here, except for an inverse relationship between the stress enzyme AA and status. The mostly null results, obtained from conversations where there was little or nothing at stake, suggest that T and C (and their interaction) are not relevant to emergent status in the absence of serious competition. 
26587843	Different approaches like providing augmented feedback (aF), applying an external focus of attention (EF), or rewarding participants with money (RE) have been shown to instantly enhance motor performance. So far, these approaches have been tested either in separate studies or directly against each other. However, there is no study that combined aF, EF, and/or RE to test whether this provokes additional benefits. The aim of the present study was therefore to identify the most powerful combination.Eighteen participants performed maximal countermovement jumps in six different conditions: neutral (NE), aF, RE, aF + EF, aF + RE, and aF + EF + RE.	Participants demonstrated the highest jump heights with aF + EF, followed by aF + EF + RE, aF + RE, aF, RE, and finally, NE. Activity of the M. rectus femoris differed significantly between conditions resulting in lower muscular activity in aF + EF and aF + EF + RE compared with NE. All other parameters, such as ground reaction forces and joint angles, were comparable across conditions.	This is the first study showing superior performance when combining aF with EF. As reduced muscular activity was found only in conditions with EF, it is argued in line with the constrained action hypothesis that adopting an EF improves movement efficiency. In contrast, aF seems to rather enhance (intrinsic) motivation. However, monetary reward did not further amplify performance.	
26586823	During value-based decision-making, individuals consider the various options and select the one that provides the maximum subjective value. Although the brain integrates abstract information to compute and compare these values, the only behavioral outcome is often the decision itself. However, if the options are visual stimuli, during deliberation the brain moves the eyes from one stimulus to the other. Previous work suggests that saccade vigor, i.e., peak velocity as a function of amplitude, is greater if reward is associated with the visual stimulus. This raises the possibility that vigor during the free viewing of options may be influenced by the valuation of each option. Here, humans chose between a small, immediate monetary reward and a larger but delayed reward. As the deliberation began, vigor was similar for the saccades made to the two options but diverged 0.5 s before decision time, becoming greater for the preferred option. This difference in vigor increased as a function of the difference in the subjective values that the participant assigned to the delayed and immediate options. After the decision was made, participants continued to gaze at the options, but with reduced vigor, making it possible to infer timing of the decision from the sudden drop in vigor. Therefore, the subjective value that the brain assigned to a stimulus during decision-making affected the motor system via the vigor with which the eyes moved toward that stimulus.We find that, as individuals deliberate between two rewarding options and arrive at a decision, the vigor with which they make saccades to each option reflects a real-time evaluation of that option. With deliberation, saccade vigor diverges between the two options, becoming greater for the option that the individual will eventually choose. The results suggest a shared element between the network that assigns value to a stimulus during the process of decision-making and the network that controls vigor of movements toward that stimulus.	
26586084	Motivation is underpinned by cost-benefit valuations where costs-such as physical effort or outcome risk-are subjectively weighed against available rewards. However, in many environments risks pertain not to the variance of outcomes, but to variance in the possible levels of effort required to obtain rewards (effort risks). Moreover, motivation is often guided by the extent to which cognitive-not physical-effort devalues rewards (effort discounting). Yet, very little is known about the mechanisms that underpin the influence of cognitive effort risks or discounting on motivation. We used two cost-benefit decision-making tasks to probe subjective sensitivity to cognitive effort (number of shifts of spatial attention) and to effort risks. Our results show that shifts of spatial attention when monitoring rapidly presented visual stimuli are perceived as effortful and devalue rewards. Additionally, most people are risk-averse, preferring safe, known amounts of effort over risky offers. However, there was no correlation between their effort and risk sensitivity. We show for the first time that people are averse to variance in the possible amount of cognitive effort to be exerted. These results suggest that cognitive effort sensitivity and risk sensitivity are underpinned by distinct psychological and neurobiological mechanisms. 
26585964	Our understanding of human morality has dramatically improved in the last decades, thanks to efforts carried out with scientific methods, in addition to the traditional speculative approach. Substantial contributions and relevant empirical data have come from neuroscience, psychology, genetics, comparative ethology, anthropology, and the social sciences. In this fruitful synergy, one useful approach is still missing: computational modeling. More precisely, a neurocomputational model aimed at simulating forms of moral behavior, to our knowledge, has not yet been designed. The purpose of this work is to start filling this gap, proposing MOral Neural Engine (MONE), a model that simulates the emergence of moral cognition. The neural engine in this model is assumed to be based in frontal areas, specifically the orbitofrontal and the ventromedial prefrontal cortex, and in connections to limbic areas involved in emotions and reward, such as the ventral striatum and the amygdala. Moral cognition is probably the result of a collection of several different neural processes, activated depending on the type of moral problem, each associated with a variety of emotions. This model, in its first implementation, deals with only a single moral situation: stealing someone's food, a transgression that typically elicits guilt, learned in the model from the angry facial expressions of the victim. 
26582981	The lateral habenula (LHb) plays a role in a wide variety of behaviors ranging from maternal care, to sleep, to various forms of cognition. One prominent theory with ample supporting evidence is that the LHb serves to relay basal ganglia and limbic signals about negative outcomes to midbrain monoaminergic systems. This makes it likely that the LHb is critically involved in behavioral flexibility as all of these systems have been shown to contribute when flexible behavior is required. Behavioral flexibility is commonly examined across species and is impaired in various neuropsychiatric conditions including autism, depression, addiction, and schizophrenia; conditions in which the LHb is thought to play a role. Therefore, a thorough examination of the role of the LHb in behavioral flexibility serves multiple functions including understanding possible connections with neuropsychiatric illnesses and additional insight into its role in cognition in general. Here, we assess the LHb's role in behavioral flexibility through comparisons of the roles its afferent and efferent pathways are known to play. Additionally, we provide new evidence supporting the LHb contributions to behavioral flexibility through organization of specific goal directed actions under cognitively demanding conditions. Specifically, in the first experiment, a majority of neurons recorded from the LHb were found to correlate with velocity on a spatial navigation task and did not change significantly when reward outcomes were manipulated. Additionally, measurements of local field potential (LFP) in the theta band revealed significant changes in power relative to velocity and reward location. In a second set of experiments, inactivation of the LHb with the gamma-aminobutyric acid (GABA) agonists baclofen and muscimol led to an impairment in a spatial/response based repeated probabilistic reversal learning task. Control experiments revealed that this impairment was likely due to the demands of repeated switching behaviors as rats were unimpaired on initial discrimination acquisition or retention of probabilistic learning. Taken together, these novel findings compliment other work discussed supporting a role for the LHb in action selection when cognitive or emotional demands are increased. Finally, we discuss future mechanisms by which a superior understanding of the LHb can be obtained through additional examination of behavioral flexibility tasks. 
26581305	Temporal difference learning models propose phasic dopamine signaling encodes reward prediction errors that drive learning. This is supported by studies where optogenetic stimulation of dopamine neurons can stand in lieu of actual reward. Nevertheless, a large body of data also shows that dopamine is not necessary for learning, and that dopamine depletion primarily affects task performance. We offer a resolution to this paradox based on an hypothesis that dopamine encodes the precision of beliefs about alternative actions, and thus controls the outcome-sensitivity of behavior. We extend an active inference scheme for solving Markov decision processes to include learning, and show that simulated dopamine dynamics strongly resemble those actually observed during instrumental conditioning. Furthermore, simulated dopamine depletion impairs performance but spares learning, while simulated excitation of dopamine neurons drives reward learning, through aberrant inference about outcome states. Our formal approach provides a novel and parsimonious reconciliation of apparently divergent experimental findings. 
26580235	Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss maintenance, reducing appetite, and also food reward, via unclear mechanisms.To investigate the role of elevated satiety gut hormones after RYGB, we examined food hedonic-reward responses after their acute post-prandial suppression.	These were randomized, placebo-controlled, double-blind, crossover experimental medicine studies.	Two groups, more than 5 months after RYGB for obesity (n = 7-11), compared with nonobese controls (n = 10), or patients after gastric banding (BAND) surgery (n = 9) participated in the studies.	Studies were performed after acute administration of the somatostatin analog octreotide or saline. In one study, patients after RYGB, and nonobese controls, performed a behavioral progressive ratio task for chocolate sweets. In another study, patients after RYGB, and controls after BAND surgery, performed a functional magnetic resonance imaging food picture evaluation task.	Octreotide increased both appetitive food reward (breakpoint) in the progressive ratio task (n = 9), and food appeal (n = 9) and reward system blood oxygen level-dependent signal (n = 7) in the functional magnetic resonance imaging task, in the RYGB group, but not in the control groups.	Octreotide suppressed postprandial plasma peptide YY, glucagon-like peptide-1, and fibroblast growth factor-19 after RYGB. The reduction in plasma peptide YY with octreotide positively correlated with the increase in brain reward system blood oxygen level-dependent signal in RYGB/BAND subjects, with a similar trend for glucagon-like peptide-1.	Enhanced satiety gut hormone responses after RYGB may be a causative mechanism by which anatomical alterations of the gut in obesity surgery modify behavioral and brain reward responses to food.	
26580209	Individuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. Event-related oscillations (EROs) have been used to effectively measure brain (dys)function during cognitive tasks in individuals with alcoholism and related disorders and in those at risk to develop these disorders. The current study examines ERO theta power during reward processing as well as impulsivity in adolescent and young adult subjects at high risk for alcoholism.EROs were recorded during a monetary gambling task (MGT) in 12-25 years old participants (N = 1821; males = 48%) from high risk alcoholic families (HR, N = 1534) and comparison low risk community families (LR, N = 287) from the Collaborative Study on the Genetics of Alcoholism (COGA). Impulsivity scores and prevalence of externalizing diagnoses were also compared between LR and HR groups.	HR offspring showed lower theta power and decreased current source density (CSD) activity than LR offspring during loss and gain conditions. Younger males had higher theta power than younger females in both groups, while the older HR females showed more theta power than older HR males. Younger subjects showed higher theta power than older subjects in each comparison. Differences in topography (i.e., frontalization) between groups were also observed. Further, HR subjects across gender had higher impulsivity scores and increased prevalence of externalizing disorders compared to LR subjects.	As theta power during reward processing is found to be lower not only in alcoholics, but also in HR subjects, it is proposed that reduced reward-related theta power, in addition to impulsivity and externalizing features, may be related in a predisposition to develop alcoholism and related disorders.	

26579025	We recently showed that rapidly stopping an action in the face of a reward-related stimulus reduces the subjective value of that stimulus (Wessel et al., 2014). In that study, there were three phases. In an initial learning phase, geometric shapes were associated with monetary value via implicit learning. In a subsequent treatment phase, half the shapes were paired with action stopping, and half were not. In a final auction phase, shapes that had been paired with stopping in the treatment phase were subjectively perceived as less valuable compared to those that were not. Exploratory post hoc analyses showed that the stopping-induced devaluation effect was larger for participants with greater explicit knowledge of stimulus values. Here, we repeated the study in 65 participants to systematically test whether the level of explicit knowledge influences the degree of devaluation. The results replicated the core result that action stopping reduces stimulus value. Furthermore, they showed that this effect was indeed significantly larger in participants with more explicit knowledge of the relative stimulus values in the learning phase. These results speak to the robustness of the stopping-induced devaluation effect, and furthermore imply that behavioral therapies using stopping could be successful in devaluing real-world stimuli, insofar as stimulus values are explicitly represented. Finally, to facilitate future investigations into the applicability of these findings, as well as the mechanisms underlying stopping-induced stimulus devaluation, we herein provide open source code for the behavioral paradigm. 
26578929	According to dominant neuropsychological theories of affect, emotions signal salience of events and in turn facilitate a wide spectrum of response options or action tendencies. Valence of an emotional experience is pivotal here, as it alters reward and punishment processing, as well as the balance between safety and risk taking, which can be translated into changes in the exploration-exploitation trade-off during reinforcement learning (RL). To test this idea, we compared the behavioral performance of three groups of participants that all completed a variant of a standard probabilistic learning task, but who differed regarding which mood state was actually induced and maintained (happy, sad or neutral). To foster a change from an exploration to an exploitation-based mode, we removed feedback information once learning was reliably established. Although changes in mood were successful, learning performance was balanced between the three groups. Critically, when focusing on exploitation-driven learning only, they did not differ either. Moreover, mood valence did not alter the learning rate or exploration per se, when titrated using complementing computational modeling. By comparing systematically these results to our previous study (Bakic et al., 2014), we found that arousal levels did differ between studies, which might account for limited modulatory effects of (positive) mood on RL in the present case. These results challenge the assumption that mood valence alone is enough to create strong shifts in the way exploitation or exploration is eventually carried out during (probabilistic) learning. In this context, we discuss the possibility that both valence and arousal are actually necessary components of the emotional mood state to yield changes in the use and exploration of incentives cues during RL. 
26578926	Expression of learned stimulus-reward associations based on context is essential for regulation of behavior to meet situational demands. Contextual regulation improves during development, although the developmental progression of relevant neural and cognitive processes is not fully specified. We therefore measured neural correlates of flexible, contextual expression of stimulus-reward associations in pre/early-adolescent children (ages 9-13 years) and young adults (ages 19-22 years). After reinforcement learning using standard parameters, a contextual reversal manipulation was used whereby contextual cues indicated that stimulus-reward associations were the same as previously reinforced for some trials (consistent trials) or were reversed on other trials (inconsistent trials). Subjects were thus required to respond according to original stimulus-reward associations vs. reversed associations based on trial-specific contextual cues. Children and young adults did not differ in reinforcement learning or in relevant functional magnetic resonance imaging (fMRI) correlates. In contrast, adults outperformed children during contextual reversal, with better performance specifically for inconsistent trials. fMRI signals corresponding to this selective advantage included greater activity in lateral prefrontal cortex (LPFC), hippocampus, and dorsal striatum for young adults relative to children. Flexible expression of stimulus-reward associations based on context thus improves via adolescent development, as does recruitment of brain regions involved in reward learning and contextual expression of memory. HighlightsEarly-adolescent children and young adults were equivalent in reinforcement learning.Adults outperformed children in contextual expression of stimulus-reward associations.Adult advantages correlated with increased activity of relevant brain regions.Specific neurocognitive developmental changes support better contextual regulation. 
26578919	Iron deficiency is the most common nutritional deficiency in humans, affecting more than two billion people worldwide. Early-life iron deficiency can lead to irreversible deficits in learning and memory. The pig represents a promising model animal for studying such deficits, because of its similarities to humans during early development. We investigated the effects of pre-weaning dietary iron deficiency in piglets on growth, blood parameters, cognitive performance, and brain histology later in life. Four to six days after birth, 10 male sibling pairs of piglets were taken from 10 different sows. One piglet of each pair was given a 200 mg iron dextran injection and fed a control milk diet for 28 days (88 mg Fe/kg), whereas the other sibling was given a saline injection and fed an iron deficient (ID) milk diet (21 mg Fe/kg). Due to severely retarded growth of two of the ID piglets, only eight ID piglets were tested behaviorally. After dietary treatment, all piglets were fed a balanced commercial pig diet (190-240 mg Fe/kg). Starting at 7.5 weeks of age, piglets were tested in a spatial cognitive holeboard task. In this task, 4 of 16 holes contain a hidden food reward, allowing measurement of working (short-term) memory and reference (long-term) memory (RM) simultaneously. All piglets received 40-60 acquisition trials, followed by a 16-trial reversal phase. ID piglets showed permanently retarded growth and a strong decrease in blood iron parameters during dietary treatment. After treatment, ID piglets' blood iron values restored to normal levels. In the holeboard task, ID piglets showed impaired RM learning during acquisition and reversal. Iron staining at necropsy at 12 weeks of age showed that ID piglets had fewer iron-containing cells in hippocampal regions CA1 and dentate gyrus (DG). The number of iron-containing cells in CA3 correlated positively with the average RM score during acquisition across all animals. Our results support the hypothesis that early-life iron deficiency leads to lasting cognitive deficits. The piglet as a model animal, tested in the holeboard, can be useful in future research for assessing long-term cognitive effects of early-life diets or diet-induced deficiencies. 
26578917	Sign-tracking rats show heightened sensitivity to food- and drug-associated cues, which serve as strong incentives for driving reward seeking. We hypothesized that this enhanced incentive drive is accompanied by an inflexibility when incentive value changes. To examine this we tested rats in Pavlovian outcome devaluation or second-order conditioning prior to the assessment of sign-tracking tendency. To assess behavioral flexibility we trained rats to associate a light with a food outcome. After the food was devalued by pairing with illness, we measured conditioned responding (CR) to the light during an outcome devaluation probe test. The level of CR during outcome devaluation probe test correlated with the rats' subsequent tracking tendency, with sign-tracking rats failing to suppress CR to the light after outcome devaluation. To assess Pavlovian incentive learning, we trained rats on first-order (CS+, CS-) and second-order (SOCS+, SOCS-) discriminations. After second-order conditioning, we measured CR to the second-order cues during a probe test. Second-order conditioning was observed across all rats regardless of tracking tendency. The behavioral inflexibility of sign-trackers has potential relevance for understanding individual variation in vulnerability to drug addiction. 
26576941	Excessive alcohol (EtOH) drinking is difficult to model in animals despite the extensive human literature demonstrating that stress increases EtOH consumption.The current experiments show escalations in voluntary EtOH drinking caused by a history of social defeat stress and intermittent access to EtOH in C57BL/6J mice compared to non-stressed mice given intermittent EtOH or continuous EtOH. To explore a mechanistic link between stress and drinking, we studied the role of corticotropin-releasing factor type-1 receptors (CRF-R1) in the dopamine-rich ventral tegmental area (VTA).	Intra-VTA infusions of a CRF-R1 antagonist, CP376395, infused into the VTA dose-dependently and selectively reduced intermittent EtOH intake in stressed and non-stressed mice, but not in mice given continuous EtOH. In contrast, intra-VTA infusions of the CRF-R2 antagonist astressin2B non-specifically suppressed both EtOH and H2O drinking in the stressed group without effects in the non-stressed mice. Using in vivo microdialysis in the nucleus accumbens (NAc) shell, we observed that stressed mice drinking EtOH intermittently had elevated levels of tonic dopamine concentrations compared to non-stressed drinking mice. Also, VTA CP376395 potentiated dopamine output to the NAc only in the stressed group causing further elevations of dopamine post-infusion.	These findings illustrate a role for extrahypothalamic CRF-R1 as especially important for stress-escalated EtOH drinking beyond schedule-escalated EtOH drinking. CRF-R1 may be a mechanism for balancing the dysregulation of stress and reward in alcohol use disorders.	
26575108	Valuable monetary rewards can boost human performance on various effortful tasks even when the value of the rewards is presented too briefly to allow for strategic decision making. However, the mechanism by which briefly-presented reward information influences performance has remained unclear. One possibility is that performance after briefly-presented reward information is primarily boosted via activation of the dopamine reward system, whereas performance after very visible reward information is driven more by strategic processes. To examine this hypothesis, we first presented participants with a task in which they could earn rewards of relatively low (1 cent) or high (10 cents) value, and the value information was presented either briefly (17 ms) or for an extended duration (300 ms). Furthermore, responsiveness of the dopamine system was indirectly estimated with a measure of risk taking, the Balloon Analogue Risk Task (BART). Results showed that performance after high- compared to low-value rewards was indeed related to the BART scores only when reward information was presented briefly. These results are suggestive of the possibility that brief presentation of reward information boosts performance directly via activating the dopamine system, whereas extended presentation of reward information leads to more strategic reward-driven behavior.
26573957	Dopamine signals reward in animal brains. A single presentation of a sugar reward to Drosophila activates distinct subsets of dopamine neurons that independently induce short- and long-term olfactory memories (STM and LTM, respectively). In this study, we show that a recurrent reward circuit underlies the formation and consolidation of LTM. This feedback circuit is composed of a single class of reward-signaling dopamine neurons (PAM-α1) projecting to a restricted region of the mushroom body (MB), and a specific MB output cell type, MBON-α1, whose dendrites arborize that same MB compartment. Both MBON-α1 and PAM-α1 neurons are required during the acquisition and consolidation of appetitive LTM. MBON-α1 additionally mediates the retrieval of LTM, which is dependent on the dopamine receptor signaling in the MB α/β neurons. Our results suggest that a reward signal transforms a nascent memory trace into a stable LTM using a feedback circuit at the cost of memory specificity. 
26572896	Long-term cannabis and cocaine use has been associated with impairments in reversal learning. However, how acute cannabis and cocaine administration affect reversal learning in humans is not known.In this study, we aimed to establish the acute effects of administration of cannabis and cocaine on valence-dependent reversal learning as a function of DRD2 Taq1A (rs1800497) and COMT Val108/158Met (rs4680) genotype.	A double-blind placebo-controlled randomized 3-way crossover design was used. Sixty-one regular poly-drug users completed a deterministic reversal learning task under the influence of cocaine, cannabis, and placebo that enabled assessment of both reward- and punishment-based reversal learning.	Proportion correct on the reversal learning task was increased by cocaine, but decreased by cannabis. Effects of cocaine depended on the DRD2 genotype, as increases in proportion correct were seen only in the A1 carriers, and not in the A2/A2 homozygotes. COMT genotype did not modulate drug-induced effects on reversal learning.	These data indicate that acute administration of cannabis and cocaine has opposite effects on reversal learning. The effects of cocaine, but not cannabis, depend on interindividual genetic differences in the dopamine D2 receptor gene.	
26569435	Reward has been shown to change behavior as a result of incentive learning (by motivating the individual to increase their effort) and instrumental learning (by increasing the frequency of a particular behavior). However, Palminteri et al. (2011) demonstrated that reward can also improve the incidental learning of a motor skill even when participants are unaware of the relationship between the reward and the motor act. Nonetheless, it remains unknown whether these effects of reward are the indirect results of manipulations of top-down factors. To identify the locus of the benefit associated with rewarded incidental learning, we used a chord-learning task (Seibel, 1963) in which the correct performance of some chords was consistently rewarded with points necessary to complete the block whereas the correct performance of other chords was not rewarded. Following training, participants performed a transfer phase without reward and then answered a questionnaire to assess explicit awareness about the rewards. Experiment 1 revealed that rewarded chords were performed more quickly than unrewarded chords, and there was little awareness about the relationship between chords and reward. Experiment 2 obtained similar findings with simplified responses to show that the advantage for rewarded stimulus combinations reflected more efficient binding of stimulus-response (S-R) associations, rather than a response bias for rewarded associations or improved motor learning. These results indicate that rewards can be used to significantly improve the learning of S-R associations without directly manipulating top-down factors. (PsycINFO Database Record 
26567342	The odor localization strategy induced by odors learned via differential conditioning of the proboscis extension response was investigated in honeybees. In response to reward-associated but not non-reward-associated odors, learners walked longer paths than non-learners and control bees. When orange odor reward association was learned, the path length and the body turn angles were small during odor stimulation and greatly increased after stimulation ceased. In response to orange odor, bees walked locally with alternate left and right turns during odor stimulation to search for the reward-associated odor source. After odor stimulation, bees walked long paths with large turn angles to explore the odor plume. For clove odor, learning-related modulations of locomotion were less pronounced, presumably due to a spontaneous preference for orange in the tested population of bees. This study is the first to describe how an odor-reward association modulates odor-induced walking in bees. 
26567253	To explore the acceptability, mechanisms and consequences of provider incentives for smoking cessation and breast feeding as part of the Benefits of Incentives for Breastfeeding and Smoking cessation in pregnancy (BIBS) study.Cross-sectional survey and qualitative interviews.	Scotland and North West England.	Early years professionals: 497 survey respondents included 156 doctors; 197 health visitors/maternity staff; 144 other health staff. Qualitative interviews or focus groups were conducted with 68 pregnant/postnatal women/family members; 32 service providers; 22 experts/decision-makers; 63 conference attendees.	Early years professionals were surveyed via email about the acceptability of payments to local health services for reaching smoking cessation in pregnancy and breastfeeding targets. Agreement was measured on a 5-point scale using multivariable ordered logit models. A framework approach was used to analyse free-text survey responses and qualitative data.	Health professional net agreement for provider incentives for smoking cessation targets was 52.9% (263/497); net disagreement was 28.6% (142/497). Health visitors/maternity staff were more likely than doctors to agree: OR 2.35 (95% CI 1.51 to 3.64; p<0.001). Net agreement for provider incentives for breastfeeding targets was 44.1% (219/497) and net disagreement was 38.6% (192/497). Agreement was more likely for women (compared with men): OR 1.81 (1.09 to 3.00; p=0.023) and health visitors/maternity staff (compared with doctors): OR 2.54 (95% CI 1.65 to 3.91; p<0.001). Key emergent themes were 'moral tensions around acceptability', 'need for incentives', 'goals', 'collective or divisive action' and 'monitoring and proof'. While provider incentives can focus action and resources, tensions around the impact on relationships raised concerns. Pressure, burden of proof, gaming, box-ticking bureaucracies and health inequalities were counterbalances to potential benefits.	Provider incentives are favoured by non-medical staff. Solutions which increase trust and collaboration towards shared goals, without negatively impacting on relationships or increasing bureaucracy are required.	
26566901	The ability of honey bees to evaluate differences in food type and value is crucial for colony success, but these assessments are made by individuals who bring food to the hive, eating little, if any, of it themselves. We tested the hypothesis that responses to food type (pollen or nectar) and value involve different subsets of brain regions, and genes responsive to food. mRNA in situ hybridization of c-jun revealed that brain regions responsive to differences in food type were mostly different from regions responsive to differences in food value, except those dorsal and lateral to the mushroom body calyces, which responded to all three. Transcriptomic profiles of the mushroom bodies generated by RNA sequencing gave the following results: (1) responses to differences in food type or value included a subset of molecular pathways involved in the response to food reward; (2) genes responsive to food reward, food type and food value were enriched for (the Gene Ontology categories) mitochondrial and endoplasmic reticulum activity; (3) genes responsive to only food and food type were enriched for regulation of transcription and translation; and (4) genes responsive to only food and food value were enriched for regulation of neuronal signaling. These results reveal how activities necessary for colony survival are channeled through the reward system of individual honey bees.
26564686	Classical economic models are predicated on the idea that the ultimate aim of choice is to maximize utility or reward. In contrast, an alternative perspective highlights the fact that adaptive behavior requires agents' to model their environment and minimize surprise about the states they frequent. We propose that choice behavior can be more accurately accounted for by surprise minimization compared to reward or utility maximization alone. Minimizing surprise makes a prediction at variance with expected utility models; namely, that in addition to attaining valuable states, agents attempt to maximize the entropy over outcomes and thus 'keep their options open'. We tested this prediction using a simple binary choice paradigm and show that human decision-making is better explained by surprise minimization compared to utility maximization. Furthermore, we replicated this entropy-seeking behavior in a control task with no explicit utilities. These findings highlight a limitation of purely economic motivations in explaining choice behavior and instead emphasize the importance of belief-based motivations. 
26564255	Lack of physical engagement, productivity, and initiative-so-called "behavioral apathy"--is a common problem with significant impact, both personal and economic. Here, we investigate whether there might be a biological basis to such lack of motivation using a new effort and reward-based decision-making paradigm, combined with functional and diffusion-weighted imaging. We hypothesized that behavioral apathy in otherwise healthy people might be associated with differences in brain systems underlying either motivation to act (specifically in effort and reward-based decision-making) or in action processing (transformation of an intention into action). The results demonstrate that behavioral apathy is associated with increased effort sensitivity as well as greater recruitment of neural systems involved in action anticipation: supplementary motor area (SMA) and cingulate motor zones. In addition, decreased structural and functional connectivity between anterior cingulate cortex (ACC) and SMA were associated with increased behavioral apathy. These findings reveal that effort sensitivity and translation of intentions into actions might make a critical contribution to behavioral apathy. We propose a mechanism whereby inefficient communication between ACC and SMA might lead to increased physiological cost--and greater effort sensitivity--for action initiation in more apathetic people.
26564233	Rats emit 50-kHz ultrasonic vocalizations (USVs) in response to pleasurable stimuli, and these USVs are considered a tool for investigating reward and motivation.This study aimed to clarify how activity of adenosine A2A receptors, which modulate reward and motivation, influences 50-kHz USV emission in rats.	Rats received one of the following treatments in a test cage: (1) acute administration of the A2A receptor agonist CGS 21680 (0.05-0.2 mg/kg, i.p.) during social interactions; (2) long-term amphetamine (1 or 2 mg/kg, i.p.) or morphine (7.5 mg/kg, s.c.) administration on alternate days, alone or with CGS 21680, followed after 7 days of discontinuation by test cage re-exposure, to assess drug-conditioning effects, and thereafter drug challenge; (3) acute administration of the D1/D2 receptor agonist apomorphine (4 mg/kg, i.p.), alone or with CGS 21680; and (4) long-term administration of the non-selective A1/A2A receptor antagonist caffeine (15 mg/kg, i.p.), on alternate days. USVs and locomotor activity were evaluated throughout the treatments.	CGS 21680 attenuated 50-kHz USV emission stimulated by social interactions, amphetamine, apomorphine, and morphine, and rats administered CGS 21680 with amphetamine or morphine emitted fewer conditioned 50-kHz USVs upon test cage re-exposure, compared with rats administered amphetamine or morphine alone. Moreover, CGS 21680 administration prevented long-term changes in locomotor activity in amphetamine- and morphine-treated rats. Finally, caffeine had no effect on 50-kHz USVs.	These results indicate that activation of A2A receptors attenuates 50-kHz USV emission in rats and further elucidate how these receptors modulate the motivational properties of natural and pharmacological stimuli.	
26562909	In natural scenes, many objects compete for visual selection. However, it is not always clear why certain objects win this competition. I will demonstrate that the eye movement system lives in a constant state of competition among different oculomotor programs. This competition is not limited to the competition between the current goals of the observer and salient objects in the environment but incorporates independent influences from memory, reward, and emotional systems. These involuntary and automatic biases often overcome the goal-directed selection and expose severe limits in goal-driven control. There is also a striking similarity in the way that these very different sources of bias activate the oculomotor system and compete for representation. The inputs from various information sources are integrated in the common map in the oculomotor system for the sole purpose of improving the efficiency of oculomotor selection. 
26562666	The insular cortex (IC) has been related to various reinforcing behavioral processes. This study examined the effect of electrical stimulation of the posterior agranular IC on concurrent place preferences. Two groups of animals and their respective controls underwent rewarding brain stimulation every day or on alternate days. While the rats stimulated every other day maintained their preference for the place associated with brain stimulation, those stimulated every day evidenced a reduction in their place preference, suggesting tolerance to the stimulation's rewarding effect. A 15% increase in the current intensity produced a recovery of the preferences of the daily-stimulated rats but had no effect on those stimulated on alternate days. These results are discussed in terms of the rewarding effects induced by different electrical and chemical rewarding agents.
26562004	Uptake of preschool vaccinations is less than optimal. Financial incentives and quasi-mandatory policies (restricting access to child care or educational settings to fully vaccinated children) have been used to increase uptake internationally, but not in the UK.To provide evidence on the effectiveness, acceptability and economic costs and consequences of parental financial incentives and quasi-mandatory schemes for increasing the uptake of preschool vaccinations.	Systematic review, qualitative study and discrete choice experiment (DCE) with questionnaire.	Community, health and education settings in England.	Qualitative study - parents and carers of preschool children, health and educational professionals. DCE - parents and carers of preschool children identified as 'at high risk' and 'not at high risk' of incompletely vaccinating their children.	Qualitative study - focus groups and individual interviews. DCE - online questionnaire.	The review included studies exploring the effectiveness, acceptability or economic costs and consequences of interventions that offered contingent rewards or penalties with real material value for preschool vaccinations, or quasi-mandatory schemes that restricted access to 'universal' services, compared with usual care or no intervention. Electronic database, reference and citation searches were conducted.	Systematic review - there was insufficient evidence to conclude that the interventions considered are effective. There was some evidence that the quasi-mandatory interventions were acceptable. There was insufficient evidence to draw conclusions on economic costs and consequences. Qualitative study - there was little appetite for parental financial incentives. Quasi-mandatory schemes were more acceptable. Optimising current services was consistently preferred to the interventions proposed. DCE and questionnaire - universal parental financial incentives were preferred to quasi-mandatory interventions, which were preferred to targeted incentives. Those reporting that they would need an incentive to vaccinate their children completely required around £110. Those who did not felt that the maximum acceptable incentive was around £70.	Systematic review - a number of relevant studies were excluded as they did not meet the study design inclusion criteria. Qualitative study - few partially and non-vaccinating parents were recruited. DCE and questionnaire - data were from a convenience sample.	There is little current evidence on the effectiveness or economic costs and consequences of parental financial incentives and quasi-mandatory interventions for preschool vaccinations. Universal incentives are likely to be more acceptable than targeted ones. Preferences concerning incentives versus quasi-mandatory interventions may depend on the context in which these are elicited.	Further evidence is required on (i) the effectiveness and optimal configuration of parental financial incentive and quasi-mandatory interventions for preschool vaccinations - if effectiveness is confirmed, further evidence is required on how to communicate this to stakeholders and the impact on acceptability; and (ii) the acceptability of parental financial incentive and quasi-mandatory interventions for preschool vaccinations to members of the population who are not parents of preschool children or relevant health professionals. Further consideration should be given to (i) incorporating reasons for non-vaccination into new interventions for promoting vaccination uptake; and (ii) how existing services can be optimised.	This study is registered as PROSPERO CRD42012003192.	The National Institute for Health Research Health Technology Assessment programme.	
26561601	Cholinergic and GABAergic projections from the horizontal diagonal band (HDB) and medial preoptic area (MCPO) of the basal forebrain to the olfactory system are associated with odor discrimination and odor learning, as well as modulation of neural responses in olfactory structures. Whereas pharmacological and lesion studies give insights into the functional role of these modulatory inputs on a slow timescale, the response dynamics of neurons in the HDB/MCPO during olfactory behaviors have not been investigated. In this study we examined how these neurons respond during two olfactory behaviors: spontaneous investigation of odorants and odor-reward association learning. We observe rich heterogeneity in the response dynamics of individual HDB/MCPO neurons, with a substantial fraction of neurons exhibiting task-related modulation. HDB/MCPO neurons show both rapid and transient responses during bouts of odor investigation and slow, long-lasting modulation of overall response rate based on behavioral demands. Specifically, baseline rates were higher during the acquisition phase of an odor-reward association than during spontaneous investigation or the recall phase of an odor reward association. Our results suggest that modulatory projections from the HDB/MCPO are poised to influence olfactory processing on multiple timescales, from hundreds of milliseconds to minutes, and are therefore capable of rapidly setting olfactory network dynamics during odor processing and learning. 
26559000	Individuals with a family history of alcoholism are at much greater risk for developing an alcohol use disorder (AUD) than youth or adults without such history. A large body of research suggests that there are premorbid differences in brain structure and function in family history positive (FHP) individuals relative to their family history negative (FHN) peers.This review summarizes the existing literature on neurobiological phenotypes present in FHP youth and adults by describing findings across neurophysiological and neuroimaging studies.	Neuroimaging studies have shown FHP individuals differ from their FHN peers in amygdalar, hippocampal, basal ganglia, and cerebellar volume. Both increased and decreased white matter integrity has been reported in FHP individuals compared with FHN controls. Functional magnetic resonance imaging studies have found altered inhibitory control and working memory-related brain response in FHP youth and adults, suggesting neural markers of executive functioning may be related to increased vulnerability for developing AUDs in this population. Additionally, brain activity differences in regions involved in bottom-up reward and emotional processing, such as the nucleus accumbens and amygdala, have been shown in FHP individuals relative to their FHN peers.	It is critical to understand premorbid neural characteristics that could be associated with cognitive, reward-related, or emotional risk factors that increase risk for AUDs in FHP individuals. This information may lead to the development of neurobiologically informed prevention and intervention studies focused on reducing the incidence of AUDs in high-risk youth and adults.	
26558790	The role of basal ganglia in motivational processes has been under scrutiny in recent decades, with increasing evidence from clinical studies of cognitive and motivational deficits in patients with basal ganglia lesions. Tonically active neurons (TANs), the presumed striatal cholinergic interneurons, could be important actors in integrating and relaying motivational information arising from various modalities. Their multiphasic responses to rewards and to conditioned stimuli associated with reward conferred them a role in limbic processes. They are also modulated by a task's motor aspect. Recent studies suggest they are influenced by the context in which behavioral responses are expressed. To investigate the role of TANs in motor-limbic interaction processes, we recorded 169 TANs in the striatum of two monkeys performing a motivational task, in which they had to develop a variable force to receive different amounts of reward in response to visual stimuli. Our results reveal new features of TANs response properties. First, TANs usually responded either by a pause or an elevation of discharge rate to the visual cues and the reward, with few neurons combining both pause and rebound. Second, the elevations of discharge rate after the cues were most sensitive to the least valuable (high force or small reward) task conditions. Finally, the responses of TANs to the visual cues were time locked on the onset of the animal's movement. TANs' population and responses could thus play a role in signaling less attractive situations, those with either a high motor demand and/or small reward.Tonically active neurons (TANs) are known for their responses to unpredictable positive or negative events. However, here we show that TANs respond by a pause or an increase in their activity to all rewarding events in a task in which combined visual cues indicate to the monkeys the levels of force to produce and the upcoming reward. Unlike the pause, the increase in activity is modulated by task parameters and is most sensitive to the least attractive task conditions (high force and/or small reward). TANs' responses triggered by cue occurrence are also modulated by movement-related information (movement onset). We therefore propose here that TANs could play a role, via their action on striatal projections neurons, in maintaining high cost/low benefit ratio behaviors.	
26558777	Epigenetic processes that regulate histone acetylation play an essential role in behavioral and molecular responses to cocaine. To date, however, only a small fraction of the mechanisms involved in the addiction-associated acetylome have been investigated. Members of the bromodomain and extraterminal (BET) family of epigenetic "reader" proteins (BRD2, BRD3, BRD4, and BRDT) bind acetylated histones and serve as a scaffold for the recruitment of macromolecular complexes to modify chromatin accessibility and transcriptional activity. The role of BET proteins in cocaine-induced plasticity, however, remains elusive. Here, we used behavioral, pharmacological, and molecular techniques to examine the involvement of BET bromodomains in cocaine reward. Of the BET proteins, BRD4, but not BRD2 or BRD3, was significantly elevated in the nucleus accumbens (NAc) of mice and rats following repeated cocaine injections and self-administration. Systemic and intra-accumbal inhibition of BRD4 with the BET inhibitor, JQ1, attenuated the rewarding effects of cocaine in a conditioned place preference procedure but did not affect conditioned place aversion, nor did JQ1 alone induce conditioned aversion or preference. Investigating the underlying mechanisms, we found that repeated cocaine injections enhanced the binding of BRD4, but not BRD3, to the promoter region of Bdnf in the NAc, whereas systemic injection of JQ1 attenuated cocaine-induced expression of Bdnf in the NAc. JQ1 and siRNA-mediated knockdown of BRD4 in vitro also reduced expression of Bdnf. These findings indicate that disrupting the interaction between BET proteins and their acetylated lysine substrates may provide a new therapeutic avenue for the treatment of drug addiction.Proteins involved in the "readout" of lysine acetylation marks, referred to as BET bromodomain proteins (including BRD2, BRD3, BRD4, and BRDT), have been shown to be key regulators of chromatin dynamics and disease, and BET inhibitors are currently being studied in several clinical trials. However, their role in addiction-related phenomena remains unknown. In the current studies, we revealed that BRD4 is elevated in the nucleus accumbens and recruited to promoter regions of addiction-related genes following repeated cocaine administration, and that inhibition of BRD4 attenuates transcriptional and behavioral responses to cocaine. Together, these studies reveal that BET inhibitors may have therapeutic utility in the treatment of cocaine addiction.	
26558775	Rodent models of anxiety have implicated the ventral hippocampus in approach-avoidance conflict processing. Few studies have, however, examined whether the human hippocampus plays a similar role. We developed a novel decision-making paradigm to examine neural activity when participants made approach/avoidance decisions under conditions of high or absent approach-avoidance conflict. Critically, our task required participants to learn the associated reward/punishment values of previously neutral stimuli and controlled for mnemonic and spatial processing demands, both important issues given approach-avoidance behavior in humans is less tied to predation and foraging compared to rodents. Participants played a points-based game where they first attempted to maximize their score by determining which of a series of previously neutral image pairs should be approached or avoided. During functional magnetic resonance imaging, participants were then presented with novel pairings of these images. These pairings consisted of images of congruent or opposing learned valences, the latter creating conditions of high approach-avoidance conflict. A data-driven partial least squares multivariate analysis revealed two reliable patterns of activity, each revealing differential activity in the anterior hippocampus, the homolog of the rodent ventral hippocampus. The first was associated with greater hippocampal involvement during trials with high as opposed to no approach-avoidance conflict, regardless of approach or avoidance behavior. The second pattern encompassed greater hippocampal activity in a more anterior aspect during approach compared to avoid responses, for conflict and no-conflict conditions. Multivoxel pattern classification analyses yielded converging findings, underlining a role of the anterior hippocampus in approach-avoidance conflict decision making.Approach-avoidance conflict has been linked to anxiety and occurs when a stimulus or situation is associated with reward and punishment. Although rodent work has implicated the hippocampus in approach-avoidance conflict processing, there is limited data on whether this role applies to learned, as opposed to innate, incentive values, and whether the human hippocampus plays a similar role. Using functional neuroimaging with a novel decision-making task that controlled for perceptual and mnemonic processing, we found that the human hippocampus was significantly active when approach-avoidance conflict was present for stimuli with learned incentive values. These findings demonstrate a role for the human hippocampus in approach-avoidance decision making that cannot be explained easily by hippocampal-dependent long-term memory or spatial cognition.	
26558708	Abnormal reward processing is suggested to underlie the formation of psychotic symptoms, likely driven by elevated ventral striatal (VS) dopamine levels. Functional magnetic resonance imaging studies reveal alterations of VS activity during reward processing in patients with chronic psychosis and first episode of psychosis, as well as individuals at high risk for psychosis, but findings are inconclusive, conflicting, and difficult to subject to meta-analysis without introducing bias because several studies reported that findings were not statistically significant but did not report statistics.To assess the differences between patients with schizophrenia spectrum disorders and healthy controls in VS activation during reward processing.	Web of Knowledge database (incorporating Web of Science and MEDLINE) until July 2015, including references of eligible articles and reviews.	Functional magnetic resonance imaging studies comparing VS activity during monetary reward processing between patients with schizophrenia spectrum disorders or clinical or genetic high-risk state for psychosis and healthy controls.	Statistics and thresholds related to the main outcome measures and potential moderators were independently retrieved by 2 investigators. Effect sizes were analyzed using MetaNSUE, a random-effects method that enables the unbiased inclusion of nonstatistically significant unreported effects.	Effect size of the group differences in VS activity, and correlation between VS activity and negative and positive symptom scores in patients.	The meta-analysis included 23 studies (917 patients) for reward anticipation, 9 studies (358 patients) for reward feedback, and 8 studies (314 patients) for reward prediction error. We found significant bilateral VS hypoactivation during reward anticipation (23 studies, n = 917) in patients compared with healthy controls (left/right Cohen d, -0.50/-0.70; P < .001). Left VS abnormality was more severe in patients with high scores of negative symptoms during reward anticipation (r = -0.41; P < .001). Patients also showed hypoactivation during reward feedback (left/right d, -0.57/-0.56; P < .001). Simulations showed that exclusion of studies with nonstatistically significant unreported effects was associated with a strong bias (d bias = 0.22), whereas estimations using MetaNSUE were unbiased even when statistics were seldom reported (d bias < 0.001).	This meta-analysis provides evidence that patients with psychosis demonstrate VS hypoactivation during reward anticipation. The assessment of VS prediction errors seems to be promising, but more studies are needed to draw valid conclusions.	
26558617	Impaired goal-directed motivation represents a debilitating class of symptoms common to psychological disorders including schizophrenia and some affective disorders. Despite the known negative impact of impaired motivation, there are currently no effective pharmacological interventions to treat these symptoms.Here, we evaluate the effectiveness of the serotonin 2C (5-HT2C) receptor selective ligand, SB242084, as a potential pharmacological intervention for enhancing goal-directed motivation in mice. The studies were designed to identify not only efficacy but also the specific motivational processes that were affected by the drug treatment.	We tested subjects following treatment with SB242084 (0.75 mg/kg) in several operant lever pressing assays including the following: a progressive ratio (PR) schedule of reinforcement, an effort-based choice task, a progressive hold down task (PHD), and various food intake tests.	Acute SB242084 treatment leads to an increase in instrumental behavior. Using a battery of behavioral tasks, we demonstrate that the major effect of SB242084 is an increase in the amount of responses and duration of effort that subjects will make for food rewards. This enhancement of behavior is not the result of non-specific hyperactivity or arousal nor is it due to changes in food consumption.	Because of this specificity of action, we suggest that the 5-HT2C receptor warrants further attention as a novel therapeutic target for treating pathological impairments in goal-directed motivation.	
26557064	Multivariate pattern analysis can reveal new information from neuroimaging data to illuminate human cognition and its disturbances. Here, we develop a methodological approach, based on multivariate statistical/machine learning and time series analysis, to discern cognitive processing stages from functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) time series. We apply this method to data recorded from a group of healthy adults whilst performing a virtual reality version of the delayed win-shift radial arm maze (RAM) task. This task has been frequently used to study working memory and decision making in rodents. Using linear classifiers and multivariate test statistics in conjunction with time series bootstraps, we show that different cognitive stages of the task, as defined by the experimenter, namely, the encoding/retrieval, choice, reward and delay stages, can be statistically discriminated from the BOLD time series in brain areas relevant for decision making and working memory. Discrimination of these task stages was significantly reduced during poor behavioral performance in dorsolateral prefrontal cortex (DLPFC), but not in the primary visual cortex (V1). Experimenter-defined dissection of time series into class labels based on task structure was confirmed by an unsupervised, bottom-up approach based on Hidden Markov Models. Furthermore, we show that different groupings of recorded time points into cognitive event classes can be used to test hypotheses about the specific cognitive role of a given brain region during task execution. We found that whilst the DLPFC strongly differentiated between task stages associated with different memory loads, but not between different visual-spatial aspects, the reverse was true for V1. Our methodology illustrates how different aspects of cognitive information processing during one and the same task can be separated and attributed to specific brain regions based on information contained in multivariate patterns of voxel activity. 
26556504	Evidence that primary rewards (e.g., food and drugs of abuse) are discounted more than money is frequently attributed to money's high degree of liquidity, or exchangeability for many commodities. The present study provides some evidence against this liquidity hypothesis by contrasting delay discounting of monetary rewards (liquid) and non-monetary commodities (non-liquid) that are self-relevant and utility-matched. Ninety-seven (97) undergraduate students initially completed a conventional binary-choice delay discounting of money task. Participants returned one week later and completed a self-relevant commodity delay discounting task. Both conventional hypothesis testing and more-conservative tests of statistical equivalence revealed correspondence in rate of delay discounting of money and self-relevant commodities, and in one magnitude condition, less discounting for the latter. The present results indicate that liquidity of money cannot fully account for the lower rate of delay discounting compared to non-money rewards. 
26555614	Amphetamine (AMPH) abuse is a world concern and a serious public health problem. Repeated administration of high doses of AMPH induces neuropsychiatric consequences, including addiction, reward and psychosis, whose pharmacological treatment has shown limited effectiveness. The m-trifluoromethyl-diphenyldiselenide [(m-CF3-PhSe)2] has been documented as a promising pharmacological agent in different animal models related to oxidative damage. In this study, we examined the influence of (m-CF3-PhSe)2 on withdrawal following re-exposure to AMPH. Wistar rats received d,l-AMPH or saline in the conditioned place preference (CPP) paradigm for 8days. Then, half of each initial (AMPH or saline) experimental group was treated with (m-CF3-PhSe)2 or vehicle, resulting in four final groups: i) Saline/vehicle; ii) (m-CF3-PhSe)2/saline; iii) AMPH/vehicle; and iv) AMPH/(m-CF3-PhSe)2. After fourteen days of (m-CF3-PhSe)2 treatment, animals were re-exposed to AMPH or vehicle in the CPP paradigm for three more days in order to assess drug re-conditioning and memory/locomotor activity, performed 24h after AMPH re-exposure in the CPP and the Y maze, respectively. Subsequently, ex-vivo assays were carried out in samples of the prefrontal cortex (PFC) of the animals. The (m-CF3-PhSe)2 treatment was able to prevent AMPH-induced re-conditioning symptoms in rats. Behavioral observations in the Y maze task showed no significant changes. AMPH exposure was able to increase 5-HT uptake as well as oxidative damage in the PFC, whereas (m-CF3-PhSe)2 treatment exerted a preventative effect against these alterations. The current findings suggest that (m-CF3-PhSe)2 might be considered a promising therapeutic tool for AMPH-induced addiction. 
26555354	Food intake is a complex behavior that can occur or cease to occur for a multitude of reasons. Decisions about where, when, what, and how much to eat are not merely reflexive responses to food-relevant stimuli or to changes in energy status. Rather, feeding behavior is modulated by various contextual factors and by previous experiences. The data reviewed here support the perspective that neurons in multiple hippocampal subregions constitute an important neural substrate linking the external context, the internal context, and mnemonic and cognitive information to control both appetitive and ingestive behavior. Feeding behavior is heavily influenced by hippocampal-dependent mnemonic functions, including episodic meal-related memories and conditional learned associations between food-related stimuli and postingestive consequences. These mnemonic processes are undoubtedly influenced by both external and internal factors relating to food availability, location, and physiological energy status. The afferent and efferent neuroanatomical connectivity of the subregions of the hippocampus is reviewed with regard to the integration of visuospatial and olfactory sensory information (the external context) with endocrine and gastrointestinal interoceptive stimuli (the internal context). Also discussed are recent findings demonstrating that peripherally derived endocrine signals act on receptors in hippocampal neurons to reduce (leptin, glucagon-like peptide-1) or increase (ghrelin) food intake and learned food reward-driven responding, thereby highlighting endocrine and neuropeptidergic signaling in hippocampal neurons as a novel substrate of importance in the higher-order regulation of feeding behavior.
26555033	Investigating the effects of serotonergic antidepressants on neural correlates of visual erotic stimulation revealed decreased reactivity within the dopaminergic reward network along with decreased subjective sexual functioning compared with placebo. However, a global dampening of the reward system under serotonergic drugs is not intuitive considering clinical observations of their beneficial effects in the treatment of depression. Particularly, learning signals as coded in prediction error processing within the dopaminergic reward system can be assumed to be rather enhanced as antidepressant drugs have been demonstrated to facilitate the efficacy of psychotherapeutic interventions relying on learning processes. Within the same study sample, we now explored the effects of serotonergic and dopaminergic/noradrenergic antidepressants on prediction error signals compared with placebo by functional MRI. A total of 17 healthy male participants (mean age: 25.4 years) were investigated under the administration of paroxetine, bupropion and placebo for 7 days each within a randomized, double-blind, within-subject cross-over design. During functional MRI, we used an established monetary incentive task to explore neural prediction error signals within the bilateral nucleus accumbens as region of interest within the dopaminergic reward system. In contrast to diminished neural activations and subjective sexual functioning under the serotonergic agent paroxetine under visual erotic stimulation, we revealed unaffected or even enhanced neural prediction error processing within the nucleus accumbens under this antidepressant along with unaffected behavioural processing. Our study provides evidence that serotonergic antidepressants facilitate prediction error signalling and may support suggestions of beneficial effects of these agents on reinforced learning as an essential element in behavioural psychotherapy. 
26554843	The inhibition of impulsive response tendencies that conflict with goal-directed action is a key component of executive control. An emerging literature reveals that the proficiency of inhibitory control is modulated by expected or unexpected opportunities to earn reward or avoid punishment. However, less is known about how inhibitory control is impacted by the processing of task-irrelevant stimulus information that has been associated previously with particular outcomes (reward or punishment) or response tendencies (action or inaction). We hypothesized that stimulus features associated with particular action-valence tendencies, even though task irrelevant, would modulate inhibitory control processes. Participants first learned associations between stimulus features (color), actions, and outcomes using an action-valence learning task that orthogonalizes action (action, inaction) and valence (reward, punishment). Next, these stimulus features were embedded in a Simon task as a task-irrelevant stimulus attribute. We analyzed the effects of action-valence associations on the Simon task by means of distributional analysis to reveal the temporal dynamics. Learning patterns replicated previously reported biases; inherent, Pavlovian-like mappings (action-reward, inaction-punishment avoidance) were easier to learn than mappings conflicting with these biases (action-punishment avoidance, inaction-reward). More importantly, results from two experiments demonstrated that the easier to learn, Pavlovian-like action-valence associations interfered with the proficiency of inhibiting impulsive actions in the Simon task. Processing conflicting associations led to more proficient inhibitory control of impulsive actions, similar to Simon trials without any association. Fast impulsive errors were reduced for trials associated with punishment in comparison to reward trials or trials without any valence association. These findings provide insight into the temporal dynamics of task irrelevant information associated with action and valence modulating cognitive control. We discuss putative mechanisms that might explain these interactions. 
26554387	Mesolimbic dopamine (DA) regulates behavioral activation and effort-related decision-making in motivated behaviors. Mesolimbic DA D2 receptors are co-localized with adenosine A2A receptors, and they interact in an antagonistic manner.A T-maze task was developed to assess dopaminergic involvement in preference between a reinforcer that involves vigorous voluntary activity (running wheel) and a reinforcer that requires minimal behavioral activation (sucrose pellets). Haloperidol (D2 antagonist) was administered to adenosine A2A receptor knockout (A2AKO) and wild-type (WT) littermate controls to assess the involvement of these two receptors in the selection of running wheel activity versus sucrose consumption.	Under control conditions, mice spent more time running and less time eating. In WT mice, haloperidol reduced time running but actually increased time-consuming sucrose. However, A2AKO mice did not show the haloperidol-induced shift from running wheel activity to sucrose intake. Prefeeding reduced sucrose consumption in the T-maze in both strains, indicating that this paradigm is sensitive to motivational devaluation. Haloperidol increased c-Fos immunoreactivity in anterior cingulate cortex (ACg) and nucleus accumbens (Acb) core of WT but not KO mice.	These results indicate that after DA antagonism, the preference for vigorous physical activity is reduced, while palatable food selection increases. Adenosine A2A receptor deletion provides resistance to these effects of D2 receptor antagonism. These two receptors in Acb core and ACg seem to be involved in the regulation of the intrinsic reinforcing characteristics of voluntary exercise but not in the regulation of the primary reinforcing characteristics of palatable sedentary reinforcers.	
26552417	Pavlovian conditioning is the process by which we learn relationships between stimuli and thus constitutes a basic building block for how the brain constructs representations of the world. We first review the major concepts of Pavlovian conditioning and point out many of the pervasive misunderstandings about just what conditioning is. This brings us to a modern redefinition of conditioning as the process whereby experience with a conditional relationship between stimuli bestows these stimuli with the ability to promote adaptive behavior patterns that did not occur before the experience. Working from this framework, we provide an in-depth analysis of two examples, fear conditioning and food-based appetitive conditioning, which include a description of the only partially overlapping neural circuitry of each. We also describe how these circuits promote the basic characteristics that define Pavlovian conditioning, such as error-correction-driven regulation of learning. 
26551907	A diverse class of stimuli, including certain foods, substances, media, and economic behaviours, may be described as 'reward-oriented' in that they provide immediate reinforcement with little initial investment. Neurophysiological and personality concepts, including dopaminergic dysfunction, reward sensitivity and rash impulsivity, each predict the existence of a latent behavioural trait that leads to increased consumption of all stimuli in this class. Whilst bivariate relationships (co-morbidities) are often reported in the literature, to our knowledge, a multivariate investigation of this possible trait has not been done. We surveyed 1,194 participants (550 male) on their typical weekly consumption of 11 types of reward-oriented stimuli, including fast food, salt, caffeine, television, gambling products, and illicit drugs. Confirmatory factor analysis was used to compare models in a 3×3 structure, based on the definition of a single latent factor (none, fixed loadings, or estimated loadings), and assumed residual covariance structure (none, a-priori / literature based, or post-hoc / data-driven). The inclusion of a single latent behavioural 'consumption' factor significantly improved model fit in all cases. Also confirming theoretical predictions, estimated factor loadings on reward-oriented indicators were uniformly positive, regardless of assumptions regarding residual covariances. Additionally, the latent trait was found to be negatively correlated with the non-reward-oriented indicators of fruit and vegetable consumption. The findings support the notion of a single behavioural trait leading to increased consumption of reward-oriented stimuli across multiple modalities. We discuss implications regarding the concentration of negative lifestyle-related health behaviours. 
26551356	While a growing body of research has suggested that the mesocorticolimbic dopamine systems play a key role in decision making under risk, how the nucleus accumbens (NAC) is involved in the acquisition of risk choice behavior remains unclear. This study used a T-maze task to assess risk-based decision making in which the rat was required to assess the risk by choosing to enter either a small and certain reward arm or a large but uncertain reward arm of the maze. The latter option, when chosen, resulted in provision of 2, 4, or 8 sweeten pellets with a probability (p) of 0.5, 0.25, or 0.125, respectively. Thus the latter arm provided three different conditions of reward ratio, compared to the choice of former arm, which always provided 1 pellet with p=1. This risk choice task was then run with the expected value being equality between the binary choice options. The experimental rats first received an excitoneurotoxic lesion affecting either the NAC or the dorsolateral striatum (DLS) and this was followed by post-lesion behavioral examination. The sham lesion control rats acquired a stable risk choice with regard to each reward ratio over a 10-day test. The pattern of choice behavior appeared in risk-seeking when p=0.5 to obtain 2 pellets, and was risk-averse when larger reward resulted in lower p. The NAC lesion significantly disrupted the acquisition of the aforementioned risk choice behavior and apparently shifted the choice into a risk-averse style for all three reward ratios. No such effect was observed in the rats with DLS lesions. Neither the gross motor action nor the discrimination of different reward magnitudes was impaired by the lesions affecting either the NAC or DLS as assessed by an additional experiment. These findings suggest that firstly there is heterogeneity between NAC and DLS with respect to risk-based decision making, and that secondly the NAC is involved and critical to the acquisition of behavioral choice under risk, specially when the expected value of the reward under the two choice options is equal. 
26551275	Animals may remember an important location with reference to one or more visual landmarks. In the laboratory, birds and mammals often preferentially use landmarks near a goal ("local landmarks") to return to that location at a later date. Although we know very little about how animals in the wild use landmarks to remember locations, mammals in the wild appear to prefer to use distant landmarks to return to rewarded locations. To examine what cues wild birds use when returning to a goal, we trained free-living hummingbirds to search for a reward at a location that was specified by three nearby visual landmarks. Following training we expanded the landmark array to test the extent that the birds relied on the local landmarks to return to the reward. During the test the hummingbirds' search was best explained by the birds having used the experimental landmarks to remember the reward location. How the birds used the landmarks was not clear and seemed to change over the course of each test. These wild hummingbirds, then, can learn locations in reference to nearby visual landmarks. 
26549454	Behavioral changes in response to reward require monitoring past behavior relative to present outcomes. This is thought to involve a fine coordination between the hippocampus (HIPP), which stores and replays memories of past events, and cortical regions such as cingulate cortex, responsible for behavioral planning. Sharp-wave ripple (SWR)-mediated memory replay in the HIPP of awake rodents contributes to learning, but cortical responses to hippocampal SWR during wakefulness are not known. We now show that in rats, during quiet-wakefulness, cingulate neurons exhibit significant responses to SWR, as well as increased modulation by the accompanying hippocampal local field potential slow-γ oscillation, a rhythm associated with intra-hippocampal information processing. The magnitude of cingulate neurons' responses to SWR is significantly correlated with the degree of their modulation by HIPP slow-γ. We hypothesize that during pauses cingulate neurons transiently access episodic information concerning previous choices, replayed by HIPP SWR, to evaluate past trajectories in light of their outcome. 
26549151	Two experiments were conducted to examine whether checking one's own work can be motivated by monetary reward and punishment. Participants were randomly assigned to one of three conditions: a flat-rate payment for completing the task (Control); payment increased for error-free performance (Reward); payment decreased for error performance (Punishment). Experiment 1 (N = 90) was conducted with liberal arts students, using a general data-entry task. Experiment 2 (N = 90) replicated Experiment 1 with clinical students and a safety-critical 'cover story' for the task. In both studies, Reward and Punishment resulted in significantly fewer errors, more frequent and longer checking, than Control. No such differences were obtained between the Reward and Punishment conditions. It is concluded that error consequences in terms of monetary reward and punishment can result in more accurate task performance and more rigorous checking behaviour than errors without consequences. However, whether punishment is more effective than reward, or vice versa, remains inconclusive.
26549118	The aim of this study was to examine delay discounting in girls and boys with ADHD-Combined type (ADHD-C) relative to typically developing (TD) children on two tasks that differ in the extent to which the rewards and delays were experienced by participants. Children ages 8-12 years with ADHD-C (n=65; 19 girls) and TD controls (n=55; 15 girls) completed two delay discounting tasks involving a series of choices between smaller, immediate and larger, delayed rewards. The classic delay discounting task involved choices about money at delays of 1-90 days and only some of the outcomes were actually experienced by the participants. The novel real-time discounting task involved choices about an immediately consumable reward (playing a preferred game) at delays of 25-100 s, all of which were actually experienced by participants. Participants also provided subjective ratings of how much they liked playing the game and waiting to play. Girls with ADHD-C displayed greater delay discounting compared to boys with ADHD-C and TD girls and boys on the real-time discounting task. Diagnostic group differences were not evident on the classic discounting task. In addition, children with ADHD-C reported wanting to play the game more and liking waiting to play the game less than TD children. This novel demonstration of greater delay discounting among girls with ADHD-C on a discounting task in which the rewards are immediately consumable and the delays are experienced in real-time informs our understanding of sex differences and motivational processes in children with ADHD. (JINS, 2016, 22, 12-23). 
26548468	It is significant when a young person encounters drugs for the first time. Research has shown that 70% of later addicts try the drugs during the five-year period of adolescence. Youngsters tend to try new experinces; they are high risk-takers, seek novelty and are sensitive to pressure from the peer group. However, the juvenile central nervous system reacts differently when taking drugs, than it happens in an older age. Damage could occur on critical regions of the brain. Addictive drugs may give rise to changes in multiple system of memory, that could maintain the addiction for a long time. Drug use overrides and modifies the natural reward system, induces further drug-seeking, independently from the sensations of drug use.
26546747	Frustration can be defined as an emotional state generated by the omission or devaluation in the quantity or quality of an expected appetitive reward. Thus, reactivity to a reward is affected by prior experience with the different reinforcer values of that reward. This phenomenon is known as incentive relativity, and can be studied by different paradigms. Although methodologically simple, the exploration of a novel open field (OF) is a complex situation that involves several behavioral processes, including stress induction and novelty detection. OF exposure can enhance or block the acquisition of associative and non-associative memories. These experiments evaluated the effect of OF exploration on frustration and the role played by the cholinergic system in this phenomenon. OF exploration before first or second trial of incentive downshift modulated the expression of frustration. This effect of OF was blocked by the administration of scopolamine either before or after OF exploration. These results indicate that the cholinergic system is involved in the acquisition and consolidation of OF information.
26546080	Uncertainty preferences are typically studied in neutral, nonsocial contexts. This approach, however, fails to capture the dynamic factors that influence choices under uncertainty in the real world. Our goal was twofold: to test whether uncertainty valuation is similar across social and nonsocial contexts, and to investigate the effects of acute stress on uncertainty preferences. Subjects completed matched gambling and trust games following either a control or a stress manipulation. Those who were not under stress exhibited no differences between the amount of money gambled and the amount of money entrusted to partners. In comparison, stressed subjects gambled more money but entrusted less money to partners. We further found that irrespective of stress, subjects were highly attuned to irrelevant feedback in the nonsocial, gambling context, believing that every loss led to a greater chance of winning (the gamblers' fallacy). However, when deciding to trust a stranger, control subjects behaved rationally, treating each new interaction as independent. Stress compromised this adaptive behavior, increasing sensitivity to irrelevant social feedback. 
26545853	Experiences affect mood, which in turn affects subsequent experiences. Recent studies suggest two specific principles. First, mood depends on how recent reward outcomes differ from expectations. Second, mood biases the way we perceive outcomes (e.g., rewards), and this bias affects learning about those outcomes. We propose that this two-way interaction serves to mitigate inefficiencies in the application of reinforcement learning to real-world problems. Specifically, we propose that mood represents the overall momentum of recent outcomes, and its biasing influence on the perception of outcomes 'corrects' learning to account for environmental dependencies. We describe potential dysfunctions of this adaptive mechanism that might contribute to the symptoms of mood disorders. 
26544532	The tendency to discount larger future benefits in favor of smaller immediate gains (i.e., temporal discounting) is relevant to the issue of obesity. Successful weight loss requires individuals to sacrifice immediate culinary pleasures in favor of future health gains. Based on the notion that increasing the vividness of one's future self may mitigate temporal discounting and promote the ability to delay gratification, we examined whether viewing one's weight-reduced self (i.e., the ideal self) in a virtual environment can decrease temporal discounting and lead to better regulation of dietary practices. Seventy-six undergraduates who had reported an intention to lose weight were recruited to participate in a laboratory experiment and were randomly assigned to interact with either the weight-reduced self (experimental condition) or the present self (control condition) by looking into a dressing mirror in a virtual fitting room. A temporal-discounting task and a taste test were subsequently administered. Results showed that, compared with control participants, participants who viewed their weight-reduced avatars ate less ice cream in a taste test and were more likely to choose a sugar-free drink as a reward. The discounting rate mediated the association between the avatar manipulation and the amount of ice cream eaten in the subsequent taste test. Overall, our findings suggest that a computer-generated image of one's weight-reduced self may assist in resisting impulses that promote immediate gratification over delayed benefits. This research provides a new approach for controlling impulsive behavior such as dietary regulation and weight control. 
26543027	The β-lactam antibiotic ceftriaxone (CTX) reduces cocaine reinforcement and relapse in preclinical assays through a mechanism involving activation of glutamate transporter subtype 1 (GLT-1). However, its poor brain penetrability and intravenous administration route may limit its therapeutic utility for indications related to CNS diseases. An alternative is clavulanic acid (CA), a structural analog of CTX that retains the β-lactam core required for GLT-1 activity but displays enhanced brain penetrability and oral activity relative to CTX. Here, we tested the hypothesis that CA (1, 10 mg/kg ip) would enhance GLT-1 expression and decrease cocaine self-administration (SA) in mice, but at lower doses than CTX. Experiments revealed that GLT-1 transporter expression in the nucleus accumbens of mice treated with repeated CA (1, 10 mg/kg) was enhanced relative to saline-treated mice. Repeated CA treatment (1 mg/kg) reduced the reinforcing efficacy of cocaine (0.56 mg/kg/inf) in mice maintained on a progressive-ratio (PR) schedule of reinforcement but did not affect acquisition of cocaine SA under fixed-ratio responding or acquisition or retention of learning. These findings suggest that the β-lactamase inhibitor CA can activate the cellular glutamate reuptake system in the brain reward circuit and reduce cocaine's reinforcing efficacy at 100-fold lower doses than CTX.
26542814	Conditioned stimuli (CSs) come to function as CSs by acquiring the capacity to activate the same mesocorticolimbic dopamine (DA) neurons activated by primary rewards, producing conditioned activation of these neurons and their associated motivational states. This model stipulates that CSs activate mesocorticolimbic DA systems through the activation of glutamate receptors on DA neurons in the ventral tegmental area (VTA). We tested the hypothesis that glutamate receptor stimulation in the VTA is necessary for the expression of conditioned approach. Rats were tested in a conditioned approach protocol that consisted of 7 consecutive conditioning sessions (light presentations and food were paired), one session with no light or food and one test session with only light stimulus (CS-only) presentations. The number of head entries during the CS and pre-CS (baseline) periods was used to calculate difference scores. Bilateral VTA microinjections of glutamate receptor antagonists were made prior to the CS-only session. Kynurenic acid (ionotropic glutamate receptor antagonist; 1.125-4.5 μg/0.5 μl) significantly reduced difference scores compared to vehicle (0 μg), whereas MCPG (metabotropic glutamate receptor antagonist; 1.875-7.5 μg), AP-5 (NMDA antagonist; 0.03125-2.0 μg), and NBQX (AMPA antagonist; 0.5-4.0 μg) had no effects. When AP-5 and NBQX were administered simultaneously at doses of 0.25/4.0 and 2.0/4.0 μg, respectively, the combination significantly reduced the difference scores compared to 0/0 μg, indicating a reduction in the expression of conditioned approach. These findings indicate that expression of conditioned approach learning requires NMDA or AMPA receptor stimulation in the VTA.
26542703	Research in crustaceans offers a valuable perspective for studying the neural implementation of conserved behavioral phenomena, including motivation, escape, aggression, and drug-sensitive reward. The present work adds to this literature by demonstrating that crayfish successfully learn to respond to spatially contingent cues. An integrated video-tracking system automatically delivered a mild electric shock when a test animal entered or remained on a substrate paired with punishment. Following a few instances of shock delivery, crayfish quickly learned to avoid these areas. Comparable changes in substrate preference were not exhibited by yoked controls, but locomotion differed significantly from both pre-conditioning levels and from those of their masters receiving shock in a contingent fashion. The results of this work provide valuable insights into the principles governing avoidance learning in an invertebrate system and provide a behavioral template for exploring the neural changes during associative learning. Serving as a case study, this project introduces a new computer framework for the automated control of learning paradigms. Based on routines contained within the JavaGrinders library (free download at iEthology.com), it integrates real-time video tracking with robotic interfaces, and provides a suitable framework for implementing automated learning paradigms. 
26541373	Self-affirmation theory posits that people are motivated to maintain a positive self-view and that threats to perceived self-competence are met with resistance. When threatened, self-affirmations can restore self-competence by allowing individuals to reflect on sources of self-worth, such as core values. Many questions exist, however, about the underlying mechanisms associated with self-affirmation. We examined the neural mechanisms of self-affirmation with a task developed for use in a functional magnetic resonance imaging environment. Results of a region of interest analysis demonstrated that participants who were affirmed (compared with unaffirmed participants) showed increased activity in key regions of the brain's self-processing (medial prefrontal cortex + posterior cingulate cortex) and valuation (ventral striatum + ventral medial prefrontal cortex) systems when reflecting on future-oriented core values (compared with everyday activities). Furthermore, this neural activity went on to predict changes in sedentary behavior consistent with successful affirmation in response to a separate physical activity intervention. These results highlight neural processes associated with successful self-affirmation, and further suggest that key pathways may be amplified in conjunction with prospection. 
26539771	To examine the main and interactive effects of effort-reward imbalance (ERI) and selection, optimization, and compensation (SOC) strategy on depressive symptoms among the working population in the City of Kumning, China.We assessed the separate and combined effects of low versus high ERI and good versus poor SOC strategy on depressive symptoms using multivariable logistic regression analyses in a population-based sample (N = 2457).	High ERI and poor SOC were significantly associated with depressive symptoms, respectively. In employees with both high ERI and poor SOC, the odds ratio was highly elevated as compared with the reference group (low ERI and good SOC).	If our findings are confirmed by prospective studies, health promotion programs in work settings might consider SOC as an integral part to mitigate the adverse mental health effects of ERI.	
26539293	In this review, we explore how reward signals shape perceptual learning in animals and humans. Perceptual learning is the well-established phenomenon by which extensive practice elicits selective improvement in one's perceptual discrimination of basic visual features, such as oriented lines or moving stimuli. While perceptual learning has long been thought to rely on 'top-down' processes, such as attention and decision-making, a wave of recent findings suggests that these higher-level processes are, in fact, not necessary.  Rather, these recent findings indicate that reward signals alone, in the absence of the contribution of higher-level cognitive processes, are sufficient to drive the benefits of perceptual learning. Here, we will review the literature tying reward signals to perceptual learning. Based on these findings, we propose dual underlying mechanisms that give rise to perceptual learning: one mechanism that operates 'automatically' and is tied directly to reward signals, and another mechanism that involves more 'top-down', goal-directed computations. 
26538334	Drug-associated contextual cues contribute to drug craving and relapse after abstinence, which is a major challenge to drug addiction treatment. Previous studies showed that disrupting memory reconsolidation impairs drug reward memory. However, the underlying mechanisms remain elusive. Although actin polymerization is involved in memory formation, its role in the reconsolidation of drug reward memory is unknown. In addition, the specific brain areas responsible for drug memory have not been fully identified. In the present study, we found that inhibiting actin polymerization in the nucleus accumbens (NAc) shell, but not the NAc core, abolishes morphine-induced conditioned place preference (CPP) by disrupting its reconsolidation in rats. Moreover, this effect persists for more than 2 weeks by a single injection of the actin polymerization inhibitor, which is not reversed by a morphine-priming injection. Furthermore, the application of actin polymerization inhibitor outside the reconsolidation window has no effect on morphine-associated contextual memory. Taken together, our findings first demonstrate that inhibiting actin polymerization erases morphine-induced CPP by disrupting its reconsolidation. Our study suggests that inhibition of actin polymerization during drug memory reconsolidation may be a potential approach to prevent drug relapse. 
26536818	The orexin/hypocretin system is important for reward-seeking behaviors, however less is known about its function in non-homeostatic feeding. Environmental influences, particularly cues for food can stimulate feeding in the absence of hunger and lead to maladaptive overeating behavior. The key components of the neural network that mediates this cue-induced overeating in sated rats include lateral hypothalamus, amygdala, and medial prefrontal cortex (mPFC), yet the neuropharmacological mechanisms within this network remain unknown. The current study investigated a causal role for orexin in cue-driven feeding, and examined the neural substrates through which orexin mediates this effect. Systemic administration of the orexin-1 receptor (OX1R) antagonist SB-334867 had no effect on baseline eating, but significantly reduced cue-driven consumption in sated rats. Complementary neural analysis revealed that decreased cue-induced feeding under SB-334867 increased Fos expression in mPFC and paraventricular thalamus. These results demonstrate that OX1R signaling critically regulates cue-induced feeding, and suggest orexin is acting through prefrontal cortical and thalamic sites to drive eating in the absence of hunger. These findings inform our understanding of how food-associated cues override signals from the body to promote overeating, and indicate OX1R antagonism as a potential pharmacologic target for treatment of disordered eating in humans. 

26535896	Two important ideas about associative learning have emerged in recent decades: (1) Animals are Bayesian learners, tracking their uncertainty about associations; and (2) animals acquire long-term reward predictions through reinforcement learning. Both of these ideas are normative, in the sense that they are derived from rational design principles. They are also descriptive, capturing a wide range of empirical phenomena that troubled earlier theories. This article describes a unifying framework encompassing Bayesian and reinforcement learning theories of associative learning. Each perspective captures a different aspect of associative learning, and their synthesis offers insight into phenomena that neither perspective can explain on its own. 
26531068	The similarity between gambling disorder (GD) and drug addiction has recently been recognized at the diagnostic level. Understanding the core cognitive processes involved in these addiction disorders, and in turn their neurobiological mechanisms, remains a research priority due to the enormous benefits such knowledge would have in enabling effective treatment design. Animal models can be highly informative in this regard. Although numerous rodent behavioural paradigms that capture different facets of gambling-like behaviour have recently been developed, the motivational power of cues in biasing individuals towards risky choice has so far received little attention despite the central role played by drug-paired cues in successful laboratory models of chemical dependency. Here, we review some of the comparatively simple paradigms in which reward-paired cues are known to modulate behaviour in rodents, such as sign-tracking, Pavlovian-to-instrumental transfer and conditioned reinforcement. Such processes are thought to play an important role in mediating responding for drug reward, and the need for future studies to address whether similar processes contribute to cue-driven risky choice is highlighted. 
26530810	Two main theoretical models have been used to assess the impact of psychosocial work factors on blood pressure (BP): the demand-control (DC) model and the effort-reward imbalance (ERI) model. Previous studies have mostly used a single time point exposure to examine this association.To examine the effect of repeated job strain and ERI exposure on (1) ambulatory BP (ABP) evolution over 5 years and (2) hypertension incidence over 5 years.	The design is a prospective cohort study. The study population was composed of 1394 white-collar workers (568 men and 826 women). They were assessed three times during a 5-year period (years 1, 3 and 5). At each time, psychosocial work factors were measured using validated scales and ABP was measured every 15 min during a working day.	Men who were chronically exposed over 5 years to an active job had a higher cumulative incidence of hypertension (RR=2.05, 95% CI 1.36 to 3.09), compared with never-exposed men. In women, ERI exposure onset was associated with higher increases in systolic ABP (+2.5 mm Hg). No association was found between chronic high-strain exposure and ABP.	Chronic exposure to active jobs in men led to a higher risk of hypertension and ERI exposure onset in women led to increases in systolic ABP. Results from the present study highlight the need to consider chronic exposure in order to fully capture the deleterious effect of adverse psychosocial work stressors on cardiovascular health.	
26530404	Biobehavioral features associated with binge-eating disorder (BED) have been investigated; however, few systematic reviews to date have described neuroimaging findings from studies of BED. Emerging functional and structural studies support BED as having unique and overlapping neural features as compared with other disorders. Neuroimaging studies provide evidence linking heightened responses to palatable food cues with prefrontal areas, particularly the orbitofrontal cortex (OFC), with specific relationships to hunger and reward-sensitivity measures. While few studies to date have investigated non-food-cue responses; these suggest a generalized hypofunctioning in frontostriatal areas during reward and inhibitory control processes. Early studies applying neuroimaging to treatment efforts suggest that targeting neural function underlying motivational processes may prove important in the treatment of BED. 
26529522	Previous theoretical studies of animal and human behavioral learning have focused on the dichotomy of the value-based strategy using action value functions to predict rewards and the model-based strategy using internal models to predict environmental states. However, animals and humans often take simple procedural behaviors, such as the "win-stay, lose-switch" strategy without explicit prediction of rewards or states. Here we consider another strategy, the finite state-based strategy, in which a subject selects an action depending on its discrete internal state and updates the state depending on the action chosen and the reward outcome. By analyzing choice behavior of rats in a free-choice task, we found that the finite state-based strategy fitted their behavioral choices more accurately than value-based and model-based strategies did. When fitted models were run autonomously with the same task, only the finite state-based strategy could reproduce the key feature of choice sequences. Analyses of neural activity recorded from the dorsolateral striatum (DLS), the dorsomedial striatum (DMS), and the ventral striatum (VS) identified significant fractions of neurons in all three subareas for which activities were correlated with individual states of the finite state-based strategy. The signal of internal states at the time of choice was found in DMS, and for clusters of states was found in VS. In addition, action values and state values of the value-based strategy were encoded in DMS and VS, respectively. These results suggest that both the value-based strategy and the finite state-based strategy are implemented in the striatum. 
26529486	Global cerebral ischemia in rodents, which mimics cardiac arrest in humans, is associated with a surge in endocannabinoids and increased transmission of dopamine and glutamate leading to excitotoxic cell death. The current study assessed the role of CB1 receptor activation at the moment of an ischemic insult on ensuing regulation of stress and reward signaling molecules, neuronal injury and anxiety-like behavior. Male Wistar rats were separated into 4 groups (n=10/group); sham and ischemic rats administered the CB1 endocannabinoid receptor antagonist AM251 (2mg/kg, i.p.) 30min prior to global cerebral ischemia, and vehicle-treated counterparts. The effects of CB1 receptor blockade on corticotropin-releasing hormone (CRH), vesicular glutamate transporter 2 (vGluT2), tyrosine hydroxylase (TH) and dopamine receptor 1 (DRD1) signaling expression, together with CA1 neuronal damage and anxiety-like behaviors were assessed. Our findings show attenuated CA1 injury and behavioral deficits in AM251-treated ischemic rats. AM251-pretreatment also partially or completely reversed ischemia-induced alterations in TH-ir expression at the hippocampus, ventral tegmental area (VTA), nucleus accumbens (NAc) and basolateral amygdala (BLA), normalized DRD1-ir at the medial forebrain bundle, and diminished BLA and PVN-CRH expression. All groups showed comparable vGluT2 expression at the BLA and PVN-parvocellular subdivision. These findings support a determinant role of CB1 receptor activation at time of ischemia on functional recovery. They also support "state-dependent" effects of endocannabinoids, raising considerations in the development of effective molecules to regulate HPA axis function and mood disorders following cardiac arrest and stroke. 
26529423	Our decisions are based on parallel and competing systems of goal-directed and habitual learning, systems which can be impaired in pathological behaviours. Here we focus on the influence of motivation and compare reward and loss outcomes in subjects with obsessive-compulsive disorder (OCD) on model-based goal-directed and model-free habitual behaviours using the two-step task. We further investigate the relationship with acquisition learning using a one-step probabilistic learning task. Forty-eight OCD subjects and 96 healthy volunteers were tested on a reward and 30 OCD subjects and 53 healthy volunteers on the loss version of the two-step task. Thirty-six OCD subjects and 72 healthy volunteers were also tested on a one-step reversal task. OCD subjects compared with healthy volunteers were less goal oriented (model-based) and more habitual (model-free) to reward outcomes with a shift towards greater model-based and lower habitual choices to loss outcomes. OCD subjects also had enhanced acquisition learning to loss outcomes on the one-step task, which correlated with goal-directed learning in the two-step task. OCD subjects had greater stay behaviours or perseveration in the one-step task irrespective of outcome. Compulsion severity was correlated with habitual learning in the reward condition. Obsession severity was correlated with greater switching after loss outcomes. In healthy volunteers, we further show that greater reward magnitudes are associated with a shift towards greater goal-directed learning further emphasizing the role of outcome salience. Our results highlight an important influence of motivation on learning processes in OCD and suggest that distinct clinical strategies based on valence may be warranted. 
26528158	Recent research suggests that obesity is linked to prominent alterations in learning and decision-making. This general difference may also underlie the preference for immediately consumable, highly palatable but unhealthy and high-calorie foods. Such poor food-related inter-temporal decision-making can explain weight gain; however, it is not yet clear whether this deficit can be generalized to other domains of inter-temporal decision-making, for example financial decisions. Further, little is known about the stability of decision-making behavior in obesity, especially in the presence of rewarding cues. To answer these questions, obese and lean participants (n = 52) completed two sessions of a novel priming paradigm including a computerized monetary delay discounting task. In the first session, general differences between groups in financial delay discounting were measured. In the second session, we tested the general stability of discount rates. Additionally, participants were primed by affective visual cues of different contextual categories before making financial decisions. We found that the obese group showed stronger discounting of future monetary rewards than the lean group, but groups did not differ in their general stability between sessions nor in their sensitivity toward changes in reward magnitude. In the obese group, a fast decrease of subjective value over time was directly related to a higher tendency for opportunistic eating. Obese in contrast to lean people were primed by the affective cues, showing a sex-specific pattern of priming direction. Our findings demonstrate that environments rich of cues, aiming at inducing unhealthy consumer decisions, can be highly detrimental for obese people. It also underscores that obesity is not merely a medical condition but has a strong cognitive component, meaning that current dietary and medical treatment strategies may fall too short. 
26526306	Musculoskeletal pain has been found to co-occur with psychosocial job stress. However, different conceptualizations of job stress exist, each emphasizing different aspects of the work environment, and it is unknown which of these aspects show the strongest associations with musculoskeletal pain. Further, these associations may differ for white-collar vs. blue-collar job types, but this has not been tested. The present study examined the independent and combined contributions of Effort-RewardImbalance (ERI), Job-Demand-Control (JDC) and Organizational Justice (OJ) to musculoskeletal pain symptoms among white- and blue-collar workers.Participants of a cross-sectional study (n=1634) completed validated questionnaires measuring ERI, JDC, and OJ, and reported the frequency of pain during the previous year at four anatomical locations (lower back, neck or shoulder, arms and hands, and knees/feet). Pain reports were summarized into a single musculoskeletal symptom score (MSS). Analyses were stratified for white- and blue-collar workers.	Among white-collar workers, ERI and OJ were independently associated with MSS. In addition to these additive effects, significant 2-way and 3-way interactions indicated a synergistic effect of job stressors in relation to reported pain. In blue-collar workers, ERI and JDC independently associated with MSS, and a significant 3-way interaction was observed showing that the combination of job stressors exceeded an additive effect.	ERI influences pain symptoms in both occupational groups. OJ was independent significant predictor only among white-collar workers, whereas JDC had additive predictive utility exclusively among blue-collar workers. Simultaneous exposure to multiple job stress factors appeared to synergize pain symptom reporting.	
26524587	Fraudulent business practices, such as those leading to the Enron scandal and the conviction of Bernard Madoff, evoke a strong sense of public outrage. But fraudulent or dishonest actions are not exclusive to the realm of big corporations or to evil individuals without consciences. Dishonest actions are all too prevalent in everyone's daily lives, because people are constantly encountering situations in which they can gain advantages by cutting corners. Whether it's adding a few dollars in value to the stolen items reported on an insurance claim form or dropping outlier data points from a figure to make a paper sound more interesting, dishonesty is part of the human condition. Here, we explore how people rationalize dishonesty, the implications for scientific research, and what can be done to foster a culture of research integrity. 
26524484	The large impact of loss of reward on behavior has been well documented in adult populations. However, whether responsiveness to loss relative to gain is similarly elevated in child versus adult populations remains unclear. It is also unclear whether relations between incentive behaviors and self-reported reward/punishment sensitivity are similar within different developmental stages. To investigate these questions, 7- to 10-year-old children (N = 70) and young adults (N = 70) completed the Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scale, along with 2 probabilistic incentive tasks assessing gain approach and loss avoidance behavior. BIS/BAS subscales were calculated per Pagliaccio et al. (2015), which established an age invariant model of the BIS/BAS. Bias toward responses more frequently followed by gain feedback and away from responses more frequently followed by loss feedback, approach, and avoidance behavior, respectively, were quantified via signal detection statistics. Gain approach behavior did not differ across age groups; however, children exhibited significantly elevated loss avoidance relative to adults. Children also showed greater reductions in accuracy and slower RTs specifically following loss feedback relative to adults. Interestingly, despite age group differences in loss avoidance behavior, relations between self-report measures and approach/avoidance behaviors were similar across age groups. Participants reporting elevated motivation (BAS Drive) showed both elevated gain approach and elevated loss avoidance, with both types of behavior predicting unique variance in BAS Drive. Results highlight the often-neglected developmental and motivational roles of responsiveness to loss of reward.
26522867	Schizophrenia is characterized by substantial dysfunctions of reward processing, leading to detrimental consequences for decision-making. The neurotransmitter dopamine is responsible for the transmission of reward signals and also known to be involved in the mechanism of psychosis. Using functional magnetic resonance imaging (fMRI), sixteen medicated patients with schizophrenia and sixteen healthy controls performed the 'desire-reason dilemma' (DRD) paradigm. This paradigm allowed us to directly investigate reward-related brain activations depending on the interaction of bottom-up and top-down mechanisms, when a previously conditioned reward stimulus had to be rejected to achieve a superordinate long-term goal. Both patients and controls showed significant activations in the mesolimbic reward system. In patients with schizophrenia, however, we found a significant hyperactivation of the left ventral striatum (vStr) when they were allowed to accept the conditioned reward stimuli, and a reduced top-down regulation of activation in the ventral striatum (vStr) and ventral tegmental area (VTA) while having to reject the immediate reward to pursue the superordinate task-goal. Moreover, while healthy subjects exhibited a negative functional coupling of the vStr with both the anteroventral prefrontal cortex (avPFC) and the ventromedial prefrontal cortex (VMPFC) in the dilemma situation, this functional coupling was significantly impaired in the patient group. These findings provide evidence for an increased ventral striatal activation to reward stimuli and an impaired top-down control of reward signals by prefrontal brain regions in schizophrenia. 
26522619	A fundamental prerequisite for goal-directed action is to encode the contingencies between responses (R) producing specific outcomes (O) in specific stimulus conditions (S). The present study aimed to characterize the functional neuroanatomy of different associational sub-components of such S-R-O contingencies during the first few trials of exposure. We devised a novel paradigm that was suited to distinguish BOLD activation patterns related to S-R, R-O, and the full S-R-O contingency. Different from previous studies our experimental design ensured that stimulus-related processes and outcome-related processes were maximally comparable, as both were learned incidentally and lacked intrinsic incentive value, and different from trial-and-error learning situations, outcomes did not serve a special role as performance feedback. We observed contingency-related dissociations between SMA, lateral OFC, and large parts of the reward system including central OFC, anterior striatum and midbrain areas. While the lateral OFC was involved in processing differential outcomes irrespective of a predictive stimulus context, the SMA was specifically engaged when differential outcomes could be predicted by the stimulus. By contrast, the activation pattern of reward system areas suggested that these regions serve a role in integrating non-incentive differential outcome information and incentive common outcome information. Together, these results support the notion that striatal and orbitofrontal regions are involved in outcome-related processes beyond trial-and-error S-R learning, that is, when outcomes are non-incentive and do not serve as reinforcing feedback that drives learning. Furthermore, our results clarify the role of the SMA in outcome-related processes thereby supporting current versions of ideomotor theory.
26521965	Elucidation of reinforcement mechanisms in associative learning is an important subject in neuroscience. In mammals, dopamine neurons are thought to play critical roles in mediating both appetitive and aversive reinforcement. Our pharmacological studies suggested that octopamine and dopamine neurons mediate reward and punishment, respectively, in crickets, but recent studies in fruit-flies concluded that dopamine neurons mediates both reward and punishment, via the type 1 dopamine receptor Dop1. To resolve the discrepancy between studies in different insect species, we produced Dop1 knockout crickets using the CRISPR/Cas9 system and found that they are defective in aversive learning with sodium chloride punishment but not appetitive learning with water or sucrose reward. The results suggest that dopamine and octopamine neurons mediate aversive and appetitive reinforcement, respectively, in crickets. We suggest unexpected diversity in neurotransmitters mediating appetitive reinforcement between crickets and fruit-flies, although the neurotransmitter mediating aversive reinforcement is conserved. This study demonstrates usefulness of the CRISPR/Cas9 system for producing knockout animals for the study of learning and memory. 
26521964	The glutamatergic system may play a vital role in regulating neurobehavioral effects of various drugs of abuse. In the present study, we evaluated the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective antagonist of the type 5 metabotropic glutamate receptor (mGluR5) on the acquisition, expression and reinstatement of ethanol conditioned place preference (CPP). In the ethanol acquisition study, mice were conditioned with saline or ethanol (20% v/v, 2g/kg) on alternating days for 8 consecutive days and were given MPEP 10 min before ethanol conditioning. In another experiment, animals were conditioned with 2g/kg ethanol and MPEP was administered 10 min prior to the post-conditioning test. In a reinstatement study, following the extinction phase, animals were pretreated with MPEP 10 min prior to a priming injection of 1.0 g/kg ethanol. The mGluR5 antagonist MPEP significantly reduced the expression and the reinstatement in dose-dependent manner, but not acquisition of ethanol-induced CPP. These results indicate that mGluR5 may be involved in the expression and reinstatement of conditioned rewarding effects of ethanol, but not the acquisition of ethanol, which provide an evidence that mGluR5 blockade might make dissociable contributions during the training (acquisition phase), the performance of behavior (expression phase) and reinstatement.
26521171	The current research attempted to decrease individuals' rates of delay discounting by introducing decoys that are similar but inferior to delayed rewards. Two experiments in the current study compared patterns of delay discounting generated by repeated choices between two hypothetical monetary rewards in the absence or presence of a decoy. Binary questionnaires (i.e., decoy absent) included questions with two options: a smaller-sooner (SS) reward and a larger-later (LL) reward. Trinary questionnaires (i.e., decoy present) included questions with three options: an SS reward, an LL reward, and a decoy. If an option is at least as rewarding on every dimension of value as an alternative and the option is more rewarding than an alternative on at least one dimension, then the option is considered to dominate the alternative (Wedell, 1991). The first experiment assessed the influence of decoys dominated by LL rewards (LL(-) decoys), which were constructed to be similar (on the dimension of amount) but inferior (on the dimension of delay) to LL rewards. The second experiment examined the effects of counterbalancing the order of binary and trinary questionnaires. In the first experiment, participants discounted to a lesser degree when LL(-) decoys were present as compared to when they were absent. In the second experiment, participants only discounted to a lesser degree on trinary questionnaires with LL(-) decoys when they had not previously completed binary questionnaires. Patterns of discounting generated by binary questionnaires were similar to those generated by trinary questionnaires when decoys are present; however, the degree to which individuals discounted delayed rewards was affected by the number of and type of options that were available. The current results join previous evidence suggesting that rates of delay discounting are sensitive to a variety of contextual influences. 
26520354	While previous research has demonstrated the powerful influence of pleasant and unpleasant music on emotions, the present study utilizes functional magnetic resonance imaging (fMRI) to assess the positive and negative emotional responses as demonstrated in the brain when listening to music convolved with varying room acoustic conditions. During fMRI scans, subjects rated auralizations created in a simulated concert hall with varying reverberation times. The analysis detected activations in the dorsal striatum, a region associated with anticipation of reward, for two individuals for the highest rated stimulus, though no activations were found for regions associated with negative emotions in any subject. 
26520256	Research distinguishes between a habitual, model-free system motivated toward immediately rewarding actions, and a goal-directed, model-based system motivated toward actions that improve future state. We examined the balance of processing in these two systems during state-based decision-making. We tested a regulatory fit hypothesis (Maddox & Markman, 2010) that predicts that global trait motivation affects the balance of habitual- vs. goal-directed processing but only through its interaction with the task framing as gain-maximization or loss-minimization. We found support for the hypothesis that a match between an individual's chronic motivational state and the task framing enhances goal-directed processing, and thus state-based decision-making. Specifically, chronic promotion-focused individuals under gain-maximization and chronic prevention-focused individuals under loss-minimization both showed enhanced state-based decision-making. Computational modeling indicates that individuals in a match between global chronic motivational state and local task reward structure engaged more goal-directed processing, whereas those in a mismatch engaged more habitual processing. 
26519603	The neuropeptide oxytocin interacts with mesolimbic dopamine neurons to mediate reward associated with filial behaviors, but also other rewarding behaviors such as eating or taking drugs of abuse. Based on its efficacy to decrease intake of other abused substances, oxytocin administration is implicated as a possible treatment for excessive alcohol consumption. We tested this hypothesis by measuring ethanol intake in male Sprague-Dawley rats injected with oxytocin or saline using two different ethanol self-administration paradigms. First, a dose-response curve was constructed for oxytocin inhibition of fluid intake using a modified drinking-in-the-dark model with three bottles containing .05% saccharine, 10% ethanol in saccharine, and 15% ethanol in saccharine. Doses of oxytocin tested were 0.05, 0.1, 0.3, and 0.5mg/kg (I.P.). Next, rats received 0.3mg/kg oxytocin preceding operant sessions in which they were trained to lever-press for either plain gelatin or ethanol gelatin in order to compare oxytocin inhibition of ethanol intake versus caloric intake. For the three-bottle choice study, rats consumed significantly less ethanol when treated with the three higher doses of oxytocin on the injection day. In the operant study, 0.3mg/kg oxytocin significantly decreased ethanol gel consumption to a greater extent than plain gel consumption, both in terms of the amount of gel eaten and calories consumed. These data affirm oxytocin's efficacy for decreasing ethanol intake in rats, and confirm clinical studies suggesting oxytocin as a potential treatment for alcoholism. 
26518686	Previous research using the Gambling Outcome Expectancies Scale (GOES; Flack and Morris in J Gambl Stud, 2015. doi: 10.1007/s10899-014-9484-z ) revealed the instrument has excellent psychometric properties and differentially predicts gambling frequency and problem gambling scores. However, like the existing gambling motivation scales, the GOES psychometric properties and predictive utility have not been tested outside of cross sectional studies. The current study used a prospective survey design to redress this issue. Eight hundred and ninety-three participants, drawn from the general community, completed the second wave of the gambling survey. Temporal invariance testing revealed the GOES was reliable. Furthermore, the ability of the GOES to predict gambling behaviour using baseline and concurrent measures of gambling outcome expectancies was demonstrated. Specifically, consistent with the Wave 1 results, the gambling outcome expectancies that reflect diverse reasons for gambling (e.g., social, escape, and money) preferentially predicted gambling frequency whereas the narrower range of emotion focused reasons (e.g., excitement, escape, and ego enhancement) predicted gambling problems. Considered in light of the Wave 1 findings, these results underscore the need for gambling harm minimisation initiatives to take into account the emotion-oriented reasons for gambling. 
26518307	For decades sequential sampling models have successfully accounted for human and monkey decision-making, relying on the standard assumption that decision makers maintain a pre-set decision standard throughout the decision process. Based on the theoretical argument of reward rate maximization, some authors have recently suggested that decision makers become increasingly impatient as time passes and therefore lower their decision standard. Indeed, a number of studies show that computational models with an impatience component provide a good fit to human and monkey decision behavior. However, many of these studies lack quantitative model comparisons and systematic manipulations of rewards. Moreover, the often-cited evidence from single-cell recordings is not unequivocal and complimentary data from human subjects is largely missing. We conclude that, despite some enthusiastic calls for the abandonment of the standard model, the idea of an impatience component has yet to be fully established; we suggest a number of recently developed tools that will help bring the debate to a conclusive settlement.
26516682	Most reinforcement learning models assume that the reward signal arrives after the activity that led to the reward, placing constraints on the possible underlying cellular mechanisms. Here we show that dopamine, a positive reinforcement signal, can retroactively convert hippocampal timing-dependent synaptic depression into potentiation. This effect requires functional NMDA receptors and is mediated in part through the activation of the cAMP/PKA cascade. Collectively, our results support the idea that reward-related signaling can act on a pre-established synaptic eligibility trace, thereby associating specific experiences with behaviorally distant, rewarding outcomes. This finding identifies a biologically plausible mechanism for solving the 'distal reward problem'. 
26516171	Social approval is a reward that uses abstract social reinforcers to guide interpersonal interactions. Few studies have specifically explored social reward processing and its related neural substrates in schizophrenia. Fifteen patients with schizophrenia and fifteen healthy controls participated in a two-part study to explore the functional neural correlates of social approval. In the first session, participants were led to believe their personality would be assessed based on their results from various questionnaires and an interview. Participants were then presented with the results of their supposed evaluation in the scanner, while engaging in a relevant fMRI social approval task. Subjects provided subjective reports of pleasure associated with receiving self-directed positive or negative feedback. Higher activation of the right parietal lobe was found in controls compared with individuals with schizophrenia. Both groups rated traits from the high social reward condition as more pleasurable than the low social reward condition, while intergroup differences emerged in the low social reward condition. Positive correlations were found in patients only between subjective ratings of positive feedback and right insula activation, and a relevant behavioural measure. Evidence suggests potential neural substrates underlying the cognitive representation of social reputation in schizophrenia. 
26515931	Previous work with psychophysically based studies suggests that electrolytic lesion of the habenula, which lies in the dorsal diencephalic conduction system (DDC), degrades the intracranial self-stimulation (ICSS). This experiment was aimed at studying the importance of the DDC in brain stimulation reward, and its connections with other areas that support operant responding for brain stimulation. For this purpose, rats were implanted with stimulating electrodes at the dorsal raphe (DR) and lateral hypothalamus (LH), and lesioning electrodes in the medial forebrain bundle (MFB) and the DDC. Rats were trained to self-administer the stimulation at three different current intensities and were tested daily for changes in reward thresholds, defined as the pulse frequency required for half-maximal responding. The lesions were done at the DDC and the MFB, and were separated by two weeks interval during which the rats were tested for self-stimulation. At the end of the experiment, rats were transcardially perfused and their brains collected to determine the extent of the lesions and the locations of the stimulation sites. Results show that lesions at both the DDC and MFB produce larger and longer-lasting increases in the reward thresholds (upto 0.40 log10 units) than lesions at either pathway alone (upto 0.25 log10 units), and were more effective in attenuating the reward induced by the LH stimulation. These results suggest that there exist two parallel pathways, the MFB and the DDC, which could constitute a viable route for the reward signal triggered by ICSS.
26515905	We compared the sensitivity of standard single-shot 2D echo planar imaging (EPI) to three advanced EPI sequences, i.e., 2D multi-echo EPI, 3D high resolution EPI and 3D dual-echo fast EPI in fixed effect and random effects group level fMRI analyses at 3T. The study focused on how well the variance reduction in fixed effect analyses achieved by advanced EPI sequences translates into increased sensitivity in the random effects group level analysis. The sensitivity was estimated in a functional MRI experiment of an emotional learning and a reward based learning tasks in a group of 24 volunteers. Each experiment was acquired with the four different sequences. The task-related response amplitude, contrast level and respective t-value were proxies for the functional sensitivity across the brain. All three advanced EPI methods increased the sensitivity in the fixed effects analyses, but standard single-shot 2D EPI provided a comparable performance in random effects group analysis when whole brain coverage and moderate resolution are required. In this experiment inter-subject variability determined the sensitivity of the random effects analysis for most brain regions, making the impact of EPI pulse sequence improvements less relevant or even negligible for random effects analyses. An exception concerns the optimization of EPI reducing susceptibility-related signal loss that translates into an enhanced sensitivity e.g. in the orbitofrontal cortex for multi-echo EPI. Thus, future optimization strategies may best aim at reducing inter-subject variability for higher sensitivity in standard fMRI group studies at moderate spatial resolution. 
26515451	Several studies have examined dogs' (Canis lupus familiaris) comprehension and use of human communicative cues. Relatively few studies have, however, examined the effects of human affective behavior (i.e., facial and vocal expressions) on dogs' exploratory and point-following behavior. In two experiments, we examined dogs' frequency of following an adult's pointing gesture in locating a hidden reward or treat when it occurred silently, or when it was paired with a positive or negative facial and vocal affective expression. Like prior studies, the current results demonstrate that dogs reliably follow human pointing cues. Unlike prior studies, the current results also demonstrate that the addition of a positive affective facial and vocal expression, when paired with a pointing gesture, did not reliably increase dogs' frequency of locating a hidden piece of food compared to pointing alone. In addition, and within the negative facial and vocal affect conditions of Experiment 1 and 2, dogs were delayed in their exploration, or approach, toward a baited or sham-baited bowl. However, in Experiment 2, dogs continued to follow an adult's pointing gesture, even when paired with a negative expression, as long as the attention-directing gesture referenced a baited bowl. Together these results suggest that the addition of affective information does not significantly increase or decrease dogs' point-following behavior. Rather these results demonstrate that the presence or absence of affective expressions influences a dogs' exploratory behavior and the presence or absence of reward affects whether they will follow an unfamiliar adult's attention-directing gesture. 

26511522	While the neural control of glucoregulatory responses to insulin-induced hypoglycemia is beginning to be elucidated, brain sites responsible for behavioral responses to hypoglycemia are relatively poorly understood. To help elucidate central control mechanisms associated with hypoglycemia unawareness, we first evaluated the effect of recurrent hypoglycemia on a simple behavioral measure, the robust feeding response to hypoglycemia, in rats. First, food intake was significantly, and similarly, increased above baseline saline-induced intake (1.1 ± 0.2 g; n = 8) in rats experiencing a first (4.4 ± 0.3; n = 8) or third daily episode of recurrent insulin-induced hypoglycemia (IIH, 3.7 ± 0.3 g; n = 9; P < 0.05). Because food intake was not impaired as a result of prior IIH, we next developed an alternative animal model of hypoglycemia-induced behavioral arousal using a conditioned place preference (CPP) model. We found that hypoglycemia severely blunted previously acquired CPP in rats and that recurrent hypoglycemia prevented this blunting. Pretreatment with a brain penetrant, selective orexin receptor-1 antagonist, SB-334867A, blocked hypoglycemia-induced blunting of CPP. Recurrently hypoglycemic rats also showed decreased preproorexin expression in the perifornical hypothalamus (50%) but not in the adjacent lateral hypothalamus. Pretreatment with sertraline, previously shown to prevent hypoglycemia-associated glucoregulatory failure, did not prevent blunting of hypoglycemia-induced CPP prevention by recurrent hypoglycemia. This work describes the first behavioral model of hypoglycemia unawareness and suggests a role for orexin neurons in mediating behavioral responses to hypoglycemia. 
26511245	Optimal behavior requires striking a balance between exploiting tried-and-true options or exploring new possibilities. Neuroimaging studies have identified different brain regions in humans where neural activity is correlated with exploratory or exploitative behavior, but it is unclear whether this activity directly implements these choices or simply reflects a byproduct of the behavior. Moreover, it remains unknown whether arbitrating between exploration and exploitation can be influenced with exogenous methods, such as brain stimulation. In our study, we addressed these questions by selectively upregulating and downregulating neuronal excitability with anodal or cathodal transcranial direct current stimulation over right frontopolar cortex during a reward-learning task. This caused participants to make slower, more exploratory or faster, more exploitative decisions, respectively. Bayesian computational modeling revealed that stimulation affected how much participants took both expected and obtained rewards into account when choosing to exploit or explore: Cathodal stimulation resulted in an increased focus on the option expected to yield the highest payout, whereas anodal stimulation led to choices that were less influenced by anticipated payoff magnitudes and were more driven by recent negative reward prediction errors. These findings suggest that exploration is triggered by a neural mechanism that is sensitive to prior less-than-expected choice outcomes and thus pushes people to seek out alternative courses of action. Together, our findings establish a parsimonious neurobiological mechanism that causes exploration and exploitation, and they provide new insights into the choice features used by this mechanism to direct decision-making.
26511241	Some individuals are better at learning about rewarding situations, whereas others are inclined to avoid punishments (i.e., enhanced approach or avoidance learning, respectively). In reinforcement learning, action values are increased when outcomes are better than predicted (positive prediction errors [PEs]) and decreased for worse than predicted outcomes (negative PEs). Because actions with high and low values are approached and avoided, respectively, individual differences in the neural encoding of PEs may influence the balance between approach-avoidance learning. Recent correlational approaches also indicate that biases in approach-avoidance learning involve hemispheric asymmetries in dopamine function. However, the computational and neural mechanisms underpinning such learning biases remain unknown. Here we assessed hemispheric reward asymmetry in striatal activity in 34 human participants who performed a task involving rewards and punishments. We show that the relative difference in reward response between hemispheres relates to individual biases in approach-avoidance learning. Moreover, using a computational modeling approach, we demonstrate that better encoding of positive (vs negative) PEs in dopaminergic midbrain regions is associated with better approach (vs avoidance) learning, specifically in participants with larger reward responses in the left (vs right) ventral striatum. Thus, individual dispositions or traits may be determined by neural processes acting to constrain learning about specific aspects of the world.
26510167	A substantial proportion of schizophrenia liability can be explained by additive genetic factors. Risk profile scores (RPS) directly index risk using a summated total of common risk variants weighted by their effect. Previous studies suggest that schizophrenia RPS predict alterations to neural networks that support working memory and verbal fluency. In this study, we apply schizophrenia RPS to fMRI data to elucidate the effects of polygenic risk on functional brain networks during a probabilistic-learning neuroimaging paradigm. The neural networks recruited during this paradigm have previously been shown to be altered to unmedicated schizophrenia patients and relatives of schizophrenia patients, which may reflect genetic susceptibility. We created schizophrenia RPS using summary data from the Psychiatric Genetic Consortium (Schizophrenia Working Group) for 83 healthy individuals and explore associations between schizophrenia RPS and blood oxygen level dependency (BOLD) during periods of choice behavior (switch-stay) and reflection upon choice outcome (reward-punishment). We show that schizophrenia RPS is associated with alterations in the frontal pole (PWHOLE-BRAIN-CORRECTED  = 0.048) and the ventral striatum (PROI-CORRECTED  = 0.036), during choice behavior, but not choice outcome. We suggest that the common risk variants that increase susceptibility to schizophrenia can be associated with alterations in the neural circuitry that support the processing of changing reward contingencies. Hum Brain Mapp 37:491-500, 2016. © 2015 Wiley Periodicals, Inc. 
26509111	Finding neurobiological markers for neurodevelopmental disorders, such as attention deficit and hyperactivity disorder (ADHD), is a major objective of clinicians and neuroscientists. We examined if functional Magnetic Resonance Imaging (fMRI) data from a few distinct visuospatial working memory (VSWM) tasks enables accurately detecting cases with ADHD. We tested 20 boys with ADHD combined type and 20 typically developed (TD) boys in four VSWM tasks that differed in feedback availability (feedback, no-feedback) and reward size (large, small). We used a multimodal analysis based on brain activity in 16 regions of interest, significantly activated or deactivated in the four VSWM tasks (based on the entire participants' sample). Dimensionality of the data was reduced into 10 principal components that were used as the input variables to a logistic regression classifier. fMRI data from the four VSWM tasks enabled a classification accuracy of 92.5%, with high predicted ADHD probability values for most clinical cases, and low predicted ADHD probabilities for most TDs. This accuracy level was higher than those achieved by using the fMRI data of any single task, or the respective behavioral data. This indicates that task-based fMRI data acquired while participants perform a few distinct VSWM tasks enables improved detection of clinical cases. 
26508707	Gut-brain hormones such as ghrelin have recently been suggested to have a role in reward regulation. Ghrelin was traditionally known to regulate food intake and body weight homoeostasis. In addition, recent work has pin-pointed that this peptide has a novel role in drug-induced reward, including morphine-induced increase in the extracellular levels of accumbal dopamine in rats. Herein the effect of the ghrelin receptor (GHS-R1A) antagonist, JMV2959, on morphine-induced activation of the mesolimbic dopamine system was investigated in mice. In addition, the effects of JMV2959 administration on opioid peptide levels in reward related areas were investigated. In the present series of experiment we showed that peripheral JMV2959 administration, at a dose with no effect per se, attenuates the ability of morphine to cause locomotor stimulation, increase the extracellular levels of accumbal dopamine and to condition a place preference in mice. JMV2959 administration significantly increased tissue levels of Met-enkephalin-Arg(6)Phe(7) in the ventral tegmental area, dynorphin B in hippocampus and Leu-enkephalin-Arg(6) in striatum. We therefore hypothesise that JMV2959 prevents morphine-induced reward via stimulation of delta receptor active peptides in striatum and ventral tegmental areas. In addition, hippocampal peptides that activate kappa receptor may be involved in JMV2959׳s ability to regulate memory formation of reward. Given that development of drug addiction depends, at least in part, of the effects of addictive drugs on the mesolimbic dopamine system the present data suggest that GHS-R1A antagonists deserve to be elucidated as novel treatment strategies of opioid addiction. 
26506254	Two experiments examined the relationship between reward processing and impulsive choice. In Experiment 1, rats chose between a smaller-sooner (SS) reward (1 pellet, 10 s) and a larger-later (LL) reward (1, 2, and 4 pellets, 30 s). The rats then experienced concurrent variable-interval 30-s schedules with variations in reward magnitude to evaluate reward magnitude discrimination. LL choice behavior positively correlated with reward magnitude discrimination. In Experiment 2, rats chose between an SS reward (1 pellet, 10 s) and an LL reward (2 and 4 pellets, 30 s). The rats then received either a reward intervention which consisted of concurrent fixed-ratio schedules associated with different magnitudes to improve their reward magnitude discrimination, or a control task. All rats then experienced a post-intervention impulsive choice task followed by a reward magnitude discrimination task to assess intervention efficacy. The rats that received the intervention exhibited increases in post-intervention LL choice behavior, and made more responses for larger-reward magnitudes in the reward magnitude discrimination task, suggesting that the intervention heightened sensitivities to reward magnitude. The results suggest that reward magnitude discrimination plays a key role in individual differences in impulsive choice, and could be a potential target for further intervention developments.
26506187	In 2013, the Canadian Armed Forces (CAF) implemented the Fitness for Operational Requirements of Canadian Armed Forces Employment (FORCE), a field expedient fitness test designed to predict the physical requirements of completing common military tasks. Given that attaining this minimal physical fitness standard may not represent a challenge to some personnel, a fitness incentive program was requested by the chain of command to recognize and reward fitness over and above the minimal standard. At the same time, it was determined that the CAF would benefit from a measure of general health-related fitness, in addition to this measure of operational fitness. The resulting incentive program structure is based on gender and 8 age categories. The results on the 4 elements of the FORCE evaluation were converted to a point scale from which normative scores were derived, where the median score corresponds to the bronze level, and silver, gold, and platinum correspond to a score which is 1, 2, and 3 SDs above this median, respectively. A suite of rewards including merit board point toward promotions and recognition on the uniform and material rewards was developed. A separate group rewards program was also tabled, to recognize achievements in fitness at the unit level. For general fitness, oxygen capacity was derived from FORCE evaluation results and combined with a measure of abdominal circumference. Fitness categories were determined based on relative risks of mortality and morbidity for each age and gender group. Pilot testing of this entire program was performed with 624 participants to assess participants' reactions to the enhanced test, and also to verify logistical aspects of the electronic data capture, calculation, and transfer system. The newly dubbed fitness profile program was subsequently approved by the senior leadership of the CAF and is scheduled to begin a phased implementation in June 2015.
26505905	We propose and test three statistical models for the analysis of children's responses to the balance scale task, a seminal task to study proportional reasoning. We use a latent class modelling approach to formulate a rule-based latent class model (RB LCM) following from a rule-based perspective on proportional reasoning and a new statistical model, the Weighted Sum Model, following from an information-integration approach. Moreover, a hybrid LCM using item covariates is proposed, combining aspects of both a rule-based and information-integration perspective. These models are applied to two different datasets, a standard paper-and-pencil test dataset (N = 779), and a dataset collected within an online learning environment that included direct feedback, time-pressure, and a reward system (N = 808). For the paper-and-pencil dataset the RB LCM resulted in the best fit, whereas for the online dataset the hybrid LCM provided the best fit. The standard paper-and-pencil dataset yielded more evidence for distinct solution rules than the online data set in which quantitative item characteristics are more prominent in determining responses. These results shed new light on the discussion on sequential rule-based and information-integration perspectives of cognitive development. 
26504214	Marijuana exerts profound effects on human social behavior, but the neural substrates underlying such effects are unknown. Here we report that social contact increases, whereas isolation decreases, the mobilization of the endogenous marijuana-like neurotransmitter, anandamide, in the mouse nucleus accumbens (NAc), a brain structure that regulates motivated behavior. Pharmacological and genetic experiments show that anandamide mobilization and consequent activation of CB1 cannabinoid receptors are necessary and sufficient to express the rewarding properties of social interactions, assessed using a socially conditioned place preference test. We further show that oxytocin, a neuropeptide that reinforces parental and social bonding, drives anandamide mobilization in the NAc. Pharmacological blockade of oxytocin receptors stops this response, whereas chemogenetic, site-selective activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus stimulates it. Genetic or pharmacological interruption of anandamide degradation offsets the effects of oxytocin receptor blockade on both social place preference and cFos expression in the NAc. The results indicate that anandamide-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward. Deficits in this signaling mechanism may contribute to social impairment in autism spectrum disorders and might offer an avenue to treat these conditions. 
26503684	Laboratory attempts to identify relationships between personality and cooperative behaviour in humans have generated inconsistent results. This may partially stem from different practices in psychology and economics laboratories, with both hypothetical players and incentives typical only in the former. Another possible cause is insufficient consideration of the contexts within which social dilemmas occur. Real social dilemmas are often governed by institutions that change the payoff structure via rewards and punishments. However, such 'strong situations' will not necessarily suppress the effects of personality. On the contrary, they may affect some personalities differentially. Extraversion and neuroticism, reflecting variation in reward and punishment sensitivity, should predict modification of cooperative behaviour following changes to the payoff structure. We investigate interactions between personality and a punishment situation via two versions of a public goods game. We find that, even in a strong situation, personality matters and, moreover, it is related to strategic shifts in cooperation. Extraversion is associated with a shift from free-riding to cooperation in the presence of punishment, agreeableness is associated with initially higher contributions regardless of game, and, contrary to our predictions, neuroticism is associated with lower contributions regardless of game. Results should lead to new hypotheses that relate variation in biological functioning to individual differences in cooperative behaviour and that consider three-way interactions among personality, institutional context and sociocultural background. 
26503322	Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate-putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices. 
26501177	Drug overdose now exceeds car accidents as the leading cause of accidental death in the United States. Of those drug overdoses, a large percentage of the deaths are due to heroin and/or pharmaceutical overdose, specifically misuse of prescription opioid analgesics. It is imperative, then, that we understand the mechanisms that lead to opioid abuse and addiction. The rewarding actions of opioids are mediated largely by the mu-opioid receptor (MOR), and signaling by this receptor is modulated by various interacting proteins. The neurotransmitter dopamine also contributes to opioid reward, and opioid addiction has been linked to reduced expression of dopamine D2 receptors (D2R) in the brain. That said, it is not known if alterations in the expression of these proteins relate to drug exposure and/or to the "addiction-like" behavior exhibited for the drug. Here, we held total drug self-administration constant across acquisition and showed that reduced expression of the D2R and the MOR interacting protein, Wntless, in the medial prefrontal cortex was associated with greater addiction-like behavior for heroin in general and with a greater willingness to work for the drug in particular. In contrast, reduced expression of the D2R in the nucleus accumbens and hippocampus was correlated with greater seeking during signaled nonavailability of the drug. Taken together, these data link reduced expression of both the D2R and Wntless to the explicit motivation for the drug rather than to differences in total drug intake per se.
26501176	The head direction system is composed of neurons found in a number of connected brain areas that fire in a sharply tuned, directional way. The function of this system, however, has not been fully established. To assess this, we devised a novel spatial landmark task, comparable to the paradigms in which stimulus control has been assessed for spatially tuned neurons. The task took place in a large cylinder and required rats to dig in a specific sand cup, from among 16 alternatives, to obtain a food reward. The reinforced cup was in a fixed location relative to a salient landmark, and probe sessions confirmed that the landmark exerted stimulus control over the rats' cup choices. To assess the contribution of the head direction cell system to this memory task, half of the animals received ibotenic acid infusions into the lateral mammillary nuclei (LMN), an essential node in the head direction network, while the other received sham lesions. No differences were observed in performance of this task between the 2 groups. Animals with LMN lesions were impaired, however, in reversal learning on a water maze task. These results suggest that the LMN, and potentially the head direction cell system, are not essential for the use of visual landmarks to guide spatial behavior.
26500290	The vicarious reward we receive from watching likable others obtaining a positive outcome is a pervasive phenomenon, yet its neural correlates are poorly understood. Here, we conducted a series of functional magnetic resonance imaging experiments to test the hypothesis that the brain areas responsible for action observation and reward processing work in a coordinated fashion during vicarious reward. In the first experiment (manipulation phase), the participant was instructed to cheer for a particular player in a two-player competitive game (Rock-Paper-Scissors). This manipulation made participants feel more unity with that player and resulted in unity-related activation in the premotor area during action observation. In the following main experiment, the participant witnessed the previously cheered-for or non-cheered-for player succeed in a new solitary game (a stopwatch game). The ventromedial prefrontal cortex (vmPFC) was activated when the cheered-for player succeeded in the game but not when the other player did. Interestingly, this vmPFC activation was functionally connected with premotor activation only during the cheered-for player's success. These results suggest that vicarious reward is processed in the vmPFC-premotor network, which is activated specifically by the success of the other person with whom the individual feels unity and closeness. 
26499261	Artificial rewards, such as visual arts and music, produce pleasurable feelings. Popular songs in the verse-chorus form provide a useful model for understanding the neural mechanisms underlying the processing of artificial rewards, because the chorus is usually the most rewarding element of a song. In this functional magnetic resonance imaging (fMRI) study, the stimuli were excerpts of 10 popular songs with a tensioned verse-to-chorus transition. We examined the neural correlates of three phases of reward processing: (1) reward-anticipation during the verse-to-chorus transition, (2) reward-gain during the first phrase of the chorus, and (3) reward-loss during the unexpected noise followed by the verse-to-chorus transition. Participants listened to these excerpts in a risk-reward context because the verse was followed by either the chorus or noise with equal probability. The results showed that reward-gain and reward-loss were associated with left- and right-biased temporoparietal junction activation, respectively. The bilateral temporoparietal junctions were active during reward-anticipation. Moreover, we observed left-biased lateral orbitofrontal activation during reward-anticipation, whereas the medial orbitofrontal cortex was activated during reward-gain. The findings are discussed in relation to the cognitive and emotional aspects of reward processing. 
26499083	Binge eating disorder is characterized by excessive, uncontrollable consumption of palatable food within brief periods of time. Excessive intake of palatable food is thought to be driven by hedonic, rather than energy homeostatic, mechanisms. However, reward processing does not only comprise consummatory actions; a key component is represented by the anticipatory phase directed at procuring the reward. This phase is highly influenced by environmental food-associated stimuli, which can robustly enhance the desire to eat even in the absence of physiological needs. The opioid system (endogenous peptides and their receptors) has been strongly linked to the rewarding aspects of palatable food intake, and perhaps represents the key system involved in hedonic overeating. Here we review evidence suggesting that the opioid system can also be regarded as one of the systems that regulates the anticipatory incentive processes preceding binge eating hedonic episodes. 
26498173	A cigarette purchase task (CPT) is a behavioral economic measure of the reinforcing value of smoking in monetary terms (ie, cigarette demand). This study investigated whether cigarette demand predicted response to contingent monetary rewards for abstinence among individuals with substance use disorders. It also sought to replicate evidence for greater price sensitivity at whole-dollar pack price transitions (ie, left-digit effects).Participants (N = 338) were individuals in residential substance use disorder treatment who participated in a randomized controlled trial that compared contingent vouchers to noncontingent vouchers for smoking abstinence. Baseline demand indices were used to predict number of abstinent days during the 14-day voucher period (after the reduction lead-in) and at 1 and 3 months afterward.	Demand indices correlated with measures of smoking and nicotine dependence. As measured by elasticity, intensity and O max, higher demand significantly predicted fewer abstinent exhaled carbon monoxide readings during voucher period for individuals in the noncontingent vouchers condition. Breakpoint exhibited a trend-level association with abstinent exhaled carbon monoxide readings. Demand indices did not predict abstinence in the contingent vouchers group, and did not predict abstinence at 1- and 3-month follow-ups. Left-digit price transitions were associated with significantly greater reductions in consumption.	The association of cigarette demand with smoking behavior only in the group for whom abstinence was not incentivized indicates that CPT assesses the value of smoking more than the value of money per se and that vouchers counteract the effects of the intrinsic reinforcing value of cigarettes. Results provide initial short-term evidence of predictive validity for the CPT indices.	This study provides the first evidence of the validity of the CPT for predicting early response to brief advice for smoking cessation plus nicotine replacement in smokers with substance dependence. However, demand for cigarettes did not predict voucher-based treatment response, indicating that incentives serve as a powerful motivator not to smoke that acts in opposition to the intrinsic reinforcing value of cigarettes and that the indices reflect the value of smoking more than the value of money per se.	
26497691	Cigarette smoking is influenced by nicotine’s effects on dopaminergic activity in the mesocorticolimbic pathway. This activity appears to be moderated by genetic variation, specifically a variable number tandem repeat (VNTR) polymorphism in the third exon of the dopamine receptor gene (DRD4).We examined whether this polymorphism along with three DRD4 single-nucleotide polymorphisms (SNPs: rs936460, rs936461, and rs12280580) moderate the influence of nicotine on subjective responses to cigarettes.	White, non-Hispanic smokers (n = 96, cigarettes/day ≥15) attended two double-blind, counterbalanced experimental sessions, each preceded by overnight smoking abstinence. Participants smoked four nicotine (8.9 mg) or placebo (1.0 mg) cigarettes per session, with each cigarette followed by completion of the modified Cigarette Evaluation Questionnaire (mCEQ).	We examined the mCEQ composite score via 2 × 2 × 4 ANOVAs with genotype (major homozygotes versus minor carriers) as the between-subject factor and nicotine content and smoking bout as within-subject factors. Although DRD4 VNTR variation did not moderate overall nicotine response, there was a moderation of nicotine response over successive cigarettes. Smokers with fewer than seven repeats for the DRD4 VNTR reported markedly reduced craving, increased satisfaction, and a greater calming effect in response to earlier smoked nicotine cigarettes, whereas those with seven or more repeats did not. In addition, minor carriers for all three DRD4 SNPs displayed blunted overall response to nicotine.	These findings provide support for DRD4 variation as an informative predictor of subjective responses to nicotine. We discuss how these data may lead to improved tailoring of smoking cessation pharmacotherapies.	
26497623	Learning deficit is a clinical feature of many mental disorders and is hypothesized to result from an inability to integrate information in neural systems. We showed that transgenic mice expressing a dominant-negative form of DISC1, a risk gene for neuropsychiatric disorders, exhibited impaired performance in a reward-place association task when combined with a mild isolation stress. CA1 cells in the mutant mice showed normal place cell properties, but their activity at the goal zone was diminished. This abnormality in hippocampal activity at the goal zone during the task may underlie the learning deficit observed in the DISC1 mutant mice. 
26497268	Substantial evidence indicates that decision outcomes are typically evaluated relative to expectations learned from relatively long sequences of previous outcomes. This mechanism is thought to play a key role in general learning and adaptation processes but relatively little is known about the determinants of outcome evaluation when the capacity to learn from series of prior events is difficult or impossible. To investigate this issue, we examined how the feedback-related negativity (FRN) is modulated by information briefly presented before outcome evaluation. The FRN is a brain potential time-locked to the delivery of decision feedback and it is widely thought to be sensitive to prior expectations. We conducted a multi-trial gambling task in which outcomes at each trial were fully randomised to minimise the capacity to learn from long sequences of prior outcomes. Event-related potentials for outcomes (Win/Loss) in the current trial (Outcomet) were separated according to the type of outcomes that occurred in the preceding two trials (Outcomet-1 and Outcomet-2). We found that FRN voltage was more positive during the processing of win feedback when it was preceded by wins at Outcomet-1 compared to win feedback preceded by losses at Outcomet-1. However, no influence of preceding outcomes was found on FRN activity relative to the processing of loss feedback. We also found no effects of Outcomet-2 on FRN amplitude relative to current feedback. Additional analyses indicated that this effect was largest for trials in which participants selected a decision different to the gamble chosen in the previous trial. These findings are inconsistent with models that solely relate the FRN to prediction error computation. Instead, our results suggest that if stable predictions about future events are weak or non-existent, then outcome processing can be determined by affective systems. More specifically, our results indicate that the FRN is likely to reflect the activity of positive affective systems in these contexts. Importantly, our findings indicate that a multifactorial explanation of the nature of the FRN is necessary and such an account must incorporate affective and motivational factors in outcome processing.
26496795	Sprague-Dawley rats selectively-bred for susceptibility to stress in our laboratory (Susceptible, or SUS rats) voluntarily consume large amounts of alcohol, and amounts that have, as shown here, pharmacological effects, which normal rats will not do. In this paper, we explore neural events in the brain that underlie this propensity to readily consume alcohol. Activity of locus coeruleus neurons (LC), the major noradrenergic cell body concentration in the brain, influences firing of ventral tegmentum dopaminergic cell bodies of the mesocorticolimbic system (VTA-DA neurons), which mediate rewarding aspects of alcohol. We tested the hypothesis that in SUS rats alcohol potently suppresses LC activity to markedly diminish LC-mediated inhibition of VTA-DA neurons, which permits alcohol to greatly increase VTA-DA activity and rewarding aspects of alcohol. Electrophysiological single-unit recording of LC and VTA-DA activity showed that in SUS rats alcohol decreased LC burst firing much more than in normal rats and as a result markedly increased VTA-DA activity in SUS rats while having no such effect in normal rats. Consistent with this, in a behavioral test for reward using conditioned place preference (CPP), SUS rats showed alcohol, given by intraperitoneal (i.p.) injection, to be rewarding. Next, manipulation of LC activity by microinfusion of drugs into the LC region of SUS rats showed that (a) decreasing LC activity increased alcohol intake and increasing LC activity decreased alcohol intake in accord with the formulation described above, and (b) increasing LC activity blocked both the rewarding effect of alcohol in the CPP test and the usual alcohol-induced increase in VTA-DA single-unit activity seen in SUS rats. An important ancillary finding in the CPP test was that an increase in LC activity was rewarding by itself, while a decrease in LC activity was aversive; consequently, effects of LC manipulations on alcohol-related reward in the CPP test were perhaps even larger than evident in the test. Finally, when increased LC activity was associated with (i.e., conditioned to) i.p. alcohol, subsequent alcohol consumption by SUS rats was markedly reduced, indicating that SUS rats consume large amounts of alcohol because of rewarding physiological consequences requiring increased VTA-DA activity. The findings reported here are consistent with the view that the influence of alcohol on LC activity leading to changes in VTA-DA activity strongly affects alcohol-mediated reward, and may well be the basis of the proclivity of SUS rats to avidly consume alcohol. 
26496502	The processing of a visual stimulus can be subdivided into a number of stages. Upon stimulus presentation there is an early phase of feedforward processing where the visual information is propagated from lower to higher visual areas for the extraction of basic and complex stimulus features. This is followed by a later phase where horizontal connections within areas and feedback connections from higher areas back to lower areas come into play. In this later phase, image elements that are behaviorally relevant are grouped by Gestalt grouping rules and are labeled in the cortex with enhanced neuronal activity (object-based attention in psychology). Recent neurophysiological studies revealed that reward-based learning influences these recurrent grouping processes, but it is not well understood how rewards train recurrent circuits for perceptual organization. This paper examines the mechanisms for reward-based learning of new grouping rules. We derive a learning rule that can explain how rewards influence the information flow through feedforward, horizontal and feedback connections. We illustrate the efficiency with two tasks that have been used to study the neuronal correlates of perceptual organization in early visual cortex. The first task is called contour-integration and demands the integration of collinear contour elements into an elongated curve. We show how reward-based learning causes an enhancement of the representation of the to-be-grouped elements at early levels of a recurrent neural network, just as is observed in the visual cortex of monkeys. The second task is curve-tracing where the aim is to determine the endpoint of an elongated curve composed of connected image elements. If trained with the new learning rule, neural networks learn to propagate enhanced activity over the curve, in accordance with neurophysiological data. We close the paper with a number of model predictions that can be tested in future neurophysiological and computational studies. 
26494513	Orexinergic projections derived from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) and the nucleus accumbens (NAc), play a key role in the acquisition of conditioned place preference (CPP) induced by LH stimulation. On the other hand, there are several studies which support the idea of the existence of a cross-talk between the orexinergic and cannabinoid systems. Nevertheless, the function and how both systems interact in the reward circuit remain unknown. In this study, the authors tried to clarify the role of orexin-2 receptor (OX2r) within the VTA and NAc in the development of reward-related behaviors after chemical stimulation of the LH and also find out the involvement of CB1 cannabinoid receptors in this phenomenon. Animals were implanted by two separate cannulae into the LH and VTA or NAc, unilaterally. The CPP paradigm was done; and conditioning scores were recorded. The results showed that administration of TCS OX2 29 as a selective OX2r antagonist (1, 3 and 10 nM/rat) into the VTA or NAc just 5 min before microinjection of carbachol (250 nM/0.5 μl saline), a cholinergic agonist, into the LH during the 3-day conditioning phase, could dose-dependently inhibit the development of LH stimulation-induced CPP. Furthermore, concurrent injection of ineffective doses of TCS OX2 29 and AM251, as a CB1 receptor antagonist, into the NAc could reduce conditioning scores. The findings of this study showed that the OX2 receptor has a critical role in modulating reward circuit in the VTA and NAc, when the LH was stimulated by carbachol. Moreover, we suggest the existence of an interaction between orexinergic and cannabinoid systems within the VTA and NAc in place preference induced by LH stimulation.
26494380	It is now well established that the visual attention system is shaped by reward learning. When visual features are associated with a reward outcome, they acquire high priority and can automatically capture visual attention. To date, evidence for value-driven attentional capture has been limited entirely to the visual system. In the present study, I demonstrate that previously reward-associated sounds also capture attention, interfering more strongly with the performance of a visual task. This finding suggests that value-driven attention reflects a broad principle of information processing that can be extended to other sensory modalities and that value-driven attention can bias cross-modal stimulus competition.
26494275	Midbrain dopamine (DA) neurons are proposed to signal reward prediction error (RPE), a fundamental parameter in associative learning models. This RPE hypothesis provides a compelling theoretical framework for understanding DA function in reward learning and addiction. New studies support a causal role for DA-mediated RPE activity in promoting learning about natural reward; however, this question has not been explicitly tested in the context of drug addiction. In this review, we integrate theoretical models with experimental findings on the activity of DA systems, and on the causal role of specific neuronal projections and cell types, to provide a circuit-based framework for probing DA-RPE function in addiction. By examining error-encoding DA neurons in the neural network in which they are embedded, hypotheses regarding circuit-level adaptations that possibly contribute to pathological error signaling and addiction can be formulated and tested. 
26494272	In this issue of Neuron, Sippy et al. (2015) provide the clearest evidence to date that information is differentially encoded in the direct and indirect pathways of the striatum. The results support the classical notion that the direct pathway plays a critical role in initiating actions.
26493973	The resolution of an approach-avoidance conflict induced by ambivalent information involves the appraisal of the incentive value of the outcomes and associated stimuli to orchestrate an appropriate behavioral response. Much research has been directed at delineating the neural circuitry underlying approach motivation and avoidance motivation separately. Very little research, however, has examined the neural substrates engaged at the point of decision making when opposing incentive motivations are experienced simultaneously. We hereby examine the role of the dorsal and ventral hippocampus (HPC) in a novel approach-avoidance decision making paradigm, revisiting a once popular theory of HPC function, which posited the HPC to be the driving force of a behavioral inhibition system that is activated in situations of imminent threat. Rats received pre-training excitotoxic lesions of the dorsal or ventral HPC, and were trained to associate different non-spatial cues with appetitive, aversive and neutral outcomes in three separate arms of the radial maze. On the final day of testing, a state of approach-avoidance conflict was induced by simultaneously presenting two cues of opposite valences, and comparing the time the rats spent interacting with the superimposed 'conflict' cue, and the neutral cue. The ventral HPC-lesioned group showed significant preference for the conflict cue over the neutral cue, compared to the dorsal HPC-lesioned, and control groups. Thus, we provide evidence that the ventral, but not dorsal HPC, is a crucial component of the neural circuitry concerned with exerting inhibitory control over approach tendencies under circumstances in which motivational conflict is experienced.
26493575	The Iowa Gambling Task (IGT) is widely used to study decision-making differences between several clinical and healthy populations. Unlike the healthy participants, clinical participants have difficulty choosing between advantageous options, which yield long-term benefits, and disadvantageous options, which give high immediate rewards but lead to negative profits. However, recent studies have found that healthy participants avoid the options with a higher frequency of losses regardless of whether or not they are profitable in the long run. The aim of this study was to control for the confounding effect of the frequency of losses between options to improve the performance of healthy participants on the IGT.Eighty healthy participants were randomly assigned to the original IGT or a modified version of the IGT that diminished the gap in the frequency of losses between options.	The participants who used the modified IGT version learned to make better decisions based on long-term profit, as indicated by an earlier ability to discriminate good from bad options, and took less time to make their choices.	This research represents an advance in the study of decision making under uncertainty by showing that emotion-based learning is improved by controlling for the loss-frequency bias effect.	
26492726	The attentional blink (AB) is a compelling psychological phenomenon wherein observers are less likely to identify a second target (T2) when it appears approximately 200 ms after a first target (T1) in a rapidly presented stream of items. The present investigation examined how monetary motivation could impact the AB when participants were differentially motivated to identify T1 versus T2. Participants completed one of three conditions where the only difference across conditions was a motivational manipulation: a standard AB task (control condition), a motivated condition with T1 worth double the points of T2, or a motivated condition with T1 worth half the points of T2 (points in the motivated conditions were linked to a possible monetary bonus). Motivation had an expected influence on overall performance as both motivated conditions had higher overall T1 accuracy relative to the control condition. More specific to the question at hand, the AB was exacerbated (ie T2 performance was worse shortly after T1) when T1 was worth more than T2. This finding suggests that participants overallocated attentional resources to T1 processing at the expense of T2 processing, and it supports current theories of the AB.
26491992	Decision biases can distort cost-benefit evaluations of uncertain risks, leading to risk management policy decisions with predictably high retrospective regret. We argue that well-documented decision biases encourage learning aversion, or predictably suboptimal learning and premature decision making in the face of high uncertainty about the costs, risks, and benefits of proposed changes. Biases such as narrow framing, overconfidence, confirmation bias, optimism bias, ambiguity aversion, and hyperbolic discounting of the immediate costs and delayed benefits of learning, contribute to deficient individual and group learning, avoidance of information seeking, underestimation of the value of further information, and hence needlessly inaccurate risk-cost-benefit estimates and suboptimal risk management decisions. In practice, such biases can create predictable regret in selection of potential risk-reducing regulations. Low-regret learning strategies based on computational reinforcement learning models can potentially overcome some of these suboptimal decision processes by replacing aversion to uncertain probabilities with actions calculated to balance exploration (deliberate experimentation and uncertainty reduction) and exploitation (taking actions to maximize the sum of expected immediate reward, expected discounted future reward, and value of information). We discuss the proposed framework for understanding and overcoming learning aversion and for implementing low-regret learning strategies using regulation of air pollutants with uncertain health effects as an example. 
26491989	Behavioral research has found evidence supporting reward dominance in adolescence with externalizing disorders, but findings from neuroimaging studies have been largely heterogeneous. We examined the Feedback-Related Negativity (FRN) and P3b in relation to self-reported externalizing behavior among 78 adolescents (11-18 yrs) during a monetary gambling task with concurrent high-density electroencephalogram. As expected, the P3b and the FRN demonstrated greater evoked activity to reward and punishment, respectively. Further, high externalizing behavior was associated with greater P3b difference and reduced FRN difference in response to reward and punishment, suggesting that externalizing behaviors may be associated with both reward dominance and reduced feedback-monitoring. 
26491430	Human intrinsic motivation is of great importance in human behavior. However, although researchers have focused on this topic for decades, its neural basis was still unclear. The current study employed event-related potentials to investigate the neural disparity between an interesting stop-watch (SW) task and a boring watch-stop task (WS) to understand the neural mechanisms of intrinsic motivation. Our data showed that, in the cue priming stage, the cue of the SW task elicited smaller N2 amplitude than that of the WS task. Furthermore, in the outcome feedback stage, the outcome of the SW task induced smaller FRN amplitude and larger P300 amplitude than that of the WS task. These results suggested that human intrinsic motivation did exist and that it can be detected at the neural level. Furthermore, intrinsic motivation could be quantitatively indexed by the amplitude of ERP components, such as N2, FRN, and P300, in the cue priming stage or feedback stage. Quantitative measurements would also be convenient for intrinsic motivation to be added as a candidate social factor in the construction of a machine learning model. 
26490862	The role of neurons in the substantia nigra (SN) and ventral tegmental area (VTA) of the midbrain in contributing to the elicitation of reward prediction errors during appetitive learning has been well established. Less is known about the differential contribution of these midbrain regions to appetitive versus aversive learning, especially in humans. Here we scanned human participants with high-resolution fMRI focused on the SN and VTA while they participated in a sequential Pavlovian conditioning paradigm involving an appetitive outcome (a pleasant juice), as well as an aversive outcome (an unpleasant bitter and salty flavor). We found a degree of regional specialization within the SN: Whereas a region of ventromedial SN correlated with a temporal difference reward prediction error during appetitive Pavlovian learning, a dorsolateral area correlated instead with an aversive expected value signal in response to the most distal cue, and to a reward prediction error in response to the most proximal cue to the aversive outcome. Furthermore, participants' affective reactions to both the appetitive and aversive conditioned stimuli more than 1 year after the fMRI experiment was conducted correlated with activation in the ventromedial and dorsolateral SN obtained during the experiment, respectively. These findings suggest that, whereas the human ventromedial SN contributes to long-term learning about rewards, the dorsolateral SN may be particularly important for long-term learning in aversive contexts.The role of the substantia nigra (SN) and ventral tegmental area (VTA) in appetitive learning is well established, but less is known about their contribution to aversive compared with appetitive learning, especially in humans. We used high-resolution fMRI to measure activity in the SN and VTA while participants underwent higher-order Pavlovian learning. We found a regional specialization within the SN: a ventromedial area was selectively engaged during appetitive learning, and a dorsolateral area during aversive learning. Activity in these areas predicted affective reactions to appetitive and aversive conditioned stimuli over 1 year later. These findings suggest that, whereas the human ventromedial SN contributes to long-term learning about rewards, the dorsolateral SN may be particularly important for long-term learning in aversive contexts.	
26490515	Perceived ownership has been shown to impact a variety of cognitive processes: attention, memory, and--more recently--reward processing. In the present experiment we examined whether or not perceived ownership would interact with the construct of value-the relative worth of an object. Participants completed a simple gambling game in which they gambled either for themselves or for another while electroencephalographic data were recorded. In a key manipulation, gambles for oneself or for another were for either small or large rewards. We tested the hypothesis that value affects the neural response to self-gamble outcomes, but not other-gamble outcomes. Our experimental data revealed that while participants learned the correct response option for both self and other gambles, the reward positivity evoked by wins was impacted by value only when gambling for oneself. Importantly, our findings provide additional evidence for a self-ownership bias in cognitive processing and further demonstrate the insensitivity of the medial-frontal reward system to gambles for another.
26489046	The current study examined, for the first time, the effect of cue-intention association, as well as the effects of promised extrinsic rewards, on prospective memory in young children, aged 5-years-old (n = 39) and 7-years-old (n = 40). Children were asked to name pictures for a toy mole, whilst also having to remember to respond differently to certain target pictures (prospective memory task). The level to which the target picture was associated with the intention was manipulated across two conditions (low- or high-association) for all participants, whilst half of the participants were promised a reward for good prospective memory performance. Results showed a main effect of age, with the 7-year-olds outperforming the 5-year-olds. Furthermore, there was a main effect of reward, with those promised a reward performing better than those who were not. No effect was found for cue-association, with the participants of both age groups performing equally well in both association conditions. No significant interactions were found between any of the variables. The potentially important role of reward in young children's everyday prospective memory tasks, and possible reasons for the lack of a reflexive-associative effect, are discussed. 
26488770	German child care workers' job satisfaction is influenced by the consequences of unfavourable underlying conditions. Child care workers tend to suffer from psychosocial stress, as they feel that their work is undervalued. The objective of the present study is to investigate how the psychosocial factors of the effort-reward imbalance (ERI) model influence musculoskeletal symptoms (MS) and the risk of burnout. To our knowledge this is the first study investigating the association between the factors of the ERI model and MS in child care workers.Data from 199 child care workers were examined in a cross-sectional study. Psychosocial factors were recorded with the ERI questionnaire. MS was recorded with the Nordic Questionnaire and risk of burnout with the Personal Burnout scale of the Copenhagen Burnout Inventory. Multivariate analysis was performed using linear and logistic regression models. The response rate was 57%. In most of the sample (65%), an effort-reward imbalance was observed. 56% of the child care workers were at risk of burnout and 58% reported MS. Factors associated with risk of burnout were subjective noise exposure (OR: 4.4, 95%CI: 1.55-12.29) and overcommitment (OR: 3.4; 95%CI: 1.46-7.75). There were statistically significant associations between MS and overcommitment (low back pain-OR: 2.2, 95%CI: 1.04-4.51), low control (overall MS OR: 3.8; 95%CI: 1.68-3.37) and risk of burnout (overall MS OR: 2.3, 95%CI: 1.01-5.28). For ERI no statistically significant associations were found with reference to risk of burnout or MS.	Overcommitment in child care workers is related to MS and risk of burnout. There is also evidence that low control is associated with MS and subjective noise exposure with risk of burnout. Effort-reward imbalance is not related to either outcome. This occupational health risk assessment identifies changeable working factors in different types of facilities.	
26488590	The onset of adolescence is associated with an increase in the behavioral tendency to explore and seek novel experiences. However, this exploration has rarely been quantified, and its neural correlates during this period remain unclear. Previously, activity within specific regions of the rostrolateral PFC (rlPFC) in adults has been shown to correlate with the tendency for exploration. Here we investigate a recently developed task to assess individual differences in strategic exploration, defined as the degree to which the relative uncertainty of rewards directs responding toward less well-evaluated choices, in 62 girls aged 11-13 years from whom resting state fMRI data were obtained in a separate session. Behaviorally, this task divided our participants into groups of explorers (n = 41) and nonexplorers (n = 21). When seed ROIs within the rlPFC were used to interrogate resting state fMRI data, we identified a lateralized connection between the rlPFC and posterior putamen/insula whose strength differentiated explorers from nonexplorers. On the basis of Granger causality analyses, the preponderant direction of influence may proceed from posterior to anterior. Together, these data provide initial evidence concerning the neural basis of exploratory tendencies at the onset of adolescence. 
26488410	Imidacloprid (IMI), a neonicotinoid used for its high selective toxicity to insects, is one of the most commonly used pesticides. However, its effect on beneficial insects such as the honeybee Apis mellifera L is still controversial. As young adult workers perform in-hive duties that are crucial for colony maintenance and survival, we aimed to assess the effect of sublethal IMI doses on honeybee behaviour during this period. Also, because this insecticide acts as a cholinergic-nicotinic agonist and these pathways take part in insect learning and memory processes; we used IMI to assess their role and the changes they suffer along early adulthood. We focused on appetitive behaviours based on the proboscis extension response. Laboratory reared adults of 2 to 10 days of age were exposed to sublethal IMI doses (0.25 or 0.50ng) administered orally or topically prior to behavioural assessment. Modification of gustatory responsiveness and impairment of learning and memory were found as a result of IMI exposure. These outcomes differed depending on age of evaluation, type of exposure and IMI dose, being the youngest bees more sensitive and the highest oral dose more toxic. Altogether, these results imply that IMI administered at levels found in agroecosystems can reduce sensitivity to reward and impair associative learning in young honeybees. Therefore, once a nectar inflow with IMI traces is distributed within the hive, it could impair in-door duties with negative consequences on colony performance. 
26484383	Human immunodeficiency virus (HIV) is often contracted through engaging in risky reward-motivated behaviors such as needle sharing and unprotected sex. Understanding the factors that make an individual more vulnerable to succumbing to the temptation to engage in these risky behaviors is important to limiting the spread of HIV. One potential source of this vulnerability concerns the degree to which an individual is able to resist paying attention to irrelevant reward information. In the present study, we examine this possible link by characterizing individual differences in value-based attentional bias in a sample of HIV+ individuals with varying histories of risk-taking behavior. Participants learned associations between experimental stimuli and monetary reward outcome. The degree of attentional bias for these reward-associated stimuli, reflected in their ability to capture attention when presented as task-irrelevant distractors, was then assessed both immediately and six months following reward learning. Value-driven attentional capture was related to substance abuse history and non-planning impulsiveness during the time leading up to contraction of HIV as measured via self-report. These findings suggest a link between the ability to ignore reward-associated information and prior HIV-related risk-taking behavior. Additionally, particular aspects of HIV-associated neurocognitive disorders were related to attentional bias, including motor deficits commonly associated with HIV-induced damage to the basal ganglia. 
26483212	Suicidal vulnerability has been related to impaired value-based decision-making and increased sensitivity to social threat, mediated by the prefrontal cortex. Using functional magnetic resonance imaging, we aimed at replicating these previous findings by measuring brain activation during the Iowa Gambling Task and an emotional faces viewing task. Participants comprised 15 euthymic suicide attempters (history of depression and suicidal behavior) who were compared with 23 euthymic patient controls (history of depression without suicidal history) and 35 healthy controls. The following five model-based regions of interest were investigated: the orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (VLPFC), anterior cingulate cortex (ACC), medial (MPFC) and dorsal prefrontal cortex (DPFC). Suicide attempters relative to patient controls showed (1) increased response to angry vs. neutral faces in the left OFC and the VLPFC, as previously reported; (2) increased response to wins vs. losses in the right OFC, DPFC and ACC; (3) decreased response to risky vs. safe choices in the left DPFC; and (4) decreased response to sad vs. neutral faces in the right ACC. This study links impaired valuation processing (here for signals of social threat, sadness and reward) to prefrontal cortex dysfunction in suicide attempters. These long-term deficits may underlie the impaired decision-making and social difficulties found in suicide attempters. 
26482910	Alcohol dependence is associated with a dysregulated dopamine system modulating reward, craving and cognition. The monoamine stabilizer (-)-OSU6162 (OSU6162) can counteract both hyper- and hypo-dopaminergic states and we recently demonstrated that it attenuates alcohol-mediated behaviors in long-term drinking rats. The present Phase II exploratory human laboratory study investigated to our knowledge for the first time the effects of OSU6162 on cue- and priming-induced craving in alcohol dependent individuals. Fifty-six alcohol dependent individuals were randomized to a 14-day-treatment period of OSU6162 or placebo after their baseline impulsivity levels had been determined using the Stop Signal Task. On Day 15, participants were subjected to a laboratory alcohol craving test comprised of craving sessions induced by: i) active - alcohol specific cues, ii) neutral stimuli and iii) priming - intake of an alcoholic beverage (0.20g ethanol/kg bodyweight). Subjective ratings of alcohol craving were assessed using the shortened version of the Desire for Alcohol Questionnaire and visual analog scales (VAS). OSU6162 treatment had no significant effect on cue-induced alcohol craving, but significantly attenuated priming-induced craving. Exploratory analysis revealed that this effect was driven by the individuals with high baseline impulsivity. In addition, OSU6162 significantly blunted the subjective liking of the consumed alcohol (VAS). Although the present 14-day-treatment period, showed that OSU6162 was safe and well tolerated, this exploratory human laboratory study was not designed to evaluate the efficacy of OSU6162 to affect alcohol consumption. Thus a larger placebo-controlled efficacyclinical trial is needed to further investigate the potential of OSU6162 as a novel medication for alcohol dependence. 
26482890	Near-misses occur across many forms of gambling and are rated as unpleasant while simultaneously increasing the motivation to continue playing. On slot machines, the icon position relative to the payline moderates the effects of near-misses, with near-misses before the payline increasing motivation, and near-misses after the payline being rated as aversive. Near-misses are also known to increase physiological arousal compared to full-misses, but physiological measures to date have not been able to dissociate positive and negative emotional responses. The present study measured facial electromyography at the corrugator (brow) and zygomaticus (cheek) sites, as well as electrodermal activity (EDA), following gambling outcomes on a two-reel slot machine simulation in 77 novice gamblers. Behavioral data was collected using trial-by-trial ratings of motivation and valence. Wins were rated as more pleasant and increased motivation to continue playing, compared to non-win outcomes. Wins were also accompanied by increased EDA and zygomaticus activity. Near-misses after the payline were rated as more aversive than other non-wins, and this was accompanied by increased EDA and zygomaticus activity. Near-misses before the payline increased motivation to continue playing, and were accompanied by increased EDA. Thus, both subjective and physiological responses to near-misses differ for events falling either side of the payline. The 'near-miss effect' is not a unitary phenomenon. Facial EMG has differential sensitivity to positive and negative valence and may be a useful measure for future studies of gambling behavior. 
26481327	Associating reward to task performance has been shown to benefit scores of cognitive functions. Importantly, this typically entails associating reward to the execution of a response, hence intertwining action-related processes with motivational ones. However, recently, preparatory action requirements (go/no-go) and outcome valence (reward/punishment) were elegantly separated using a cued orthogonalized go/no-go task. Functional magnetic resonance imaging results from this task showed that typical areas of the "reward network," like the dopaminergic midbrain and the striatum, predominantly encode action rather than valence, displaying enhanced activity when preparing for action (go) compared to inaction (no-go). In the current study, we used ERPs to probe for differences in preparatory state related to cognitive effort in this task, which has similarly been linked to reward-network activity. Importantly, the contingent negative variation, which is linked to effortful cognitive preparation processes during cue-target intervals, was clearly observed in go trials but not in no-go trials. Moreover, target-locked ERP results (N1 and P3) suggested that attention to the target was enhanced when an action had to be performed (go trials), and typical inhibition-related ERP components were not observed in no-go trials, suggesting a lack of active response inhibition. Finally, feedback-related P3 results could suggest that correct feedback was valued more in motivated go trials, again implying that more effort was required to correctly perform the task. Together, these results indicate that the anticipation of action compared to inaction simultaneously entails differences in mental effort, highlighting the need for further dissociation of these concepts. 
26480843	In pollination, plants provide food reward to pollinators who in turn enhance plant reproduction by transferring pollen, making the relationship largely cooperative; however, because the interests of plants and pollinators do not always align, there exists the potential for conflict, where it may benefit both to cheat the other [1, 2]. Plants may even resort to chemistry: caffeine, a naturally occurring, bitter-tasting, pharmacologically active secondary compound whose main purpose is to detract herbivores, is also found in lower concentrations in the nectar of some plants, even though nectar, unlike leaves, is made to be consumed by pollinators. [corrected]. A recent laboratory study showed that caffeine may lead to efficient and effective foraging by aiding honeybee memory of a learned olfactory association [4], suggesting that caffeine may enhance bee reward perception. However, without field data, the wider ecological significance of caffeinated nectar remains difficult to interpret. Here we demonstrate in the field that caffeine generates significant individual- and colony-level effects in free-flying worker honeybees. Compared to a control, a sucrose solution with field-realistic doses of caffeine caused honeybees to significantly increase their foraging frequency, waggle dancing probability and frequency, and persistency and specificity to the forage location, resulting in a quadrupling of colony-level recruitment. An agent-based model also demonstrates how caffeine-enhanced foraging may reduce honey storage. Overall, caffeine causes bees to overestimate forage quality, tempting the colony into sub-optimal foraging strategies, which makes the relationship between pollinator and plant less mutualistic and more exploitative. VIDEO ABSTRACT.
26479590	Neural activity in visual area V4 is enhanced when attention is directed into neuronal receptive fields. However, the source of this enhancement is unclear, as most physiological studies have manipulated attention by changing the absolute reward associated with a particular location as well as its value relative to other locations. We trained monkeys to discriminate the orientation of two stimuli presented simultaneously in different hemifields while we independently varied the reward magnitude associated with correct discrimination at each location. Behavioral measures of attention were controlled by the relative value of each location. By contrast, neurons in V4 were consistently modulated by absolute reward value, exhibiting increased activity, increased gamma-band power and decreased trial-to-trial variability whenever receptive field locations were associated with large rewards. These data challenge the notion that the perceptual benefits of spatial attention rely on increased signal-to-noise in V4. Instead, these benefits likely derive from downstream selection mechanisms. 
26478780	What bees learn during pollen collection, and how they might discriminate between flowers on the basis of the quality of this reward, is not well understood. Recently we showed that bees learn to associate colors with differences in pollen rewards. Extending these findings, we present here additional evidence to suggest that the strength and time-course of memory formation may differ between pollen- and sucrose-rewarded bees. Color-naïve honeybees, trained with pollen or sucrose rewards to discriminate colored stimuli, were found to differ in their responses when recalling learnt information after reversal training. Such differences could affect the decision-making and foraging dynamics of individual bees when collecting different types of floral rewards. 
26478777	The Aesop's Fable paradigm - in which subjects drop stones into tubes of water to obtain floating out-of-reach rewards - has been used to assess causal understanding in rooks, crows, jays and human children. To date, the performance of corvids suggests that they can recognize the functional properties of a variety of objects including size, weight and solidity, and they seem to be more capable of learning from causal information than arbitrary information. However, 2 alternative explanations for their performance have yet to be ruled out. The perceptual-motor feedback hypothesis suggests that subjects may attend solely to the movement of the reward, repeating actions which bring the reward closer, while the object-bias hypothesis suggests that subjects could pass certain tasks by preferring to handle objects that resemble natural stones. Here we review our current understanding of performance on the Aesop's Fable tasks, and suggest that studies controlling for feedback and object preferences will help us determine exactly what animals understand about the cause and effect of water displacement. 
26478254	Chemically-mediated orientation is essential for many animals that must locate sites containing resources such as mates or food. One way to find these areas is by using publically-available information from other individuals. We tested a freshwater snail, Physa gyrina, for chemoreception of conspecific cues and predicted they could discriminate between cues based on information regarding hunger levels. We placed 'tracker' snails into a 2-arm arena where they could either follow or avoid an area previously used by a 'marker' snail. The hunger levels of both trackers and markers was manipulated, being either starved or fed. Starved and fed trackers did not differ in their following response when markers were hungry, but starved trackers were significantly more likely to follow fed markers, compared to fed trackers that tended to avoid areas used by fed markers. This outcome suggests that P. gyrina uses conspecific chemical cues to find food and potentially in some situations to avoid intra-specific food competition. 
26478196	There exists a continuous spectrum of overeating, where at the extremes there are casual overindulgences and at the other a 'pathological' drive to consume palatable foods. It has been proposed that pathological eating behaviors may be the result of addictive appetitive behavior and loss of ability to regulate the consumption of highly processed foods containing refined carbohydrates, fats, salt, and caffeine. In this review, we highlight the genetic similarities underlying substance addiction phenotypes and overeating compulsions seen in individuals with binge eating disorder. We relate these similarities to findings from neuroimaging studies on reward processing and clinical diagnostic criteria based on addiction phenotypes. The abundance of similarities between compulsive overeating and substance addictions puts forth a case for a 'food addiction' phenotype as a valid, diagnosable disorder. 
26477973	Neonicotinoids are often applied as systemic seed treatments to crops and have reported negative impact on pollinators when they appear in floral nectar and pollen. Recently, we found that bees in a two-choice assay prefer to consume solutions containing field-relevant doses of the neonicotinoid pesticides, imidacloprid (IMD) and thiamethoxam (TMX), to sucrose alone. This suggests that neonicotinoids enhance the rewarding properties of sucrose and that low, acute doses could improve learning and memory in bees. To test this, we trained foraging-age honeybees to learn to associate floral scent with a reward containing nectar-relevant concentrations of IMD and TMX and tested their short (STM) and long-term (LTM) olfactory memories. Contrary to our predictions, we found that none of the solutions enhanced the rate of olfactory learning and some of them impaired it. In particular, the effect of 10 nM IMD was observed by the second conditioning trial and persisted 24 h later. In most other groups, exposure to IMD and TMX affected STM but not LTM. Our data show that negative impacts of low doses of IMD and TMX do not require long-term exposure and suggest that impacts of neonicotinoids on olfaction are greater than their effects on rewarding memories. 
26477734	The rewarding properties of drugs in the mammalian system depend on their ability to activate appetitive motivational states. The associated underlying mechanism is strongly conserved in evolution and invertebrates have recently emerged as a powerful new model in addiction research. The natural reward system in crayfish has surprisingly proven sensitive to human drugs of abuse, providing a new model for research into the basic biological mechanisms of drug addiction. In this study, we examined the presence of natural reward systems in crayfish, and then characterized its sensitivity to 2.5 μg/g, 5.0 μg/g and 10.0 μg/g doses of methamphetamine (METH). Using the conditioned place preference (CPP) paradigm, we demonstrated that irrespective of the number of doses of METH injected into the pericardial system, crayfish seek out a particular tactile environment that had previously been paired with the METH. This study demonstrates that crayfish offer a comparative and complementary approach in addiction research. It contributes an evolutionary context to our understanding of a key component in learning and of natural reward as an important life-sustaining process.
26477717	Inhibitory interneurons are the fundamental constituents of neural circuits that organize network outputs. The striatum as part of the basal ganglia is involved in reward-directed behaviors. However, the role of the inhibitory interneurons in this process remains unclear, especially in behaving monkeys. We recorded the striatal single neuron activity while monkeys performed reward-directed hand or eye movements. Presumed parvalbumin-containing GABAergic interneurons (fast-spiking neurons, FSNs) were identified based on narrow spike shapes in three independent experiments, though they were a small population (4.2%, 42/997). We found that FSNs are characterized by high-frequency and less-bursty discharges, which are distinct from the basic firing properties of the presumed projection neurons (phasically active neurons, PANs). Besides, the encoded information regarding actions and outcomes was similar between FSNs and PANs in terms of proportion of neurons, but the discharge selectivity was higher in PANs than that of FSNs. The coding of actions and outcomes in FSNs and PANs was consistently observed under various behavioral contexts in distinct parts of the striatum (caudate nucleus, putamen, and anterior striatum). Our results suggest that FSNs may enhance the discharge selectivity of postsynaptic output neurons (PANs) in encoding crucial variables for a reward-directed behavior. 
26477378	Midbrain dopamine neurons have long been implicated in the rewarding effect produced by electrical brain stimulation of the medial forebrain bundle (MFB). These neurons are excited trans-synaptically, but their precise role in intracranial self-stimulation (ICSS) has yet to be determined. This study assessed the hypothesis that midbrain dopamine neurons are in series with the directly stimulated substrate for self-stimulation of the MFB and either perform spatio-temporal integration of synaptic input from directly activated MFB fibers or relay the results of such integration to efferent stages of the reward circuitry. Psychometric current-frequency trade-off functions were derived from ICSS performance, and chemometric trade-off functions were derived from stimulation-induced dopamine transients in the nucleus accumbens (NAc) shell, measured by means of fast-scan cyclic voltammetry. Whereas the psychometric functions decline monotonically over a broad range of pulse frequencies and level off only at high frequencies, the chemometric functions obtained with the same rats and electrodes are either U-shaped or level off at lower pulse frequencies. This discrepancy was observed when the dopamine transients were recorded in either anesthetized or awake subjects. The lack of correspondence between the psychometric and chemometric functions is inconsistent with the hypothesis that dopamine neurons projecting to the NAc shell constitute an entire series stage of the neural circuit subserving self-stimulation of the MFB. 
26476153	Behavioural responses to photos are often used to infer what animals understand about their social environment, but are rarely validated against the same stimuli in real life. If subjects' responses to photos do not reflect responses to the same live stimuli, it is difficult to conclude what happens in reality based on photo responses alone. We compared capuchins' responses to photos versus live stimuli in an identical scenario within research cubicles. Subjects had the opportunity to approach food placed in front of an alpha group member and, in a separate condition, photos depicting the same individual. Subjects' latencies to approach food when placed in front of the real alpha negatively correlated with time subjects spent in close proximity to the alpha in their main enclosure. We therefore predicted subjects' latencies to approach food in the presence of photos would positively correlate with their latencies to approach food in the presence of the real alpha inside the cubicles, but negatively correlate with time they spent in proximity to the alpha in their enclosure. Neither prediction was supported. While not necessarily surprising, we explain why these results should be an important reminder that care is needed when interpreting results from photo studies. 
26475784	Given that the vast majority of functional magnetic resonance imaging (fMRI) studies of drug cue reactivity use unisensory visual cues, but that multisensory cues may elicit greater craving-related brain responses, the current study sought to compare the fMRI BOLD response to unisensory visual and multisensory, visual plus odor, smoking cues in 17 nicotine-dependent adult cigarette smokers. Brain activation to smoking-related, compared to neutral, pictures was assessed under cigarette smoke and odorless odor conditions. While smoking pictures elicited a pattern of activation consistent with the addiction literature, the multisensory (odor+picture) smoking cues elicited significantly greater and more widespread activation in mainly frontal and temporal regions. BOLD signal elicited by the multisensory, but not unisensory cues, was significantly related to participants' level of control over craving as well. Results demonstrated that the co-presentation of cigarette smoke odor with smoking-related visual cues, compared to the visual cues alone, elicited greater levels of craving-related brain activation in key regions implicated in reward. These preliminary findings support future research aimed at a better understanding of multisensory integration of drug cues and craving. 

26473906	Teachers' job satisfaction is one of the key factors in institutional dynamics and is generally considered to be the primary variable by which the effectiveness of an organization's human resource is evaluated. The objectives of this study were to assess the level of job satisfaction among university teachers and to clarify the associated factors.A cross-sectional study was conducted between November 2013 and January 2014. Teachers from six universities in Shenyang, China were randomly sampled. The job satisfaction scale Minnesota Satisfaction Questionnaire (MSQ), perceived organizational support (POS), psychological capital questionnaire (PCQ-24), and effort-reward imbalance scale (ERI) together with questions about demographic and working factors were administered in questionnaires distributed to 1500 university teachers. Hierarchical linear regression analyses were performed to explore the related factors.	1210 effective responses were obtained (effective respondent rate 80.7%). The average score of overall job satisfaction was 69.71. Hierarchical linear regression analysis revealed that turnover intention, occupational stress and chronic disease all had negative impacts on job satisfaction, whereas perceived organizational support, psychological capital and higher monthly income were positively associated with job satisfaction among the university teachers. Age was also linked to the level of job satisfaction. All the variables explained 60.7% of the variance in job satisfaction.	Chinese university teachers had a moderate level of job satisfaction. Demographic and working characteristics were associated factors for job satisfaction. Perceived organizational support showed the strongest association with job satisfaction. RESULTS of the study indicate that improving the perceived organizational support may increase the level of job satisfaction for university teachers.	
26473618	Sleep plays a crucial role in the consolidation of newly acquired memories. Yet, how our brain selects the noteworthy information that will be consolidated during sleep remains largely unknown. Here we show that post-learning sleep favors the selectivity of long-term consolidation: when tested three months after initial encoding, the most important (i.e., rewarded, strongly encoded) memories are better retained, and also remembered with higher subjective confidence. Our brain imaging data reveals that the functional interplay between dopaminergic reward regions, the prefrontal cortex and the hippocampus contributes to the integration of rewarded associative memories. We further show that sleep spindles strengthen memory representations based on reward values, suggesting a privileged replay of information yielding positive outcomes. These findings demonstrate that post-learning sleep determines the neural fate of motivationally-relevant memories and promotes a value-based stratification of long-term memory stores. 
26473170	Belief updating-the process by which an agent alters an internal model of its environment-is a core function of the CNS. Recent theory has proposed broad principles by which belief updating might operate, but more precise details of its implementation in the human brain remain unclear. In order to address this question, we studied how two components of the human event-related potential encoded different aspects of belief updating. Participants completed a novel perceptual learning task while electroencephalography was recorded. Participants learned the mapping between the contrast of a dynamic visual stimulus and a monetary reward and updated their beliefs about a target contrast on each trial. A Bayesian computational model was formulated to estimate belief states at each trial and was used to quantify the following two variables: belief update size and belief uncertainty. Robust single-trial regression was used to assess how these model-derived variables were related to the amplitudes of the P3 and the stimulus-preceding negativity (SPN), respectively. Results showed a positive relationship between belief update size and P3 amplitude at one fronto-central electrode, and a negative relationship between SPN amplitude and belief uncertainty at a left central and a right parietal electrode. These results provide evidence that belief update size and belief uncertainty have distinct neural signatures that can be tracked in single trials in specific ERP components. This, in turn, provides evidence that the cognitive mechanisms underlying belief updating in humans can be described well within a Bayesian framework. 

26472529	Increasing evidence supports an important role for the brain's reward circuitry in controlling mood under normal conditions and contributing importantly to the pathophysiology and symptomatology of a range of mood disorders, such as depression. Here we focus on the nucleus accumbens (NAc), a critical component of the brain's reward circuitry, in depression and other stress-related disorders. The prominence of anhedonia, reduced motivation, and decreased energy level in most individuals with depression supports the involvement of the NAc in these conditions. We concentrate on several transcription factors (CREB, ΔFosB, SRF, NFκB, and β-catenin), which are altered in the NAc in rodent depression models--and in some cases in the NAc of depressed humans, and which produce robust depression- or antidepressant-like effects when manipulated in the NAc in animal models. These studies of the NAc have established novel approaches toward modeling key symptoms of depression in animals and could enable the development of antidepressant medications with fundamentally new mechanisms of action.
26471712	The ability to learn from errors or the positive outcomes of one's actions has been connected to a differential functionality of the mesolimbic dopamine system. Variations in dopaminergic transmission and D2-receptor (DRD2) density in the striatum may thereby incline the individual to be either more reward- or punishment-sensitive. The steroid hormones estradiol (E2) and progesterone (PROG) are known to modulate dopaminergic tone. While E2 may enhance dopaminergic release and reduces DRD2, PROG may oppose these effects and attenuates dopaminergic responses. In women, marked changes in the concentration of these hormones occur across the menstrual cycle. Hence, the aim of this study was to assess whether reinforcement learning is modulated by menstrual cycle phase. Fifteen female subjects underwent fMRI while performing a probabilistic feedback learning task twice during their menstrual cycle--once in a phase dominated by E2 (late follicular phase), and a second time in the presence of high PROG (mid luteal phase).The goal of the learning task was to select the more frequently rewarded symbols from 3 symbol pairs, which was enforced by probabilistic feedback. A behavioral post-test examined learning performance and the tendency towards reward or punishment sensitivity (i.e., preference to choose the most often rewarded symbol 'A' or to avoid the least often rewarded symbol 'B', respectively). We found that individual reward sensitivity was enhanced in the follicular relative to the luteal phase, while the ability to learn from negative feedback was compromised. In contrast, during the luteal phase this behavior was reversed and women showed an enhanced punishment learning bias. On the neural level, activation of the dorsal anterior cingulate cortex and adjacent rostral cingulate zone (dACC/RCZ) was decreased when subjects received negative feedback in the follicular relative to the luteal phase. Additionally, in the luteal phase an enhanced ability to learn from negative feedback was accompanied by a stronger signal in the dACC/RCZ in response to negative feedback. These findings provide initial evidence for intra-individual differences in reward and punishment sensitivity due to naturally occurring hormonal changes across the menstrual cycle.
26471420	Mefloquine continues to be a key drug used for malaria chemoprophylaxis and treatment, despite reports of adverse events like depression and anxiety. It is unknown how mefloquine acts within the central nervous system to cause depression and anxiety or why some individuals are more vulnerable. We show that intraperitoneal injection of mefloquine in mice, when coupled to subthreshold social defeat stress, is sufficient to produce depression-like social avoidance behavior. Direct infusion of mefloquine into the nucleus accumbens (NAc), a key brain reward region, increased stress-induced social avoidance and anxiety behavior. In contrast, infusion into the ventral hippocampus had no effect. Whole cell recordings from NAc medium spiny neurons indicated that mefloquine application increases the frequency of spontaneous excitatory postsynaptic currents, a synaptic adaptation that we have previously shown to be associated with increased susceptibility to social defeat stress. Together, these data demonstrate a role for the NAc in mefloquine-induced depression and anxiety-like behaviors. 
26471057	A key element of behavioral flexibility is to quickly learn to modify or reverse previously acquired stimulus-response associations. Such reversal learning (RL) can either be driven by feedback or by explicit instruction, informing either retrospectively or prospectively about the changed response requirements. Neuroimaging studies have thus far exclusively focused either on feedback-driven RL or on instructed initial learning of novel rules. The present study examined the neural basis of instructed RL as compared to instructed initial learning, separately assessing reversal-related instruction-based encoding processes and reversal-related control processes required for implementing reversed rules under competition from the initially learned rules. We found that instructed RL is partly supported by similar regions as feedback-driven RL, including lateral orbitofrontal cortex (lOFC) and anterior dorsal caudate. Encoding-related activation in both regions determined resilience against response competition during subsequent memory-based reversal implementation. Different from feedback-driven RL, instruction-based RL relied heavily on the generic fronto-parietal cognitive control network--not for encoding but for reversal-related control processes during memory-based implementation. These findings are consistent with a model of partly decoupled, yet interacting, systems of (i) symbolic rule representations that are instantaneously updated upon instruction and (ii) pragmatic representations of reward-associated S-R links mediating the enduring competition from initially learned rules.
26469930	Cues associated with rewarding events acquire value themselves as a result of the incentive value of the reward being transferred to the cue. Consequently, presentation of a reward-paired cue can trigger reward-seeking behaviours towards the cue itself (i.e. sign-tracking). The ventral pallidum (VP) has been demonstrated to be involved in a number of motivated behaviours, both conditioned and unconditioned. However, its contribution to the acquisition of incentive value is unknown. Using a discriminative autoshaping procedure with levers, the effects of disrupting VP activity in rats on the emergence of sign-tracking was investigated using chemogenetics, i.e. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Transient disruption of VP neurons [activation of the inhibitory hM4D(Gi) DREADD through systemic injections of clozapine N-oxide (CNO) prior to each autoshaping session] impaired acquisition of sign-tracking (lever press rate) without having any effect on approach to the site of reward delivery (i.e. goal-tracking) or on the expression of sign-tracking after it was acquired. In addition, electrophysiological recordings were conducted in freely behaving rats following VP DREADD activation. The majority of VP units that were responsive to CNO injections exhibited rapid inhibition relative to baseline, a subset of CNO-responsive units showed delayed excitation, and a smaller subset displayed a mixed response of inhibition and excitation following CNO injections. It is argued that disruption of VP during autoshaping specifically disrupted the transfer of incentive value that was attributed to the lever cue, suggesting a surprisingly fundamental role for the VP in acquiring, compared with expressing, Pavlovian incentive values.
26469745	Controlling an inappropriate response tendency in the face of a reward-predicting stimulus likely depends on the strength of the reward-driven activation, the strength of a putative top-down control process, and their relative timing. We developed a rewarded go/no-go paradigm to investigate such dynamics. Participants made rapid responses (on go trials) to high versus low reward-predicting stimuli and sometimes had to withhold responding (on no-go trials) in the face of the same stimuli. Behaviorally, for high versus low reward stimuli, responses were faster on go trials, and there were more errors of commission on no-go trials. We used single-pulse TMS to map out the corticospinal excitability dynamics, especially on no-go trials where control is needed. For successful no-go trials, there was an early rise in motor activation that was then sharply reduced beneath baseline. This activation-reduction pattern was more pronounced for high- versus low-reward trials and in individuals with greater motivational drive for reward. A follow-on experiment showed that, when participants were fatigued by an effortful task, they made more errors on no-go trials for high versus low reward stimuli. Together, these studies show that, when a response is inappropriate, reward-predicting stimuli induce early motor activation, followed by a top-down effortful control process (which we interpret as response suppression) that depends on the strength of the preceding activation. Our findings provide novel information about the activation-suppression dynamics during control over reward-driven actions, and they illustrate how fatigue or depletion leads to control failures in the face of reward. 
26469133	Offspring of depressed parents are at risk for developing depression at rates higher than the general population. One potential mechanism linking parent and offspring depression involves attenuated reward function. Despite the importance of social incentives for adolescents, no previous studies have relied on active social incentive reward paradigms in youth at risk for depression. The present study examined differences in youth self- and parent-report measures of and neural response to social reward between youth of mothers with and those of mothers without a history of depression.Imaging data were collected on 10 youth with a depressed parent and 23 youth without depressed parent, which included a task examining neural response to social rewards. Youth and parents also completed self-report measures of social reward.	Offspring of depressed parents had lower levels of parent-reported affiliation and reduced neural response to social reward in the ventral striatum and anterior cingulate cortex than offspring of parents without a history of depression. Higher parent-reported affiliation was associated with greater ventral striatal response to social reward. Data suggest that risk status differences in ventral striatal response to social acceptance may be accounted for by affiliation. No differences were found in youth self-reports of behavior.	The results suggest that attenuated response to social reward, assessed through neurobiology and behavior, may be mechanistically linked to the etiology and pathophysiology of depression. Targeting social interest and engagement may be a new direction in preventing the onset of depressive disorders in youth.	
26468206	Arc ensembles in adult rat olfactory bulb (OB) and anterior piriform cortex (PC) were assessed after discrimination training on highly similar odor pairs. Nonselective α- and β-adrenergic antagonists or saline were infused in the OB or anterior PC during training. OB adrenergic blockade slowed, but did not prevent, odor discrimination learning. After criterion performance, Arc ensembles in anterior piriform showed enhanced stability for the rewarded odor and pattern separation for the discriminated odors as described previously. Anterior piriform adrenergic blockade prevented acquisition of similar odor discrimination and of OB ensemble changes, even with extended overtraining. Mitral and granule cell Arc ensembles in OB showed enhanced stability for rewarded odor only in the saline group. Pattern separation was not seen in the OB. Similar odor discrimination co-occurs with increased stability in rewarded odor representations and pattern separation to reduce encoding overlap. The difficulty of similar discriminations may relate to the necessity to both strengthen rewarded representations and weaken overlap across similar representations.We show for the first time that adrenoceptors in anterior piriform cortex (aPC) must be engaged for adult rats to learn to discriminate highly similar odors. Loss of adrenergic activation in olfactory bulb (OB) slows, but does not prevent, discrimination learning. Both increased stability of the rewarded odor representation and increased pattern separation of the rewarded and unrewarded odors in aPC accompany successful discrimination. In the OB, rewarded odors increase in ensemble stability, but there is no evidence of pattern separation. We suggest that the slow acquisition of similar odor discriminations is related to the differing plasticity requirements for increased stability and pattern separation.	
26468202	Transient changes in striatal dopamine (DA) concentration are considered to encode a reward prediction error (RPE) in reinforcement learning tasks. Often, a phasic DA change occurs concomitantly with a dip in striatal acetylcholine (ACh), whereas other neuromodulators, such as adenosine (Adn), change slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs for these neuromodulators in striatal medium spiny neurons (MSNs), which play important roles in plasticity. However, little is known about the interaction between these neuromodulators via GPCRs. The interaction between these transient neuromodulator changes and the effect on cAMP/PKA signaling via Golf- and Gi/o-coupled GPCR are studied here using quantitative kinetic modeling. The simulations suggest that, under basal conditions, cAMP/PKA signaling could be significantly inhibited in D1R+ MSNs via ACh/M4R/Gi/o and an ACh dip is required to gate a subset of D1R/Golf-dependent PKA activation. Furthermore, the interaction between ACh dip and DA peak, via D1R and M4R, is synergistic. In a similar fashion, PKA signaling in D2+ MSNs is under basal inhibition via D2R/Gi/o and a DA dip leads to a PKA increase by disinhibiting A2aR/Golf, but D2+ MSNs could also respond to the DA peak via other intracellular pathways. This study highlights the similarity between the two types of MSNs in terms of high basal AC inhibition by Gi/o and the importance of interactions between Gi/o and Golf signaling, but at the same time predicts differences between them with regard to the sign of RPE responsible for PKA activation.Dopamine transients are considered to carry reward-related signal in reinforcement learning. An increase in dopamine concentration is associated with an unexpected reward or salient stimuli, whereas a decrease is produced by omission of an expected reward. Often dopamine transients are accompanied by other neuromodulatory signals, such as acetylcholine and adenosine. We highlight the importance of interaction between acetylcholine, dopamine, and adenosine signals via adenylyl-cyclase coupled GPCRs in shaping the dopamine-dependent cAMP/PKA signaling in striatal neurons. Specifically, a dopamine peak and an acetylcholine dip must interact, via D1 and M4 receptor, and a dopamine dip must interact with adenosine tone, via D2 and A2a receptor, in direct and indirect pathway neurons, respectively, to have any significant downstream PKA activation.	
26468198	Adolescence is characterized by drastic behavioral adaptations and comprises a particularly vulnerable period for the emergence of various psychiatric disorders. Growing evidence reveals that the pathophysiology of these disorders might derive from aberrations of normal neurodevelopmental changes in the adolescent brain. Understanding the molecular underpinnings of adolescent behavior is therefore critical for understanding the origin of psychopathology, but the molecular mechanisms that trigger adolescent behavior are unknown. Here, we hypothesize that the cannabinoid type-1 receptor (CB1R) may play a critical role in mediating adolescent behavior because enhanced endocannabinoid (eCB) signaling has been suggested to occur transiently during adolescence. To study enhanced CB1R signaling, we introduced a missense mutation (F238L) into the rat Cnr1 gene that encodes for the CB1R. According to our hypothesis, rats with the F238L mutation (Cnr1(F238L)) should sustain features of adolescent behavior into adulthood. Gain of function of the mutated receptor was demonstrated by in silico modeling and was verified functionally in a series of biochemical and electrophysiological experiments. Mutant rats exhibit an adolescent-like phenotype during adulthood compared with wild-type littermates, with typical high risk/novelty seeking, increased peer interaction, enhanced impulsivity, and augmented reward sensitivity for drug and nondrug reward. Partial inhibition of CB1R activity in Cnr1(F238L) mutant rats normalized behavior and led to a wild-type phenotype. We conclude that the activity state and functionality of the CB1R is critical for mediating adolescent behavior. These findings implicate the eCB system as an important research target for the neuropathology of adolescent-onset mental health disorders.We present the first rodent model with a gain-of-function mutation in the cannabinoid type-1 receptor (CB1R). Adult mutant rats exhibit an adolescent-like phenotype with typical high risk seeking, impulsivity, and augmented drug and nondrug reward sensitivity. Adolescence is a critical period for suboptimal behavioral choices and the emergence of neuropsychiatric disorders. Understanding the basis of these disorders therefore requires a comprehensive knowledge of how adolescent neurodevelopment triggers behavioral reactions. Our behavioral observations in adult mutant rats, together with reports on enhanced adolescent CB1R signaling, suggest a pivotal role for the CB1R in an adolescent brain as an important molecular mediator of adolescent behavior. These findings implicate the endocannabinoid system as a notable research target for adolescent-onset mental health disorders.	
26468190	The basal forebrain (BF) houses major ascending projections to the entire neocortex that have long been implicated in arousal, learning, and attention. The disruption of the BF has been linked with major neurological disorders, such as coma and Alzheimer's disease, as well as in normal cognitive aging. Although it is best known for its cholinergic neurons, the BF is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific BF cell types have led to a renaissance in the study of the BF and are beginning to yield new insights about cell-type-specific circuit mechanisms during behavior. These approaches enable us to determine the behavioral conditions under which cholinergic and noncholinergic BF neurons are activated and how they control cortical processing to influence behavior. Here we discuss recent advances that have expanded our knowledge about this poorly understood brain region and laid the foundation for future cell-type-specific manipulations to modulate arousal, attention, and cortical plasticity in neurological disorders.Although the basal forebrain is best known for, and often equated with, acetylcholine-containing neurons that provide most of the cholinergic innervation of the neocortex, it is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific cell types in the basal forebrain have led to a renaissance in this field and are beginning to dissect circuit mechanisms in the basal forebrain during behavior. This review discusses recent advances in the roles of basal forebrain cholinergic and noncholinergic neurons in cognition via their dynamic modulation of cortical activity.	
26468187	Adaptive decision making to eat is crucial for survival, but in anorexia nervosa, the brain persistently supports reduced food intake despite a growing need for energy. How the brain persists in reducing food intake, sometimes even to the point of death and despite the evolution of multiple mechanisms to ensure survival by governing adaptive eating behaviors, remains mysterious. Neural substrates belong to the reward-habit system, which could differ among the eating disorders. The present review provides an overview of neural circuitry of restrictive food choice, binge eating, and the contribution of specific serotonin receptors. One possibility is that restrictive food intake critically engages goal-directed (decision making) systems and "habit," supporting the view that persistent caloric restriction mimics some aspects of addiction to drugs of abuse.An improved understanding of the neural basis of eating disorders is a timely challenge because these disorders can be deadly. Up to 70 million of people in the world suffer from eating disorders. Anorexia nervosa affects 1-4% of women in United States and is the first cause of death among adolescents in Europe. Studies relying on animal models suggest that decision making to eat (or not) can prevail over actual energy requirements due to emotional disturbances resulting in abnormal habitual behavior, mimicking dependence. These recent studies provide a foundation for developing more specific and effective interventions for these disorders.	
26467523	Internal representations of action-outcome relationships are necessary for flexible adaptation of motivated behavior in dynamic environments. Prefrontal cortex (PFC) is implicated in flexible planning and execution of goal-directed actions, but little is known about how information about action-outcome relationships is represented across functionally distinct regions of PFC. Here, we observe distinct patterns of action-evoked single unit activity in the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) during a task in which the relationship between outcomes and actions was independently manipulated. The mPFC encoded changes in the number of actions required to earn a reward, but not fluctuations in outcome magnitude. In contrast, OFC neurons decreased firing rates as outcome magnitude was increased, but were insensitive to changes in action requirement. A subset of OFC neurons also tracked outcome availability. Pre-outcome anticipatory activity in both mPFC and OFC was altered when reward expectation was reduced, but did not differ with outcome magnitude. These data provide novel evidence that PFC regions encode distinct information about the relationship between actions and impending outcomes during action execution. 
26465113	Spatial learning requires the hippocampus, and the replay of spatial sequences during hippocampal sharp wave-ripple (SPW-R) events of quiet wakefulness and sleep is believed to play a crucial role. To test whether the coordination of VTA reward prediction error signals with these replayed spatial sequences could contribute to this process, we recorded from neuronal ensembles of the hippocampus and VTA as rats performed appetitive spatial tasks and subsequently slept. We found that many reward responsive (RR) VTA neurons coordinated with quiet wakefulness-associated hippocampal SPW-R events that replayed recent experience. In contrast, coordination between RR neurons and SPW-R events in subsequent slow wave sleep was diminished. Together, these results indicate distinct contributions of VTA reinforcement activity associated with hippocampal spatial replay to the processing of wake and SWS-associated spatial memory. 
26464985	Two theories regarding the role for dopamine neurons in learning include the concepts that their activity serves as a (1) mechanism that confers incentive salience onto rewards and associated cues and/or (2) contingency teaching signal reflecting reward prediction error. While both theories are provocative, the causal role for dopamine cell activity in either mechanism remains controversial. In this study mice that either fully or partially lacked NMDARs in dopamine neurons exclusively, as well as appropriate controls, were evaluated for reward-related learning; this experimental design allowed for a test of the premise that NMDA/glutamate receptor (NMDAR)-mediated mechanisms in dopamine neurons, including NMDA-dependent regulation of phasic discharge activity of these cells, modulate either the instrumental learning processes or the likelihood of pavlovian cues to become highly motivating incentive stimuli that directly attract behavior. Loss of NMDARs in dopamine neurons did not significantly affect baseline dopamine utilization in the striatum, novelty evoked locomotor behavior, or consumption of a freely available, palatable food solution. On the other hand, animals lacking NMDARs in dopamine cells exhibited a selective reduction in reinforced lever responses that emerged over the course of instrumental learning. Loss of receptor expression did not, however, influence the likelihood of an animal acquiring a pavlovian conditional response associated with attribution of incentive salience to reward-paired cues (sign tracking). These data support the view that reductions in NMDAR signaling in dopamine neurons affect instrumental reward-related learning but do not lend support to hypotheses that suggest that the behavioral significance of this signaling includes incentive salience attribution. 
26464966	Disrupting maladaptive memories may provide a novel form of treatment for neuropsychiatric disorders, but little is known about the neurochemical mechanisms underlying the induction of lability, or destabilization, of a retrieved consolidated memory. Destabilization has been theoretically linked to the violation of expectations during memory retrieval, which, in turn, has been suggested to correlate with prediction error (PE). It is well-established that PE correlates with dopaminergic signaling in limbic forebrain structures that are critical for emotional learning. The basolateral amygdala is a key neural substrate for the reconsolidation of pavlovian reward-related memories, but the involvement of dopaminergic mechanisms in inducing lability of amygdala-dependent memories has not been investigated. Therefore, we tested the hypothesis that dopaminergic signaling within the basolateral amygdala is required for the destabilization of appetitive pavlovian memories by investigating the effects dopaminergic and protein synthesis manipulations on appetitive memory reconsolidation in rats. Intra-amygdala administration of either the D1-selective dopamine receptor antagonist SCH23390 or the D2-selective dopamine receptor antagonist raclopride prevented memory destabilization at retrieval, thereby protecting the memory from the effects of an amnestic agent, the protein synthesis inhibitor anisomycin. These data show that dopaminergic transmission within the basolateral amygdala is required for memory labilization during appetitive memory reconsolidation. 
26464265	We recently established that the monoamine stabilizer (-)-OSU6162 (OSU6162) decreased voluntary alcohol-mediated behaviors, including alcohol intake and cue/priming-induced reinstatement, in long-term drinking rats, while blunting alcohol-induced dopamine output in the nucleus accumbens (NAc) of alcohol-naïve rats. Therefore, we hypothesized that OSU6162 attenuates alcohol-mediated behaviors by blunting alcohol's rewarding effects. Here, we evaluated the effects of long-term drinking and OSU6162 treatment (30 mg/kg, sc) on basal and alcohol-induced (2.5 g/kg, ip) NAc dopamine outputs in Wistar rats after 10 months of intermittent access to 20% alcohol. The results showed that basal and alcohol-induced NAc dopamine outputs were significantly lower in long-term drinking rats, compared with alcohol-naïve rats. In the long-term drinking rats, OSU6162 slowly increased and maintained the dopamine output significantly elevated compared with baseline for at least 4 hours. Furthermore, OSU6162 pre-treatment did not blunt the alcohol-induced output in the long-term drinking rats, a finding that contrasted with our previous results in alcohol-naïve rats. Finally, OSU6162 did not induce conditioned place preference (CPP) in either long-term drinking or alcohol-naïve rats, indicating that OSU6162 has no reinforcing properties. To verify that the CPP results were not due to memory acquisition impairment, we demonstrated that OSU6162 did not affect novel object recognition. In conclusion, these results indicate that OSU6162 attenuates alcohol-mediated behaviors by counteracting NAc dopamine deficits in long-term drinking rats and that OSU6162 is not rewarding on its own. Together with OSU6162's beneficial side-effect profile, the present study merits evaluation of OSU6162's clinical efficacy to attenuate alcohol use in alcohol-dependent patients.

26463617	Previous studies showed that rats and pigeons can count their responses, and the resultant count-based judgments exhibit the scalar property (also known as Weber's Law), a psychophysical property that also characterizes interval-timing behavior. Animals were found to take a nearly normative account of these well-established endogenous uncertainty characteristics in their time-based decision-making. On the other hand, no study has yet tested the implications of scalar property of numerosity representations for reward-rate maximization in count-based decision-making. The current study tested mice on a task that required them to press one lever for a minimum number of times before pressing the second lever to collect the armed reward (fixed consecutive number schedule, FCN). Fewer than necessary number of responses reset the response count without reinforcement, whereas emitting responses at least for the minimum number of times reset the response counter with reinforcement. Each mouse was tested with three different FCN schedules (FCN10, FCN20, FCN40). The number of responses emitted on the first lever before pressing the second lever constituted the main unit of analysis. Our findings for the first time showed that mice count their responses with scalar property. We then defined the reward-rate maximizing numerical decision strategies in this task based on the subject-based estimates of the endogenous counting uncertainty. Our results showed that mice learn to maximize the reward-rate by incorporating the uncertainty in their numerosity judgments into their count-based decisions. Our findings extend the scope of optimal temporal risk-assessment to the domain of count-based decision-making.
26462571	Recent findings have revealed that pharmacological enhancement of dopaminergic (DA) function by the administration of a dopaminergic precursor (dihydroxy-l-phenylalanine; l-DOPA) increases an optimism bias in humans. This effect is due to l-DOPA's impairment of the ability to update beliefs in response to undesirable information about the future. To test whether an 'optimistic' bias is also mediated by dopamine in animals, first, two groups of rats received either a dopaminergic precursor, l-DOPA, or a D2 receptor antagonist, haloperidol, and were subsequently tested using the ambiguous-cue interpretation (ACI) paradigm. To test whether similar effects might be observed when manipulating another neurotransmitter implicated in learning about reward and punishment, we administered the serotonin (5-HT) reuptake inhibitor escitalopram to a third group of animals and the selective and irreversible tryptophan hydroxylase inhibitor para-chlorophenylalanine (PCPA) to a fourth group. The results of our study demonstrated that prolonged (2 weeks), but not acute, l-DOPA administration induced optimistic bias in rats. Neither acute nor chronic treatment with the other tested compounds had significant effects on the cognitive judgment bias of rats. The convergence of these results with human studies suggests the translational validity of the ambiguous-cue interpretation paradigm in testing the effects of pharmacological manipulations on cognitive judgment bias (optimism/pessimism) in rats. 
26460026	Effort and reward jointly shape many human decisions. Errors in predicting the required effort needed for a task can lead to suboptimal behavior. Here, we show that effort estimations can be biased when retrospectively reestimated following receipt of a rewarding outcome. These biases depend on the contingency between reward and task difficulty and are stronger for highly contingent rewards. Strikingly, the observed pattern accords with predictions from Bayesian cue integration, indicating humans deploy an adaptive and rational strategy to deal with inconsistencies between the efforts they expend and the ensuing rewards. 
26459164	Processing of performance-related feedback is an essential prerequisite for adaptive behavior. Even though in everyday life feedback is rarely immediate, to date very few studies have investigated whether the feedback-related negativity (FRN), a relative negativity in the ERP approximately 200 to 300 ms after feedback that is sensitive to feedback valence and predictability, is modulated by feedback timing, and findings are inconsistent. The present study investigated effects of gradually increasing feedback delays on feedback processing in the FRN time window. Subjects completed a probabilistic learning task in which feedback was provided after short, intermediate, or long delays. Difference wave-based analyses showed that amplitudes decreased linearly with increasing feedback delay. A distinct pattern was observed for the FRN as defined in the original waveforms, with FRN amplitudes being largest for long and smallest for short delays. This pattern of results is consistent with the notion that the neural systems underlying feedback processing vary depending on feedback timing. The gradually reduced difference wave signal might reflect a gradual shift away from processing in frontostriatal circuits toward medial temporal involvement. To what extent increased signal amplitudes for longer delays in the original waveforms are related to processing in certain brain structures will need to be determined in future studies. 
26459117	Binge eating is a key symptom of many eating disorders (e.g. binge eating disorder, bulimia nervosa, anorexia nervosa binge/purge type), yet the neurobiological underpinnings of binge eating are poorly understood. The mesocorticolimbic reward circuit, including the nucleus accumbens and the medial prefrontal cortex, is likely involved because this circuit mediates the hedonic value and incentive salience of palatable foods (PF). Here we tested the hypothesis that higher propensity for binge eating is associated with a heightened response (i.e., Fos induction) of the nucleus accumbens and medial prefrontal cortex to PF, using an animal model that identifies binge eating prone (BEP) and binge eating resistant (BER) rats. Forty adult female Sprague-Dawley rats were given intermittent access to PF (high fat pellets) 3×/week for 3 weeks. Based on a pattern of either consistently high or consistently low PF consumption across these feeding tests, 8 rats met criteria for categorization as BEP, and 11 rats met criteria for categorization as BER. One week after the final feeding test, BEP and BER rats were either exposed to PF in their home cages or were given no PF in their home cages for 1h prior to perfusion, leading to three experimental groups for the Fos analysis: BEPs given PF, BERs given PF, and a No PF control group. The total number of Fos-immunoreactive (Fos-ir) cells in the nucleus accumbens core and shell, and the cingulate, prelimbic, and infralimbic regions of the medial prefrontal cortex was estimated by stereological analysis. PF induced higher Fos expression in the nucleus accumbens shell and core and in the prelimbic and infralimbic cortex of BEP rats compared to No PF controls. Throughout the nucleus accumbens and medial prefrontal cortex, PF induced higher Fos expression in BEP than in BER rats, even after adjusting for differences in PF intake. Differences in the neural activation pattern between BEP and BER rats were more robust in prefrontal cortex than in nucleus accumbens. These data confirm that PF activates brain regions responsible for encoding the incentive salience and hedonic properties of PF, and suggest that binge eating proneness is associated with enhanced responses to PF in brain regions that exert executive control over food reward.
26457770	Heroin dependence is associated with deficits in impulsivity, which is also a core feature of attention deficit hyperactivity disorder (ADHD). This study aimed to explore the association between childhood ADHD symptoms and cognitive and motor impulsivity among abstinent individuals with a history of heroin dependence.Thirty-two abstinent Bulgarian males with a history of heroin dependence participated in the study. Self-rated childhood ADHD symptoms were obtained using the Wender-Utah Rating Scale. Cognitive impulsivity was measured using the Iowa Gambling Task (IGT), an index of impulsive decision making, and the Delayed Reward Discounting Task (DRDT), a measure of intertemporal choice. Motor impulsivity was indexed with the Stop Signal Task (SST), a measure of response inhibition.	Participants, whose average age was 27.66 years (SD = 2.7), had an average ADHD symptom score of 36.6 (SD = 18.6), had roughly 7 years (SD = 2.9) of heroin use, and had been abstinent for just over a year (M = 402.5 days, SD = 223.8). Linear regression analyses revealed that self-reported ADHD symptoms predicted impulsive decision making (IGT), but not delayed discounting (DRDT) or response inhibition (SST).	Self-reported childhood ADHD symptoms do not uniformly predict impulsivity among abstinent individuals with heroin dependence. Results suggest the IGT may be more sensitive to externalizing psychopathology among individuals with heroin dependence than other measures of impulsivity.	
26456562	High multivitamin (HV) content in gestational diets has long-term metabolic effects in rat offspring. These changes are associated with in utero modifications of gene expression in hypothalamic food intake regulation. However, the role of fat-soluble vitamins in mediating these effects has not been explored. Vitamin A is a plausible candidate due to its role in gene methylation. Vitamin A intake above requirements during pregnancy affects the development of neurocircuitries involved in food intake and reward regulation. Pregnant Wistar rats were fed AIN-93G diets with the following content: recommended multivitamins (1-fold multivitamins: RV), high vitamin A (10-fold vitamin A: HA) or HV with only recommended vitamin A (10-fold multivitamins, 1-fold vitamin A: HVRA). Body weight, food intake and preference, mRNA expression and DNA methylation of hippocampal dopamine-related genes were assessed in male offspring brains at different developmental windows: birth, weaning and 14weeks postweaning. HA offspring had changes in dopamine-related gene expression at all developmental windows and DNA hypermethylation in the dopamine receptor 2 promoter region compared to RV offspring. Furthermore, HA diet lowered sucrose preference but had no effect on body weight and expression of hypothalamic genes. In contrast, HVRA offspring showed only at adulthood changes in expression of hippocampal genes and a modest effect on hypothalamic genes. High vitamin A intake alone in gestational diets has long-lasting programming effects on the dopaminergic system that are further translated into decreased sucrose preference but not food intake. 
26456353	The prefrontal cortex (PFC) is critical for higher-order cognitive functions, including decision-making. In psychiatric conditions such as schizophrenia, prefrontal dysfunction co-occurs with pronounced alterations in decision-making ability. These alterations include a diminished ability to utilize probabilistic reinforcement in guiding future choice, and a reduced willingness to expend effort to receive reward. Among the neurochemical abnormalities observed in the PFC of individuals with schizophrenia are alterations in the production and function of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). To probe how PFC GABA hypofunction may contribute to alterations in cost/benefit decision-making, we assessed the effects GABAA-receptor antagonist bicuculline (BIC; 50 ng in 0.5 μl saline/hemisphere) infusion in the medial PFC of rats during performance on a series of well-validated cost/benefit decision-making tasks. Intra-PFC BIC reduced risky choice and reward sensitivity during probabilistic discounting and decreased the preference for larger rewards associated with a greater effort cost, similar to the behavioral sequelae observed in schizophrenia. Additional experiments revealed that these treatments did not alter instrumental responding on a progressive ratio schedule, nor did they impair the ability to discriminate between reward and no reward. However, BIC induced a subtle but consistent impairment in preference for larger vs. smaller rewards of equal cost. BIC infusion also increased decision latencies and impaired the ability to "stay on task" as indexed by reduced rates of instrumental responding. Collectively, these results implicate prefrontal GABAergic dysfunction as a key contributing factor to abnormal decision-making observed in schizophrenia and other neuropsychiatric conditions with similar neurobiological and behavioral alterations.
26456134	d-Cycloserine (DCS) enhances extinction processes in animals. Although classical conditioning is hypothesized to play a pivotal role in the aetiology of appetitive motivation problems, no research has been conducted on the effect of DCS on the reduction of context specificity of extinction in human appetitive learning, while facilitation hereof is relevant in the context of treatment of problematic reward-seeking behaviors.Female participants were presented with two conditioned stimuli (CSs) that either predicted (CS+) or did not predict (CS-) a potential sexual reward (unconditioned stimulus (US); genital vibrostimulation). Conditioning took place in context A and extinction in context B. Subjects received DCS (125mg) or placebo directly after the experiment on day 1 in a randomized, double-blind, between-subject fashion (Placebo n=31; DCS n=31). Subsequent testing for CS-evoked conditioned responses (CRs) in both the conditioning (A) and the extinction context (B) took place 24h later on day 2. Drug effects on consolidation were then assessed by comparing the recall of sexual extinction memories between the DCS and the placebo groups.	Post learning administration of DCS facilitates sexual extinction memory consolidation and affects extinction's fundamental context specificity, evidenced by reduced conditioned genital and subjective sexual responses, relative to placebo, for presentations of the reward predicting cue 24h later outside the extinction context.	DCS makes appetitive extinction memories context-independent and prevents the return of conditioned response. NMDA receptor glycine site agonists may be potential pharmacotherapies for the prevention of relapse of appetitive motivation disorders with a learned component.	
26455867	Originally studied for its role in energy homeostasis, the paraventricular nucleus of the thalamus (PVT) has recently gained attention because of its involvement in the modulation of drug-directed behavior. The posterior part of the PVT (pPVT) is connected with brain structures that modulate motivated behavior, and we tested whether the pPVT plays a pivotal role in cocaine seeking. The aim of the present study was to investigate whether transient inactivation of the pPVT prevents cue-induced reinstatement of cocaine seeking but not natural reward seeking. Male Wistar rats were trained to associate a discriminative stimulus (S(+)) with the availability of cocaine or a highly palatable conventional reinforcer, sweetened condensed milk (SCM). Following extinction, the cocaine S(+) and SCM S(+) elicited comparable levels of reinstatement. Intra-pPVT administration of the γ-aminobutyric acid-A (GABAA) and GABAB receptor agonists muscimol and baclofen (0.06 and 0.6mM, respectively) prior to the presentation of the cocaine or SCM S(+) completely prevented the reinstatement of cocaine seeking, with no statistically significant effects on SCM seeking. These data show that the pPVT plays an important role in neuronal mechanisms that drive cocaine-seeking behavior. 

26454816	Can beneficial ends justify morally questionable means? To investigate how monetary outcomes influence the neural responses to lying, we used a modified, cheap talk sender-receiver game in which participants were the direct recipients of lies and truthful statements resulting in either beneficial or harmful monetary outcomes. Both truth-telling (vs lying) as well as beneficial (vs harmful) outcomes elicited higher activity in the nucleus accumbens. Lying (vs truth-telling) elicited higher activity in the supplementary motor area, right inferior frontal gyrus, superior temporal sulcus and left anterior insula. Moreover, the significant interaction effect was found in the left amygdala, which showed that the monetary outcomes modulated the neural activity in the left amygdala only when truth-telling rather than lying. Our study identified a neural network associated with the reception of lies and truth, including the regions linked to the reward process, recognition and emotional experiences of being treated (dis)honestly. 
26454481	The auditory system is stunning in its capacity for change: a single neuron can modulate its tuning in minutes. Here we articulate a conceptual framework to understand the biology of auditory learning where an animal must engage cognitive, sensorimotor, and reward systems to spark neural remodeling. Central to our framework is a consideration of the auditory system as an integrated whole that interacts with other circuits to guide and refine life in sound. Despite our emphasis on the auditory system, these principles may apply across the nervous system. Understanding neuroplastic changes in both normal and impaired sensory systems guides strategies to improve everyday communication. 
26454185	Late adolescents are under increased risk of developing depressive symptoms. Behavioral activation is an effective treatment for subthreshold depression, which can prevent the development of subthreshold depression into a major depressive disorder. However, the neural mechanisms underlying the efficacy of behavioral activation have not been clearly understood. We investigated neural responses during reward processing by individuals with subthreshold depression to clarify the neural mechanisms of behavioral activation.Late adolescent university students with subthreshold depression (n=15, age 18-19 years) as indicated by a high score on the Beck's Depression Inventory-ll (BDI-ll) and 15 age-matched controls with a low BDI-ll score participated in functional magnetic resonance imaging scanning conducted during a monetary incentive delay task on two occasions. The Individuals in the subthreshold depression group received five, weekly behavioral activation sessions between the two scanning sessions. Moreover, they did not receive any medication until the study was completed.	Behavioral activation significantly reduced depressive symptoms. Moreover, compared to the changes in brain functions in the control group, the behavioral activation group showed functional changes during loss anticipation in brain structures that mediates cognitive and emotional regulation, including the left ventrolateral prefrontal cortex and angular gyrus.	Replication of the study with a larger sample size is required to increase the generalizability of these results.	Behavioral activation results in improved functioning of the fronto-parietal region during loss anticipation. These results increase our understanding of the mechanisms underlying specific psychotherapies.	
26454156	Relapse of previously extinguished fear presents a significant, pervasive obstacle to the successful long-term treatment of anxiety and trauma-related disorders. Thus, identification of a novel means to enhance fear extinction to stand the passage of time and generalize across contexts is of the utmost importance. Acute bouts of exercise can be used as inexpensive, noninvasive treatment strategies to reduce anxiety, and have been shown to enhance memory for extinction when performed in close temporal proximity to the extinction session. However, it is unclear whether acute exercise can be used to prevent relapse of fear, and the neural mechanisms underlying this potential effect are unknown. The current study therefore examined whether acute exercise during extinction of auditory fear can protect against the later relapse of fear. Male F344 rats lacking an extended history of wheel running were conditioned to fear a tone CS and subsequently extinguished within either a freely mobile running wheel, a locked wheel, or a control context lacking a wheel. Rats exposed to fear extinction within a freely mobile wheel ran during fear extinction, and demonstrated reduced fear as well as attenuated corticosterone levels during re-exposure to the extinguished CS during the relapse test in a novel context 1week later. Examination of cfos mRNA patterns elicited by re-exposure to the extinguished CS during the relapse test revealed that acute exercise during extinction decreased activation of brain circuits classically involved in driving fear expression and interestingly, increased activity within neurons of the direct striatal pathway involved in reward signaling. These data suggest that exercise during extinction reduces relapse through a mechanism involving the direct pathway of the striatum. It is suggested that a positive affective state could become associated with the CS during exercise during extinction, thus resulting in a relapse-resistant extinction memory. 
26450814	Reward sensitivity and possible alterations in the dopaminergic-reward system are associated with obesity. We therefore aimed to investigate the influence of dopamine depletion on food-reward processing. We investigated 34 female subjects in a randomized placebo-controlled, within-subject design (body mass index (BMI)=27.0 kg/m(2) ±4.79 SD; age=28 years ±4.97 SD) using an acute phenylalanine/tyrosine depletion drink representing dopamine depletion and a balanced amino acid drink as the control condition. Brain activity was measured with functional magnetic resonance imaging during a 'wanting' and 'liking' rating of food items. Eating behavior-related traits and states were assessed on the basis of questionnaires. Dopamine depletion resulted in reduced activation in the striatum and higher activation in the superior frontal gyrus independent of BMI. Brain activity during the wanting task activated a more distributed network than during the liking task. This network included gustatory, memory, visual, reward, and frontal regions. An interaction effect of dopamine depletion and the wanting/liking task was observed in the hippocampus. The interaction with the covariate BMI was significant in motor and control regions but not in the striatum. Our results support the notion of altered brain activity in the reward and prefrontal network with blunted dopaminergic action during food-reward processing. This effect is, however, independent of BMI, which contradicts the reward-deficiency hypothesis. This hints to the hypothesis suggesting a different or more complex mechanism underlying the dopaminergic reward function in obesity. 
26449761	Substance use disorders (SUDs) can be viewed as a pathology of neuroadaptation. The pharmacological overstimulation of neural mechanisms of reward, motivated learning and memory leads to drug-seeking behavior. A critical characteristic of SUDs is the appearance of craving, the motivated desire and urge to use, which is a main focus of current pharmacological and behavioral therapies. Recent proof-of-concept studies have tested the effects of noninvasive brain stimulation on craving. Although its mechanisms of action are not fully understood, this approach shows interesting potential in tuning down craving and possibly consumption of diverse substances. This article reviews available results on the use of repetitive transcranial magnetic stimulation (rTMS) and transcranial electrical stimulation (tES) in SUDs, specifically tobacco, alcohol and psychostimulant use disorders. We discuss several important factors that need to be addressed in future works to improve clinical assessment and effects of noninvasive brain stimulation in SUDs. Factors discussed include brain stimulation devices and parameters, study designs, brain states and subjects' characteristics. 
26449720	Alcohol use disorders are associated with deficits in adaptive behavior. While some behavioral impairments that are associated with alcohol use disorders may predate exposure to drugs of abuse, others may result directly from exposure to drugs of abuse, including alcohol. Identifying a causal role for how alcohol exposure leads to these impairments will enable further investigation of the neurobiological mechanisms by which it acts to dysregulate adaptive behavior.In the present study, we examined the effects of chronic intermittent ethanol exposure (CIE) on the use of reward-paired cues to guide consummatory behaviors in a mouse model, and further, how manipulations of mGluR2/3 signaling-known to be dysregulated after chronic alcohol exposure-may alter the expression of this behavior.	Adult male C57B/6J mice were trained to self-administer 10 % ethanol and exposed to CIE via vapor inhalation. After CIE exposure, mice were trained in a Pavlovian task wherein a cue (tone) was paired with the delivery of a 10 % sucrose unconditioned stimulus. The use of the reward-paired cue to guide licking behavior was determined across training. The effect of systemic mGluR2/3 manipulation on discrimination between cue-on and cue-off intervals was assessed by administration of the mGluR2/3 agonist LY379268 or the antagonist LY341495 prior to a testing session.	Exposure to CIE resulted in reductions in discrimination between cue-on and cue-off intervals, with CIE-exposed mice exhibiting significantly lower consummatory behavior during reward-paired cues than air controls. In addition, systemic administration of an mGluR2/3 agonist restored the use of reward-paired cues in CIE-exposed animals without impacting behavior in air controls. Conversely, administration of an mGluR2/3 antagonist mimicked the effects of CIE on cue-guided licking behavior, indicating that mGluR2/3 signaling can bidirectionally regulate the ability to use reward-paired cues to guide behavior.	Together, these data suggest that chronic ethanol exposure drives impairments in the ability to use reward-paired cues to adaptively regulate behavior and that mGluR2/3 receptors represent a therapeutic target for restoration of these deficits in behavioral control in the alcoholic.	
26449406	Currently, there is a high prevalence of antidepressant prescription rates within juvenile populations, yet little is known about the potential long-lasting consequences of such treatments, particularly on subsequent responses to drugs of abuse. To address this issue at the preclinical level, we examined whether adolescent exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, results in changes to the sensitivity of the rewarding properties of cocaine in adulthood. Separate groups of male c57bl/6 mice were exposed to FLX (0 or 20 mg/kg) for 15 consecutive days either during adolescence (postnatal days [PD] 35-49) or adulthood (PD 65-79). Twenty-one days after FLX treatment, behavioral responsivity to cocaine (0, 2.5, 5, 10, or 20 mg/kg) conditioned place preference was assessed. Our data shows that mice pretreated with FLX during adolescence, but not during adulthood, display an enhanced dose-dependent preference to the environment paired with cocaine (5 or 10 mg/kg) when compared to age-matched saline pretreated controls. Taken together, our findings suggest that adolescent exposure to FLX increases sensitivity to the rewarding properties of cocaine, later in life. 
26448391	Iconic gestures-communicative acts using hand or body movements that resemble their referent-figure prominently in theories of language evolution and development. This study contrasted the abilities of chimpanzees (N=11) and 4-year-old human children (N=24) to comprehend novel iconic gestures. Participants learned to retrieve rewards from apparatuses in two distinct locations, each requiring a different action. In the test, a human adult informed the participant where to go by miming the action needed to obtain the reward. Children used the iconic gestures (more than arbitrary gestures) to locate the reward, whereas chimpanzees did not. Some children also used arbitrary gestures in the same way, but only after they had previously shown comprehension for iconic gestures. Over time, chimpanzees learned to associate iconic gestures with the appropriate location faster than arbitrary gestures, suggesting at least some recognition of the iconicity involved. These results demonstrate the importance of iconicity in referential communication. 
26447226	To examine the role of genetic and environmental factors in the pathogenesis of alcohol dependence in a Spanish cohort of women and men.We analyzed the relationship between 56 genetic variants in 7 genes associated with the dopaminergic reward pathway and excessive alcohol consumption. The study sample (N = 1533, of which 746 were women) consisted of 653 heavy consumers and 880 very low consumers from the Spanish subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Single nucleotide polymorphisms (SNPs) were genotyped using a customized array. Lifestyle variables were also examined to assess associations between genetic and environmental factors.	No statistically significant differences were found between cases and controls for the allele frequencies in five genes: TH, SLC18A2, DRD1, DRD3 and COMT. Conversely, some alleles of the 12 SNPs from the DRD2 locus and the 5 from the MAOA locus showed significant associations with excessive alcohol consumption. Namely, rs10891556 (DRD2) proved to be the only SNP positively correlated with excessive alcohol consumption in both sexes. DRD2 rs1800497 and rs877138 were significantly associated in men, whereas DRD2 rs17601612 and rs4936271 and MAOA rs5906898 were associated with excessive alcohol consumption in women. A correspondence analysis provided an overall lifestyle profile of excessive drinkers, who were predominantly men who smoked, had large intakes of meat, small intakes of fruit and vegetables, whose jobs did not require high education levels and who engaged in little physical activity.	It has shown the influence of dopaminergic pathway in the genetics of alcohol dependence with differences between men and women and providing a lifestyle profile of excessive drinkers.	
26446615	Alongside impulsive suicide attempts, clinicians encounter highly premeditated suicidal acts, particularly in older adults. We have previously found that in contrast to the more impulsive suicide attempters' inability to delay gratification, serious and highly planned suicide attempts were associated with greater willingness to wait for larger rewards. This study examined neural underpinnings of intertemporal preference in suicide attempters. We expected that impulsivity and suicide attempts, particularly poorly planned ones, would predict altered paralimbic subjective value representations. We also examined lateral prefrontal and paralimbic correlates of premeditation in suicidal behavior.A total of 48 participants aged 46-90 years underwent extensive clinical and cognitive characterization and completed the delay discounting task in the scanner: 26 individuals with major depression (13 with and 13 without history of suicide attempts) and 22 healthy controls.	More impulsive individuals displayed greater activation in the precuneus/posterior cingulate cortex (PCC) to value difference favoring the delayed option. Suicide attempts, particularly better-planned ones, were associated with deactivation of the lateral prefrontal cortex (lPFC) in response to value difference favoring the immediate option. Findings were robust to medication exposure, depression severity and possible brain damage from suicide attempts, among other confounders. Finally, in suicide attempters longer reward delays were associated with diminished parahippocampal responses.	Impulsivity was associated with an altered paralimbic (precuneus/PCC) encoding of value difference during intertemporal choice. By contrast, better-planned suicidal acts were associated with altered lPFC representations of value difference. The study provides preliminary evidence of impaired decision processes in both impulsive and premeditated suicidal behavior.	
26446228	The hippocampus (HPC) is known to play an important role in learning, a process dependent on synaptic plasticity; however, the molecular mechanisms underlying this are poorly understood. ΔFosB is a transcription factor that is induced throughout the brain by chronic exposure to drugs, stress, and variety of other stimuli and regulates synaptic plasticity and behavior in other brain regions, including the nucleus accumbens. We show here that ΔFosB is also induced in HPC CA1 and DG subfields by spatial learning and novel environmental exposure. The goal of the current study was to examine the role of ΔFosB in hippocampal-dependent learning and memory and the structural plasticity of HPC synapses. Using viral-mediated gene transfer to silence ΔFosB transcriptional activity by expressing ΔJunD (a negative modulator of ΔFosB transcriptional function) or to overexpress ΔFosB, we demonstrate that HPC ΔFosB regulates learning and memory. Specifically, ΔJunD expression in HPC impaired learning and memory on a battery of hippocampal-dependent tasks in mice. Similarly, general ΔFosB overexpression also impaired learning. ΔJunD expression in HPC did not affect anxiety or natural reward, but ΔFosB overexpression induced anxiogenic behaviors, suggesting that ΔFosB may mediate attentional gating in addition to learning. Finally, we found that overexpression of ΔFosB increases immature dendritic spines on CA1 pyramidal cells, whereas ΔJunD reduced the number of immature and mature spine types, indicating that ΔFosB may exert its behavioral effects through modulation of HPC synaptic function. Together, these results suggest collectively that ΔFosB plays a significant role in HPC cellular morphology and HPC-dependent learning and memory.Consolidation of our explicit memories occurs within the hippocampus, and it is in this brain region that the molecular and cellular processes of learning have been most closely studied. We know that connections between hippocampal neurons are formed, eliminated, enhanced, and weakened during learning, and we know that some stages of this process involve alterations in the transcription of specific genes. However, the specific transcription factors involved in this process are not fully understood. Here, we demonstrate that the transcription factor ΔFosB is induced in the hippocampus by learning, regulates the shape of hippocampal synapses, and is required for memory formation, opening up a host of new possibilities for hippocampal transcriptional regulation.	
26446224	Empathy--the capacity to understand and resonate with the experiences of others--can depend on the ability to predict when others are likely to receive rewards. However, although a plethora of research has examined the neural basis of predictions about the likelihood of receiving rewards ourselves, very little is known about the mechanisms that underpin variability in vicarious reward prediction. Human neuroimaging and nonhuman primate studies suggest that a subregion of the anterior cingulate cortex in the gyrus (ACCg) is engaged when others receive rewards. Does the ACCg show specialization for processing predictions about others' rewards and not one's own and does this specialization vary with empathic abilities? We examined hemodynamic responses in the human brain time-locked to cues that were predictive of a high or low probability of a reward either for the subject themselves or another person. We found that the ACCg robustly signaled the likelihood of a reward being delivered to another. In addition, ACCg response significantly covaried with trait emotion contagion, a necessary foundation for empathizing with other individuals. In individuals high in emotion contagion, the ACCg was specialized for processing others' rewards exclusively, but for those low in emotion contagion, this region also responded to information about the subject's own rewards. Our results are the first to show that the ACCg signals probabilistic predictions about rewards for other people and that the substantial individual variability in the degree to which the ACCg is specialized for processing others' rewards is related to trait empathy.Successfully cooperating, competing, or empathizing with others can depend on our ability to predict when others are going to get something rewarding. Although many studies have examined how the brain processes rewards we will get ourselves, very little is known about vicarious reward processing. Here, we show that a subregion of the anterior cingulate cortex in the gyrus (ACCg) shows a degree of specialization for processing others' versus one's own rewards. However, the degree to which the ACCg is specialized varies with people's ability to empathize with others. This new insight into how vicarious rewards are processed in the brain and vary with empathy may be key for understanding disorders of social behavior, including psychopathy and autism.	


26444572	The self-medication hypothesis assumes that symptoms related to potential monoaminergic deficits in depression may be relieved by drug abuse. The aim of this study was to elucidate the neurotransmitter changes in a rat model of depression by measuring their levels in the nucleus accumbens shell, which is typically involved in the drug of abuse acquisition mechanism.Depression was modelled by the olfactory bulbectomy (OBX) in Wistar male rats. In vivo microdialysis was performed, starting from the baseline and following after a single methamphetamine injection and behaviour was monitored. The determination of neurotransmitters and their metabolites was performed by high-performance liquid chromatography combined with mass spectrometry.	OBX animals had lower basal levels of dopamine and serotonin and their metabolites. However, γ-aminobutyric acid (GABA) and glutamate levels were increased. The methamphetamine injection induced stronger dopamine and serotonin release in the OBX rats and lower release of glutamate in comparison with sham-operated rats; GABA levels did not differ significantly.	This study provides an evidence of mesolimbic neurotransmitter changes in the rat model of depression which may elucidate mechanisms underlying intravenous self-administration studies in which OBX rats were demonstrated to have higher drug intake in comparison to intact controls.	
26443682	Anxiety disorders are presumably associated with negative memory. Psychological therapies are widely used to treat this mental deficit in human beings based on the view that positive memory competes with negative memory and relieves anxiety status. Cellular and molecular processes underlying psychological therapies remain elusive. Therefore, we have investigated its mechanisms based on a mouse model in which food reward at one open-arm of the elevated plus-maze was used for training mice to form reward memory and challenge the open arms. Mice with the reward training showed increased entries and stay time in reward open-arm versus neutral open-arm as well as in open-arms versus closed-arms. Accompanying with reward memory formation and anxiety relief, glutamatergic synaptic transmission in dentate gyrus in vivo and dendritic spines in granule cells became upregulated. This synaptic up-regulation was accompanied by the expression of more protein kinase C (PKC) in the dendritic spines. The inhibition of PKC by chelerythrine impaired the formation of reward memory, the relief of anxiety-related behavior and the up-regulation of glutamate synapses. Our results suggest that reward-induced positive memory relieves mouse anxiety-related behavior by strengthening synaptic efficacy and PKC in the hippocampus, which imply the underlying cellular and molecular processes involved in the beneficial effects of psychological therapies treating anxiety disorders.
26443679	Early life stress (ELS) is strongly associated with negative outcomes in adulthood, including reduced motivation and increased negative mood. The mechanisms mediating these relations, however, are poorly understood. We examined the relation between exposure to ELS and reward-related brain activity, which is known to predict motivation and mood, at age 26, in a sample followed since kindergarten with annual assessments. Using functional neuroimaging, we assayed individual differences in the activity of the ventral striatum (VS) during the processing of monetary rewards associated with a simple card-guessing task, in a sample of 72 male participants. We examined associations between a cumulative measure of ELS exposure and VS activity in adulthood. We found that greater levels of cumulative stress during childhood and adolescence predicted lower reward-related VS activity in adulthood. Extending this general developmental pattern, we found that exposure to stress early in development (between kindergarten and grade 3) was significantly associated with variability in adult VS activity. Our results provide an important demonstration that cumulative life stress, especially during this childhood period, is associated with blunted reward-related VS activity in adulthood. These differences suggest neurobiological pathways through which a history of ELS may contribute to reduced motivation and increased negative mood. 
26442751	The Behavioral Inhibition System (BIS) and the Behavioral Activation System (BAS) have been theorized as neural systems that regulate approach/withdrawal behaviors. Behavioral activation/inhibition balance may change in neurodegenerative disease based on underlying alterations in systems supporting motivation and approach/withdrawal behaviors, which may in turn be reflected in neuropsychiatric symptoms.A total of 187 participants (31 patients diagnosed with behavioral variant of FTD [bvFTD], 13 semantic variant of primary progressive aphasia [svPPA], 14 right temporal variant FTD [rtFTD], 54 Alzheimer's disease [AD], and 75 older healthy controls [NCs]) were included in this study. Changes in behavioral inhibition/activation were measured using the BIS/BAS scale. We analyzed the correlation between regional atrophy pattern and BIS/BAS score, using voxel-based morphometry (VBM).	ADs had significantly higher BIS scores than bvFTDs and NCs. bvFTDs activation-reward response (BAS-RR) was significantly lower than ADs and NCs, though their activation-drive (BAS-D) was significantly higher than in ADs. Both AD and rtFTD patients had abnormally low activation fun-seeking (BAS-FS) scores. BIS score correlated positively with right anterior cingulate and middle frontal gyrus volume, as well as volume in the right precentral gyrus and left insula/operculum.	AD, bvFTD, and rtFTD patients show divergent patterns of change in approach/withdrawal reactivity. High BIS scores correlated with preservation of right-predominant structures involved in task control and self-protective avoidance of potentially negative reinforcers. Damage to these regions in bvFTD may create a punishment insensitivity that underlies patients' lack of self-consciousness in social contexts.	
26442633	Cooperative decision rules have so far been shown experimentally mainly in mammal species that have variable and complex social networks. However, these traits should not necessarily be restricted to mammals. Therefore, we tested cooperative problem solving in ravens. We showed that, without training, nine ravens spontaneously cooperated in a loose-string task. Corroborating findings in several species, ravens' cooperative success increased with increasing inter-individual tolerance levels. Importantly, we found this in both a forced dyadic setting, and in a group setting where individuals had an open choice to cooperate with whomever. The ravens, moreover, also paid attention to the resulting reward distribution and ceased cooperation when being cheated upon. Nevertheless, the ravens did not seem to pay attention to the behavior of their partners while cooperating, and future research should reveal whether this is task specific or a general pattern. Given their natural propensity to cooperate and the results we present here, we consider ravens as an interesting model species to study the evolution of, and the mechanisms underlying cooperation. 
26441782	Children are exceptional, even 'super,' imitators but comparatively poor independent problem-solvers or innovators. Yet, imitation and innovation are both necessary components of cumulative cultural evolution. Here, we explored the relationship between imitation and innovation by assessing children's ability to generate a solution to a novel problem by imitating two different action sequences demonstrated by two different models, an example of imitation by combination, which we refer to as "summative imitation." Children (N = 181) from 3 to 5 years of age and across three experiments were tested in a baseline condition or in one of six demonstration conditions, varying in the number of models and opening techniques demonstrated. Across experiments, more than 75% of children evidenced summative imitation, opening both compartments of the problem box and retrieving the reward hidden in each. Generally, learning different actions from two different models was as good (and in some cases, better) than learning from 1 model, but the underlying representations appear to be the same in both demonstration conditions. These results show that summative imitation not only facilitates imitation learning but can also result in new solutions to problems, an essential feature of innovation and cumulative culture. 
26441781	Ribot's (1896) long standing definition of anhedonia as "the inability to experience pleasure" has been challenged recently following progress in affective neuroscience. In particular, accumulating evidence suggests that reward consists of multiple subcomponents of wanting, liking and learning, as initially outlined by Berridge and Robinson (2003), and these processes have been proposed to relate to appetitive, consummatory and satiety phases of a pleasure cycle. Building on this work, we recently proposed to reconceptualize anhedonia as "impairments in the ability to pursue, experience, and/or learn about pleasure, which is often, but not always accessible to conscious awareness." (Rømer Thomsen et al., 2015). This framework is in line with Treadway and Zald's (2011) proposal to differentiate between motivational and consummatory types of anhedonia, and stresses the need to combine traditional self-report measures with behavioral measures or procedures. In time, this approach may lead to improved clinical assessment and treatment. In line with our reconceptualization, increasing evidence suggests that reward processing deficits are not restricted to impaired hedonic impact in major psychiatric disorders. Successful translations of animal models have led to strong evidence of impairments in the ability to pursue and learn about reward in psychiatric disorders such as major depressive disorder, schizophrenia, and addiction. It is of high importance that we continue to systematically target impairments in all phases of reward processing across disorders using behavioral testing in combination with neuroimaging techniques. This in turn has implications for diagnosis and treatment, and is essential for the purposes of identifying the underlying neurobiological mechanisms. Here I review recent progress in the development and application of behavioral procedures that measure subcomponents of anhedonia across relevant patient groups, and discuss methodological caveats as well as implications for assessment and treatment. 
26441703	Adults with unipolar depression typically show poor episodic memory for positive material, but the neuroscientific mechanisms responsible for this deficit have not been characterized. I suggest a simple hypothesis: weak memory for positive material in depression reflects disrupted communication between the mesolimbic dopamine pathway and medial temporal lobe (MTL) memory systems during encoding. This proposal draws on basic research showing that dopamine release in the hippocampus is critical for the transition from early- to late-phase long-term potentiation (LTP) that marks the conversion of labile, short-term memories into stable, long-term memories. Neuroimaging and pharmacological data from healthy humans paint a similar picture: activation of the mesolimbic reward circuit enhances encoding and boosts retention. Unipolar depression is characterized by anhedonia-loss of pleasure-and reward circuit dysfunction, which is believed to reflect negative effects of stress on the mesolimbic dopamine pathway. Thus, I propose that the MTL is deprived of strengthening reward signals in depressed adults and memory for positive events suffers accordingly. Although other mechanisms are important, this hypothesis holds promise as an explanation for positive memory deficits in depression. 
26439527	Goal-directed sensorimotor transformation drives important aspects of mammalian behavior. The striatum is thought to play a key role in reward-based learning and action selection, receiving glutamatergic sensorimotor signals and dopaminergic reward signals. Here, we obtain whole-cell membrane potential recordings from the dorsolateral striatum of mice trained to lick a reward spout after a whisker deflection. Striatal projection neurons showed strong task-related modulation, with more depolarization and action potential firing on hit trials compared to misses. Direct pathway striatonigral neurons, but not indirect pathway striatopallidal neurons, exhibited a prominent early sensory response. Optogenetic stimulation of direct pathway striatonigral neurons, but not indirect pathway striatopallidal neurons, readily substituted for whisker stimulation evoking a licking response. Our data are consistent with direct pathway striatonigral neurons contributing a "go" signal for goal-directed sensorimotor transformation leading to action initiation. VIDEO ABSTRACT. 
26439267	The prefrontal cortex (PFC) supports goal-directed actions and exerts cognitive control over behavior, but the underlying coding and mechanism are heavily debated. We present evidence for the role of goal coding in PFC from two converging perspectives: computational modeling and neuronal-level analysis of monkey data. We show that neural representations of prospective goals emerge by combining a categorization process that extracts relevant behavioral abstractions from the input data and a reward-driven process that selects candidate categories depending on their adaptive value; both forms of learning have a plausible neural implementation in PFC. Our analyses demonstrate a fundamental principle: goal coding represents an efficient solution to cognitive control problems, analogous to efficient coding principles in other (e.g., visual) brain areas. The novel analytical-computational approach is of general interest because it applies to a variety of neurophysiological studies. 
26439185	The goal of this experiment was to examine whether a conditioned place preference could be established in humans using a secondary reinforcer that provided little obvious reward to the participants. Two experiments were conducted to answer this question. In Experiment 1, 244 undergraduates were placed into a VR environment consisting of two visually distinct rooms connected by a door. Throughout the experiment, one room was randomly paired with occasional point rewards while the other unique room was never paired with rewards. Participants received thee pairings in each room. After a short break, a test session was administered, and participants were given free access to the entire VR environment and no point rewards were administered. On the test day, we observe that participants displayed a significant CPP for the room paired with points, as evidenced by significant differences in rating each of the rooms in terms of enjoyment. In Experiment 2, 77 undergraduates were tested using a biased conditioning approach in which an initial test session was conducted to obtain the participant's preferred room bias, and then the least-preferred room was designated as the points reward room for each participant. Using this biased conditioning approach, participants spent a significantly greater amount of time in the points-paired room. In this case, participants showed preferences based on explicit and implicit measures. These results suggest new approaches to examine the role of secondary reinforcers in nontraditional addictions such as internet, gaming, and gambling dependencies. 
26439074	Feedback negativity (FN) is an event-related potential elicited by monetary reward and loss; it is thought to relate to reward-related neural activity and has been linked to depression in children and adults. In the current study, we examined the stability of FN, and its relationship with depression in adolescents, over 2 years in 45 8- to 13-year-old children. From Time 1 to Time 2, FN in response to monetary loss and in response to monetary gain showed moderate to strong reliability (rs = .64 and .67, respectively); these relationships remained significant even when accounting for related variables. FN also demonstrated high within-session reliability. Moreover, the relationship between a blunted FN and greater depression observed at Time 1 was reproduced at Time 2, and the magnitude of FN at Time 1 predicted depressive symptomatology at Time 2. These findings are consistent with the hypothesis that FN and its relationship with depression remain consistent over the course of development, and that FN may prospectively predict later depressive symptomatology. The current results suggest that FN may be suitable as a biomarker of depressive symptoms during adolescence. 
26438205	There is growing evidence that unpredictability and uncertainty can alter reward system functioning. The present study examined the impact of (1) a task-irrelevant unpredictable relative to predictable context and (2) individual differences in intolerance of uncertainty (IU) on the reward-related positivity (RewP), an event-related potential (ERP) response to monetary gains relative to losses. Specifically, 64 participants listened to predictable and unpredictable tone sequences while electroencephalography was recorded during a monetary gambling task. Participants also completed the Intolerance of Uncertainty Scale, which measures both cognitive distress (prospective IU) and behavioral inhibition (inhibitory IU) elicited by uncertainty, in addition to the Depression Anxiety Stress Scale-21 and Penn State Worry Questionnaire. Results indicated that the RewP was reduced during the unpredictable relative to the predictable context. Greater self-reported anxiety elicited by the unpredictable context was associated with a decreased RewP, and a decreased RewP was associated with poorer lose-shift behavioral adjustment. Furthermore, the RewP mediated the relationship between self-reported anxiety elicited by the unpredictable context and lose-shift behavioral adjustment. The IU subscales demonstrated the opposite relationship with the RewP across both contexts-inhibitory IU was associated with an attenuated RewP and prospective IU was associated with an enhanced RewP. In contrast, anxiety, depression, stress, and worry symptomatology were not associated with the RewP. This is the first study to demonstrate that an unpredictable context and individual differences in the degree to which people cannot tolerate uncertainty impact an ERP measure of reward system functioning.
26436765	Aging in humans and rhesus monkeys is commonly associated with motor function decrements including dexterity, speed, and strength. Despite their longevity and phylogenetic relatedness to humans, the effects of aging on motor function in non-human apes have been minimally studied. We conducted two experiments with western lowland gorillas (11-54 years of age) to determine whether aged gorillas exhibit motor deficits similar to those seen in other species. In experiment one, gorillas extracted up to 12 food rewards lodged in holes of a Lexan board. Extraction rates were calculated for eight test sessions. A repeated measures ANOVA revealed no main effects of session or sex on extraction rate, but a significant main effect of age. Comparisons between the first and last sessions showed that experience significantly improved extraction rates in young but not aged gorillas. In experiment two, gorillas retrieved a hex nut from three differently shaped rods with each hand for a reward. Latencies of retrieval were calculated for 16 test sessions. A repeated measures ANOVA revealed significant main effects of age class, sex, and session. There were significant interactions between session and sex, session and age, and session, sex, and age. These findings held when analyzing each rod shape separately. Post hoc comparisons revealed that young gorillas were significantly faster at the task than aged gorillas, and females were faster than males. This finding held only for the question mark shaped rod when analyzing each rod shape separately. Comparisons between the first and last sessions showed that experience did not significantly improve latencies in either age or sex class. The direction of these results are congruent with previous findings in humans and monkeys and suggest that aged gorillas experience deficits in bimanual coordination compared to younger gorillas and that age and sex influence fine motor ability in gorillas.
26435524	Given the strong evidence for neurological alterations at the basis of drug dependence, functional magnetic resonance imaging (fMRI) represents an important tool in the clinical neuroscience of addiction. fMRI cue-reactivity paradigms represent an ideal platform to probe the involvement of neurobiological pathways subserving the reward/motivation system in addiction and potentially offer a translational mechanism by which interventions and behavioral predictions can be tested. Thus, this review summarizes the research that has applied fMRI cue-reactivity paradigms to the study of adult substance use disorder treatment responses. Studies utilizing fMRI cue-reactivity paradigms for the prediction of relapse and as a means to investigate psychosocial and pharmacological treatment effects on cue-elicited brain activation are presented within four primary categories of substances: alcohol, nicotine, cocaine and opioids. Lastly, suggestions for how to leverage fMRI technology to advance addiction science and treatment development are provided. 
26434862	Given the importance of sun protection in the prevention of skin cancer, this study was designed to determine predictors of sun-protective practices among a sample of Iranian female college students based on protection motivation theory (PMT) variables.In this cross-sectional study, a total of 201 female college students in Iran University of Medical Sciences were selected. Demographic and PMT variables were assessed with a 67-item questionnaire. Multiple linear regression was used to identify demographic and PMT variables that were associated with sun-protective practices and intention.	one percent of participants always wore a hat with a brim, 3.5% gloves and 15.9% sunglasses while outdoors. Only 10.9% regularly had their skin checked by a doctor. Perceived rewards, response efficacy, fear, self-efficacy and marital status were the five variables which could predict 39% variance of participants intention to perform sun-protective practices. Also, intention and response cost explained 31% of the variance of sun-protective practices.	These predictive variables may be used to develop theory-based education interventions interventions to prevent skin cancer among college students.	
26434783	Cognitive-behavioral treatments for chronic pain typically target pain-related fear; exposure in vivo is a common treatment focusing on disconfirming harm expectancy of feared movements. Exposure therapy is tailored on Pavlovian extinction; an alternative fear reduction technique that also alters stimulus valence is counterconditioning. We compared both procedures to reduce pain-related fear using a voluntary joystick movement paradigm. Participants were randomly allocated to the counterconditioning or extinction group. During fear acquisition, moving the joystick in 2 directions (conditioned stimulus [CS+]) was followed by a painful electrocutaneous stimulus (pain-unconditioned stimulus [US]), whereas moving the joystick in 2 other directions was not (CS-). During fear reduction, 1 CS+ was extinguished, but another CS+ was still followed by pain in the extinction group; in the counterconditioning group, 1 CS+ was extinguished and followed by a monetary reward-US, and another CS+ was followed by both USs (pain-US and reward-US). The results indicate that counterconditioning effectively reduces pain-related fear but that it does not produce deeper fear reduction than extinction. Adding a reward-US to a painful movement attenuated neither fear nor the intensity/unpleasantness of the pain. Both procedures changed stimulus valence. We contend that changing the affective valence of feared movements might improve fear reduction and may prevent relapse.This article reports no immediate differences between counterconditioning and extinction in reducing pain-related fear in the laboratory. Unexpectedly, both methods also altered stimulus valence. However, we cautiously suggest that methods explicitly focusing on altering the affective valence of feared movements may improve the long-term effectiveness of fear reduction and prevent relapse.	

26433773	Reward-processing involves two temporal stages characterized by two distinct neural processes: reward-anticipation and reward-outcome. Intriguingly, very little research has examined the relationship between neural processes involved in reward-anticipation and reward-outcome. To investigate this, one needs to consider the heterogeneity of reward-processing within each stage. To identify different stages of reward processing, we adapted a reward time-estimation task. While EEG data were recorded, participants were instructed to button-press 3.5s after the onset of an Anticipation-Cue and received monetary reward for good time-estimation on the Reward trials, but not on No-Reward trials. We first separated reward-anticipation into event related potentials (ERPs) occurring at three sub-stages: reward/no-reward cue-evaluation, motor-preparation and feedback-anticipation. During reward/no-reward cue-evaluation, the Reward-Anticipation Cue led to a smaller N2 and larger P3. During motor-preparation, we report, for the first time, that the Reward-Anticipation Cue enhanced the Readiness Potential (RP), starting approximately 1s before movement. At the subsequent feedback-anticipation stage, the Reward-Anticipation Cue elevated the Stimulus-Preceding Negativity (SPN). We also separated reward-outcome ERPs into different components occurring at different time-windows: the Feedback-Related Negativity (FRN), Feedback-P3 (FB-P3) and Late-Positive Potentials (LPP). Lastly, we examined the relationship between reward-anticipation and reward-outcome ERPs. We report that individual-differences in specific reward-anticipation ERPs uniquely predicted specific reward-outcome ERPs. In particular, the reward-anticipation Early-RP (1-.8s before movement) predicted early reward-outcome ERPs (FRN and FB-P3), whereas, the reward-anticipation SPN most strongly predicted a later reward-outcome ERP (LPP). Results have important implications for understanding the nature of the relationship between reward-anticipation and reward-outcome neural-processes. 
26432096	Dopamine (DA) transmission within cortico-limbic-striatal circuitry is integral in modulating decisions involving reward uncertainty. The basolateral amygdala (BLA) also plays a role in these processes, yet how DA transmission within this nucleus regulates cost/benefit decision making is unknown.We investigated the contribution of DA transmission within the BLA to risk/reward decision making assessed with a probabilistic discounting task.	Rats were well-trained to choose between a small/certain reward and a large/risky reward, with the probability of obtaining the larger reward decreasing (100-12.5 %) or increasing (12.5-100 %) over a session. We examined the effects of antagonizing BLA D1 (SCH 23390, 0.1-1 μg) or D2 (eticlopride, 0.1-1 μg) receptors, as well as intra-BLA infusions of agonists for D1 (SKF 81297, 0.1-1 μg) and D2 (quinpirole, 1-10 μg) receptors. We also assessed how DA receptor stimulation may induce differential effects related to baseline levels of risky choice.	BLA D1 receptor antagonism reduced risky choice by decreasing reward sensitivity, whereas D2 antagonism did not affect overall choice patterns. Stimulation of BLA D1 receptors optimized decision making in a baseline-dependent manner: in risk-averse rats, infusions of a lower dose of SKF81297 increased risky choice when reward probabilities were high (50 %), whereas in risk-prone rats, this drug reduced risky choice when probabilities were low (12.5 %). Quinpirole reduced risky choice in risk-prone rats, enhancing lose-shift behavior.	These data highlight previously uncharacterized roles for BLA DA D1 and D2 receptors in biasing choice during risk/reward decision making through mediation of reward/negative feedback sensitivity.	
26431993	The neural systems that afford our ability to evaluate rewards and punishments are impacted by a variety of external factors. Here, we demonstrate that increased cognitive load reduces the functional efficacy of a reward processing system within the human medial-frontal cortex. In our paradigm, two groups of participants used performance feedback to estimate the exact duration of one second while electroencephalographic (EEG) data was recorded. Prior to performing the time estimation task, both groups were instructed to keep their eyes still and avoid blinking in line with well established EEG protocol. However, during performance of the time-estimation task, one of the two groups was provided with trial-to-trial-feedback about their performance on the time-estimation task and their eye movements to induce a higher level of cognitive load relative to participants in the other group who were solely provided with feedback about the accuracy of their temporal estimates. In line with previous work, we found that the higher level of cognitive load reduced the amplitude of the feedback-related negativity, a component of the human event-related brain potential associated with reward evaluation within the medial-frontal cortex. Importantly, our results provide further support that increased cognitive load reduces the functional efficacy of a neural system associated with reward processing. 
26431681	Weight loss outcomes in lifestyle interventions for obesity are primarily a function of sustained adherence to a reduced-energy diet, and most lapses in diet adherence are precipitated by temptation from palatable food. The high nonresponse and relapse rates of lifestyle interventions suggest that current temptation management approaches may be insufficient for most participants. In this conceptual review, we discuss three neurobehavioral processes (attentional bias, temporal discounting, and the cold-hot empathy gap) that emerge during temptation and contribute to lapses in diet adherence. Characterizing the neurobehavioral profile of temptation highlights an important distinction between temptation resistance strategies aimed at overcoming temptation while it is experienced, and temptation prevention strategies that seek to avoid or minimize exposure to tempting stimuli. Many temptation resistance and temptation prevention strategies heavily rely on executive functions mediated by prefrontal systems that are prone to disruption by common occurrences such as stress, insufficient sleep, and even exposure to tempting stimuli. In contrast, commitment strategies are a set of devices that enable individuals to manage temptation by constraining their future choices, without placing heavy demands on executive functions. These concepts are synthesized in a conceptual model that categorizes temptation management approaches based on their intended effects on reward processing and degree of reliance on executive functions. We conclude by discussing the implications of our model for strengthening temptation management approaches in future lifestyle interventions, tailoring these approaches based on key individual difference variables, and suggesting high-priority topics for future research. 
26430123	Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction. 

26429728	Because the role of dopamine (DA) D3 receptors has been investigated primarily in relation to cocaine-related behaviors little is known of the role of these receptors in heroin seeking.To investigate the effect of the selective DA D3 receptor antagonist, SR 21502, on cue-induced reinstatement of heroin seeking and heroin conditioned place preference (CPP).	In experiment 1, rats were trained to self-administer intravenous heroin for 15 days followed by extinction. Following extinction animals were treated with one of several SR 21502 doses (0, 7.5, 10 or 15mg/kg) and a cue-induced reinstatement test was conducted. In experiment 2, animals were conditioned to experience heroin in one compartment of a CPP apparatus and saline in the other. On the test day animals were treated with 0, 3.75, 7.5, 10 or 15mg/kg of SR 21502 and tested for their CPP.	The results from experiment 1 showed a significant dose-related reduction in cue-induced reinstatement of active lever pressing in the 7.5 and 10mg groups and an absence of the reinstatement effect in the 15mg group. In experiment 2, animals treated with vehicle or 3.75mg of SR 21502 showed significant heroin place preferences but those treated with the higher doses showed no CPP.	Our findings suggest that DA D3 receptors play a significant role in heroin approach behaviors driven by conditioned stimuli. As such, we propose that SR 21502 holds potential as an effective pharmacotherapeutic agent for relapse prevention and should be studied further.	
26428667	Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established.
26427645	Spatial contextual cueing reflects an incidental form of learning that occurs when spatial distractor configurations are repeated in visual search displays. Recently, it was reported that the efficiency of contextual cueing can be modulated by reward. We replicated this behavioral finding and investigated its neural basis with fMRI. Reward value was associated with repeated displays in a learning session. The effect of reward value on context-guided visual search was assessed in a subsequent fMRI session without reward. Structures known to support explicit reward valuation, such as ventral frontomedial cortex and posterior cingulate cortex, were modulated by incidental reward learning. Contextual cueing, leading to more efficient search, went along with decreased activation in the visual search network. Retrosplenial cortex played a special role in that it showed both a main effect of reward and a reward×configuration interaction and may thereby be a central structure for the reward modulation of context-guided visual search. 
26427639	Dopamine dysregulation syndrome (DDS) in Parkinson's disease (PD) patients refers to the compulsive use of dopaminergic replacement therapy and has serious psycho-social consequences. Mechanisms underlying DDS are not clear although has been linked to dysfunctional brain reward networks.With fMRI, we investigate behavioral and neural response to drug-cues in six PD DDS patients and 12 PD control patients in both the ON and OFF medication state. Behavioral measures of liking, wanting and subjectively 'feeling ON medication' were also collected.	Behaviorally, PD DDS patients feel less ON and want their drugs more at baseline compared to PD controls. Following drug-cue exposure, PD DDS patients feel significantly more ON medication, which correlates with significant increases in reward related regions.	The results demonstrate that exposure to drug-cues increases the subjective feeling of being 'ON' medication which corresponds to dysfunctional activation in reward related regions in PD DDS patients. These findings should be extended in future studies. Visual stimuli being sufficient to elicit behavioral response through neuroadaptations could have direct implications to the management of addictive behavior.	
26427596	Lorcaserin (Lorqess, Belviq(®)) is a selective 5-HT(2C) receptor agonist that has received FDA approval for the treatment of obesity. 5-HT(2C) receptor agonists are also efficacious in decreasing multiple aspects of cocaine motivation and reward in preclinical models. This would suggest that lorcaserin is a clinically available therapeutic with the potential to treat cocaine addiction. Here we report the effects of lorcaserin (0.1 mg/kg-1.0 mg/kg) on multiple aspects of cocaine-related behaviours in rats. We find that lorcaserin dose-dependently decreases cocaine self-administration on progressive and fixed ratio schedules of reinforcement. Lorcaserin also reduces reinstatement of cocaine-seeking behaviour in response to priming injections of cocaine and/or reintroduction of cocaine-associated cues. Finally, lorcaserin dose-dependently decreases cocaine-induced hyperlocomotion. Our results, when considered in concert with similar emergent findings in non-human primates, strongly support continued research into the potential of lorcaserin as a clinical treatment for cocaine addiction.
26426086	This article considers the potential benefits that applying design principles from contemporary video games may have on enhancing therapy experiences.Six principles of video game design are presented, and their relevance for enriching clinical experiences is discussed.	The motivational and learning benefits of each design principle have been discussed in the education literature as having positive impacts on student motivation and learning and are related here to aspects of clinical practice. The essential experience principle suggests connecting all aspects of the experience around a central emotion or cognitive connection. The discovery principle promotes indirect learning in focused environments. The risk-taking principle addresses the uncertainties clients face when attempting newly learned skills in novel situations. The generalization principle encourages multiple opportunities for skill transfer. The reward system principle directly relates to the scaffolding of frequent and varied feedback in treatment. Last, the identity principle can assist clients in using their newly learned communication skills to redefine self-perceptions.	These principles highlight areas for research and interventions that may be used to reinforce or advance current practice.	
26424164	Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders, such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Here we hypothesize that ghrelin, an orexigenic hormone produced by the stomach and known to increase food reward behavior, also increases impulsivity. In order to assess the impact of ghrelin on impulsivity, rats were trained in three complementary tests of impulsive behavior and choice: differential reinforcement of low rate (DRL), go/no-go, and delay discounting. Ghrelin injection into the lateral ventricle increased impulsive behavior, as indicated by reduced efficiency of performance in the DRL test, and increased lever pressing during the no-go periods of the go/no-go test. Central ghrelin stimulation also increased impulsive choice, as evidenced by the reduced choice for large rewards when delivered with a delay in the delay discounting test. In order to determine whether signaling at the central ghrelin receptors is necessary for maintenance of normal levels of impulsive behavior, DRL performance was assessed following ghrelin receptor blockade with central infusion of a ghrelin receptor antagonist. Central ghrelin receptor blockade reduced impulsive behavior, as reflected by increased efficiency of performance in the DRL task. To further investigate the neurobiological substrate underlying the impulsivity effect of ghrelin, we microinjected ghrelin into the ventral tegmental area, an area harboring dopaminergic cell bodies. Ghrelin receptor stimulation within the VTA was sufficient to increase impulsive behavior. We further evaluated the impact of ghrelin on dopamine-related gene expression and dopamine turnover in brain areas key in impulsive behavior control. This study provides the first demonstration that the stomach-produced hormone ghrelin increases impulsivity and also indicates that ghrelin can change two major components of impulsivity-motor and choice impulsivity. 
26423787	Obesity is a significant problem in the United States, with roughly one third of adults having a body mass index (BMI) over thirty. Recent evidence from human studies suggests that pre-existing differences in the function of mesolimbic circuits that mediate motivational processes may promote obesity and hamper weight loss. However, few preclinical studies have examined pre-existing neurobehavioral differences related to the function of mesolimbic systems in models of individual susceptibility to obesity. Here, we used selectively bred obesity-prone and obesity-resistant rats to examine 1) the effect of a novel "junk-food" diet on the development of obesity and metabolic dysfunction, 2) over-consumption of "junk-food" in a free access procedure, 3) motivation for food using instrumental procedures, and 4) cocaine-induced locomotor activity as an index of general mesolimbic function. As expected, eating a sugary, fatty, "junk-food" diet exacerbated weight gain and increased fasted insulin levels only in obesity-prone rats. In addition, obesity-prone rats continued to over-consume junk-food during discrete access testing, even when this same food was freely available in the home cage. Furthermore, when asked to press a lever to obtain food in an instrumental task, rates of responding were enhanced in obesity-prone versus obesity-resistant rats. Finally, obesity-prone rats showed a stronger locomotor response to 15 mg/kg cocaine compared to obesity-resistant rats prior to any diet manipulation. This enhanced sensitivity to this dose of cocaine is indicative of basal differences in the function of mesolimbic circuits in obesity-prone rats. We speculate that pre-existing differences in motivational systems may contribute to over-consumption and enhanced motivation in susceptible individuals.
26423070	Bees are model organisms for the study of learning and memory, yet nearly all such research to date has used a single reward, nectar. Many bees collect both nectar (carbohydrates) and pollen (protein) on a single foraging bout, sometimes from different plant species. We tested whether individual bumblebees could learn colour associations with nectar and pollen rewards simultaneously in a foraging scenario where one floral type offered only nectar and the other only pollen. We found that bees readily learned multiple reward-colour associations, and when presented with novel floral targets generalized to colours similar to those trained for each reward type. These results expand the ecological significance of work on bee learning and raise new questions regarding the cognitive ecology of pollination. 
26422986	Drugs of abuse can "hijack" synaptic plasticity, a physiological basis of learning and memory, establishing maladaptations that can promote drug addiction. A wealth of data supports the existence and importance of neuroadaptations in excitatory neurotransmission upon drug exposure. Recent discoveries, however, have shown that inhibitory neurotransmission mediated by G protein-gated inwardly rectifying potassium (K(+)) (GIRK/Kir3) channels is also subject to adaptation triggered by exposure to drugs of abuse. GIRK channels are expressed in neuronal populations relevant to reward and reward-related behaviors, where their activation by neurotransmitters such as GABA, dopamine, and adenosine reduces neuronal excitability. Studies in animal models have implicated GIRK channels in a number of behaviors including reward. Drugs of abuse also affect the inhibitory neurotransmission mediated by GIRK channels. These changes might be important for the development, maintenance, or relapse of addiction, making GIRK channels promising targets for novel addiction therapies. 
26421603	While gambling has traditionally been viewed as an adult activity, there is a growing body of research that a significant number of adolescents are not only gambling but are experiencing gambling related problems. As ease of access via Internet wagering has increased, so too have some of the concomitant problems. Social casino gambling, often thought of gambling without risking one's money through the use of virtual currency, has become increasingly popular. The current review examines whether we should be concerned over its widespread use and whether such social games should be regulated. 
26420783	The expectation of reward is known to enhance a consolidation of long-term memory for events. We tested whether this effect is driven by positive valence or action requirements tied to expected reward. Using a functional magnetic resonance imaging (fMRI) paradigm in young adults, novel images predicted gain or loss outcomes, which in turn were either obtained or avoided by action or inaction. After 24 h, memory for these images reflected a benefit of action as well as a congruence of action requirements and valence, namely, action for reward and inaction for avoidance. fMRI responses in the hippocampus, a region known to be critical for long-term memory function, reflected the anticipation of inaction. In contrast, activity in the putamen mirrored the congruence of action requirement and valence, whereas other basal ganglia regions mirrored overall action benefits on long-lasting memory. The findings indicate a novel type of functional division between the hippocampus and the basal ganglia in the motivational regulation of long-term memory consolidation, which favors remembering events that are worth acting for. 
26418152	Elevated β-amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer's disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the "transfer" of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative "transfer learning" task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APPswe PS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle β-amyloid-induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg-SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal-dependent learning may be useful for early identification of AD-like pathology.
26416969	The ability to categorize stimuli - predator or prey, friend or foe - is an essential feature of the decision-making process. Underlying that ability is the development of an internally generated category boundary to generate decision outcomes. While classic temporal difference reinforcement models assume midbrain dopaminergic neurons underlie the prediction error required to learn boundary location, these neurons also demonstrate a robust response to nonreward incentive stimuli. More recent models suggest that this may reflect a motivational aspect to performing a task which should be accounted for when modeling dopaminergic neuronal behavior. To clarify the role of substantia nigra dopamine neurons in uncertain perceptual decision making, we investigated their behavior using single neuron extracellular recordings in patients with Parkinson's disease undergoing deep brain stimulation. Subjects underwent a simple auditory categorical decision-making task in which they had to classify a tone as either low- or high-pitched relative to an explicit threshold tone and received feedback but no reward. We demonstrate that the activity of human SN dopaminergic neurons is predictive of perceptual categorical decision outcome and is modulated by uncertainty. Neuronal activity was highest during difficult (uncertain) decisions that resulted in correct responses and lowest during easy decisions that resulted in incorrect responses. This pattern of results is more consistent with a "motivational" role with regards to perceptual categorization and suggests that dopamine neurons are most active when critical information - as represented by uncertainty - is available for learning decision boundaries. 
26416843	The financial sector has seen an increase in the number of cases of violence and stress, which can result in adverse health outcomes, including depressive symptoms, but studies related to stress at work and depression for these workers are scarce.To investigate the association between exposure to psychosocial work stressors and depressive symptoms in bank employees.	A self-administered questionnaire was completed by a sample of bank employees in Pará and Amapá, Brazil. The survey assessed sociodemographic characteristics, mental health (Patient Health Questionnaire-9), Demand-Control-Support and Effort-Reward Imbalance (ERI). Outcomes included two levels of depressive symptoms: major depressive symptoms (MDS) and other forms of depressive symptoms (ODS). Logistic regression models were used to estimate associations between depressive symptoms, the two job stress models and relevant covariates.	Of 2806 eligible subjects, there were 1445 respondents (52% response rate) and the final analyses included 1046 participants. The overall prevalence of depressive symptoms was 32% (MDS = 18%; ODS = 14%), with no statistically significant difference between men and women. High demands, low levels of control and low social support were associated with MDS and/or ODS, adjusted for gender, age and other work-related conditions. High effort/low reward, over-commitment and ERI were also associated with MDS and ODS.	Psychosocial conditions in banking activity involving high strain, low social support at work, high effort with low reward and over-commitment may represent possible risk factors for depressive symptoms in bank employees.	
26416785	Young people frequently socialize together in contexts that encourage risky decision making, pointing to a need for research into how susceptibility to peer influence is related to individual differences in the neural processing of decisions during sequentially escalating risk. We applied a novel analytic approach to analyze EEG activity from college-going students while they completed the Balloon Analogue Risk Task (BART), a well-established risk-taking propensity assessment. By modeling outcome-processing-related changes in the P200 and feedback-related negativity (FRN) sequentially within each BART trial as a function of pump order as an index of increasing risk, our results suggest that analyzing the BART in a progressive fashion may provide valuable new insights into the temporal neurophysiological dynamics of risk taking. Our results showed that a P200, localized to the left caudate nucleus, and an FRN, localized to the left dACC, were positively correlated with the level of risk taking and reward. Furthermore, consistent with our hypotheses, the rate of change in the FRN was higher among college students with greater self-reported resistance to peer influence. 
26416017	Focusing attention on a target creates a center-surround inhibition such that distractors located close to the target do not capture attention. Recent research showed that a distractor can break through this surround inhibition when associated with reward. However, the brain basis for this reward-based attention is unclear. In this fMRI study, we presented a distractor associated with high or low reward at different distances from the target. Behaviorally the low-reward distractor did not capture attention and thus did not cause interference, whereas the high-reward distractor captured attention only when located near the target. Neural activity in extrastriate cortex mirrored the behavioral pattern. A comparison between the high-reward and the low-reward distractors presented near the target (i.e., reward-based attention) and a comparison between the high-reward distractors located near and far from the target (i.e., spatial attention) revealed a common frontoparietal network, including inferior frontal gyrus and inferior parietal sulcus as well as the visual cortex. Reward-based attention specifically activated the anterior insula (AI). Dynamic causal modelling showed that reward modulated the connectivity from AI to the frontoparietal network but not the connectivity from the frontoparietal network to the visual cortex. Across participants, the reward-based attentional effect could be predicted both by the activity in AI and by the changes of spontaneous functional connectivity between AI and ventral striatum before and after reward association. These results suggest that AI encodes reward-based salience and projects it to the stimulus-driven attentional network, which enables the reward-associated distractor to break through the surround inhibition in the visual cortex.
26415059	Increases in marijuana use in recent years highlight the importance of understanding how marijuana affects mental health. Of particular relevance is the effect of marijuana use on anxiety and depression given that marijuana use is highest among late adolescents/early adults, the same age range in which risk for anxiety and depression is the highest. Here we examine how marijuana use moderates the effects of temperament on level of anxiety and depression in a prospective design in which baseline marijuana use and temperament predict anxiety and depression 1 year later. We found that harm avoidance (HA) is associated with higher anxiety and depression a year later, but only among those low in marijuana use. Those higher in marijuana use show no relation between HA and symptoms of anxiety and depression. Marijuana use also moderated the effect of novelty seeking (NS), with symptoms of anxiety and depression increasing with NS only among those with high marijuana use. NS was unrelated to symptoms of anxiety and depression among those low in marijuana use. The temperament dimension of reward dependence was unrelated to anxiety and depression symptoms. Our results suggest that marijuana use does not have an invariant relationship with anxiety and depression, and that the effects of relatively stable temperament dimensions can be moderated by other contextual factors.
26414700	Rodent models of spinal cord injury are critical for the development of treatments for upper limb motor impairment in humans, but there are few methods for measuring forelimb strength of rodents, an important outcome measure. We developed a novel robotic device--the Robotic Rehabilitator of the Rodent Upper Extremity (RUE)--that requires rats to voluntarily reach for and pull a bar to retrieve a food reward; the resistance of the bar can be programmed. We used RUE to train forelimb strength of 16 rats three times per week for 23 weeks before and 38 weeks after a mild (100 kdyne) unilateral contusion at the cervical level 5 (C5). We measured maximum force produced when RUE movement was unexpectedly blocked. We compared this blocked pulling force (BPF) to weekly measures of forelimb strength obtained with a previous, well-established method: the grip strength meter (GSM). Before injury, BPF was 2.6 times higher (BPF, 444.6 ± 19.1 g; GSM, 168.4 ± 3.1 g) and 4.9 times more variable (p < 0.001) than pulling force measured with the GSM; the two measurement methods were uncorrelated (R(2) = 0.03; p = 0.84). After injury, there was a significant decrease in BPF of 134.35 g ± 14.71 g (p < 0.001). Together, our findings document BPF as a repeatable measure of forelimb force production, sensitive to a mild spinal cord injury, which comes closer to measuring maximum force than the GSM and thus may provide a useful measure for quantifying the effects of treatment in rodent models of SCI.
26414030	This study was designed to investigate the associations between psychosocial work factors, using well-known theoretical models and emerging concepts, and self-reported health in the national population of French employees.This study was based on the data of the French national representative SUMER 2010 survey. The sample included 46,962 employees, 26,883 men and 20,079 women, with an 87% participation rate. Self-reported health was measured by means of a single question and was analysed as a binary variable. Psychosocial work factors included factors related to job strain and effort-reward imbalance models, workplace violence and working hours. Associations between psychosocial work factors and self-reported health were studied using weighted logistic regression models adjusted for covariates (age, occupation, economic activity, and other types of occupational exposure).	Low decision latitude (skill discretion and decision authority), high psychological demands, low social support (from supervisors for men), low reward (low esteem and low job promotion for both genders and job insecurity for men), bullying and verbal abuse for both genders were associated with self-reported health.	This study emphasizes the role of psychosocial work factors as risk factors for poor self-reported health and suggests that the implementation of preventive measures to reduce exposure to psychosocial work factors should be an objective for the improvement of health at work.	
26413478	Amotivation in schizophrenia is a central predictor of poor functioning, and is thought to occur due to deficits in anticipating future rewards, suggesting that impairments in anticipating pleasure can contribute to functional disability in schizophrenia. In healthy comparison (HC) participants, reward anticipation is associated with activity in frontal-striatal networks. By contrast, schizophrenia (SZ) participants show hypoactivation within these frontal-striatal networks during this motivated anticipatory brain state. Here, we examined neural activation in SZ and HC participants during the anticipatory phase of stimuli that predicted immediate upcoming reward and punishment, and during the feedback/outcome phase, in relation to trait measures of hedonic pleasure and real-world functional capacity. SZ patients showed hypoactivation in ventral striatum during reward anticipation. Additionally, we found distinct differences between HC and SZ groups in their association between reward-related immediate anticipatory neural activity and their reported experience of pleasure. HC participants recruited reward-related regions in striatum that significantly correlated with subjective consummatory pleasure, while SZ patients revealed activation in attention-related regions, such as the IPL, which correlated with consummatory pleasure and functional capacity. These findings may suggest that SZ patients activate compensatory attention processes during anticipation of immediate upcoming rewards, which likely contribute to their functional capacity in daily life. 
26412353	Parkinson's disease is associated with progressive degeneration of mesolimbic dopaminergic neurons that are involved in reward-based behavior learning, including rewarding effects of food consumption and drugs of abuse. The importance of this pathway in development of addictive behaviors led us to hypothesize that medical disorders related to poor impulse control may occur less frequently among patients with Parkinson's disease than those with other progressive neurodegenerative disorders such as Alzheimer's disease. Retrospective cross-sectional study of all patients treated for Parkinson's disease and Alzheimer's disease in a community based clinic during a two-year period. Associations were summarized using odds ratios (OR) and 95% confidence intervals (95% CI) estimated from logistic regression models, adjusted for differences in gender distribution between the groups. A total of 106 patients with Parkinson's disease and 72 patients with Alzheimer's disease were included. Patients with Parkinson's disease were less likely to have either past substance use (adjusted OR = 0.035, 95% CI = 0.009 - 0.130) or presence of co-morbid medical conditions related to poor dietary choices (adjusted OR = 0.157, 95% CI = 0.062 - 0.397). Co-morbid medical conditions related to poor impulse control occur less frequently among those with Parkinson's disease than those with Alzheimer's disease. These findings are consistent with dysfunction of dopamine dependent pathways involved in addiction during the presymptomatic phase of Parkinson's disease and support a biological basis for addiction. 
26410743	Impulse control disorders (ICDs) occur in a subset of patients with Parkinson's disease (PD) who are receiving dopamine replacement therapy. In this study, we aimed to investigate structural abnormalities within the mesocortical and limbic cortices and subcortical structures in PD patients with ICDs. We studied 18 PD patients with ICDs, 18 PD patients without ICDs and a group of 24 age and sex-matched healthy controls. Cortical thickness (CTh) and subcortical nuclei volume analyses were carried out using the automated surface-based analysis package FreeSurfer (version 5.3.0). We found significant differences in MRI measures between the three groups. There was volume loss in the nucleus accumbens of both PD patients with ICDs and without ICDs compared to the control group. In addition, PD patients with ICDs showed significant atrophy in caudate, hippocampus and amygdala compared to the group of healthy controls. PD patients with ICDs had significant increased cortical thickness in rostral anterior cingulate cortex and frontal pole compared to PD patients without ICDs. Cortical thickness in rostral anterior cingulate and frontal pole was increased in PD patients with ICDs compared to the control group, but the differences failed to reach corrected levels of statistical significance. PD patients with ICDs showed increased cortical thickness in medial prefrontal regions. We speculate that these findings reflect either a pre-existing neural trait vulnerability to impulsivity or the expression of a maladaptive synaptic plasticity under non-physiological dopaminergic stimulation. 
26409320	The purpose of this study was to explore the effects of slow-wave disruption on positive and negative word recognition in a sample of healthy control participants and those with major depressive disorder. Prior to sleep, participants learned a set of emotional and neutral words during an encoding task by responding whether or not the word described them. Following baseline sleep, participants underwent one night of selective slow-wave disruption by auditory stimuli. Accuracy and reaction time to a recognition word set, including both positive and negative words, was assessed in the morning. Repeated-measures ANOVA revealed a significant interaction between word valence and condition, with positive words recognized significantly faster than negative words after disruption, in only healthy control participants. There were no significant results in those with major depressive disorder, or with regard to accuracy. These results may add to the increasing body of literature suggesting a hedonic bias to positive stimuli following sleep disruption. 
26409030	In addition to its classical role in mediating responses to pain, the opioid system is strongly implicated in the regulation of social behavior. In young laboratory animals, low doses of opioid analgesic drugs reduce responses to isolation distress and increase play behavior. However, little is known about how opioid drugs affect responses to social stimuli in humans. Here we examined the effects of buprenorphine, a mu-opioid partial agonist and kappa-antagonist, on three dimensions of social processing: (i) responses to simulated social rejection, (ii) attention to emotional facial expressions, and (iii) emotional responses to images with and without social content. Healthy adults (N=36) attended two sessions during which they received either placebo or 0.2mg sublingual buprenorphine in randomized order, under double-blind conditions. Ninety minutes after drug administration, they completed three behavioral tasks: (i) a virtual ball-toss game in which they were first included and then excluded by the other players; (ii) an attention task in which they were shown pairs of faces (one emotional and one neutral), while the direction of their gazes was recorded using electrooculography, and (iii) a picture-viewing task, in which they rated standardized images with and without social content. During the ball-toss game, buprenorphine decreased perceived social rejection. During the attention task, the drug reduced initial attention to fearful facial expressions, without influencing attention to angry, happy, or sad faces. Finally, during the picture-viewing task, buprenorphine increased ratings of positivity of images with social content without affecting ratings of nonsocial images. These results suggest that even at low doses, opioid analgesic drugs reduce responses to some types of negative social stimuli while enhancing positive responses to social stimuli. This provides further support for the role of the opioid system in mediating responses to social rejection and social reward. 
26408038	Extraverts are better than introverts at building rapport, but it remains unknown what they do behaviorally to better connect with other individuals. We hypothesized that extraverts mimic more than introverts as a way to build rapport; however, we predicted that this social skillfulness of extraverts emerges only when they are motivated to affiliate. In Study 1, we found that extraversion predicted increased mimicry when an affiliation goal was present, but not when an affiliation goal was absent. In Study 2, we found that mimicry mediates the relationship between extraversion and rapport, but only when an affiliation goal is present. Our findings are the first to identify a behavior that extraverts engage in that helps them build rapport. Furthermore, our studies show that this skillfulness of extraverts emerges only when they are motivated to affiliate, providing evidence in favor of the reward-sensitivity-as-core model of extraversion over the sociability-as-core model of extraversion. 
26407959	The motivation to seek out and consume rewards has evolutionarily been driven by the urge to fulfill physiological needs. However in a modern society dominated more by plenty than scarcity, we tend to think of motivation as fueled by the search for pleasure. Here, we argue that two separate but interconnected subcortical and unconscious processes direct motivation: "wanting" and "liking." These two psychological and neuronal processes and their related brain structures typically work together, but can become dissociated, particularly in cases of addiction. In drug addiction, for example, repeated consumption of addictive drugs sensitizes the mesolimbic dopamine system, the primary component of the "wanting" system, resulting in excessive "wanting" for drugs and their cues. This sensitizing process is long-lasting and occurs independently of the "liking" system, which typically remains unchanged or may develop a blunted pleasure response to the drug. The result is excessive drug-taking despite minimal pleasure and intense cue-triggered craving that may promote relapse long after detoxification. Here, we describe the roles of "liking" and "wanting" in general motivation and review recent evidence for a dissociation of "liking" and "wanting" in drug addiction, known as the incentive sensitization theory (Robinson and Berridge 1993). We also make the case that sensitization of the "wanting" system and the resulting dissociation of "liking" and "wanting" occurs in both gambling disorder and food addiction. 
26407494	Behavioral inhibition (BI) is an early developing trait associated with cautiousness and development of clinical depression and anxiety. Little is known about the neural basis of BI and its predictive importance concerning risk for internalizing disorders. We looked at functional connectivity of the default-mode network (DMN) and salience network (SN), given their respective roles in self-relational and threat processing, in the risk for internalizing disorders, with an emphasis on determining the functional significance of these networks for BI.We used functional magnetic resonance imaging to scan, during the resting state, children and adolescents 8 to 17 years of age who were either at high familial risk (HR; n = 16) or low familial risk (LR; n = 18) for developing clinical depression and/or anxiety. Whole-brain DMN and SN functional connectivity were estimated for each participant and compared across groups. We also compared the LR and HR groups on levels of BI and anxiety, and incorporated these data into follow-up neurobehavioral correlation analyses.	The HR group, relative to the LR group, showed significantly decreased DMN connectivity with the ventral striatum and bilateral sensorimotor cortices. Within the HR group, trait BI increased as DMN connectivity with the ventral striatum and sensorimotor cortex decreased. The HR and LR groups did not differ with respect to SN connectivity.	Our findings show, in the risk for internalizing disorders, a negative functional relation between brain regions supporting self-relational processes and reward prediction. These findings represent a potential neural substrate for behavioral inhibition in the risk for clinical depression and anxiety.	
26407298	Preferences for risky choices have often been shown to be unstable and context-dependent. Though people generally avoid gambles with mixed outcomes, a phenomenon often attributed to loss aversion, contextual factors can impact this dramatically. For example, people typically prefer risky options after a financial loss, while generally choosing safer options after a monetary gain. However, it is unclear what exactly contributes to these preference shifts as a function of prior outcomes, as these gain/loss outcomes are usually confounded with participant performance, and therefore it is unclear whether these effects are driven purely by the monetary gains or losses, or rather by success or failure at the actual task. Here, we experimentally separated the effects of monetary gains/losses from performance success/failure prior to a standard risky choice. Participants performed a task in which they experienced contextual effects: 1) monetary gain or loss based directly on performance, 2) monetary gain or loss that was randomly awarded and was, crucially, independent from performance, and 3) success or failure feedback based on performance, but without any monetary incentive. Immediately following these positive/negative contexts, participants were presented with a gain-loss gamble that they had to decide to either play or pass. We found that risk preferences for identical sets of gambles were biased by positive and negative contexts containing monetary gains and losses, but not by contexts containing performance feedback. This data suggests that the observed framing effects are driven by aversion for monetary losses and not simply by the positive or negative valence of the context, or by potential moods resulting from positive or negative contexts. These results highlight the specific context dependence of risk preferences. 
26407227	Transitive inference (the ability to infer that B > D given that B > C and C > D) is a widespread characteristic of serial learning, observed in dozens of species. Despite these robust behavioral effects, reinforcement learning models reliant on reward prediction error or associative strength routinely fail to perform these inferences. We propose an algorithm called betasort, inspired by cognitive processes, which performs transitive inference at low computational cost. This is accomplished by (1) representing stimulus positions along a unit span using beta distributions, (2) treating positive and negative feedback asymmetrically, and (3) updating the position of every stimulus during every trial, whether that stimulus was visible or not. Performance was compared for rhesus macaques, humans, and the betasort algorithm, as well as Q-learning, an established reward-prediction error (RPE) model. Of these, only Q-learning failed to respond above chance during critical test trials. Betasort's success (when compared to RPE models) and its computational efficiency (when compared to full Markov decision process implementations) suggests that the study of reinforcement learning in organisms will be best served by a feature-driven approach to comparing formal models. 
26406722	Optical spike-timing-dependent plasticity (STDP) synapses form the basis of learning in photonic neuromorphic system. In biological neural systems, STDP synapses generally have multiplicative boundary mechanisms, and can be modulated by a third factor such as dopamine. Analogously, we introduce a third factor into optical STDP: The current-injection of semiconductor optical amplifiers can be modified in an adaptive way according to local or global feedback signals. The local one is present synaptic weight, which elicits an optical weight-dependent STDP, while the global one is a reward signal. We demonstrate that the optical weight-dependent STDP can emulate the behavior of biological STDP synapses more closely, and can be seen as an intermediate configuration between additive and multiplicative STDP, which balances stability and competition among synapses. Simulation studies with scalable photonic neurons further show that optical STDP with reward modulation enables reward-based reinforcement learning. 
26404495	Losing a job or significant other are examples of incentive loss that result in negative emotional reactions. The occurrence of negative life events is associated with increased drinking (Keyes, Hatzenbuehler, & Hasin, 2011). Further, certain genotypes are more likely to drink alcohol in response to stressful negative life events (Blomeyer et al., 2008; Covault et al., 2007). Shared genetic factors may contribute to alcohol drinking and emotional reactivity, but this relationship is not currently well understood. We used an incentive downshift paradigm to address whether emotional reactivity is elevated in mice predisposed to drink alcohol. We also investigated if ethanol drinking is influenced in High Alcohol Preferring mice that had been exposed to an incentive downshift. Incentive downshift procedures have been widely utilized to model emotional reactivity, and involve shifting a high reward group to a low reward and comparing the shifted group to a consistently rewarded control group. Here, we show that replicate lines of selectively bred High Alcohol Preferring mice exhibited larger successive negative contrast effects than their corresponding replicate Low Alcohol Preferring lines, providing strong evidence for a genetic association between alcohol drinking and susceptibility to the emotional effects of negative contrast. These mice can be used to study the shared neurological and genetic underpinnings of emotional reactivity and alcohol preference. Unexpectedly, an incentive downshift suppressed ethanol drinking immediately following an incentive downshift. This could be due to a specific effect of negative contrast on ethanol consumption or a suppressive effect on consummatory behavior in general. These data suggest that either alcohol intake does not provide the anticipated negative reinforcement, or that a single test was insufficient for animals to learn to drink following incentive downshift. However, the emotional intensity following incentive downshift provides initial evidence that this type of emotional reactivity may be a predisposing factor in alcoholism. 
26404367	Some individuals exhibit a weak satiety response to food and may be susceptible to overconsumption. The current study identified women showing consistently low or high satiety responses to standardised servings of food across four separate days and compared them on behavioural, psychological and physiological risk factors for overeating and future weight gain. In a crossover design, 30 female participants (age: 28.0 ± 10.6; body mass index (BMI): 23.1 ± 3.0) recorded sensations of hunger in the post-prandial period following four graded energy level breakfasts. Satiety quotients were calculated to compare individuals on satiety responsiveness across conditions. Body composition, resting metabolic rate (RMR), energy intake, food reward and craving, and eating behaviour traits were assessed under controlled laboratory conditions. A distinct low satiety phenotype (LSP) was identified with good consistency across separate study days. These individuals had a higher RMR, greater levels of disinhibition and reported feeling lower control over food cravings. Further, they consumed more energy and exhibited greater wanting for high-fat food. The inverse pattern of characteristics was observed in those exhibiting a consistently high satiety phenotype (HSP). Weak satiety responsiveness is a reliable trait identifiable using the satiety quotient. The LSP was characterised by distinct behavioural and psychological characteristics indicating a risk for overeating, compared to HSP. 
26403657	Understanding the neurobiological substrates that encode learning about food-associated cues and how those signals are modulated is of great clinical importance especially in light of the worldwide obesity problem. Inappropriate or maladaptive responses to food-associated cues can promote over-consumption, leading to excessive energy intake and weight gain. Chronic exposure to foods rich in fat and sugar alters the reinforcing value of foods and weakens inhibitory neural control, triggering learned, but maladaptive, associations between environmental cues and food rewards. Thus, responses to food-associated cues can promote cravings and food-seeking by activating mesocorticolimbic dopamine neurocircuitry, and exert physiological effects including salivation. These responses may be analogous to the cravings experienced by abstaining drug addicts that can trigger relapse into drug self-administration. Preventing cue-triggered eating may therefore reduce the over-consumption seen in obesity and binge-eating disorder. In this review we discuss recent research examining how cues associated with palatable foods can promote reward-based feeding behaviours and the potential involvement of appetite-regulating peptides including leptin, ghrelin, orexin and melanin concentrating hormone. These peptide signals interface with mesolimbic dopaminergic regions including the ventral tegmental area to modulate reactivity to cues associated with palatable foods. Thus, a novel target for anti-obesity therapeutics is to reduce non-homeostatic, reward driven eating behaviour, which can be triggered by environmental cues associated with highly palatable, fat and sugar rich foods. 
26402458	Effective perceptual decisions rely upon combining sensory information with knowledge of the rewards available for different choices. However, it is not known where reward signals interact with the multiple stages of the perceptual decision-making pathway and by what mechanisms this may occur. We combined electrical microstimulation of functionally specific groups of neurons in visual area V5/MT with performance-contingent reward manipulation, while monkeys performed a visual discrimination task. Microstimulation was less effective in shifting perceptual choices towards the stimulus preferences of the stimulated neurons when available reward was larger. Psychophysical control experiments showed this result was not explained by a selective change in response strategy on microstimulated trials. A bounded accumulation decision model, applied to analyse behavioural performance, revealed that the interaction of expected reward with microstimulation can be explained if expected reward modulates a sensory representation stage of perceptual decision-making, in addition to the better-known effects at the integration stage. 
26400942	Research over the past decade indicates a novel role for epigenetic mechanisms in memory formation. Of particular interest is chromatin modification by histone deacetylases (HDACs), which, in general, negatively regulate transcription. HDAC deletion or inhibition facilitates transcription during memory consolidation and enhances long-lasting forms of synaptic plasticity and long-term memory. A key open question remains: How does blocking HDAC activity lead to memory enhancements? To address this question, we tested whether a normal function of HDACs is to gate information processing during memory formation. We used a class I HDAC inhibitor, RGFP966 (C21H19FN4O), to test the role of HDAC inhibition for information processing in an auditory memory model of learning-induced cortical plasticity. HDAC inhibition may act beyond memory enhancement per se to instead regulate information in ways that lead to encoding more vivid sensory details into memory. Indeed, we found that RGFP966 controls memory induction for acoustic details of sound-to-reward learning. Rats treated with RGFP966 while learning to associate sound with reward had stronger memory and additional information encoded into memory for highly specific features of sounds associated with reward. Moreover, behavioral effects occurred with unusually specific plasticity in primary auditory cortex (A1). Class I HDAC inhibition appears to engage A1 plasticity that enables additional acoustic features to become encoded in memory. Thus, epigenetic mechanisms act to regulate sensory cortical plasticity, which offers an information processing mechanism for gating what and how much is encoded to produce exceptionally persistent and vivid memories. Significance statement: Here we provide evidence of an epigenetic mechanism for information processing. The study reveals that a class I HDAC inhibitor (Malvaez et al., 2013; Rumbaugh et al., 2015; RGFP966, chemical formula C21H19FN4O) alters the formation of auditory memory by enabling more acoustic information to become encoded into memory. Moreover, RGFP966 appears to affect cortical plasticity: the primary auditory cortex reorganized in a manner that was unusually "tuned-in" to the specific sound cues and acoustic features that were related to reward and subsequently remembered. We propose that HDACs control "informational capture" at a systems level for what and how much information is encoded by gating sensory cortical plasticity that underlies the sensory richness of newly formed memories.
26400940	The pervasive tendency to discount the value of future rewards varies considerably across individuals and has important implications for health and well-being. Here, we used fMRI with human participants to examine whether an individual's neural representation of an imagined primary reward predicts the degree to which the value of delayed monetary payments is discounted. Because future rewards can never be experienced at the time of choice, imagining or simulating the benefits of a future reward may play a critical role in decisions between alternatives with either immediate or delayed benefits. We found that enhanced ventromedial prefrontal cortex response during imagined primary reward receipt was correlated with reduced discounting in a separate monetary intertemporal choice task. Furthermore, activity in enhanced ventromedial prefrontal cortex during reward imagination predicted temporal discounting behavior both between- and within-individual decision makers with 62% and 73% mean balanced accuracy, respectively. These results suggest that the quality of reward imagination may impact the degree to which future outcomes are discounted. Significance statement: We report a novel test of the hypothesis that an important factor influencing the discount rate for future rewards is the quality with which they are imagined or estimated in the present. Previous work has shown that temporal discounting is linked to individual characteristics ranging from general intelligence to the propensity for addiction. We demonstrate that individual differences in a neurobiological measure of primary reward imagination are significantly correlated with discounting rates for future monetary payments. Moreover, our neurobiological measure of imagination can be used to accurately predict choice behavior both between and within individuals. These results suggest that improving reward imagination may be a useful therapeutic target for individuals whose high discount rates promote detrimental behaviors.
26400938	The anterior cingulate cortex (ACC) and prefrontal cortex (PFC) are believed to coactivate during goal-directed behavior to identify, select, and monitor relevant sensory information. Here, we tested whether coactivation of neurons across macaque ACC and PFC would be evident at the level of pairwise neuronal correlations during stimulus selection in a spatial attention task. We found that firing correlations emerged shortly after an attention cue, were evident for 50-200 ms time windows, were strongest for neuron pairs in area 24 (ACC) and areas 8 and 9 (dorsal PFC), and were independent of overall firing rate modulations. For a subset of cell pairs from ACC and dorsal PFC, the observed functional spike-train connectivity carried information about the direction of the attention shift. Reliable firing correlations were evident across area boundaries for neurons with broad spike waveforms (putative excitatory neurons) as well as for pairs of putative excitatory neurons and neurons with narrow spike waveforms (putative interneurons). These findings reveal that stimulus selection is accompanied by slow time scale firing correlations across those ACC/PFC subfields implicated to control and monitor attention. This functional coupling was informative about which stimulus was selected and thus indexed possibly the exchange of task-relevant information. We speculate that interareal, transient firing correlations reflect the transient coordination of larger, reciprocally interacting brain networks at a characteristic 50-200 ms time scale. Significance statement: Our manuscript identifies interareal spike-train correlations between primate anterior cingulate and dorsal prefrontal cortex during a period where attentional stimulus selection is likely controlled by these very same circuits. Interareal correlations emerged during the covert attention shift to one of two peripheral stimuli, proceeded on a slow 50-200 ms time scale, and occurred between putative pyramidal and putative interneurons. Spike-train correlations emerged particularly for cell pairs tuned to similar contralateral target locations, thus indexing the interareal coordination of attention-relevant information. These findings characterize a possible way by which prefrontal and anterior cingulate cortex circuits implement their control functions through coordinated firing when macaque monkeys select and monitor relevant stimuli for goal-directed behaviors.
26400937	For day-to-day decisions, multiple factors influence our choice between alternatives. Two dimensions of decision making that substantially affect choice are the objective perceptual properties of the stimulus (e.g., salience) and its subjective value. Here we measure EEGs in human subjects to relate their feedback-evoked EEG responses to estimates of prediction error given a neurally derived expected value for each trial. Unlike in traditional reinforcement learning paradigms, in our experiment the reward itself is not probabilistic; rather, it is a fixed value, which, when combined with the variable stimulus salience, yields uncertainty in the choice. We find that feedback-evoked event-related potentials (ERPs), specifically those classically termed feedback-related negativity, are modulated by both the reward level and stimulus salience. Using single-trial analysis of the EEG, we show stimulus-locked EEG components reflecting perceived stimulus salience can be combined with the level of reward to create an estimate of expected reward. This expected reward is used to form a prediction error that correlates with the trial-by-trial variability of the feedback ERPs for negative, but not positive, feedback. This suggests that the valence of prediction error is more important than the valence of the actual feedback, since only positive rewards were delivered in the experiment (no penalty or loss). Finally, we show that these subjectively defined prediction errors are informative of the riskiness of the subject's choice on the subsequent trial. In summary, our work shows that neural correlates of stimulus salience interact with value information to yield neural representations of subjective expected reward. Significance statement: How we make perceptual decisions depends on sensory evidence and the value of our options. These two factors often interact to yield subjective decisions; i.e., individuals integrate sensory evidence and value to form their own estimates of expected reward. Here, we use electroencephelography to identify trial-by-trial neural activity of perceived stimulus salience, showing that this activity can be combined with the value of choice options to form a representation of expected reward. Our results provide insight into the neural processing governing the interaction between salience and value and the formation of subjective expected reward and prediction error. This work is potentially important for identifying neural markers of abnormal sensory/value processing, as is seen in some cases of psychiatric illnesses.
26400931	We recorded basolateral amygdala (BL) neurons in a seminaturalistic foraging task. Rats had to leave their nest to retrieve food in an elongated arena inhabited by a mechanical predator. There were marked trial-to-trial variations in behavior. After poking their head into the foraging arena and waiting there for a while, rats either retreated to their nest or initiated foraging. Before initiating foraging, rats waited longer on trials that followed failed than successful trials indicating that prior experience influenced behavior. Upon foraging initiation, most principal cells (Type-1) reduced their firing rate, while in a minority (Type-2) it increased. When rats aborted foraging, Type-1 cells increased their firing rates, whereas in Type-2 cells it did not change. Surprisingly, the opposite activity profiles of Type-1 and Type-2 units were also seen in control tasks devoid of explicit threats or rewards. The common correlate of BL activity across these tasks was movement velocity, although an influence of position was also observed. Thus depending on whether rats initiated movement or not, the activity of BL neurons decreased or increased, regardless of whether threat or rewards were present. Therefore, BL activity not only encodes threats or rewards, but is closely related to behavioral output. We propose that higher order cortical areas determine task-related changes in BL activity as a function of reward/threat expectations and internal states. Because Type-1 and Type-2 cells likely form differential connections with the central amygdala (controlling freezing), this process would determine whether movement aimed at attaining food or exploration is suppressed or facilitated. Significance statement: For decades, amygdala research has been dominated by pavlovian and operant conditioning paradigms. This work has led to the view that amygdala neurons signal threats or rewards, in turn causing defensive or approach behaviors. However, the artificial circumstances of conditioning studies bear little resemblance to normal life. In natural conditions, subjects are simultaneously presented with potential threats and rewards, forcing them to engage in a form of risk assessment. We examined this process using a seminaturalistic foraging task. In constant conditions of threats and rewards, amygdala activity could be high or low, depending on the rats' decisions on a given trial. Therefore, amygdala activity does not only encode threats or rewards but is also closely related to behavioral output.
26400746	Rewarding cooperation is in many ways expected behaviour from social players. However, strategies that promote antisocial behaviour are also surprisingly common, not just in human societies, but also among eusocial insects and bacteria. Examples include sanctioning of individuals who behave prosocially, or rewarding of free-riders who do not contribute to collective enterprises. We therefore study the public goods game with antisocial and prosocial pool rewarding in order to determine the potential negative consequences on the effectiveness of positive incentives to promote cooperation. Contrary to a naive expectation, we show that the ability of defectors to distribute rewards to their like does not deter public cooperation as long as cooperators are able to do the same. Even in the presence of antisocial rewarding, the spatial selection for cooperation in evolutionary social dilemmas is enhanced. Since the administration of rewards to either strategy requires a considerable degree of aggregation, cooperators can enjoy the benefits of their prosocial contributions as well as the corresponding rewards. Defectors when aggregated, on the other hand, can enjoy antisocial rewards, but due to their lack of contributions to the public good they ultimately succumb to their inherent inability to secure a sustainable future. Strategies that facilitate the aggregation of akin players, even if they seek to promote antisocial behaviour, thus always enhance the long-term benefits of cooperation. 
26398679	In addition to food intake and energy balance regulation, ghrelin mediate the rewarding and motivational properties of palatable food as well as addictive drugs. The ability of ghrelin to regulate reinforcement involves the cholinergic-dopaminergic reward link, which encompasses a cholinergic projection from the laterodorsal tegmental area (LDTg) to the ventral tegmental area (VTA) together with mesolimbic dopaminergic projections from the VTA to the nucleus accumbens (NAc). Recently, systemic ghrelin was shown to regulate sexual behavior and motivation in male mice via dopamine neurotransmission. The present study therefore elucidates the role of ghrelin and ghrelin receptor (GHS-R1A) antagonist treatment within NAc, VTA or LDTg for sexual behavior in sexually naïve male mice. Local administration of the GHSR-1A antagonist, JMV2959, into the VTA or LDTg was found to reduce the preference for female mice, the number of mounts and the duration of mounting as well as to prolong the latency to mount. This was further substantiated by the findings that ghrelin administration into the VTA or LDTg increased the number of mounts and the duration of mounting and decreased the latency to mount. Moreover, ghrelin administered into the LDTg increased the preference for female mice. Accumbal administration of ghrelin increased whereas GHS-R1A antagonist decreased the intake of palatable food, but did not alter sexual behavior. In males exposed to sexual interaction, systemic administration of ghrelin increases whereas JMV2959 decreases the turnover of dopamine in the VTA. These data suggest that ghrelin signaling within the tegmental areas is required for sexual behavior in sexually naïve male mice. 
26398327	To examine the feasibility of conducting a randomized controlled trial investigating the effectiveness of financial incentives for exercise self-monitoring in cardiac rehabilitation (CR).A 12-week, 2 parallel-arm, single-blind feasibility study design was employed. A volunteer sample of CR program graduates was randomly assigned to an exercise self-monitoring intervention only (control; n = 14; mean age ± SD, 62.7 ± 14.6 years), or an exercise self-monitoring plus incentives approach (incentive; n = 13; mean age ± SD, 63.6 ± 11.8 years). Control group participants received a "home-based" exercise self-monitoring program following CR program completion (exercise diaries could be submitted online or by mail). Incentive group participants received the "home-based" program, plus voucher-based incentives for exercise diary submissions ($2 per day). A range of feasibility outcomes is presented, including recruitment and retention rates, and intervention acceptability. Data for the proposed primary outcome of a definitive trial, aerobic fitness, are also reported.	Seventy-four CR graduates were potentially eligible to participate, 27 were enrolled (36.5% recruitment rate; twice the expected rate), and 5 were lost to followup (80% retention). Intervention acceptability was high with three-quarters of participants indicating that they would likely sign up for an incentive program at baseline. While group differences in exercise self-monitoring (the incentive "target") were not observed, modest but nonsignificant changes in aerobic fitness were noted with fitness increasing by 0.23 mL·kg-·min- among incentive participants and decreasing by 0.68 mL·kg-·min- among controls.	This preliminary study demonstrates the feasibility of studying incentives in a CR context, and the potential for incentives to be readily accepted in the broader context of the Canadian health care system.	
26396215	Coexisting workloads from professional, household and family, and caregiving activities for frail parents expose middle-aged individuals, the so-called "Sandwich Generation", to potential health risks. Current trends suggest that this situation will continue or increase. Thus SG health promotion has become a nursing concern. Most existing research considers coexisting workloads a priori pathogenic. Most studies have examined the association of one, versus two, of these three activities with health. Few studies have used a nursing perspective. This article presents the development of a framework based on a nursing model. We integrated Siegrist's Effort-Reward Imbalance middle-range theory into "Neuman Systems Model". The latter was chosen for its salutogenic orientation, its attention to preventive nursing interventions and the opportunity it provides to simultaneously consider positive and negative perceptions of SG health and SG coexisting workloads. Finally, it facilitated a theoretical identification of health protective factors. 
26394523	Gambling disorder is a psychiatric disorder characterized by persistent and recurrent problematic gambling behavior, associated with impaired functioning, reduced quality of life, and frequent divorce and bankruptcy. Gambling disorder is reclassified in the category Substance-Related and Addictive Disorders in the DSM-5 because its clinical features closely resemble those of substance use disorders, and gambling activates the reward system in brain in much the same way drugs do. Prevalence of gambling disorder in Japan is high rate because of slot machines and pachinko game are very popular in Japan. The author recommend group psychotherapy and self-help group (Gamblers Anonymous), because group dynamics make them accept their wrongdoings related to gambling and believe that they can enjoy their lives without gambling.
26394514	Smoking is the most widespread addictive behavior in the world, and it causes physical and psychological dependence on nicotine. As for physical nicotine dependence, nicotine produces rewarding effects by interacting with nicotinic acetylcholine receptors on neurons in the brain's reward system. Psychological dependence on nicotine comes with a complex psychological procedure that is based on distorted cognition which justifies their smoking behavior. Clinicians should support smokers with willingness to quit smoking comprehensively with this knowledge, although the success rate of smoking cessation is no ideal in general.
26394506	Positron emission tomography studies investigating dopamine release by drug or reward demonstrated blunted dopamine release in relation to addiction to psychostimulants such as cocaine and amphetamine. However, recent studies reported that nicotine and gambling addiction showed opposite results. Several factors such as illness stage or neurotoxicity of substances could be considered for this discrepancy. Behavioral addiction such as gambling disorder is a good target of neuroimaging because it is free from overt neurotoxicity. However, even in gambling disorder, the results of fMRI studies investigating neural response to reward are mixed. Neuroimaging together with taking the various backgrounds of patients into account should contribute not only to a better understanding of the neurobiology of addiction but also to the development of more effective and individually tailored treatment strategies for addiction.
26394377	Recent findings suggest that the dorsolateral prefrontal cortex (DLPFC), a region consistently associated with impulse control, is vulnerable to transient suppression of its activity and attendant functions by excessive stress and/or cognitive demand. Using functional magnetic resonance imaging, we show that a capacity-exceeding cognitive challenge induced decreased DLPFC activity and correlated increases in the preference for immediately available rewards. Consistent with growing evidence of a link between working memory capacity and delay discounting, the effect was inversely proportional to baseline performance on a working memory task. Subjects who performed well on the working memory task had unchanged, or even decreased, delay discounting rates, suggesting that working memory ability may protect cognitive control from cognitive challenge. 
26394333	Deficits in reward anticipation are putative mechanisms for multiple psychopathologies. Research indicates that these deficits are characterized by reduced left (relative to right) frontal electroencephalogram (EEG) activity and blood oxygenation level-dependent (BOLD) signal abnormalities in mesolimbic and prefrontal neural regions during reward anticipation. Although it is often assumed that these two measures capture similar mechanisms, no study to our knowledge has directly examined the convergence between frontal EEG alpha asymmetry and functional magnetic resonance imaging (fMRI) during reward anticipation in the same sample. Therefore, the aim of the current study was to investigate if and where in the brain frontal EEG alpha asymmetry and fMRI measures were correlated in a sample of 40 adults. All participants completed two analogous reward anticipation tasks--once during EEG data collection and the other during fMRI data collection. Results indicated that the two measures do converge and that during reward anticipation, increased relative left frontal activity is associated with increased left anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) and left orbitofrontal cortex (OFC) activation. This suggests that the two measures may similarly capture PFC functioning, which is noteworthy given the role of these regions in reward processing and the pathophysiology of disorders such as depression and schizophrenia.
26391743	Novelty seeking (NS), defined as a tendency to pursue novel and intense emotional sensations and experiences, is one of the most relevant individual factors predicting drug use among humans. High novelty seeking (HNS) individuals present an increased risk of drug use compared to low novelty seekers. The NS endophenotype may explain some of the differences observed among individuals exposed to drugs of abuse in adolescence. However, there is little research about the particular response of adolescents to drugs of abuse in function of this endophenotype, and the data that do exist are inconclusive. The present work reviews the literature regarding the influence of NS on psychostimulant reward, with particular focus on adolescent subjects. First, the different animal models of NS and the importance of this endophenotype in adolescence are discussed. Later, studies that have used the most common animal models of reward (self-administration, conditioned place preference paradigms) to evaluate how the NS trait influences the rewarding effects of psychostimulants are reviewed. Finally, possible explanations for the enhanced risk of developing substance dependence among HNS individuals are discussed. In conclusion, the studies referred to in this review show that the HNS trait is associated with: (1) increased initial sensitivity to the rewarding effects of psychostimulants, (2) a higher level of drug craving when the subject is exposed to the environmental cues associated with the drug, and (3) enhanced long-term vulnerability to relapse to drug consumption after prolonged abstinence. 
26391642	β-amyloid is hypothesized to harm neural function and cognitive abilities by perturbing synaptic transmission and plasticity in Alzheimer's disease (AD). To assess the impact of this pathology on hippocampal neurons' ability to encode flexibly environmental information across learning, we performed electrophysiological recordings of CA1 hippocampal unit activity in AD transgenic mice as they acquired an action-reward association in a spatially defined environment; the behavioral task enabled the precise timing of discrete and intentional behaviors of the animal. We found that the proportion of behavioral task-sensitive cells in wild-type (WT) mice typically increased, whereas the proportion of place cells decreased with learning. In AD mice, this learning-dependent change of cell-discharge patterns was absent, and cells exhibited similar firings from the beginning to firings attained at the late learning stage in wild-type cells. These inflexible hippocampal representations of task and space throughout learning are accompanied by remarkable alterations of local oscillatory activity in the theta and ultra-fast ripple frequencies as well as learning abilities. The present data offer new insights into the in vivo cellular and network processes by which β-amyloid and other AD mutations may exert its harmful effects to produce cognitive and behavioral impairments in early stage of AD. 
26391065	Sexual experience in male rats followed by a period of abstinence causes sensitization to d-Amphetamine (Amph) reward, evidenced by an increased conditioned place preference (CPP) for low doses of Amph. Moreover, sexual experience induces neural plasticity within the nucleus accumbens (NAc), including induction of deltaFosB, which plays a key role in Amph reward cross-sensitization. The NMDA receptor subunit NR1 is also upregulated by mating, but the functional relevance of NMDA receptors in sex experience-induced effects is unknown. Here, we examined the influence of intra-NAc MK 801 infusions on sex experience-induced NAc deltaFosB and cFos expression, as well as mating- and Amph-induced CPP in adult male rats. In experiment 1, males received MK 801 or saline into the NAc during each of 4 consecutive days of mating or handling and were tested for Amph CPP and experience-induced deltaFosB 10 days later. Intra-NAc MK 801 during sexual behavior prevented experience-induced increases in Amph CPP and NAc deltaFosB expression without affecting sexual behavior. In experiment 2, the effects of intra-NAc MK 801 on mating-induced CPP were examined by intra-NAc infusion of MK 801 or saline prior to mating on conditioning days. Intra-NAc MK 801 did not affect mating-induced CPP. Next, effects of intra-NAc MK 801 on mating-induced cFos immunoreactivity were examined. MK 801 prevented mating-induced cFos expression in NAc shell and core. Together, these results provide evidence that NAc NMDA receptor activation during sexual behavior plays a key role in mating-induced cFos and deltaFosB expression and subsequent experience-induced cross-sensitization to Amph reward. 
26390266	Despite an initial focus on negative threatening stimuli, researchers have more recently expanded the investigation of attentional biases toward positive rewarding stimuli. The present meta-analysis systematically compared attentional bias for positive compared with neutral visual stimuli across 243 studies (N = 9,120 healthy participants) that used different types of attentional paradigms and positive stimuli. Factors were tested that, as postulated by several attentional models derived from theories of emotion, might modulate this bias. Overall, results showed a significant, albeit modest (Hedges' g = .258), attentional bias for positive as compared with neutral stimuli. Moderator analyses revealed that the magnitude of this attentional bias varied as a function of arousal and that this bias was significantly larger when the emotional stimulus was relevant to specific concerns (e.g., hunger) of the participants compared with other positive stimuli that were less relevant to the participants' concerns. Moreover, the moderator analyses showed that attentional bias for positive stimuli was larger in paradigms that measure early, rather than late, attentional processing, suggesting that attentional bias for positive stimuli occurs rapidly and involuntarily. Implications for theories of emotion and attention are discussed.
26390194	Bipolar disorder (BD) is associated with increased reactivity to rewards and heightened positive affectivity. It is less clear to what extent this heightened reward sensitivity is evident across contexts and what the associated neural mechanisms might be. The present investigation used both a monetary and social incentive delay task among adults with remitted BD Type I (n = 24) and a healthy nonpsychiatric control group (HC; n = 25) using fMRI. Both whole-brain and region-of-interest analyses revealed elevated reactivity to reward receipt in the striatum, a region implicated in incentive sensitivity, in the BD group. Post hoc analyses revealed that greater striatal reactivity to reward receipt, across monetary and social reward tasks, predicted decreased self-reported positive affect when anticipating subsequent rewards in the HC but not in the BD group. Results point toward elevated striatal reactivity to reward receipt as a potential neural mechanism of persistent reward pursuit in BD.
26388749	Elucidation of reinforcing mechanisms for associative learning is an important subject in neuroscience. Based on results of our previous pharmacological studies in crickets, we suggested that octopamine and dopamine mediate reward and punishment signals, respectively, in associative learning. In fruit-flies, however, it was concluded that dopamine mediates both appetitive and aversive reinforcement, which differs from our suggestion in crickets. In our previous studies, the effect of conditioning was tested at 30 min after training or later, due to limitations of our experimental procedures, and thus the possibility that octopamine and dopamine were not needed for initial acquisition of learning was not ruled out. In this study we first established a conditioning procedure to enable us to evaluate acquisition performance in crickets. Crickets extended their maxillary palpi and vigorously swung them when they perceived some odors, and we found that crickets that received pairing of an odor with water reward or sodium chloride punishment exhibited an increase or decrease in percentages of maxillary palpi extension responses to the odor. Using this procedure, we found that octopamine and dopamine receptor antagonists impair acquisition of appetitive and aversive learning, respectively. This finding suggests that neurotransmitters mediating appetitive reinforcement differ in crickets and fruit-flies. 
26388585	Individuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. The goal of the present study is to elucidate reward processing deficits, externalizing disorders, and impulsivity as elicited by electrophysiological, clinical and behavioral measures in subjects at high risk for alcoholism from families densely affected by alcoholism in the context of brain maturation across age groups and gender.Event-related potentials (ERPs) and current source density (CSD) during a monetary gambling task (MGT) were measured in 12-25 year old offspring (N=1864) of families in the Collaborative Study on the Genetics of Alcoholism (COGA) Prospective study; the high risk (HR, N=1569) subjects were from families densely affected with alcoholism and the low risk (LR, N=295) subjects were from community families. Externalizing disorders and impulsivity scores were also compared between LR and HR groups.	HR offspring from older (16-25 years) male and younger (12-15 years) female subgroups showed lower P3 amplitude than LR subjects. The amplitude decrement was most prominent in HR males during the loss condition. Overall, P3 amplitude increase at anterior sites and decrease at posterior areas were seen in older compared to younger subjects, suggesting frontalization during brain maturation. The HR subgroups also exhibited hypofrontality manifested as weaker CSD activity during both loss and gain conditions at frontal regions. Further, the HR subjects had higher impulsivity scores and increased prevalence of externalizing disorders. P3 amplitudes during the gain condition were negatively correlated with impulsivity scores.	Older male and younger female HR offspring, compared to their LR counterparts, manifested reward processing deficits as indexed by lower P3 amplitude and weaker CSD activity, along with higher prevalence of externalizing disorders and higher impulsivity scores.	Reward related P3 is a valuable measure reflecting neurocognitive dysfunction in subjects at risk for alcoholism, as well as to characterize reward processing and brain maturation across gender and age group.	
26388147	Convergent evidence implicates regional neural responses to reward anticipation in the pathogenesis of several psychiatric disorders, such as schizophrenia, where blunted ventral striatal responses to positive reward are observed in patients and at-risk populations. In vivo oxygen amperometry measurements in the ventral striatum in awake, behaving rats reveal reward-related tissue oxygen changes that closely parallel blood oxygen level dependent (BOLD) signal changes observed in human functional magnetic resonance imaging (fMRI), suggesting that a cross-species approach targeting this mechanism might be feasible in psychopharmacology. The present study explored modulatory effects of acute, subanaesthetic doses of ketamine-a pharmacological model widely used in psychopharmacological research, both preclinically and clinically-on ventral striatum activity during performance of a reward anticipation task in both species, using fMRI in humans and in vivo oxygen amperometry in rats. In a region-of-interest analysis conducted following a cross-over placebo and ketamine study in human subjects, an attenuated ventral striatal response during reward anticipation was observed following ketamine relative to placebo during performance of a monetary incentive delay task. In rats, a comparable attenuation of ventral striatal signal was found after ketamine challenge, relative to vehicle, in response to a conditioned stimulus that predicted delivery of reward. This study provides the first data in both species demonstrating an attenuating effect of acute ketamine on reward-related ventral striatal (O2) and fMRI signals. These findings may help elucidate a deeper mechanistic understanding of the potential role of ketamine as a model for psychosis, show that cross-species pharmacological experiments targeting reward signaling are feasible, and suggest this phenotype as a promising translational biomarker for the development of novel compounds, assessment of disease status, and treatment efficacy. 
26387518	Alcohol dependence is known to be associated with steep discounting of delayed rewards, but its relation to the discounting of delayed losses and probabilistic rewards is unclear. Moreover, patterns of alcohol consumption vary considerably between communities, but previous research has not examined the relation between discounting and alcohol dependence in low-income African Americans.The goal of the present study was to determine whether low-income, alcohol-dependent African Americans differ from controls in the degree to which they discount delayed rewards, delayed losses, or probabilistic rewards.	African-American participants, both cases and controls, were recruited from the same low-income neighborhoods, and propensity-score matching was used to further control for demographic differences. Participants performed three tasks that assessed their discounting of hypothetical monetary outcomes: delayed rewards, delayed losses, and probabilistic rewards.	Alcohol-dependent cases discounted delayed gains, but not delayed losses or probabilistic gains, more steeply than their matched controls. The difference in discounting of delayed gains was localized to the male cases, whose discounting was steeper than either the male controls or the female cases; no gender difference was observed between male and female controls.	The present results extend findings regarding discounting by substance abusers to a previously unstudied group, low-income African Americans, and suggest that in this group at least, alcohol dependence, particularly in males, may be more a reflection of choosing immediate rewards than of ignoring their delayed negative consequences.	
26385462	The central nervous system (CNS) is a major player in the regulation of food intake. The gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have an important role in this regulation by relaying information about nutritional status to the CNS. We hypothesised that endogenous GLP-1 has effects on CNS reward and satiety circuits.This was a randomised, crossover, placebo-controlled intervention study, performed in a university medical centre in the Netherlands. We included patients with type 2 diabetes and healthy lean control subjects. Individuals were eligible if they were 40-65 years. Inclusion criteria for the healthy lean individuals included a BMI <25 kg/m(2) and normoglycaemia. Inclusion criteria for the patients with type 2 diabetes included BMI >26 kg/m(2), HbA1c levels between 42 and 69 mmol/mol (6.0-8.5%) and treatment for diabetes with only oral glucose-lowering agents. We assessed CNS activation, defined as blood oxygen level dependent (BOLD) signal, in response to food pictures in obese patients with type 2 diabetes (n = 20) and healthy lean individuals (n = 20) using functional magnetic resonance imaging (fMRI). fMRI was performed in the fasted state and after meal intake on two occasions, once during infusion of the GLP-1 receptor antagonist exendin 9-39, which was administered to block actions of endogenous GLP-1, and on the other occasion during saline (placebo) infusion. Participants were blinded for the type of infusion. The order of infusion was determined by block randomisation. The primary outcome was the difference in BOLD signal, i.e. in CNS activation, in predefined regions in the CNS in response to viewing food pictures.	All patients were included in the analyses. Patients with type 2 diabetes showed increased CNS activation in CNS areas involved in the regulation of feeding (insula, amygdala and orbitofrontal cortex) in response to food pictures compared with lean individuals (p ≤ 0.04). Meal intake reduced activation in the insula in response to food pictures in both groups (p ≤ 0.05), but this was more pronounced in patients with type 2 diabetes. Blocking actions of endogenous GLP-1 significantly prevented meal-induced reductions in bilateral insula activation in response to food pictures in patients with type 2 diabetes (p ≤ 0.03).	Our findings support the hypothesis that endogenous GLP-1 is involved in postprandial satiating effects in the CNS of obese patients with type 2 diabetes.	
26384852	Drug addiction is characterized, in part, by deregulation of synaptic plasticity in circuits involved in reward, stress, cue learning, and memory. This study was designed to assess whether 185 variants in 32 genes central to synaptic plasticity and signal transduction contribute to vulnerability to develop heroin and/or cocaine addiction.Analyses were conducted in a sample of 1860 subjects divided according to ancestry (African and European) and drug of abuse (heroin or cocaine).	Eighteen SNPs in 11 genes (CDK5R1, EPHA4, EPHA6, FOSL2, MAPK3, MBP, MPDZ, NFKB1, NTRK2, NTSR1, and PRKCE) showed significant associations (P < 0.01), but the signals did not survive correction for multiple testing. SNP rs230530 in the NFKB1 gene, encoding the transcription regulator NF-kappa-B, was the only SNP indicated in both ancestry groups and both addictions. This SNP was previously identified in association with alcohol addiction. SNP rs3915568 in NTSR1, which encodes neurotensin receptor, and SNP rs1389752 in MPDZ, which encodes the multiple PDZ domain protein, were previously associated with heroin addiction or alcohol addiction, respectively.	The study supports the involvement of genetic variation in signal transduction pathways in heroin and cocaine addiction and provides preliminary evidence suggesting several new risk or protective loci that may be relevant for diagnosis and treatment success.	
26384529	Sleep is disrupted during active use of methamphetamine (MA), during withdrawal from the drug, and during abstinence from its use. However, relatively little is known about possible mediatory functions of disrupted sleep in the emergence, manifestation, and maintenance of cognitive and affective symptoms of MA abuse. We hypothesise that sleep functions as a mediator for stimulant drug effects. Specifically, we propose that objectively-measured sleep parameters can be used to explain some of the variability in the experience and presentation of memory deficits and emotion dysregulation in MA abusers. After describing how important healthy sleep is to unimpaired cognitive and affective functioning, we review literature describing how sleep is disrupted in MA abuse. Then, we provide a conceptual framework for our hypothesis by explaining the relationship between MA abuse, sleep disruption, memory deficits, emotion dysregulation, and changes in reward-related brain networks. We conclude by discussing implications of the hypothesis for research and treatment. 

26381438	Addiction is the continuation of a habit in spite of negative consequences. A vast literature gives evidence that this poor decision-making behavior in individuals addicted to drugs also generalizes to laboratory decision making tasks, suggesting that the impairment in decision-making is not limited to decisions about taking drugs. In the current experiment, opioid-addicted individuals and matched controls with no history of illicit drug use were administered a probabilistic classification task that embeds both reward-based and punishment-based learning trials, and a computational model of decision making was applied to understand the mechanisms describing individuals' performance on the task. Although behavioral results showed that opioid-addicted individuals performed as well as controls on both reward- and punishment-based learning, the modeling results suggested subtle differences in how decisions were made between the two groups. Specifically, the opioid-addicted group showed decreased tendency to repeat prior responses, meaning that they were more likely to "chase reward" when expectancies were violated, whereas controls were more likely to stick with a previously-successful response rule, despite occasional expectancy violations. This tendency to chase short-term reward, potentially at the expense of developing rules that maximize reward over the long term, may be a contributing factor to opioid addiction. Further work is indicated to better understand whether this tendency arises as a result of brain changes in the wake of continued opioid use/abuse, or might be a pre-existing factor that may contribute to risk for addiction. 
26379524	Many gait training programs are based on supervised learning principles: an individual is guided towards a desired gait pattern with directional error feedback. While this results in rapid adaptation, improvements quickly disappear. This study tested the hypothesis that a reinforcement learning approach improves retention and transfer of a new gait pattern. The results of a pilot study and larger experiment are presented. Healthy subjects were randomly assigned to either a supervised group, who received explicit instructions and directional error feedback while they learned a new gait pattern on a treadmill, or a reinforcement group, who was only shown whether they were close to or far from the desired gait. Subjects practiced for 10 min, followed by immediate and overnight retention and over-ground transfer tests. The pilot study showed that subjects could learn a new gait pattern under a reinforcement learning paradigm. The larger experiment, which had twice as many subjects (16 in each group) showed that the reinforcement group had better overnight retention than the supervised group (a 32% vs. 120% error increase, respectively), but there were no differences for over-ground transfer. These results suggest that encouraging participants to find rewarding actions through self-guided exploration is beneficial for retention. 
26379482	While it is widely recognized that thinking is somehow costly, involving cognitive effort and producing mental fatigue, these costs have alternatively been assumed to exist, treated as the brain's assessment of lost opportunities, or suggested to be metabolic but with implausible biological bases. We present a model of cognitive cost based on the novel idea that the brain senses and plans for longer-term allocation of metabolic resources by purposively conserving brain activity. We identify several distinct ways the brain might control its metabolic output, and show how a control-theoretic model that models decision-making with an energy budget can explain cognitive effort avoidance in terms of an optimal allocation of limited energetic resources. The model accounts for both subject responsiveness to reward and the detrimental effects of hypoglycemia on cognitive function. A critical component of the model is using astrocytic glycogen as a plausible basis for limited energetic reserves. Glycogen acts as an energy buffer that can temporarily support high neural activity beyond the rate supported by blood glucose supply. The published dynamics of glycogen depletion and repletion are consonant with a broad array of phenomena associated with cognitive cost. Our model thus subsumes both the "cost/benefit" and "limited resource" models of cognitive cost while retaining valuable contributions of each. We discuss how the rational control of metabolic resources could underpin the control of attention, working memory, cognitive look ahead, and model-free vs. model-based policy learning. 
26379239	Model-based and model-free reinforcement learning (RL) have been suggested as algorithmic realizations of goal-directed and habitual action strategies. Model-based RL is more flexible than model-free but requires sophisticated calculations using a learnt model of the world. This has led model-based RL to be identified with slow, deliberative processing, and model-free RL with fast, automatic processing. In support of this distinction, it has recently been shown that model-based reasoning is impaired by placing subjects under cognitive load--a hallmark of non-automaticity. Here, using the same task, we show that cognitive load does not impair model-based reasoning if subjects receive prior training on the task. This finding is replicated across two studies and a variety of analysis methods. Thus, task familiarity permits use of model-based reasoning in parallel with other cognitive demands. The ability to deploy model-based reasoning in an automatic, parallelizable fashion has widespread theoretical implications, particularly for the learning and execution of complex behaviors. It also suggests a range of important failure modes in psychiatric disorders.
26378202	Primates are social animals, and their survival depends on social interactions with others. Especially important for social interactions and welfare is the observation of rewards obtained by other individuals and the comparison with own reward. The fundamental social decision variable for the comparison process is reward inequity, defined by an asymmetric reward distribution among individuals. An important brain structure for coding reward inequity may be the striatum, a component of the basal ganglia involved in goal-directed behavior. Two rhesus monkeys were seated opposite each other and contacted a touch-sensitive table placed between them to obtain specific magnitudes of reward that were equally or unequally distributed among them. Response times in one of the animals demonstrated differential behavioral sensitivity to reward inequity. A group of neurons in the striatum showed distinct signals reflecting disadvantageous and advantageous reward inequity. These neuronal signals occurred irrespective of, or in conjunction with, own reward coding. These data demonstrate that striatal neurons of macaque monkeys sense the differences between other's and own reward. The neuronal activities are likely to contribute crucial reward information to neuronal mechanisms involved in social interactions. 
26378201	To investigate how the striatum integrates sensory information with reward information for behavioral guidance, we recorded single-unit activity in the dorsal striatum of head-fixed rats participating in a probabilistic Pavlovian conditioning task with auditory conditioned stimuli (CSs) in which reward probability was fixed for each CS but parametrically varied across CSs. We found that the activity of many neurons was linearly correlated with the reward probability indicated by the CSs. The recorded neurons could be classified according to their firing patterns into functional subtypes coding reward probability in different forms such as stimulus value, reward expectation, and reward prediction error. These results suggest that several functional subgroups of dorsal striatal neurons represent different kinds of information formed through extensive prior exposure to CS-reward contingencies. 
26377910	Opioid withdrawal causes a dysphoric state that can lead to complications in pain patients and can propagate use in drug abusers and addicts. Opioid withdrawal changes the activity of neurons in the nucleus accumbens, an area rich in both opioid-binding mu opioid receptors and glutamate-binding NMDA receptors. Because the accumbens is an area important for reward and aversion, plastic changes in this area during withdrawal could alter future behaviors in animals. We discovered an increase in phosphorylation of serine 897 in the NR1 subunit of the NMDA receptor (pNR1) during acute morphine withdrawal. This serine can be phosphorylated by protein kinase A (PKA) and dephosphorylated by calcineurin. We next demonstrated that this increased pNR1 change is associated with an increase in NR1 surface expression. NR1 surface expression and pNR1 levels during acute withdrawal were both reduced by the NMDA receptor antagonist MK-801 (dizocilpine hydrogen maleate) and the PKA inhibitor H-89(N-[2-[[3-(4-bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulfonamide dihydrochloride hydrate). We also found that pNR1 levels remained high after an extended morphine withdrawal period of 2 months, correlated with reward-seeking behavior for palatable food, and were associated with a decrease in accumbal calcineurin levels. These data suggest that NR1 phosphorylation changes during the acute withdrawal phase can be long lasting and may reflect a permanent change in NMDA receptors in the accumbens. These altered NMDA receptors in the accumbens could play a role in long-lasting behaviors associated with reward and opioid use. 
26377735	The rewarding effects of alcohol can lead to progressively heavier and more frequent drinking. Since studies of reward have mainly focused on responses to higher alcohol doses, the relations between reward and moderate/sustained alcohol exposure remain unknown. Our objective was to evaluate factors affecting the reward value of low alcohol doses and risk factors for increasing alcohol doses due to reward progression caused by alcohol exposure patterns. We thus performed conditioned place preference (CPP) and ethanol (EtOH)-induced locomotor sensitization tests in mice. Low-dose EtOH (0.5 or 1 g/kg twice/week)-induced CPP was stronger than that produced by saline control treatment, but the effect decreased with increasing numbers of conditioning trials. Moderate-dose/long-term EtOH exposure induced a weaker CPP than high-dose/short-term EtOH (2 g/kg twice/week) exposure with the same total EtOH dose (8 g/kg/experiment). Acamprosate calcium, an anti-relapse drug, preclusively reduced EtOH-induced CPP. EtOH induced CPP and locomotor sensitization in black but not white chamber, although the initial preference and the basal locomotion in each chamber were equal. Therefore the brightness of the chamber had an effect on EtOH-induced sensitization. Moreover, additional studies indicated that EtOH-induced locomotor sensitization also depends on the dose but not the administration interval. Paired associative learning with EtOH exposure is a potent factor influencing the level of reward produced by EtOH. Moreover, exposure to high doses of alcohol, even on an intermittent schedule, carries a higher risk of addiction than exposure to moderate doses over longer periods. 
26377468	Adaptively interacting with our environment requires extracting information that will allow us to successfully predict reward. This can be a challenge, particularly when there are many candidate cues, and when rewards are probabilistic. Recent work has demonstrated that visual attention is allocated to stimulus features that have been associated with reward on previous trials. The ventromedial frontal lobe (VMF) has been implicated in learning in dynamic environments of this kind, but the mechanism by which this region influences this process is not clear. Here, we hypothesized that the VMF plays a critical role in guiding attention to reward-predictive stimulus features based on feedback. We tested the effects of VMF damage in human subjects on a visual search task in which subjects were primed to attend to task-irrelevant colors associated with different levels of reward, incidental to the search task. Consistent with previous work, we found that distractors had a greater influence on reaction time when they appeared in colors associated with high reward in the previous trial compared with colors associated with low reward in healthy control subjects and patients with prefrontal damage sparing the VMF. However, this reward modulation of attentional priming was absent in patients with VMF damage. Thus, an intact VMF is necessary for directing attention based on experience with cue-reward associations. We suggest that this region plays a role in selecting reward-predictive cues to facilitate future learning.There has been a swell of interest recently in the ventromedial frontal cortex (VMF), a brain region critical to associative learning. However, the underlying mechanism by which this region guides learning is not well understood. Here, we tested the effects of damage to this region in humans on a task in which rewards were linked incidentally to visual features, resulting in trial-by-trial attentional priming. Controls and subjects with prefrontal damage sparing the VMF showed normal reward priming, but VMF-damaged patients did not. This work sheds light on a potential mechanism through which this region influences behavior. We suggest that the VMF is necessary for directing attention to reward-predictive visual features based on feedback, facilitating future learning and decision-making.	
26377457	Many actions performed by animals and humans depend on an ability to learn, estimate, and produce temporal intervals of behavioral relevance. Exemplifying such learning of cued expectancies is the observation of reward-timing activity in the primary visual cortex (V1) of rodents, wherein neural responses to visual cues come to predict the time of future reward as behaviorally experienced in the past. These reward-timing responses exhibit significant heterogeneity in at least three qualitatively distinct classes: sustained increase or sustained decrease in firing rate until the time of expected reward, and a class of cells that reach a peak in firing at the expected delay. We elaborate upon our existing model by including inhibitory and excitatory units while imposing simple connectivity rules to demonstrate what role these inhibitory elements and the simple architectures play in sculpting the response dynamics of the network. We find that simply adding inhibition is not sufficient for obtaining the different distinct response classes, and that a broad distribution of inhibitory projections is necessary for obtaining peak-type responses. Furthermore, although changes in connection strength that modulate the effects of inhibition onto excitatory units have a strong impact on the firing rate profile of these peaked responses, the network exhibits robustness in its overall ability to predict the expected time of reward. Finally, we demonstrate how the magnitude of expected reward can be encoded at the expected delay in the network and how peaked responses express this reward expectancy.Heterogeneity in single-neuron responses is a common feature of neuronal systems, although sometimes, in theoretical approaches, it is treated as a nuisance and seldom considered as conveying a different aspect of a signal. In this study, we focus on the heterogeneous responses in the primary visual cortex of rodents trained with a predictable delayed reward time. We describe under what conditions this heterogeneity can arise by self-organization, and what information it can convey. This study, while focusing on a specific system, provides insight onto how heterogeneity can arise in general while also shedding light onto mechanisms of reinforcement learning using realistic biological assumptions.	
26377334	Animal models of decision-making are some of the most highly regarded psychological process models; however, there remains a disconnection between how these models are used for pre-clinical applications and the resulting treatment outcomes. This may be due to untested assumptions that different species recruit the same neural or psychological mechanisms. We propose a novel human foraging paradigm (Web-Surf Task) that we translated from a rat foraging paradigm (Restaurant Row) to evaluate cross-species decision-making similarities. We examined behavioral parallels in human and non-human animals using the respective tasks. We also compared two variants of the human task, one using videos and the other using photos as rewards, by correlating revealed and stated preferences. We demonstrate similarities in choice behaviors and decision reaction times in human and rat subjects. Findings also indicate that videos yielded more reliable and valid results. The joint use of the Web-Surf Task and Restaurant Row is therefore a promising approach for functional translational research, aiming to bridge pre-clinical and clinical lines of research using analogous tasks.
26376987	Animals react in many different ways to being watched by others. In the context of cooperation, many theories emphasize reputational effects: Individuals should cooperate more if other potential cooperators are watching. In the context of competition, individuals might want to show off their strength and prowess if other potential competitors are watching. In the current study, we observed chimpanzees and human children in three experimental conditions involving resource acquisition: Participants were either in the presence of a passive observer (observed condition), an active observer who engaged in the same task as the participant (competition condition), or in the presence of but not directly observed by a conspecific (mere presence condition). While both species worked to acquire more resources in the competition condition, children but not chimpanzees also worked to acquire more resources in the observer condition (compared to the mere presence condition). These results suggest evolutionary continuity with regard to competition-based observer effects, but an additional observer effect in young children, potentially arising from an evolutionary-based concern for cooperative reputation. 
26375513	Posttraumatic stress (PTS) symptoms are associated with alcohol-related consequences, but there is a need to understand mediators that may help explain the reasons for this relationship. Individuals with PTS may experience elevated craving and alcohol reward value (demand), which may contribute to risk for alcohol-related consequences. We examined relationships between PTS status, craving, alcohol demand, and alcohol-related consequences in PTS-positive (n = 64) and PTS-negative (n = 200) college students (M age = 21.7; 77% women; 54% Caucasian; 34% African American) who endorsed past-month alcohol use. We tested craving and alcohol demand as mediators of the relation between PTS status and alcohol-related consequences. Craving (B = .04, SE = .02, 95% CI [.01, .10]), demand intensity (B = .02, SE = .02, 95% CI [.001, .07]), and demand elasticity (B = .05, SE = .03, 95% CI [.006, .12]) significantly mediated the association between PTS symptoms and alcohol-related consequences. Craving remained a significant mediator in a multiple mediators model (B = .08, SE = .04, 95% CI [.03, .19]). Craving and alcohol demand may partially explain the relation between PTS status and alcohol-related consequences. Craving may be especially salient for individuals with PTS symptoms, as it may lead to more severe alcohol-related consequences even in the absence of elevated alcohol consumption.
26373895	Offspring of parents with bipolar disorder (BD) (BO) are at higher risk of BD than offspring of parents with non-BD psychopathology (NBO), although both groups are at higher risk than offspring of psychiatrically healthy parents (HC) for other affective and psychiatric disorders. Abnormal functioning in reward circuitry has been demonstrated previously in individuals with BD. We aimed to determine whether activation and functional connectivity in this circuitry during risky decision-making differentiated BO, NBO and HC.BO (n = 29; mean age = 13.8 years; 14 female), NBO (n = 28; mean age = 13.9 years; 12 female) and HC (n = 23; mean age = 13.7 years; 11 female) were scanned while performing a number-guessing reward task. Of the participants, 11 BO and 12 NBO had current non-BD psychopathology; five BO and four NBO were taking psychotropic medications.	A 3 (group) × 2 (conditions: win-control/loss-control) analysis of variance revealed a main effect of group on right frontal pole activation: BO showed significantly greater activation than HC. There was a significant main effect of group on functional connectivity between the bilateral ventral striatum and the right ventrolateral prefrontal cortex (Z > 3.09, cluster-p < 0.05): BO showed significantly greater negative functional connectivity than other participants. These between-group differences remained after removing youth with psychiatric disorders and psychotropic medications from analyses.	This is the first study to demonstrate that reward circuitry activation and functional connectivity distinguish BO from NBO and HC. The fact that the pattern of findings remained when comparing healthy BO v. healthy NBO v. HC suggests that these neuroimaging measures may represent trait-level neurobiological markers conferring either risk for, or protection against, BD in youth.	
26373849	We reviewed the cognitive and neurobiological commonalities between chemical and behavioral addictions. Poor impulse control, limited executive function and abnormalities in reward processing are seen in both group of entities. Brain imaging shows consistent abnormalities in frontoparietal regions and the limbic system. In drug addiction, exaggerated risk taking behavior and temporal discounting may reflect an imbalance between a hyperactive mesolimbic and hypoactive executive systems. Several cognitive distortions are found in pathological gambling that seems to harness the brain reward system that has evolved to face situations related to skill, not random chance. Abnormalities in risk assessment and impulsivity are found in variety of eating disorders, in particularly related to eating behavior. Corresponding findings in eating disorder patients include abnormalities in the limbic system, i.e. orbitofrontal cortex (OFC), striatum and insula. Similarly, internet addiction disorder is associated with risky decision making and increased choice impulsivity with corresponding discrepant activation in the dorsolateral prefrontal cortex, OFC, anterior cingulate cortex, caudate and insula. Sexual addictions are in turn associated with exaggerated impulsive choice and suggestive evidence of abnormalities in reward processing. In sum, exploration of executive function and decision making abnormalities in chemical and behavioral addictions may increase understanding in their psychopathology and yield valuable targets for therapeutic interventions. 
26373834	Sleep is thought to play an important role in memory consolidation. Here we tested whether sleep alters the subjective value associated with objects located in spatial clusters that were navigated to in a large-scale virtual town. We found that sleep enhances a generalization of the value of high-value objects to the value of locally clustered objects, resulting in an impaired memory for the value of high-valued objects. Our results are consistent with (a) spatial context helping to bind items together in long-term memory and serve as a basis for generalizing across memories and (b) sleep mediating memory effects on salient/reward-related items. 
26373829	Although several studies have examined the subcortical circuitry underlying Pavlovian-to-instrumental transfer (PIT), the role of medial prefrontal cortex in this behavior is largely unknown. Elucidating the cortical contributions to PIT will be key for understanding how reward-paired cues control behavior in both adaptive and maladaptive context (i.e., addiction). Here we use bilateral lesions in a rat model to show that infralimbic prefrontal cortex (ilPFC) is necessary for appropriate expression of PIT. Further, we show that ilPFC mediates this effect via functional connectivity with nucleus accumbens shell (NAcS). Together, these data provide the first demonstration that a specific cortico-striatal circuit is necessary for cue-invigorated reward seeking during specific PIT. 
26373473	Brain endocannabinoid (eCB) signalling influences the motivation for natural rewards (such as palatable food, sexual activity and social interaction) and modulates the rewarding effects of addictive drugs. Pathological forms of natural and drug-induced reward are associated with dysregulated eCB signalling that may derive from pre-existing genetic factors or from prolonged drug exposure. Impaired eCB signalling contributes to dysregulated synaptic plasticity, increased stress responsivity, negative emotional states and cravings that propel addiction. Understanding the contributions of eCB disruptions to behavioural and physiological traits provides insight into the eCB influence on addiction vulnerability. 
26372082	Despite much effort to decrease food intake by altering portion sizes, "super-sized" meals are the preferred choice of many. This research investigated the extent to which individuals can be subtly incentivized to choose smaller portion sizes. Three randomized experiments (2 in the lab and 1 in the field) established that individuals' choice of full-sized food portions is reduced when they are given the opportunity to choose a half-sized version with a modest nonfood incentive. This substitution effect was robust across different nonfood incentives, foods, populations, and time. Experiment 1 established the effect with children, using inexpensive headphones as nonfood incentives. Experiment 2--a longitudinal study across multiple days--generalized this effect with adults, using the mere chance to win either gift cards or frequent flyer miles as nonfood incentives. Experiment 3 demonstrated the effect among actual restaurant customers who had originally planned to eat a full-sized portion, using the mere chance to win small amounts of money. Our investigation broadens the psychology of food portion choice from perceptual and social factors to motivational determinants.
26371765	Impairments in central reward processing constitute an important aspect of the negative symptoms of schizophrenia. Despite its clinical relevance, the etiology of deficient reward processing in schizophrenia remains largely unknown. Here, we used an epidemiologically informed mouse model of schizophrenia to explore the effects of prenatal immune activation on reward-related functions. The model is based on maternal administration of the viral mimic PolyI:C and has been developed in relation to the epidemiological evidence demonstrating enhanced risk of schizophrenia and related disorders following prenatal maternal infection. We show that prenatal immune activation induces selective deficits in the expression (but not acquisition) of conditioned place preference for a natural reward (sucrose) without changing hedonic or neophobic responses to the reward. On the other hand, prenatal immune activation led to enhanced place preference for the psychostimulant drug cocaine, while it attenuated the locomotor reaction to the drug. The prenatal exposure did not alter negative reinforcement learning as assessed using a contextual fear conditioning paradigm. Our findings suggest that the nature of reward-related abnormalities following prenatal immune challenge depends on the specificity of the reward (natural reward vs drug of abuse) as well as on the valence domain (positive vs negative reinforcement learning). Moreover, our data indicate that reward abnormalities emerging in prenatally immune-challenged offspring may, at least in part, stem from an inability to retrieve previously established context-reward associations and to integrate such information for appropriate goal-directed behavior. 
26371378	Increasing motivation can positively impact cognitive performance. Here we employed a cognitive timing task that allows us to detect changes in cognitive performance that are not influenced by general activity or arousal factors such as the speed or persistence of responding. This approach allowed us to manipulate motivation using three different methods; molecular/genetic, behavioral and pharmacological. Increased striatal D2Rs resulted in deficits in temporal discrimination. Switching off the transgene improved motivation in earlier studies, and here partially rescued the temporal discrimination deficit. To manipulate motivation behaviorally, we altered reward magnitude and found that increasing reward magnitude improved timing in control mice and partially rescued timing in the transgenic mice. Lastly, we manipulated motivation pharmacologically using a functionally selective 5-HT2C receptor ligand, SB242084, which we previously found to increase incentive motivation. SB242084 improved temporal discrimination in both control and transgenic mice. Thus, while there is a general intuitive belief that motivation can affect cognition, we here provide a direct demonstration that enhancing motivation, in a variety of ways, can be an effective strategy for enhancing temporal cognition. Understanding the interaction of motivation and cognition is of clinical significance since many psychiatric disorders are characterized by deficits in both domains.
26370327	Critical development of the prefrontal cortex occurs during adolescence, a period of increased independence marked by decision making that often includes engagement in risky behaviors, such as substance use. Consumption of alcohol during adolescence has been associated with increased impulsivity that persists across the lifespan, an effect which may be caused by long-term disruptions in cortical processing of rewards. To determine if alcohol consumption alters cortical encoding of rewards of different sizes and probabilities, we gave rats limited access to alcohol in gelatin during adolescence only. In adulthood, we recorded the electrophysiological activity of individual neurons of the orbitofrontal cortex while rats performed a risk task that varied the level of risk from day-to-day. Rats that had consumed higher levels of alcohol showed increased risk preference in the task compared with control and low alcohol-consuming rats. Patterns of neuronal responses were identified using principal component analysis. Of the multiple patterns observed, only one was modulated by adolescent alcohol consumption and showed strongest modulation after reward receipt. This subpopulation of neurons showed blunted firing rates following rewards in alcohol-consuming rats, suggesting a mechanism through which adolescent alcohol exposure may have lasting effects on reward processing in the context of decision making. The differences in OFC responses between high alcohol consumers and control animals not given access to alcohol support the idea that, regardless of potential variability in innate alcohol preferences, voluntary consumption of alcohol during adolescence biases choice patterns longitudinally through alterations in cortical function. 
26367309	The future is uncertain because some forthcoming events are unpredictable and also because our ability to foresee the myriad consequences of our own actions is limited. Here we studied how humans select actions under such extrinsic and intrinsic uncertainty, in view of an exponentially expanding number of prospects on a branching multivalued visual stimulus. A triangular grid of disks of different sizes scrolled down a touchscreen at a variable speed. The larger disks represented larger rewards. The task was to maximize the cumulative reward by touching one disk at a time in a rapid sequence, forming an upward path across the grid, while every step along the path constrained the part of the grid accessible in the future. This task captured some of the complexity of natural behavior in the risky and dynamic world, where ongoing decisions alter the landscape of future rewards. By comparing human behavior with behavior of ideal actors, we identified the strategies used by humans in terms of how far into the future they looked (their "depth of computation") and how often they attempted to incorporate new information about the future rewards (their "recalculation period"). We found that, for a given task difficulty, humans traded off their depth of computation for the recalculation period. The form of this tradeoff was consistent with a complete, brute-force exploration of all possible paths up to a resource-limited finite depth. A step-by-step analysis of the human behavior revealed that participants took into account very fine distinctions between the future rewards and that they abstained from some simple heuristics in assessment of the alternative paths, such as seeking only the largest disks or avoiding the smaller disks. The participants preferred to reduce their depth of computation or increase the recalculation period rather than sacrifice the precision of computation. 
26365765	Dopamine (DA) neurons are thought to facilitate learning by signaling reward prediction errors (RPEs), the discrepancy between actual and expected reward. However, how RPEs are calculated remains unknown. It has been hypothesized that DA neurons receive RPE signals from the lateral habenula. Here, we tested how lesions of the habenular complex affect the response of optogenetically identified DA neurons in mice. We found that lesions impaired specific aspects of RPE signaling in DA neurons. The inhibitory responses caused by reward omission were greatly diminished while inhibitory responses to aversive stimuli, such as air puff-predictive cues or air puff, remained unimpaired. Furthermore, we found that after habenula lesions, DA neurons' ability to signal graded levels of positive RPEs became unreliable, yet significant excitatory responses still remained. These results demonstrate that the habenula plays a critical role in DA RPE signaling but suggest that it is not the exclusive source of RPE signals.
26365712	Optimal social functioning occasionally requires concealment of one's emotions in order to meet one's immediate goals and environmental demands. However, because emotions serve an important communicative function, their habitual suppression disrupts the flow of social exchanges and, thus, incurs significant interpersonal costs. Evidence is accruing that the disruption in social interactions, linked to habitual expressive suppression use, stems not only from intrapersonal, but also from interpersonal causes, since the suppressors' restricted affective displays reportedly inhibit their interlocutors' emotionally expressive behaviors. However, expressive suppression use is not known to lead to clinically significant social impairments. One explanation may be that over the lifespan, individuals who habitually suppress their emotions come to compensate for their interlocutors' restrained expressive behaviors by developing an increased sensitivity to nonverbal affective cues. To probe this issue, the present study used functional magnetic resonance imaging (fMRI) to scan healthy older women while they viewed silent videos of a male social target displaying nonverbal emotional behavior, together with a brief verbal description of the accompanying context, and then judged the target's affect. As predicted, perceivers who reported greater habitual use of expressive suppression showed increased neural processing of nonverbal affective cues. This effect appeared to be coordinated in a top-down manner via cognitive control. Greater neural processing of nonverbal cues among perceivers who habitually suppress their emotions was linked to increased ventral striatum activity, suggestive of increased reward value/personal relevance ascribed to emotionally expressive nonverbal behaviors. These findings thus provide neural evidence broadly consistent with the hypothesized link between habitual use of expressive suppression and compensatory development of increased responsiveness to nonverbal affective cues, while also suggesting one explanation for the suppressors' poorer cognitive performance in social situations. Moreover, our results point to a potential neural mechanism supporting the development and perpetuation of expressive suppression as an emotion regulation strategy. 
26365456	The FVB/N mice are well suited to generate transgenic animals. These mice are also particularly sensitive to seizures and neurodegeneration induced by systemic administration of chemoconvulsants and are very useful to model epilepsy. However, previous studies report strong cognitive and visual impairments suggesting this background unsuitable for behavioral analysis. In this study, we assessed and compared learning abilities of FVB/N mice to the well characterized C57BL/6 strain using the olfactory tubing maze, a non-visual hippocampus-dependent task in which the mice were trained to learn odor-reward associations. Exploratory behavior and spontaneous locomotor activity were then compared using the open field test. We demonstrated that FVB/N mice were able to learn the task, reaching at the end of the test a high percentage of correct responses. Interestingly, the performance of the FVB/N mice was at least similar to that of the C57BL/6 mice. Moreover, in contrast to previous reports, the FVB/N mice displayed a spontaneous locomotor activity lower than C57BL/6 mice. Our study demonstrated that FVB/N mice are not cognitively impaired and that their learning and memory performance can be assessed when the task is based on olfaction rather than vision.
26365195	Cocaine is a highly addictive drug that acts upon the brain's reward circuitry via the inhibition of monoamine uptake. Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine's effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors. Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between Gq/11-coupled type-1 metabotropic glutamate and α1-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C. The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo. Our results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine.
26364979	The dopamine transporter (DAT) is a major regulator of synaptic dopamine (DA) availability. It plays key roles in motor control and motor learning, memory formation, and reward-seeking behavior, is a major target of cocaine and methamphetamines, and has been assumed to be conserved among vertebrates. We have found, however, that birds, crocodiles, and lizards lack the DAT gene. We also found that the unprecedented loss of this important gene is compensated for by the expression of the noradrenaline transporter (NAT) gene, and not the serotonin transporter genes, in dopaminergic cells, which explains the peculiar pharmacology of the DA reuptake activity previously noted in bird striatum. This unexpected pattern contrasts with that of ancestral vertebrates (e.g. fish) and mammals, where the NAT gene is selectively expressed in noradrenergic cells. DA circuits in birds/reptiles and mammals thus operate with an analogous reuptake mechanism exerted by different genes, bringing new insights into gene expression regulation in dopaminergic cells and the evolution of a key molecular player in reward and addiction pathways. 
26364127	Neurobiological investigation of heroin revealed that abusers of this highly addictive substance show dysregulation in brain circuits for reward processing and cognitive control. Psychologically, personality traits related to reward processing and cognitive control differed between heroin abusers and non-abusers. Yet, there is no direct evidence on the relationship between these neurobiological and psychological findings on heroin abusers, and whether such relationship is altered in these abusers. The present study filled this research gap by integrating findings obtained via magnetic resonance imaging (structural volume and resting-state functional connectivity) and self-reported personality trait measures (Zuckerman׳s Sensation Seeking Scale and Barratt Impulsivity Scale) on 33 abstinent heroin users and 30 matched healthy controls. The key finding is a negative relationship between high sensation seeking tendency and midbrain structural volume in the heroin users. Importantly, there was stronger coupling between the midbrain and ventromedial prefrontal cortex and weaker coupling between the midbrain and dorsolateral prefrontal cortex in heroin users. Our findings offer significant insight into the neural underpinning of sensation seeking in heroin users. Importantly, the data shed light on a novel relationship between the mesolimbic-prefrontal pathway of the reward system and the high sensation seeking personality trait in heroin abusers. 
26363137	The human and rodent ventral striatal local field potentials show striking oscillations in the gamma band (~ 40-100 Hz), which have been linked to aspects of behaviour such as reward anticipation and delivery, movement initiation, learning from feedback, and decision-making. These oscillations show a rich temporal organization, whose relationship with behavioural variables is not well understood. Here, we show that, in rats performing a conditioned approach task, low-gamma and high-gamma oscillations during an immobile reward anticipation epoch were largely insensitive to outcome value, even though rats distinguished behaviourally between different outcomes, and single units encoded outcome value. Behaviour was highly stereotyped, yet we observed large variability from trial to trial in the occurrence and timing of these oscillations. Furthermore, higher-order features such as high-gamma power leading low-gamma power, and phase-amplitude coupling to lower-frequency bands, were only marginally modulated by outcome value. Moreover, these patterns closely resembled those found during off-task rest periods in which no rewards could be earned. These observations suggest a new interpretation of ventral striatal gamma oscillations as reflecting a default or resting state, with only minor and highly variable modulation by specific task-related variables.
26362736	The negative symptoms of schizophrenia have been associated with altered neural activity during both reward processing and cognitive processing. Even though increasing evidence suggests a strong interaction between these two domains, it has not been studied in relation to negative symptoms. To elucidate neural mechanisms of the reward-cognition interaction, we applied a letter variant of the n-back working memory task and varied the financial incentives for performance. In the interaction contrast, we found a significantly activated cluster in the rostral anterior cingulate cortex (ACC), the middle frontal gyrus, and the bilateral superior frontal gyrus. The interaction did not differ significantly between the patient group and a healthy control group, suggesting that patients with schizophrenia are on average able to integrate reward information and utilize this information to maximize cognitive performance. However within the patient group, we found a significant inverse correlation of ACC activity with the factor diminished expression. This finding is consistent with the model that a lack of available cognitive resources leads to diminished expression. We therefore argue that patients with diminished expression have difficulties in recruiting additional cognitive resources (as implemented in the ACC) in response to an anticipated reward. Due to this lack of cognitive resources, less processing capacity is available for effective expression, resulting in diminished expressive behavior. 
26362691	Despite the high risk of tobacco-related morbidity and mortality among low-income persons, few studies have connected low-income smokers to evidence-based treatments. We will examine a smoking cessation intervention integrated into primary care. To begin, we completed qualitative formative research to refine an intervention utilizing the services of a patient navigator trained to promote smoking cessation. Next, we will conduct a randomized controlled trial combining two interventions: patient navigation and financial incentives. The goal of the intervention is to promote smoking cessation among patients who receive primary care in a large urban safety-net hospital. Our intervention will encourage patients to utilize existing smoking cessation resources (e.g., quit lines, smoking cessation groups, discussing smoking cessation with their primary care providers). To test our intervention, we will conduct a randomized controlled trial, randomizing 352 patients to the intervention condition (patient navigation and financial incentives) or an enhanced traditional care control condition. We will perform follow-up at 6, 12, and 18 months following the start of the intervention. Evaluation of the intervention will target several implementation variables: reach (participation rate and representativeness), effectiveness (smoking cessation at 12 months [primary outcome]), unintended consequences (e.g., purchase of illicit substances with incentive money), adoption (use of intervention across primary care suites), implementation (delivery of intervention), and maintenance (smoking cessation after conclusion of intervention). Improving the implementation of smoking cessation interventions in primary care settings serving large underserved populations could have substantial public health impact, reducing cancer-related morbidity/mortality and associated health disparities.
26360089	Neuropsychiatric disorders typically manifest as problems with attentional biases, aberrant learning, dysfunctional reward systems, and an absence of top-down cognitive control by the prefrontal cortex. In view of the cost of common mental health disorders, in terms of distress to the individual and family in addition to the financial cost to society and governments, new developments for treatments that address cognitive dysfunction should be a priority so that all members of society can flourish. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate, are used as treatments for the cognitive symptoms of Alzheimer's disease and attention deficit hyperactivity disorder. However, these drugs and others, including modafinil, are being increasingly used by healthy people for enhancement purposes. Importantly for ethical and safety reasons, the drivers for this increasing lifestyle use of so-called smart drugs by healthy people should be considered and discussions must occur about how to ensure present and future pharmacological cognitive enhancers are used for the benefit of society. 
26359751	Men with antisocial personality disorder show lifelong abnormalities in adaptive decision making guided by the weighing up of reward and punishment information. Among men with antisocial personality disorder, modification of the behaviour of those with additional diagnoses of psychopathy seems particularly resistant to punishment.We did a case-control functional MRI (fMRI) study in 50 men, of whom 12 were violent offenders with antisocial personality disorder and psychopathy, 20 were violent offenders with antisocial personality disorder but not psychopathy, and 18 were healthy non-offenders. We used fMRI to measure brain activation associated with the representation of punishment or reward information during an event-related probabilistic response-reversal task, assessed with standard general linear-model-based analysis.	Offenders with antisocial personality disorder and psychopathy displayed discrete regions of increased activation in the posterior cingulate cortex and anterior insula in response to punished errors during the task reversal phase, and decreased activation to all correct rewarded responses in the superior temporal cortex. This finding was in contrast to results for offenders without psychopathy and healthy non-offenders.	Punishment prediction error signalling in offenders with antisocial personality disorder and psychopathy was highly atypical. This finding challenges the widely held view that such men are simply characterised by diminished neural sensitivity to punishment. Instead, this finding indicates altered organisation of the information-processing system responsible for reinforcement learning and appropriate decision making. This difference between violent offenders with antisocial personality disorder with and without psychopathy has implications for the causes of these disorders and for treatment approaches.	National Forensic Mental Health Research and Development Programme, UK Ministry of Justice, Psychiatry Research Trust, NIHR Biomedical Research Centre.	
26359113	Inflammation rapidly impairs mood and cognition and, when severe, can appear indistinguishable from major depression. These sickness responses are characterized by an acute reorientation of motivational state; pleasurable activities are avoided, and sensitivity to negative stimuli is enhanced. However, it remains unclear how these rapid shifts in behavior are mediated within the brain.Here, we combined computational modeling of choice behavior, experimentally induced inflammation, and functional brain imaging (functional magnetic resonance imaging) to describe these mechanisms. Using a double-blind, randomized crossover study design, 24 healthy volunteers completed a probabilistic instrumental learning task on two separate occasions, one 3 hours after typhoid vaccination and one 3 hours after saline (placebo) injection. Participants learned to select high probability reward (win £1) and avoid high probability punishment (lose £1) stimuli. An action-value learning algorithm was fit to the observed behavior, then used within functional magnetic resonance imaging analyses to identify neural coding of prediction error signals driving motivational learning.	Inflammation acutely biased behavior, enhancing punishment compared with reward sensitivity, through distinct actions on neural representations of reward and punishment prediction errors within the ventral striatum and anterior insula. Consequently, choice options leading to potential rewards were less behaviorally attractive, and those leading to punishments were more aversive.	Our findings demonstrate the neural mediation of a rapid, state-dependent reorientation of reward versus punishment sensitivity during inflammation. This mechanism may aid the adaptive reallocation of metabolic resources during acute sickness but might also account for maladaptive, motivational changes that underpin the association between chronic inflammation and depression.	
26358733	Gastric bypass surgery is an effective long-term weight loss intervention. Key to its success appears a putative shift in food preference away from high-energy-density foods associated with a reduced appetitive drive and loss of neural reactivity in the reward system of the brain towards food. Post-prandial exaggerated satiety gut hormone responses have been implicated as mediators. Whilst the positive impact of bariatric surgery on both physical and psychological outcomes for many patients is clearly evident, a subset of patients appear to be detrimentally affected by this loss of reward from food and by a lack of alternative strategies for regulating affect after surgery. Mindfulness training has emerged as a potential tool in reducing the need for immediate reward that underpins much of eating behaviour. Further research is needed to help identify patients who may be more vulnerable after gastric bypass and which forms of support may be most beneficial.
26357590	Recent evidence suggests blunted responses to rewarding stimuli in patients with post-traumatic stress disorder (PTSD). However, it is not clear whether these alterations in reward processing normalize in remitted PTSD patients.We tested behavioral and physiological responses to monetary reward in a spatial memory task in 13 accident survivors with remitted PTSD, 14 accident survivors who never had PTSD, and 16 nontrauma-exposed subjects. All accident survivors were recruited from two samples of severely physically injured patients, who had participated in previous prospective studies on the incidence of PTSD after accidental injury approximately 10 years ago. Reaction time, accuracy, skin conductance responses, and self-reported mood were assessed during the task.	Accident survivors who never had PTSD and nontrauma exposed controls reported significantly higher positive mood in the reinforced versus nonreinforced condition (P < 0.045 and P < 0.001, respectively), while there was no effect of reinforcement in remitted PTSD subjects.	Our findings suggest an alteration of the reward system in remitted PTSD. Further research is needed to investigate whether altered reward processing is a residual characteristic in PTSD after remission of symptoms or, alternatively, a preexisting risk factor for the development of PTSD after a traumatic event.	
26356934	Data sculptures are a promising type of visualizations in which data is given a physical form. In the past, they have mostly been used for artistic, communicative or educational purposes, and designers of data sculptures argue that in such situations, physical visualizations can be more enriching than pixel-based visualizations. We present the design of Activity Sculptures: data sculptures of running activity. In a three-week field study we investigated the impact of the sculptures on 14 participants' running activity, the personal and social behaviors generated by the sculptures, as well as participants' experiences when receiving these individual physical tokens generated from the specific data of their runs. The physical rewards generated curiosity and personal experimentation but also social dynamics such as discussion on runs or envy/competition. We argue that such passive (or calm) visualizations can complement nudging and other mechanisms of persuasion with a more playful and reflective look at ones' activity. 
26354923	Variations in the fat mass and obesity-associated (FTO) gene are linked to obesity. However, the underlying neurobiological mechanisms by which these genetic variants influence obesity, behavior, and brain are unknown. Given that Fto regulates D2/3R signaling in mice, we tested in humans whether variants in FTO would interact with a variant in the ANKK1 gene, which alters D2R signaling and is also associated with obesity. In a behavioral and fMRI study, we demonstrate that gene variants of FTO affect dopamine (D2)-dependent midbrain brain responses to reward learning and behavioral responses associated with learning from negative outcome in humans. Furthermore, dynamic causal modeling confirmed that FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic predisposition alters reward processing not only in obesity, but also in other disorders with altered D2R-dependent impulse control, such as addiction. Significance statement: Variations in the fat mass and obesity-associated (FTO) gene are associated with obesity. Here we demonstrate that variants of FTO affect dopamine-dependent midbrain brain responses and learning from negative outcomes in humans during a reward learning task. Furthermore, FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic vulnerability in reward processing can increase predisposition to obesity.
26354905	Rewards obtained from specific behaviors can and do change across time. To adapt to such conditions, humans need to represent and update associations between behaviors and their outcomes. Much previous work focused on how rewards affect the processing of specific tasks. However, abstract associations between multiple potential behaviors and multiple rewards are an important basis for adaptation as well. In this experiment, we directly investigated which brain areas represent associations between multiple tasks and rewards, using time-resolved multivariate pattern analysis of functional magnetic resonance imaging data. Importantly, we were able to dissociate neural signals reflecting task-reward associations from those related to task preparation and reward expectation processes, variables that were often correlated in previous research. We hypothesized that brain regions involved in processing tasks and/or rewards will be involved in processing associations between them. Candidate areas included the dorsal anterior cingulate cortex, which is involved in associating simple actions and rewards, and the parietal cortex, which has been shown to represent task rules and action values. Our results indicate that local spatial activation patterns in the inferior parietal cortex indeed represent task-reward associations. Interestingly, the parietal cortex flexibly changes its content of representation within trials. It first represents task-reward associations, later switching to process tasks and rewards directly. These findings highlight the importance of the inferior parietal cortex in associating behaviors with their outcomes and further show that it can flexibly reconfigure its function within single trials. Significance statement: Rewards obtained from specific behaviors rarely remain constant over time. To adapt to changing conditions, humans need to continuously update and represent the current association between behavior and its outcomes. However, little is known about the neural representation of behavior-outcome associations. Here, we used multivariate pattern analysis of functional magnetic resonance imaging data to investigate the neural correlates of such associations. Our results demonstrate that the parietal cortex plays a central role in representing associations between multiple behaviors and their outcomes. They further highlight the flexibility of the parietal cortex, because we find it to adapt its function to changing task demands within trials on relatively short timescales.
26354043	The endogenous endocannabinoid system has a crucial role in regulating appetite and feeding behavior in mammals, as well as working memory and reward mechanisms. In order to elucidate the possible role of cannabinoid type-1 receptors (CB1Rs) in the regulation of hippocampal plasticity in animals exposed to food restriction (FR), we limited the availability of food to a 2-h daily period for 3 weeks in Sprague-Dawley rats. FR rats showed a higher long-term potentiation at hippocampal CA1 excitatory synapses with a parallel increase in glutamate release when compared with animals fed ad libitum. FR rats showed a significant increase in the long-term spatial memory determined by Barnes maze. FR was also associated with a decreased inhibitory effect of the CB1R agonist win55,212-2 on glutamatergic field excitatory postsynaptic potentials, together with a decrease in hippocampal CB1R protein expression. In addition, hippocampal brain-derived neurotrophic factor protein levels and mushroom dendritic spine density were significantly enhanced in FR rats. Altogether, our data suggest that alterations of hippocampal CB1R expression and function in FR rats are associated with dendritic spine remodeling and functional potentiation of CA1 excitatory synapses, and these findings are consistent with increasing evidence supporting the idea that FR may improve cognitive functions. 
26352802	Gambling is an addictive disorder with serious societal and personal costs. To-date, there are no approved pharmacological treatments for gambling disorder. Evidence suggests a role for dopamine in gambling disorder and thus may provide a therapeutic target. The present study therefore aimed to investigate the effects of selective antagonists and agonists of D2, D3 and D4 receptors in a rodent analogue of the Iowa gambling task used clinically. In this rat gambling task (rGT), animals are trained to associate different response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. As in the Iowa gambling task, the optimal strategy is to avoid the tempting high-risk high-reward options, and instead favor those linked to smaller per-trial rewards but also lower punishments, thereby maximizing the amount of reward earned over time. Administration of those selective ligands did not affect decision making under the rGT. Only the D4 drug had modest effects on latency measures suggesting that D4 may contribute in some ways to decision making under this task. 
26350639	A key aspect of cooperation is partner choice: choosing the best available partner improves the chances of a successful cooperative interaction and decreases the likelihood of being exploited. However, in studies on cooperation subjects are rarely allowed to freely choose their partners. Group-living animals live in a complex social environment where they can choose among several social partners differing in, for example, sex, age, temperament, or dominance status. Our study investigated whether wild Barbary macaques succeed to cooperate using an experimental apparatus, and whether individual and social factors affect their choice of partners and the degree of cooperation. We used the string pulling task that requires two monkeys to manipulate simultaneously a rope in order to receive a food reward. The monkeys were free to interact with the apparatus or not and to choose their partner. The results showed that Barbary macaques are able to pair up with a partner to cooperate using the apparatus. High level of tolerance between monkeys was necessary for the initiation of successful cooperation, while strong social bond positively affected the maintenance of cooperative interactions. Dominance status, sex, age, and temperament of the subjects also affected their choice and performance. These factors thus need to be taken into account in cooperative experiment on animals. Tolerance between social partners is likely to be a prerequisite for the evolution of cooperation. 
26350468	Emerging evidence suggests that insomnia may disrupt reward-related brain function-a potentially important factor in the development of depressive disorder. Adolescence may be a period during which such disruption is especially problematic given the rise in the incidence of insomnia and ongoing development of neural systems that support reward processing. The present study uses longitudinal data to test the hypothesis that disruption of neural reward processing is a mechanism by which insomnia symptoms-including nocturnal insomnia symptoms (NIS) and nonrestorative sleep (NRS)-contribute to depressive symptoms in adolescent girls.Participants were 123 adolescent girls and their caregivers from an ongoing longitudinal study of precursors to depression across adolescent development. NIS and NRS were assessed annually from ages 9 to 13 years. Girls completed a monetary reward task during a functional MRI scan at age 16 years. Depressive symptoms were assessed at ages 16 and 17 years. Multivariable regression tested the prospective associations between NIS and NRS, neural response during reward anticipation, and the mean number of depressive symptoms (omitting sleep problems).	NRS, but not NIS, during early adolescence was positively associated with late adolescent dorsal medial prefrontal cortex (dmPFC) response to reward anticipation and depressive symptoms. DMPFC response mediated the relationship between early adolescent NRS and late adolescent depressive symptoms.	These results suggest that NRS may contribute to depression by disrupting reward processing via altered activity in a region of prefrontal cortex involved in affective control. The results also support the mechanistic differentiation of NIS and NRS.	
26349556	There is evidence that reward-related neural reactivity is altered in depressive disorders. Glucocorticoids influence dopaminergic transmission, which is widely implicated in reward processing. However, no studies have examined the effect of glucocorticoid receptor gene polymorphisms on reward-related neural reactivity in depressed or healthy individuals. Fifty-nine depressed individuals with major depressive disorder (n=33) or bipolar disorder (n=26), and 32 healthy individuals were genotyped for the glucocorticoid receptor BclI G/C polymorphism, and underwent functional magnetic resonance imaging during a monetary reward task. We examined the effect of the glucocorticoid receptor BclI G/C polymorphism on reward expectancy (RE; expected outcome value) and prediction error (PE; discrepancy between expected and actual outcome) related ventral striatal reactivity. There was a significant interaction between reward condition and BclI genotype (p=0.007). C-allele carriers showed higher PE than RE-related right ventral striatal reactivity (p<0.001), whereas no such difference was observed in G/G homozygotes. Accordingly, C-allele carriers showed a greater difference between PE and RE-related right ventral striatal reactivity than G/G homozygotes (p<0.005), and also showed lower RE-related right ventral striatal reactivity than G/G homozygotes (p=0.011). These findings suggest a slowed transfer from PE to RE-related ventral striatal responses during reinforcement learning in C-allele carriers, regardless of diagnosis, possibly due to altered dopamine release associated with increased sensitivity to glucocorticoids. 
26349555	Withania somnifera Dunal (Indian Ginseng) has recently been shown to impair ethanol self-administration. In order to gain further insights on the ability of the Withania somnifera standardised root extract (WSE) to affect the motivational properties of ethanol, this study investigated whether WSE may also affect ethanol (2 g/kg)-elicited conditioned place preference (CPP) and aversion (CPA). To this end male CD-1 mice were conditioned under two distinct schedules: in backward conditioning experiments ethanol was administered before mice were placed in the conditioning apparatus (CPP) while, in forward conditioning experiments, ethanol was administered immediately after removing mice from the apparatus (CPA). Following these schedules, mice developed significant CPP and CPA, respectively. Administration of WSE significantly impaired both the acquisition (50 and 100 mg/kg) and the expression (50 mg/kg) of CPP and CPA without affecting spatial memory (50 mg/kg), as determined by a two-trial memory recognition task. Overall, the study highlights the ability of WSE to interfere with both positive and negative motivational properties of ethanol and suggests that the effects of WSE may target both ethanol's motivational properties and underpinning associative learning mechanisms. In conclusion, these results cast new light on Withania somnifera as an agent potentially useful to counteract distinct aspects of ethanol effects. 

26348160	Avoiding repeated mistakes and learning to reinforce rewarding decisions is critical for human survival and adaptive actions. Yet, the neural underpinnings of the value systems that encode different decision-outcomes remain elusive. Here coupling single-trial electroencephalography with simultaneously acquired functional magnetic resonance imaging, we uncover the spatiotemporal dynamics of two separate but interacting value systems encoding decision-outcomes. Consistent with a role in regulating alertness and switching behaviours, an early system is activated only by negative outcomes and engages arousal-related and motor-preparatory brain structures. Consistent with a role in reward-based learning, a later system differentially suppresses or activates regions of the human reward network in response to negative and positive outcomes, respectively. Following negative outcomes, the early system interacts and downregulates the late system, through a thalamic interaction with the ventral striatum. Critically, the strength of this coupling predicts participants' switching behaviour and avoidance learning, directly implicating the thalamostriatal pathway in reward-based learning. 
26347645	In embodied computation (or morphological computation), part of the complexity of motor control is offloaded to the body dynamics. We demonstrate that a simple Hebbian-like learning rule can be used to train systems with (partial) embodiment, and can be extended outside of the scope of traditional neural networks. To this end, we apply the learning rule to optimize the connection weights of recurrent neural networks with different topologies and for various tasks. We then apply this learning rule to a simulated compliant tensegrity robot by optimizing static feedback controllers that directly exploit the dynamics of the robot body. This leads to partially embodied controllers, i.e., hybrid controllers that naturally integrate the computations that are performed by the robot body into a neural network architecture. Our results demonstrate the universal applicability of reward-modulated Hebbian learning. Furthermore, they demonstrate the robustness of systems trained with the learning rule. This study strengthens our belief that compliant robots should or can be seen as computational units, instead of dumb hardware that needs a complex controller. This link between compliant robotics and neural networks is also the main reason for our search for simple universal learning rules for both neural networks and robotics. 
26344390	Until recently, the outcome of medical students' research projects has mainly been assessed in terms of scientific publications, whereas other results important for students' development have been less studied. The aim of this study was to investigate medical students' experiences of learning as an outcome of the research project course.Written reflections of 50 students were analyzed by manifest inductive content analysis.	Three categories emerged: 'thinking as a scientist', 'working as a scientist', and 'personal development'. Students became more aware about the nature of knowledge, how to generate new knowledge, and developed skills in scientific thinking and critical appraisal. Unexpectedly, effects on personal characteristics, such as self-confidence, self-discipline, independence, and time management skills were also acknowledged.	We conclude that individual research projects enhance research-specific skills and competencies needed in evidence-based clinical work and are beneficial for personal and professional development.	
26343836	Striatal dopamine (DA) is central to reward-based learning. Less is known about the contribution of DA to the ability to adapt previously learned behavior in response to changes in the environment, such as a reversal of response-reward contingencies. We hypothesized that DA is involved in the rapid updating of response-reward information essential for successful reversal learning. We trained rats to discriminate between two levers, where lever availability was signaled by a non-discriminative cue. Pressing one lever was always rewarded, whereas the other lever was never rewarded. After reaching stable discrimination performance, a reversal was presented, so that the previously non-rewarded lever was now rewarded and vice versa. We used fast-scan cyclic voltammetry to monitor DA release in the ventromedial striatum. During discrimination performance (pre-reversal), cue presentation induced phasic DA release, whereas reward delivery did not. The opposite pattern was observed post-reversal: Striatal DA release emerged after reward delivery, while cue-induced release diminished. Trial-by-trial analysis showed rapid reinstatement of cue-induced DA release on trials immediately following initial correct responses. This effect of positive feedback was observed in animals that learned the reversal, but not in 'non-learners'. In contrast, neither pre-reversal responding and DA signaling, nor post-reversal DA signaling in response to negative feedback differed between learners and non-learners. Together, we show that phasic DA dynamics in the ventromedial striatum encoding reward-predicting cues are associated with positive feedback during reversal learning. Furthermore, these signals predict individual differences in learning that are not present prior to reversal, suggesting a distinct role for dopamine in the adaptation of previously learned behavior. 
26343341	Animal evidence suggests that a brain network involving the medial and rostral ventral prefrontal cortex (PFC) is central for threat response and arousal and a network involving the lateral and caudal PFC plays an important role in reward learning and behavioral control. In this study, we contrasted the neuropsychiatric effects of degeneration of the medial versus lateral PFC in 43 patients with Frontotemporal dementia (FTD) and 11 patients with Corticobasal Syndrome (CBS) using MRI, the Neuropsychiatric Inventory (NPI), and the Sorting, Tower, Twenty Questions, and Fluency tests of the Delis-Kaplan Executive Function System (D-KEFS). Deviations in MRI grey matter volume from 86 age-matched healthy control subjects were determined for the patients using FreeSurfer. Multivariate regression was used to determine which brain areas were associated with specific neuropsychiatric and cognitive symptoms. Decreased grey matter volume of the right medial ventral PFC was associated with increased anxiety and apathy, decreased volume of the right lateral ventral PFC with apathy and inappropriate repetitive behaviors, and of the left lateral ventral PFC with poor performance on the sorting and Twenty Questions task in patients with FTD and CBS. Similar to in animal studies, damage to the medial OFC appears to be associated with a disruption of arousal, and damage to the lateral OFC appears to be associated with deficits in trial-and-error learning and behavioral dysregulation. Studies of brain dysfunction in humans are valuable to bridge animal and human neuropsychiatric research. 
26343318	A "disinhibited" cognitive profile has been proposed for individuals with high reward sensitivity, characterized by increased engagement in goal-directed responses and reduced processing of negative or unexpected cues, which impairs adequate behavioral regulation after feedback in these individuals. This pattern is manifested through deficits in inhibitory control and/or increases in RT variability. In the present work, we aimed to test whether this profile is associated with the activity of functional networks during a stop-signal task using independent component analysis (ICA). Sixty-one participants underwent fMRI while performing a stop-signal task, during which a manual response had to be inhibited. ICA was used to mainly replicate the functional networks involved in the task (Zhang and Li, 2012): two motor networks involved in the go response, the left and right fronto-parietal networks for stopping, a midline error-processing network, and the default-mode network (DMN), which was further subdivided into its anterior and posterior parts. Reward sensitivity was mainly associated with greater activity of motor networks, reduced activity in the midline network during correct stop trials and, behaviorally, increased RT variability. All these variables explained 36% of variance of the SR scores. This pattern of associations suggests that reward sensitivity involves greater motor engagement in the dominant response, more distractibility and reduced processing of salient or unexpected events, which may lead to disinhibited behavior.
26342856	As shown in male rats, prior history of subjects changes behavioural and stress-responses to challenges: a two-week history of exposure to rewards at fixed intervals led to slightly, but consistently, lower physiological stress-responses and anxiety-like behaviour. Here, we tested whether similar effects are present in zebrafish (Danio rerio). After two weeks of providing Artemia (brine shrimp; Artemia salina) as food reward or flake food (Tetramin) as control at fixed intervals, zebrafish were exposed to a fear-avoidance learning task using an inhibitory avoidance protocol. Half the number of fish received a 3V shock on day 1 and were tested and sacrificed on day 2; the other half received a second 3V shock on day 2 and were tested and sacrificed on day 3. The latter was done to assess whether effects are robust, as effects in rats have been shown to be modest. Zebrafish that were given Artemia showed less inhibitory avoidance after one shock, but not after two shocks, than zebrafish that were given flake-food. Reduced avoidance behaviour was associated with lower telencepahalic gene expression levels of cannabinoid receptor 1 (cnr1) and higher gene expression levels of corticotropin releasing factor (crf). These results suggest that providing rewards at fixed intervals alters fear avoidance behaviour, albeit modestly, in zebrafish. We discuss the data in the context of similar underlying brain structures in mammals and fish. 
26342843	Sports betting is growing exponentially, is heavily marketed and successfully targets young adult males. Associated gambling problems are increasing. Therefore, understanding risk factors for problem gambling amongst sports bettors is an increasingly important area of research to inform the appropriate design and targeting of public health and treatment interventions. This study aimed to identify demographic, behavioural and normative risk factors for gambling problems amongst sports bettors. An online survey of 639 Australian sports bettors using online, telephone and retail betting channels was conducted. Results indicated that vulnerable sports bettors for higher risk gambling are those who are young, male, single, educated, and employed full-time or a full-time student. Risk of problem gambling was also found to increase with greater frequency and expenditure on sports betting, greater diversity of gambling involvement, and with more impulsive responses to betting opportunities, including in-play live action betting. Normative influences from media advertising and from significant others were also associated with greater problem gambling risk. The results of this study can inform a suite of intervention, protection and treatment initiatives targeted especially at young male adults and adolescents that can help to limit the harm from this gambling form. 
26342627	Studies in humans and rodents have demonstrated under certain conditions some reinforcing properties of modafinil, a drug being examined clinically for its potential to treat psychostimulant abuse. However, the majority of rodent studies examining the abuse potential of modafinil have used high doses that may not be clinically relevant. In fact, recent work has indicated that doses similar to those administered to humans are not reinforcing in mice.The current study examined sex differences in the ability of low-dose modafinil (0.75mg/kg, IP) to induce a conditioned place preference in mice, and assessed sex-dependent alterations in dopamine D1, D2 and DAT binding sites in reward-related regions in naïve and modafinil-treated mice.	Low-dose modafinil failed to induce a conditioned place preference in male mice, while female mice demonstrated a significant modafinil place preference. Several dopamine binding differences were also detected in naïve and modafinil-treated mice, including sex differences in D1 and D2 availability in reward-related regions, and are discussed in relation to sex-dependent differences in the reinforcing effects of modafinil and psychostimulants in general.	These findings implicate sex differences in the reinforcing properties of modafinil in mice, and indicate that clinical evaluation of the sex dependence of the reinforcing properties of modafinil in humans is warranted.	
26342220	European Americans value excitement more and calm less than Chinese. Within cultures, European Americans value excited and calm states similarly, whereas Chinese value calm more than excited states. To examine how these cultural differences influence people's immediate responses to excited vs calm facial expressions, we combined a facial rating task with functional magnetic resonance imaging. During scanning, European American (n = 19) and Chinese (n = 19) females viewed and rated faces that varied by expression (excited, calm), ethnicity (White, Asian) and gender (male, female). As predicted, European Americans showed greater activity in circuits associated with affect and reward (bilateral ventral striatum, left caudate) while viewing excited vs calm expressions than did Chinese. Within cultures, European Americans responded to excited vs calm expressions similarly, whereas Chinese showed greater activity in these circuits in response to calm vs excited expressions regardless of targets' ethnicity or gender. Across cultural groups, greater ventral striatal activity while viewing excited vs. calm expressions predicted greater preference for excited vs calm expressions months later. These findings provide neural evidence that people find viewing the specific positive facial expressions valued by their cultures to be rewarding and relevant. 
26341938	Sophisticated behavioral paradigms partnered with the emergence of increasingly selective techniques to target the basolateral amygdala (BLA) have resulted in an enhanced understanding of the role of this nucleus in learning and using reward information. Due to the wide variety of behavioral approaches many questions remain on the circumscribed role of BLA in appetitive behavior. In this review, we integrate conclusions of BLA function in reward-related behavior using traditional interference techniques (lesion, pharmacological inactivation) with those using newer methodological approaches in experimental animals that allow in vivo manipulation of cell type-specific populations and neural recordings. Secondly, from a review of appetitive behavioral tasks in rodents and monkeys and recent computational models of reward procurement, we derive evidence for BLA as a neural integrator of reward value, history, and cost parameters. Taken together, BLA codes specific and temporally dynamic outcome representations in a distributed network to orchestrate adaptive responses. We provide evidence that experiences with opiates and psychostimulants alter these outcome representations in BLA, resulting in long-term modified action. 
26341936	Recent research suggests that not only the dopamine neurotransmitter system but also the endogenous opioid system is involved in performance monitoring and the generation of prediction error signals. Heightened performance monitoring is also associated with psychopathology such as internalizing disorders. Therefore, the current study investigated the potential link between the functional opioid peptide prodynorphin (PDYN) 68 bp VNTR genetic polymorphism and neuronal correlates of performance monitoring. To this end, 47 healthy participants genotyped for this polymorphism, related to high-, intermediate-, and low-expression levels of PDYN, performed a choice-reaction task while their electroencephalogram (EEG) was recorded. On the behavioural level, no differences between the three PDYN groups could be observed. EEG data, however, showed significant differences. High PDYN expression individuals showed heightened neural error processing indicated by higher ERN amplitudes, compared to intermediate and low expression individuals. Later stages of error processing, indexed by late Pe amplitudes, and stimulus-driven conflict processing, indexed by N2 amplitudes, were not affected by PDYN genotype. The current results corroborate the notion of an indirect effect of endogenous opioids on performance monitoring, probably mediated by the mesencephalic dopamine system. Overall, enhanced ERN amplitudes suggest a hyper-active performance monitoring system in high PDYN expression individuals, and this might also be an indicator of a higher risk for internalizing disorders.
26341050	Alcohol dependence is characterized by a reduction in reward threshold, development of a negative affective state, and significant cognitive impairments. Dependence-induced glutamatergic neuroadaptations in the neurocircuitry mediating reward, affect and cognitive function are thought to underlie the neural mechanism for these alterations. These changes serve to promote increased craving for alcohol and facilitate the development of maladaptive behaviors that promote relapse to alcohol drinking during periods of abstinence.To review the extant literature on the effects of chronic alcohol exposure on glutamatergic neurotransmission and its impact on reward, affect and cognition.	Evidence from a diverse set of studies demonstrates significant enhancement of glutamatergic activity following chronic alcohol exposure. In particular, up-regulation of GluN2B-containing NMDA receptor expression and function is a commonly observed phenomenon that likely reflects activity-dependent adaptive homeostatic plasticity. However, this observation as well as other glutamatergic neuroadaptations are often circuit and cell-type specific.	Dependence-induced alterations in glutamate signaling contribute to many of the symptoms experienced in addicted individuals and can persist well into abstinence. This suggests that they play an important role in the development of behaviors that increase the probability for relapse. As our understanding of the complexity of the neurocircuitry involved in the addictive process has advanced, it has become increasingly clear that investigations of cell-type and circuit-specific effects are required to gain a more comprehensive understanding of the glutamatergic adaptations and their functional consequences in alcohol addiction.	While pharmacological treatments for alcohol dependence and relapse targeting the glutamatergic system have shown great promise in preclinical models, more research is needed to uncover novel, possibly circuit-specific, therapeutic targets that exhibit improved efficacy and reduced side effects.	
26339218	The main idea in this article is that addiction is a consequence of falling victim to decision failures that lead to preference for the addictive behaviors. Addiction is viewed as valuation disease, where the nervous system overvalues cues associated with drugs or drug-taking. Thus, addiction can be viewed as a diminished capacity to choose. Addicted individuals assign lower values to delayed rewards than to immediate ones. The preference for immediate gratification leads to self-control problems. This article highlights a number of motivational forces that can generate self-control failure. 
26335649	Recent studies have challenged the view that orbitofrontal cortex (OFC) and amygdala mediate flexible reward-guided behavior. We trained macaques to perform an object discrimination reversal task during fMRI sessions and identified a lateral OFC (lOFC) region in which activity predicted adaptive win-stay/lose-shift behavior. Amygdala and lOFC activity was more strongly coupled on lose-shift trials. However, lOFC-amygdala coupling was also modulated by the relevance of reward information in a manner consistent with a role in establishing how credit for reward should be assigned. Day-to-day fluctuations in signals and signal coupling were correlated with day-to-day fluctuation in performance. A second experiment confirmed the existence of signals for adaptive stay/shift behavior in lOFC and reflecting irrelevant reward in the amygdala in a probabilistic learning task. Our data demonstrate that OFC and amygdala each make unique contributions to flexible behavior and credit assignment.
26335648	The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and was positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease.
26335089	A recent cluster-randomized controlled trial found that offering financial incentives improves adherence to long-acting injectable antipsychotics (LAIs). The present study investigates whether the impact of incentives diminishes over time and whether the improvement in adherence is linked to the amount of incentives offered.Seventy-three teams with 141 patients with psychotic disorders (using ICD-10) were randomized to the intervention or control group. Over 1 year, patients in the intervention group received £15 (US $23) for each LAI, while control patients received treatment as usual. Adherence levels, ie, the percentage of prescribed LAIs that were received, were calculated for quarterly intervals. The amount of incentives offered was calculated from the treatment cycle at baseline. Multilevel models were used to examine the time course of the effect of incentives and the effect of the amount of incentives offered on adherence.	Adherence increased in both the intervention and the control group over time by an average of 4.2% per quarterly interval (95% CI, 2.8%-5.6%; P < .001). Despite this general increase, adherence in the intervention group remained improved compared to the control group by between 11% and 14% per quarterly interval. There was no interaction effect between time and treatment group. Further, a higher total amount of incentives was associated with poorer adherence (βbootstrapped = -0.11; 95% CIbootstrapped, -0.20 to -0.01; P = .023).	A substantial effect of financial incentives on adherence to LAIs occurs within the first 3 months of the intervention and is sustained over 1 year. A higher total amount of incentives does not increase the effect.	ISRCTN.com identifier: ISRCTN77769281 and UKCRN.org identifier: 7033.	
26334016	We frequently need to commit to a choice to achieve our goals; however, the neural processes that keep us motivated in pursuit of delayed goals remain obscure. We examined ensemble responses of neurons in macaque dorsal anterior cingulate cortex (dACC), an area previously implicated in self-control and persistence, in a task that requires commitment to a choice to obtain a reward. After reward receipt, dACC neurons signaled reward amount with characteristic ensemble firing rate patterns; during the delay in anticipation of the reward, ensemble activity smoothly and gradually came to resemble the postreward pattern. On the subset of risky trials, in which a reward was anticipated with 50% certainty, ramping ensemble activity evolved to the pattern associated with the anticipated reward (and not with the anticipated loss) and then, on loss trials, took on an inverted form anticorrelated with the form associated with a win. These findings enrich our knowledge of reward processing in dACC and may have broader implications for our understanding of persistence and self-control.
26333525	Patient adherence to medications, particularly for conditions requiring prolonged treatment such as tuberculosis (TB), is frequently less than ideal and can result in poor treatment outcomes. Material incentives to reward good behaviour and enablers to remove economic barriers to accessing care are sometimes given in the form of cash, vouchers, or food to improve adherence.To evaluate the effects of material incentives and enablers in patients undergoing diagnostic testing, or receiving prophylactic or curative therapy, for TB.	We undertook a comprehensive search of the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; Science Citation Index; and reference lists of relevant publications up to 5 June 2015.	Randomized controlled trials of material incentives in patients being investigated for TB, or on treatment for latent or active TB.	At least two review authors independently screened and selected studies, extracted data, and assessed the risk of bias in the included trials. We compared the effects of interventions using risk ratios (RR), and presented RRs with 95% confidence intervals (CI). The quality of the evidence was assessed using GRADE.	We identified 12 eligible trials. Ten were conducted in the USA: in adolescents (one trial), in injection drug or cocaine users (four trials), in homeless adults (three trials), and in prisoners (two trials). The remaining two trials, in general adult populations, were conducted in Timor-Leste and South Africa. Sustained incentive programmesOnly two trials have assessed whether material incentives and enablers can improve long-term adherence and completion of treatment for active TB, and neither demonstrated a clear benefit (RR 1.04, 95% CI 0.97 to 1.14; two trials, 4356 participants; low quality evidence). In one trial, the incentive, given as a daily hot meal, was not well received by the population due to the inconvenience of attending the clinic at midday, whilst in the other trial, nurses distributing the vouchers chose to "ration" their distribution among eligible patients, giving only to those whom they felt were most deprived.Three trials assessed the effects of material incentives and enablers on completion of TB prophylaxis with mixed results (low quality evidence). A large effect was seen with regular cash incentives given to drug users at each clinic visit in a setting with extremely low treatment completion in the control group (treatment completion 52.8% intervention versus 3.6% control; RR 14.53, 95% CI 3.64 to 57.98; one trial, 108 participants), but no effects were seen in one trial assessing a cash incentive for recently released prisoners (373 participants), or another trial assessing material incentives offered by parents to teenagers (388 participants). Single once-only incentivesHowever in specific populations, such as recently released prisoners, drug users, and the homeless, trials show that material incentives probably do improve one-off clinic re-attendance for initiation or continuation of anti-TB prophylaxis (RR 1.58, 95% CI 1.27 to 1.96; three trials, 595 participants; moderate quality evidence), and may increase the return rate for reading of tuberculin skin test results (RR 2.16, 95% CI 1.41 to 3.29; two trials, 1371 participants; low quality evidence). Comparison of different types of incentivesSingle trials in specific sub-populations suggest that an immediate cash incentive may be more effective than delaying the incentive until completion of treatment (RR 1.11, 95% CI 0.98 to 1.24; one trial, 300 participants; low quality evidence), cash incentives may be more effective than non-cash incentives (completion of TB prophylaxis: RR 1.26, 95% CI 1.02 to 1.56; one trial, 141 participants; low quality evidence; return for skin test reading: RR 1.13, 95% CI 1.07 to 1.19; one trial, 652 participants; low quality evidence); and higher cash incentives may be more effective than lower cash incentives (RR 1.08, 95% CI 1.01 to 1.16; one trial, 404 participants; low quality evidence).	Material incentives and enablers may have some positive short term effects on clinic attendance, particularly for marginal populations such as drug users, recently released prisoners, and the homeless, but there is currently insufficient evidence to know if they can improve long term adherence to TB treatment.	
26332431	The neuropeptides orexin A and B play a role in reward and feeding and are critical for arousal. However, it was not initially appreciated that most prepro-orexin synthesizing neurons are almost exclusively concentrated in the perifornical hypothalamus, which when stimulated elicits panic-associated behavior and cardiovascular responses in rodents and self-reported "panic attacks" and "fear of dying" in humans. More recent studies support a role for the orexin system in coordinating an integrative stress response. For instance, orexin neurons are highly reactive to anxiogenic stimuli, are hyperactive in anxiety pathology, and have strong projections to anxiety and panic-associated circuitry. Although the two cognate orexin receptors are colocalized in many brain regions, the orexin 2 receptor (OX2R) most robustly maps to the histaminergic wake-promoting region, while the orexin 1 receptor (OX1R) distribution is more exclusive and dense in anxiety and panic circuitry regions, such as the locus ceruleus. Overall, this suggests that OX1Rs play a critical role in mobilizing anxiety and panic responses.Here, we used a CO2 -panic provocation model to screen a dual OX1/2R antagonist (DORA-12) to globally inhibit orexin activity, then a highly selective OX1R antagonist (SORA1, Compound 56) or OX2R antagonist (SORA2, JnJ10397049) to assess OX1R and OX2R involvement.	All compounds except the SORA2 attenuated CO2 -induced anxiety-like behaviors, and all but the SORA2 and DORA attenuated CO2 -induced cardiovascular responses.	SORA1s may represent a novel method of treating anxiety disorders, with no apparent sedative effects that were present with a benzodiazepine.	
26327320	For reasons of cost and ethical concerns, models of neurodegenerative disorders such as Huntington disease (HD) are currently being developed in farm animals, as an alternative to non-human primates. Developing reliable methods of testing cognitive function is essential to determining the usefulness of such models. Nevertheless, cognitive testing of farm animal species presents a unique set of challenges. The primary aims of this study were to develop and validate a mobile operant system suitable for high throughput cognitive testing of sheep.We designed a semi-automated testing system with the capability of presenting stimuli (visual, auditory) and reward at six spatial locations. Fourteen normal sheep were used to validate the system using a two-choice visual discrimination task. Four stages of training devised to acclimatise animals to the system are also presented.	All sheep progressed rapidly through the training stages, over eight sessions. All sheep learned the 2CVDT and performed at least one reversal stage. The mean number of trials the sheep took to reach criterion in the first acquisition learning was 13.9±1.5 and for the reversal learning was 19.1±1.8.	This is the first mobile semi-automated operant system developed for testing cognitive function in sheep.	We have designed and validated an automated operant behavioural testing system suitable for high throughput cognitive testing in sheep and other medium-sized quadrupeds, such as pigs and dogs. Sheep performance in the two-choice visual discrimination task was very similar to that reported for non-human primates and strongly supports the use of farm animals as pre-clinical models for the study of neurodegenerative diseases.	
26327305	In this protocol, social motivation is measured in mice through a pair of operant conditioning paradigms. To conduct the experiments, two-chambered shuttle boxes were equipped with two operant levers (left and right) and a food receptacle in one chamber, which was then divided from the second chamber by an automated guillotine door covered by a wire grid. Different stimulus mice, rotated across testing days, served as a social stimulus behind the wire grid, and were only visible following the opening of the guillotine door. Test mice were trained to lever press in order to open the door and gain access to the stimulus partner for 15 sec. The number of lever presses required to obtain the social reward progressively increased on a fixed schedule of 3. Testing sessions ended after test mice stopped lever pressing for 5 consecutive minutes. The last reinforced ratio or breakpoint can be used as a quantitative measure of social motivation. For the second paradigm, test mice were trained to discriminate between left and right lever presses in order to obtain either a food reward or the social reward. Mice were rewarded for every 3 presses of each respective lever. The number of food and social rewards can be compared as a measurement of the value placed upon each reward. The ratio of each reward type can also be compared between mouse strains and the change in this ratio can be monitored within testing sessions to measure satiation with a given reward type. Both of these operant conditioning paradigms are highly useful for the quantification of social motivation in mouse models of autism and other disorders of social behavior. 
26325447	Rapid, phasic dopamine (DA) release in the mammalian brain plays a critical role in reward processing, reinforcement learning, and motivational control. Fast scan cyclic voltammetry (FSCV) is an electrochemical technique with high spatial and temporal (sub-second) resolution that has been utilized to examine phasic DA release in several types of preparations. In vitro experiments in single-cells and brain slices and in vivo experiments in anesthetized rodents have been used to identify mechanisms that mediate dopamine release and uptake under normal conditions and in disease models. Over the last 20 years, in vivo FSCV experiments in awake, freely moving rodents have also provided insight of dopaminergic mechanisms in reward processing and reward learning. One major advantage of the awake, freely moving preparation is the ability to examine rapid DA fluctuations that are time-locked to specific behavioral events or to reward or cue presentation. However, one limitation of combined behavior and voltammetry experiments is the difficulty of dissociating DA effects that are specific to primary rewarding or aversive stimuli from co-occurring DA fluctuations that mediate reward-directed or other motor behaviors. Here, we describe a combined method using in vivo FSCV and intra-oral infusion in an awake rat to directly investigate DA responses to oral tastants. In these experiments, oral tastants are infused directly to the palate of the rat--bypassing reward-directed behavior and voluntary drinking behavior--allowing for direct examination of DA responses to tastant stimuli.
26325355	Self-control is defined as the ability or capacity to obtain an objectively more valuable outcome rather than an objectively less valuable outcome though tolerating a longer delay or a greater effort requirement (or both) in obtaining that more valuable outcome. A number of tests have been devised to assess self-control in non-human animals, including exchange tasks. In this study, three chimpanzees (Pan troglodytes) participated in a delay of gratification task that required food exchange as the behavioral response that reflected self-control. The chimpanzees were offered opportunities to inhibit eating and instead exchange a currently possessed food item for a different (and sometimes better) item, often needing to exchange several food items before obtaining the highest valued reward. We manipulated reward type, reward size, reward visibility, delay to exchange, and location of the highest valued reward in the sequence of exchange events to compare performance within the same individuals. The chimpanzees successfully traded until obtaining the best item in most cases, although there were individual differences among participants in some variations of the test. These results support the idea that self-control is robust in chimpanzees even in contexts in which they perhaps anticipate future rewards and sustain delay of gratification until they can obtain the ultimately most valuable item. 
26325040	3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6β-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-hydroxy group, incorporating a 7,8 double bond and various N-17 alkyl substituents. The structural modifications resulted in analogs with picomolar affinities for opioid receptors. The lead compound (MP1104) was found to exhibit approximately 15-fold greater antinociceptive potency (ED50 = 0.33 mg/kg) compared with morphine, mediated through the activation of kappa- and delta-opioid receptors. Despite its kappa agonism, this lead derivative did not cause place aversion or preference in mice in a place-conditioning assay, even at doses 3 times the analgesic ED50. However, pretreatment with the lead compound prevented the reward behavior associated with cocaine in a conditioned place preference assay. Together, these results suggest the promise of dual acting kappa- and delta-opioid receptor agonists as analgesics and treatments for cocaine addiction. 
26324932	Research on the dynamics of reward-based, goal-directed decision making has largely focused on simple choice, where participants decide among a set of unitary, mutually exclusive options. Recent work suggests that the deliberation process underlying simple choice can be understood in terms of evidence integration: Noisy evidence in favor of each option accrues over time, until the evidence in favor of one option is significantly greater than the rest. However, real-life decisions often involve not one, but several steps of action, requiring a consideration of cumulative rewards and a sensitivity to recursive decision structure. We present results from two experiments that leveraged techniques previously applied to simple choice to shed light on the deliberation process underlying multistep choice. We interpret the results from these experiments in terms of a new computational model, which extends the evidence accumulation perspective to multiple steps of action. 
26324408	Cocaine addiction and depression are comorbid disorders. Although it is well recognized that 5-hydroxytryptamine (5-HT; serotonin) plays a central role in depression, our understanding of its role in addiction is notably lacking. The 5-HT system in the brain is carefully controlled by a combined process of regulating 5-HT neuron firing through 5-HT autoreceptors, neurotransmitter release, enzymatic degradation, and reuptake by transporters. This study tests the hypothesis that activation of 5-HT1A autoreceptors, which would lessen 5-HT neuron firing, contributes to cocaine-seeking behaviors. Using 5-HT neuron-specific reduction of 5-HT1A autoreceptor gene expression in mice, we demonstrate that 5-HT1A autoreceptors are necessary for cocaine conditioned place preference. In addition, using designer receptors exclusively activated by designer drugs (DREADDs) technology, we found that stimulation of the serotonergic dorsal raphe nucleus (DRN) afferents to the nucleus accumbens (NAc) abolishes cocaine reward and promotes antidepressive-like behaviors. Finally, using a rat model of compulsive-like cocaine self-administration, we found that inhibition of dorsal raphe 5-HT1A autoreceptors attenuates cocaine self-administration in rats with 6 h extended access, but not 1 h access to the drug. Therefore, our findings suggest an important role for 5-HT1A autoreceptors, and thus DRNNAc 5-HT neuronal activity, in the etiology and vulnerability to cocaine reward and addiction. Moreover, our findings support a strategy for antagonizing 5-HT1A autoreceptors for treating cocaine addiction. 
26323795	Loss-chasing is a central feature of problematic gambling, yet it remains a poorly conceived and understood concept. Loss-chasing is believed to stem from an erosion of cognitive control when gambling. The opportunity to gamble at significantly disparate stake sizes on a gambling activity is considered to be a risk factor for loss-chasing. This study investigated the impact of gambling at disparate stake sizes on executive processes integral to maintaining cognitive control when gambling, namely response inhibition and reflection impulsivity. Frequent adult non-problem gamblers (n = 32) participated in a repeated measures experiment; and gambled at three disparate stake sizes (£20, £2 and no stake per bet) on a simulated gambling task. Participants' response inhibition performance and reflection impulsivity levels after gambling at various stake sizes were compared via a go/no-go task and information sampling task, respectively. Quality of decision-making i.e. the evaluation of available information to make probability judgements was impaired after gambling at higher stakes in comparison to lower stakes, indicating an increase in reflection impulsivity. No effect on response inhibition was observed. Although exploratory, this suggests that the opportunity for participants to substantially increase stake size on a gambling activity may be a risk factor for impaired cognitive performance when gambling, and perhaps create vulnerability for within-session loss-chasing in some players. 
26323245	It has been known for some time that nucleus accumbens dopamine (DA) is involved in aspects of motivation , but theoretical approaches to understanding the functions of DA have continued to evolve based upon emerging data and novel concepts. Although it has become traditional to label DA neurons as "reward" neurons, the actual findings are more complicated than that, because they indicate that DA neurons can respond to a variety of motivationally significant stimuli. Moreover, it is important to distinguish between aspects of motivation that are differentially affected by dopaminergic manipulations. Studies that involve nucleus accumbens DA antagonism or depletion indicate that accumbens DA does not mediate primary food motivation or appetite. Nevertheless, DA is involved in appetitive and aversive motivational processes including behavioral activation , exertion of effort, sustained task engagement, and Pavlovian-to-instrumental transfer. Interference with accumbens DA transmission affects instrumental behavior in a manner that interacts with the response requirements of the task and also shifts effort-related choice behavior, biasing animals toward low-effort alternatives. Dysfunctions of mesolimbic DA may contribute to motivational symptoms seen in various psychopathologies, including depression , schizophrenia, parkinsonism, and other disorders. 
26322689	The dual mechanisms of control account suggests that cognitive control may be implemented through relatively proactive mechanisms in anticipation of stimulus onset, or through reactive mechanisms, triggered in response to changing stimulus demands. Reward incentives and task-informative cues (signaling the presence/absence of upcoming cognitive demand) have both been found to influence cognitive control in a proactive or preparatory fashion; yet, it is currently unclear whether and how such cue effects interact. We investigated this in 2 experiments using an adapted flanker paradigm, where task-informative and reward incentive cues were orthogonally manipulated on a trial-by-trial basis. In Experiment 1, results indicated that incentives not only speed reaction times, but specifically reduce both interference and facilitation effects when combined with task-informative cues, suggesting enhanced proactive attentional control. Experiment 2 manipulated the timing of incentive cue information, demonstrating that such proactive control effects were only replicated with sufficient time to process the incentive cue (early incentive); when incentive signals were presented close to target onset (late incentive) the primary effect was a speed-accuracy trade-off. Together, results suggest that advance cueing may trigger differing control strategies, and that these strategies may critically depend on both the timing-and the motivational incentive-to use such cues.
26322583	Dopamine neurons are thought to facilitate learning by comparing actual and expected reward. Despite two decades of investigation, little is known about how this comparison is made. To determine how dopamine neurons calculate prediction error, we combined optogenetic manipulations with extracellular recordings in the ventral tegmental area while mice engaged in classical conditioning. Here we demonstrate, by manipulating the temporal expectation of reward, that dopamine neurons perform subtraction, a computation that is ideal for reinforcement learning but rarely observed in the brain. Furthermore, selectively exciting and inhibiting neighbouring GABA (γ-aminobutyric acid) neurons in the ventral tegmental area reveals that these neurons are a source of subtraction: they inhibit dopamine neurons when reward is expected, causally contributing to prediction-error calculations. Finally, bilaterally stimulating ventral tegmental area GABA neurons dramatically reduces anticipatory licking to conditioned odours, consistent with an important role for these neurons in reinforcement learning. Together, our results uncover the arithmetic and local circuitry underlying dopamine prediction errors. 
26320024	Recent studies have accumulated evidences that merely reminding people of money could lead to behavioral changes including alleviating both physical pain and social distress. However, the underlying neural mechanism regarding such pain-buffering effect of money is not clear. In this paper, we applied event-related potentials (ERP) to investigate the neural effect of money reminders on induced negative emotions. Subjects were first primed of money images and subsequently viewing unpleasant pictures, while EEG was recorded. Behavioral results suggested a reduced sensitivity to unpleasant pictures after participants being reminded of money. ERP data showed that money priming, compared to neutral priming, generated a larger N2 in frontal and posterior areas, reflecting an endogenous mental conflict and the recruitment of attention resources, and a smaller late positive potential (LPP) in parietal and occipital regions, indicating a regulating process of negative emotions. Additionally, how brain responded to money and neutral stimuli were also examined, indexed by "N170-P2" complex. This study provided additional neurophysiological evidences to support previous behavioral researches on money priming and discussed the two separated neural dynamic stages involved in emotion regulation. 
26319737	Anhedonia, the diminished anticipation and pursuit of reward, is a core symptom of major depressive disorder (MDD). Trait behavioral activation (BA), as a proxy for anhedonia, and behavioral inhibition (BI) may moderate the relationship between MDD and reward-seeking. The present studies probed for reward learning deficits, potentially due to aberrant BA and/or BI, in active or remitted MDD individuals compared to healthy controls (HC). Active MDD (Study 1) and remitted MDD (Study 2) participants completed the modified monetary incentive delay task (mMIDT), a behavioral reward-seeking task whose response window parameters were individually titrated to theoretically elicit equivalent accuracy between groups. Participants completed the BI Scale and BA Reward-Responsiveness and Drive Scales. Despite individual titration, active MDD participants won significantly less money than HCs. Higher Reward-Responsiveness scores predicted more won; Drive and BI were not predictive. Remitted MDD participants' performance did not differ from controls', and trait BA and BI measures did not predict r-MDD performance. These results suggest that diminished reward-responsiveness may contribute to decreased motivation and reward pursuit during active MDD, but that reward learning is intact in remission. Understanding individual reward processing deficits in MDD may inform personalized intervention addressing anhedonia and motivation deficits in select MDD patients. 
26318270	Depressed mood, anhedonia, psychomotor retardation and alterations of circadian rhythm are core features of the depressive syndrome. Its neural correlates can be located within a frontal-striatal-tegmental neural network, commonly referred to as the reward circuit. It is the aim of this article to review literature on white matter microstructure alterations of the reward system in depression.We searched for diffusion tensor imaging (DTI)-studies that have explored neural deficits within the cingulum bundle, the uncinate fasciculus and the supero-lateral medial forebrain bundle/anterior thalamic radiation - in adolescent and adult depression (acute and remitted), melancholic depression, treatment-resistant depression and those at familial risk of depression. The relevant diffusion MRI literature was identified using PUBMED.	Thirty-five studies were included. In people at familial risk for depression the main finding was reduced fractional anisotropy (FA) in the cingulum bundle. Both increases and decreases of FA have been reported in the uncinate fasciculus in adolescents. Reductions of FA in the uncinate fasciculus and the anterior thalamic radiation/supero-lateral medial forebrain bundle during acute depressive episodes in adults were most consistently reported.	Non-quantitative approach.	Altered cingulum bundle microstructure in unaffected relatives may either indicate resilience or vulnerability to depression. Uncinate fasciculus and supero-lateral medial forebrain bundle microstructure may be altered during depressive episodes in adult MDD. Future studies call for a careful clinical stratification of clinically meaningful subgroups.	
26317636	Over 70 years since the first description of the disease, disrupted social behavior remains a core clinical feature of autistic spectrum disorder. The complex etiology of the disorder portends the need for a better understanding of the brain mechanisms that enable social behaviors, particularly those that are relevant to autism which is characterized by a failure to develop peer relationships, difficulty with emotional reciprocity and imitative play, and disrupted language and communication skills. Toward this end, the current review will examine recent progress that has been made toward understanding the neural mechanisms underlying consociate social attachments. 
26317475	Basal forebrain cholinergic neurons constitute a major neuromodulatory system implicated in normal cognition and neurodegenerative dementias. Cholinergic projections densely innervate neocortex, releasing acetylcholine to regulate arousal, attention, and learning. However, their precise behavioral function is poorly understood because identified cholinergic neurons have never been recorded during behavior. To determine which aspects of cognition their activity might support, we recorded cholinergic neurons using optogenetic identification in mice performing an auditory detection task requiring sustained attention. We found that a non-cholinergic basal forebrain population-but not cholinergic neurons-were correlated with trial-to-trial measures of attention. Surprisingly, cholinergic neurons responded to reward and punishment with unusual speed and precision (18 ± 3 ms). Cholinergic responses were scaled by the unexpectedness of reinforcement and were highly similar across neurons and two nuclei innervating distinct cortical areas. These results reveal that the cholinergic system broadcasts a rapid and precisely timed reinforcement signal, supporting fast cortical activation and plasticity. 
26315103	Dysfunctional behavioural and neural processing of reward has been found in currently depressed individuals. However, little is known about altered reward processing in remitted depressed individuals.A total of 23 medication-free individuals with remitted major depressive disorder (rMDD) and 23 matched healthy controls (HCs) performed a reward task during functional magnetic resonance imaging. We also investigated reward dependence, novelty seeking and harm avoidance using the Tridimensional Personality Questionnaire and their association with neural responses of reward processing.	Compared to HCs, individuals with rMDD exhibited enhanced responses to reward-predicting cues in the hippocampus, amygdala and superior frontal gyrus. When reward was delivered, rMDD subjects did not significantly differ from HCs. In both groups neural activity during reward anticipation was negatively correlated with harm avoidance.	Our results show that rMDD is characterized by hyperactivation in fronto-limbic regions during reward anticipation. Alterations in neural activation during reward processing might reflect an increased effort in remitted depressed individuals to allocate neural activity for executive and evaluative processes during anticipatory reward processing.	
26314945	Human decisions are guided by a variety of motivational factors, such as immediate rewards, long-term goals, and emotions. We used functional magnetic resonance imaging to investigate the dynamic functional interactions between the amygdala, the nucleus accumbens, and the prefrontal cortex that underlie the influences of emotions, desires, and rationality on human decisions. We found that increased functional connectivity between the amygdala and the nucleus accumbens facilitated the approach of an immediate reward in the presence of emotional information. Further, increased functional interactions of the anteroventral prefrontal cortex with the amygdala and the nucleus accumbens were associated with rational decisions in dilemma situations. These findings support previous animal studies by demonstrating that emotional signals from the amygdala and goal-oriented information from prefrontal cortices interface in the nucleus accumbens to guide human decisions and reward-directed actions. 
26311180	We have studied how rewards modulate the occurrence of microsaccades by manipulating the size of an expected reward and the location of the cue that sets the expectations for future reward. We found an interaction between the size of the reward and the location of the cue. When monkeys fixated on a cue that signaled the size of future reward, the frequency of microsaccades was higher if the monkey expected a large vs. a small reward. When the cue was presented at a site in the visual field that was remote from the position of fixation, reward size had the opposite effect: the frequency of microsaccades was lower when the monkey was expecting a large reward. The strength of pursuit initiation also was affected by reward size and by the presence of microsaccades just before the onset of target motion. The gain of pursuit initiation increased with reward size and decreased when microsaccades occurred just before or after the onset of target motion. The effect of the reward size on pursuit initiation was much larger than any indirect effects reward might cause through modulation of the rate of microsaccades. We found only a weak relationship between microsaccade direction and the location of the exogenous cue relative to fixation position, even in experiments where the location of the cue indicated the direction of target motion. Our results indicate that the expectation of reward is a powerful modulator of the occurrence of microsaccades, perhaps through attentional mechanisms. 
26311129	Why do people donate blood? Altruism is the common answer. However, altruism is a complex construct and to answer this question requires a systematic analysis of the insights from the biology, economics and psychology of altruism. I term this the mechanism of altruism (MOA) approach and apply it here for understanding blood donor motivation. The answer also has enormous implications for the type of interventions we choose to adopt as a society. A MOA approach so far shows that blood donors are a mixture of (i) warm-glow givers (donation is emotionally rewarding) and (ii) reluctant altruists (cooperate rather than defect when free-riding is high). Donors also show 'saintly sinning' with the extra 'moral currency' form blood donation allowing them to be less generous in other contexts. The MOA approach suggests why financial incentives, in terms of gifts/lottery tickets, are effective and suggests a number of novel interventions for donor recruitment: 'voluntary reciprocal altruism' and 'charitable incentivisation'. The MOA approach also highlights the need for an intervention developed specifically for recipients to allow them to show their gratitude to donors and for society to celebrate blood donation. It is suggests a 'Monument to Blood Donors' will achieve this. The approach suggests a number of novel research questions into (i) donor self-selection effects, (ii) conditional cooperation and (iii) construct overlap with Theory of Planned Behaviour (e.g. affective attitudes and warm-glow). The MOA offers a powerful way to understand blood donor motivations around altruism and develop theoretically driven interventions. 
26310386	Studies in children show that the development of spatial competence emerges between seven and eight years of age. Multiple memory systems (hippocampus-dependent spatial and caudate nucleus-dependent response learning) are involved in parallel processing of information during navigation. As a hippocampus-dependent spatial strategy also relies on frontoparietal executive control and working memory networks that are impaired in ADHD, we predicted that children will be more likely to adopt a response strategy as they exhibit ADHD symptoms. We tested 285 healthy children on a virtual radial-arm maze paradigm in order to test this hypothesis. We found that children displaying at least one ADHD symptom were more likely to have a perfect performance on a probe trial, which suggests that they did not rely on environmental landmarks. Children with ADHD symptoms may primarily rely on caudate nucleus-dependent response learning strategies at the expense of hippocampus-dependent spatial strategies. Repetition and reward based learning strategies, which are hallmarks of response learning, may be most effective in children exhibiting ADHD symptoms. 
26310381	Reactive attachment disorder (RAD) is characterized by markedly disturbed and developmentally inappropriate social relatedness due to parental maltreatment. RAD patients often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms, and certain RAD symptoms are difficult to discriminate from ADHD. One of the core characteristics of ADHD is a decrease in neural reward processing due to dopamine dysfunction. The aim of the present study was to determine whether the brain activity involved in reward processing in RAD patients is impaired in comparison with ADHD patients and typically developed controls. Five RAD patients, 17 typically developed (TD) controls and 17 ADHD patients aged 10-16 years performed tasks with high and low monetary reward while undergoing functional magnetic resonance imaging. ADHD patients were tested before and after 3 months treatment with osmotic release oral system-methylphenidate. Before treatment, ADHD patients showed that striatal and thalamus activities only in the tasks with low monetary reward were lower than TD controls. RAD patients showed decrease in activity of the caudate, putamen and thalamus during both the high and low monetary reward conditions in comparison with all the other groups. In RAD patients, the activity of the putamen was associated with the severity of posttraumatic stress and overt dissociation. Reward sensitivity was markedly decreased in children and adolescents with RAD, as evidenced by a diminished neural response during reward perception. This suggests that dopaminergic dysfunction exists in these patients, and may inform future dopaminergic treatment strategies for RAD. 

26307468	The stimulus-preceding negativity (SPN) is an event-related potential (ERP) reflecting anticipation. The anterior insular cortex is assumed to be one of the physiological sources of the SPN. However, the precise neural substrates of the SPN have yet to be confirmed. We therefore performed separate functional magnetic resonance imaging (fMRI) and ERP studies using the same time estimation task, followed by fMRI-constrained ERP source analysis. Dipole locations were determined by the fMRI results, while the time courses of dipole activities were modeled by the ERP data. Analysis revealed that the right anterior insula was significantly activated before delivery of the feedback stimulus, whereas the left anterior insula was not, and that the SPN mainly arose from four groups of brain regions related to, respectively: (1) the salience network, (2) reward expectation, (3) perceptual anticipation, and (4) arousal. The results suggest that the SPN pertains to multiple brain functions with complex interactions.
26306917	The co-abuse of ethanol (EtOH) and nicotine (NIC) increases the likelihood that an individual will relapse to drug use while attempting to maintain abstinence. There is limited research examining the consequences of long-term EtOH and NIC co-abuse.The current experiments determined the enduring effects of chronic EtOH, NIC, or EtOH + NIC intake on the reinforcing properties of NIC and glutamate (GLU) activity within the mesocorticolimbic (MCL) system.	Alcohol-preferring (P) rats self-administered EtOH, Sacc + NIC, or EtOH + NIC combined for 10 weeks. The reinforcing properties of 0.1-3.0 μM NIC within the nucleus accumbens shell (AcbSh) were assessed following a 2-3-week drug-free period using intracranial self-administration (ICSA) procedures. The effects of EtOH, Sacc, Sacc + NIC, or EtOH + NIC intake on extracellular levels and clearance of glutamate (GLU) in the medial prefrontal cortex (mPFC) were also determined.	Binge intake of EtOH (96-100 mg%) and NIC (21-27 mg/mL) were attained. All groups of P rats self-infused 3.0 μM NIC directly into the AcbSh, whereas only animals in the EtOH + NIC co-abuse group self-infused the 0.3 and 1.0 μM NIC concentrations. Additionally, self-administration of EtOH + NIC, but not EtOH, Sacc or Sacc + NIC, resulted in enduring increases in basal extracellular GLU levels in the mPFC.	Overall, the co-abuse of EtOH + NIC produced enduring neuronal alterations within the MCL which enhanced the rewarding properties of NIC in the AcbSh and elevated extracellular GLU levels within the mPFC.	
26305097	In two-alternative discrimination tasks, experimenters usually randomize the location of the rewarded stimulus so that systematic behavior with respect to irrelevant stimuli can only produce chance performance on the learning curves. One way to achieve this is to use random numbers derived from a discrete binomial distribution to create a 'full random training schedule' (FRS). When using FRS, however, sporadic but long laterally-biased training sequences occur by chance and such 'input biases' are thought to promote the generation of laterally-biased choices (i.e., 'output biases'). As an alternative, a 'Gellerman-like training schedule' (GLS) can be used. It removes most input biases by prohibiting the reward from appearing on the same location for more than three consecutive trials. The sequence of past rewards obtained from choosing a particular discriminative stimulus influences the probability of choosing that same stimulus on subsequent trials. Assuming that the long-term average ratio of choices matches the long-term average ratio of reinforcers, we hypothesized that a reduced amount of input biases in GLS compared to FRS should lead to a reduced production of output biases. We compared the choice patterns produced by a 'Rational Decision Maker' (RDM) in response to computer-generated FRS and GLS training sequences. To create a virtual RDM, we implemented an algorithm that generated choices based on past rewards. Our simulations revealed that, although the GLS presented fewer input biases than the FRS, the virtual RDM produced more output biases with GLS than with FRS under a variety of test conditions. Our results reveal that the statistical and temporal properties of training sequences interacted with the RDM to influence the production of output biases. Thus, discrete changes in the training paradigms did not translate linearly into modifications in the pattern of choices generated by a RDM. Virtual RDMs could be further employed to guide the selection of proper training schedules for perceptual decision-making studies. 
26303312	This manuscript summarizes the proceedings of the symposium entitled, "Stress, Palatable Food and Reward", that was chaired by Drs. Linda Rinaman and Yvonne Ulrich-Lai at the 2014 Neurobiology of Stress Workshop held in Cincinnati, OH. This symposium comprised research presentations by four neuroscientists whose work focuses on the biological bases for complex interactions among stress, food intake and emotion. First, Dr Ulrich-Lai describes her rodent research exploring mechanisms by which the rewarding properties of sweet palatable foods confer stress relief. Second, Dr Stephanie Fulton discusses her work in which excessive, long-term intake of dietary lipids, as well as their subsequent withdrawal, promotes stress-related outcomes in mice. Third, Dr Mark Wilson describes his group's research examining the effects of social hierarchy-related stress on food intake and diet choice in group-housed female rhesus macaques, and compared the data from monkeys to results obtained in analogous work using rodents. Finally, Dr Gorica Petrovich discusses her research program that is aimed at defining cortical-amygdalar-hypothalamic circuitry responsible for curbing food intake during emotional threat (i.e. fear anticipation) in rats. Their collective results reveal the complexity of physiological and behavioral interactions that link stress, food intake and emotional state, and suggest new avenues of research to probe the impact of genetic, metabolic, social, experiential and environmental factors on these interactions. 
26303264	The incretin hormone, glucagon-like peptide 1 (GLP-1), regulates gastric emptying, glucose-dependent stimulation of insulin secretion and glucagon release, and GLP-1 analogs are therefore approved for treatment of type II diabetes. GLP-1 receptors are expressed in reward-related areas such as the ventral tegmental area and nucleus accumbens, and GLP-1 was recently shown to regulate several alcohol-mediated behaviors as well as amphetamine-induced, cocaine-induced and nicotine-induced reward. The present series of experiments were undertaken to investigate the effect of the GLP-1 receptor agonist, liraglutide, on several alcohol-related behaviors in rats that model different aspects of alcohol use disorder in humans. Acute liraglutide treatment suppressed the well-documented effects of alcohol on the mesolimbic dopamine system, namely alcohol-induced accumbal dopamine release and conditioned place preference in mice. In addition, acute administration of liraglutide prevented the alcohol deprivation effect and reduced alcohol intake in outbred rats, while repeated treatment of liraglutide decreased alcohol intake in outbred rats as well as reduced operant self-administration of alcohol in selectively bred Sardinian alcohol-preferring rats. Collectively, these data suggest that GLP-1 receptor agonists could be tested for treatment of alcohol dependence in humans. 
26302782	Compared with reward seeking, punishment avoidance learning is less clearly understood at both the computational and neurobiological levels. Here we demonstrate, using computational modelling and fMRI in humans, that learning option values in a relative--context-dependent--scale offers a simple computational solution for avoidance learning. The context (or state) value sets the reference point to which an outcome should be compared before updating the option value. Consequently, in contexts with an overall negative expected value, successful punishment avoidance acquires a positive value, thus reinforcing the response. As revealed by post-learning assessment of options values, contextual influences are enhanced when subjects are informed about the result of the forgone alternative (counterfactual information). This is mirrored at the neural level by a shift in negative outcome encoding from the anterior insula to the ventral striatum, suggesting that value contextualization also limits the need to mobilize an opponent punishment learning system.
26302106	Carver and White's (1994) Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) Scales have been useful tools for studying individual differences in reward-punishment sensitivity; however, their factor structure and invariance across development have not been well tested. In the current study, we examined the factor structure of the BIS/BAS Scales across 5 age groups: 6- to 10-year-old children (N = 229), 11- to 13-year-old early adolescents (N = 311), 14- to 16-year-old late adolescents (N = 353), 18- to 22-year-old young adults (N = 844), and 30- to 45-year-old adults (N = 471). Given poor fit of the standard 4-factor model (BIS, Reward Responsivity, Drive, Fun Seeking) in the literature, we conducted exploratory factor analyses in half of the participants and identified problematic items across age groups. The 4-factor model showed poor fit in our sample, whereas removing the BAS Fun Seeking subscale and problematic items from the remaining subscales improved fit in confirmatory factor analyses conducted with the second half of the participants. The revised model showed strict invariance across age groups and by sex, indicating consistent factor structure, item loadings, thresholds, and unique or residual variances. Additionally, in our cross-sectional data, we observed nonlinear relations between age and subscale scores, where scores tended to be higher in young adulthood than in childhood and later adulthood. Furthermore, sex differences emerged across development; adolescent and adult females had higher BIS scores than males in this age range, whereas sex differences were not observed in childhood. These differences may help us to understand the rise in internalizing psychopathology in adolescence, particularly in females. Future developmental studies are warranted to examine the impact of rewording problematic items.
26301954	Men, like the male of many animal species, use gifts to build satisfactory relationships with a desired woman. From the woman's perspective, all gifts are not always equally rewarding; the reward value of a gift depends on two factors: (1) the giver and (2) the type of the gift (the gift's social meaning). In this study, we investigated how these two factors interactively determine the reward value of a gift. Specifically, we examined how the neural processing for understanding a gift's social meaning is modulated by preferences for the giver. We performed a functional magnetic resonance imaging (fMRI) study in which a female participant was asked to judge a gift from a male she was acquainted with in real life. We examined the interactive effects between (1) the female participant's attitude toward the male acquaintance (liked vs. uninteresting) and (2) the type of the gift (romantic [e.g., bouquet, earrings, and perfumes] vs. non-romantic [e.g., pencils, memo pad, and moneybox]). We found that preference for an acquaintance selectively modulated activity in the anterior cingulate cortex (ACC) in response to romantic gifts, compared to non-romantic gifts. In contrast, if the woman was indifferent toward an acquaintance, no activity modulation was observed in this area for the same gifts. In addition, the ACC showed functional connectivity with the supplementary motor area/dorsal ACC (SMA/dACC), an area within the dorsal mediofrontal cortex, suggesting that it integrates action monitoring and emotional and cognitive processing in decision-making. These results suggest that attitude toward an opposite sex member has a modulatory role in recognizing the social meaning of material goods--preference for the member is a powerful modulator of social reward processing.
26301755	Recent studies on reward-based decision-making in the presence of anxiety-related stimuli demonstrated that approach-avoidance conflicts can be assessed under controlled laboratory conditions. However, the clinical relevance of these decision conflicts has not been demonstrated. To this end, the present study investigated avoidant decisions in treatment-seeking individuals with social anxiety disorder (SAD). In a gambling task, advantageous choices to maximize gains were associated with task-irrelevant angry faces and disadvantageous choices with happy faces. The clinical relevance of avoidant decisions for in vivo anxiety in a social stress situation (public speaking) were examined (n = 44). In a subsample (n = 20), the predictive value for a reduction of avoidance following behavioral therapy was also evaluated. Results indicated a close link between more frequent avoidant decisions and elevated in vivo anxiety. Moreover, individuals who showed a deficit in the goal-directed adjustment of their decisions also showed higher and sustained distress during the social stressor and reported less decrease of avoidance following treatment. The findings highlight the importance of an avoidant decision-making style for the experience of acute distress and the maintenance of avoidance in SAD. Assessing avoidant decision-making may help to predict the response to behavioral treatments.
26301612	A magnitude effect in probability discounting is well established with humans, in which the value of a larger reward decreases more with uncertainty than the value of a smaller reward. We report 2 experiments that show that an analogous result is obtained with pigeons choosing between probabilistic food rewards in a 2-component concurrent-chains procedure. In Experiment 1, the terminal links delivered large (4-s access to food) and small (2-s access to food) rewards with either 100% or 50% probability across components. Preference for the larger reward was greater in the 100% component. In Experiment 2, the terminal links delivered reinforcement on 100% or 50% of terminal links and the rewards were large (4-s access to food) or small (2-s access to food) across components. Preference for the 100% alternative was greater when rewards were large. In both experiments, results indicate that the value of the larger reward decreased more when its probability was 50% than the value of the smaller reward, confirming the magnitude effect, and were similar regardless of whether the food and no-food outcomes for the 50% terminal links were differentially signaled. Results were predicted by an extension of the cumulative decision model (Christensen & Grace, 2010; Grace & McLean, 2006), which accounts for the effects of magnitude and probability on choice and can also explain the apparently contradictory results of prior research on the magnitude effect in delay discounting with pigeons. The model shows that a single process can account for delay and probability discounting in nonhumans, including the opposite effects of reward magnitude.
26300819	The present work explores the unconscious and/or conscious nature of learning attractive faces of same and opposite sex, that is, of stimuli that experimental and neuroimaging research has shown to be rewarding and thus highly motivating. To this end, we examined performance of men and women while classifying strings of average and attractive faces for grammaticality in the experimental task of artificial grammar learning (AGL), which reflects both conscious and unconscious processes. Subjective measures were used to assess participants' conscious and unconscious knowledge. It was found that female attractiveness impaired performance in male participants. In particular, male participants demonstrated the lowest accuracy while classifying beautiful faces of women. Conversely, female attractiveness facilitated performance in female participants. The pattern was similar for conscious and unconscious knowledge. Presumably, objects with high incentive salience, as are beautiful faces, captured resources, which were used in task relevant versus task irrelevant ways by women versus men. The present findings shed light on the relation of conscious and unconscious processing with affective and reward-related stimuli, as well as on gender differences underlying this relation. 
26300300	We have previously shown that animals acquired robust conditioned place preference (CPP) to either social interaction alone or cocaine alone. Recently it has been reported that drugs of abuse abnormally activated p38, a member of mitogen-activated protein kinase family, in the nucleus accumbens. In this study, we aimed to investigate the expression of the activated form of p38 (pp38) in the nucleus accumbens shell and core of rats expressing either cocaine CPP or social interaction CPP 1 h, 2 h and 24 h after the CPP test. We hypothesized that cocaine CPP will increase pp38 in the nucleus accumbens shell/core as compared to social interaction CPP. Surprisingly, we found that 24 h after social interaction CPP, pp38 neuronal levels were decreased in the nucleus accumbens shell to the level of naïve rats. Control saline rats that received saline in both compartments of the CPP apparatus and cocaine CPP rats showed similar enhanced p38 activation as compared to naïve and social interaction CPP rats. We also found that the percentage of neurons expressing dopaminergic receptor D2R and pp38 was also decreased in the shell of the nucleus accumbens of social interaction CPP rats as compared to controls. Given the emerging role of p38 in stress/anxiety behaviors, these results suggest that (1) social interaction reward has anti-stress effects; (2) cocaine conditioning per se does not affect p38 activation and that (3) marginal stress is sufficient to induce p38 activation in the shell of the nucleus accumbens. 
26300032	This article focuses on the shared molecular and neurogenetics of food and drug addiction tied to the understanding of reward deficiency syndrome. Reward deficiency syndrome describes a hypodopaminergic trait/state that provides a rationale for commonality in approaches for treating long-term reduced dopamine function across the reward brain regions. The identification of the role of DNA polymorphic associations with reward circuitry has resulted in new understanding of all addictive behaviors. 
26299312	Nesfatin-1 is a novel 82-amino acid anorectic peptide. Previous studies of nesfatin-1 have focused on hypothalamic and brainstem circuits implicated in feeding regulation. Recently, nesfatin-1 expression was also reported in the nucleus accumbens (NAc), amygdaloid nucleus and insular cortex of mice, areas that are related to the control of reward behavior. Therefore, it is possible that nesfatin-1 might also inhibit food intake via central reward circuits. Using electrophysiology and electrochemical and behavioral tests, we investigated the effect of nesfatin-1 on the dopaminergic reward pathway between the ventral tegmental area (VTA) and the NAc. Our results showed that injection of nesfatin-1 into the VTA significantly inhibited dark-phase cumulative food intake in mice. The excitability of VTA dopaminergic neurons was inhibited by nesfatin-1. In addition, nesfatin-1 decreased dopamine release in the NAc. Therefore, we concluded that nesfatin-1 acts on dopaminergic neurons, and these effects might contribute to the decrease of food intake that results from the injection of nesfatin-1 into the VTA. 
26298158	Understanding the impact of EGM Jackpots on gambling intensity may allow targeted strategies to be implemented that facilitate harm minimisation by acting to reduce losses of gamblers who play frequently, while maintaining the enjoyment and excitement of potential jackpots. The current study investigated the influences of Hidden and Mystery Jackpots on EGM gambling intensity. In a Hidden Jackpot, the prize value is not shown to the player, although the existence of a jackpot prize is advertised. In a Mystery Jackpot, the jackpot triggering state of the machine is unknown to players. One hundred and seven volunteers (males = 49, females = 58) played a laptop-simulated EGM with a starting $20 real-money stake and a chance to win a Jackpot ($500). Participants played for either a Hidden or Known Jackpot Value, with either a Mystery or Known winning symbol combination in a crossed design. Lastly, a control condition with no jackpot was included. Gambling intensity (speed of bets, persistence) was greater when the Jackpot value was unknown, especially when a winning-symbol combination suggested that a win was possible. While there is no evidence in the present investigation to suggest that Hidden or Mystery jackpots contribute to greater player enjoyment, there is some evidence to suggest a marginal positive contribution of hidden jackpots to risky playing behaviour. 
26297897	We tested the effect of early-life stress (ELS) - 24h maternal deprivation (MD) at postnatal day (PND) 3 - on cognitive performance and hippocampal structure in 12-17-week-old female rats. Behavioral performance was examined in: the Elevated Plus Maze, as an index for general anxiety; the rodent Iowa gambling test, probing reward-based decision making; and the object recognition and object-in-location task, to assess non-stressful contextual memory performance. We further determined hippocampal dentate gyrus (DG) volume and cell density as well as adult proliferation and neurogenesis rates. Half of the rats was treated with the glucocorticoid receptor antagonist mifepristone during a critical pre-pubertal developmental window (PNDs 26-28), in an attempt to ameliorate the potentially adverse behavioral consequences of ELS. Neither MD nor treatment with the glucocorticoid antagonist affected behavioral performance of the females in any of the tasks. Also, DG structure, proliferation and neurogenesis were not different between the groups. Lack of structural differences and a behavioral phenotype in non-stressful hippocampus dependent learning tasks fits with the lack of phenotype generally reported after ELS in female but less so in male rodents. As evident from an extensive literature review, female and male animals appear to respond more similarly to early-life adversity when tested in anxiety-related tasks. This agrees with recent findings in humans suggesting that females may be relatively resilient to the structural/hippocampal effects of childhood maltreatment, but not to the anxiety and mood-related psychopathology for which childhood maltreatment is considered a risk factor.
26297688	Water deprivation (WD) followed by water intake to satiety, produces satiation of thirst and partial rehydration (PR). Thus, WD-PR is a natural method to differentiate thirst from sodium appetite. WD-PR also produces Fos immunoreactivity (Fos-ir) in interconnected areas of a brain circuit postulated to subserve sodium appetite. In the present work, we evaluated the effect of sodium intake on Fos-ir produced by WD-PR in brain areas operationally defined according to the literature as either facilitatory or inhibitory to sodium intake. Isotonic NaCl was available for ingestion in a sodium appetite test performed immediately after a single episode of WD-PR. Sodium intake decreased Fos-ir in facilitatory areas such as the lamina terminalis (particularly subfornical organ and median preoptic nucleus), central amygdala and hypothalamic parvocellular paraventricular nucleus in the forebrain. Sodium intake also decreased Fos-ir in inhibitory areas such as the area postrema, lateral parabrachial nucleus and nucleus of the solitary tract in the hindbrain. In contrast, sodium intake further increased Fos-ir that was activated by water deprivation in the dorsal raphe nucleus, another inhibitory area localized in the hindbrain. WD-PR increased Fos-ir in the core and shell of the nucleus accumbens. Sodium intake reduced Fos-ir in both parts of the accumbens. In summary, sodium intake following WD-PR reduced Fos-ir in most facilitatory and inhibitory areas, but increased Fos-ir in another inhibitory area. It also reduced Fos-ir in a reward area (accumbens). The results suggest a functional link between sodium intake and the activity of the hindbrain-forebrain circuitry subserving reward and sodium appetite in response to water deprivation. 
26297598	Despite many health benefits, children do not consume enough fruits and vegetables (F/V). The Food Dudes program increases in-school F/V consumption, but the cost of prizes might be an adoption barrier.Our aim was to compare the effects of the Food Dudes program when prizes vs praise are used to reward F/V consumption.	We conducted a randomized controlled trial with three groups (ie, prize, praise, and control). Schools were randomly assigned to groups while approximately equating the percentage of students qualifying for free or reduced-price lunch. F/V consumption (lunch-tray photos) was assessed twice at pre-intervention and once after phase I, phase II, and at 6 months post-intervention, spanning approximately 11 months overall.	In total, 2,292 students attending six elementary schools participated, with 882, 640, and 770 in the prize, praise, and control groups, respectively.	The Food Dudes program was implemented over 4.5 months in all but the control schools. Two Food Dudes schools implemented the program with tangible prizes contingent on individual students' F/V consumption (prize group); two schools implemented Food Dudes using teacher praise instead of prizes (praise group). Follow-up data were collected 6 months post-intervention.	F/V consumption was assessed by digital imaging of lunch trays.	Linear mixed-effects modeling, including sex, grade, and baseline consumption as covariates, was performed.	Students attending the Food Dudes schools consumed more F/V than control schools after phase I, with larger differences in prize schools (92% difference) than praise schools (50% difference). After phase II, Food Dudes schools consumed 46% more F/V than control schools, with no difference between prize and praise schools. At 6-month follow-up, only prize schools consumed more F/V than control schools (0.12 cups more per child, 42.9% difference).	Social praise proved an inadequate substitute for tangible prizes within the Food Dudes program. Program-related increases in F/V consumption decreased after the intervention, underscoring the need to develop low-cost, long-term interventions to maintain and make habitual consumption of recommended levels of F/V.	
26297085	To elicit a patient's willingness to participate in a diabetes pay-for-performance for patient (P4P4P) program using a discrete choice experiment method.The survey was conducted in March 2013. Our sample was drawn from patients with diabetes at five hospitals in Taiwan (International Classification of Diseases, Ninth Revision, Clinical Modification code 250). The sample size was 838 patients. The discrete choice experiment questionnaire included the attributes monthly cash rewards, exercise time, diet control, and program duration. We estimated a bivariate probit model to derive willingness-to-accept levels after accounting for the characteristics (e.g., severity and comorbidity) of patients with diabetes.	The preferred program was a 3-year program involving 30 minutes of exercise per day and flexible diet control. Offering an incentive of approximately US $67 in cash per month appears to increase the likelihood that patients with diabetes will participate in the preferred P4P4P program by approximately 50%.	Patients with more disadvantageous characteristics (e.g., elderly, low income, greater comorbidity, and severity) could have less to gain from participating in the program and thus require a higher monetary incentive to compensate for the disutility caused by participating in the program's activities. Our result demonstrates that a modest financial incentive could increase the likelihood of program participation after accounting for the attributes of the P4P4P program and patients' characteristics.	
26296778	Orbitofrontal (OFC) circuits have been implicated in the pathophysiology of substance use disorders. The current study examined OFC functional connectivity differences in marijuana-using adolescents (MJ) and non-using healthy controls (HC).Functional magnetic resonance imaging (fMRI) resting-state data were obtained on a 3T MRI scanner on 31 HC and 43 heavy MJ smokers. Image analyses were performed between groups (MJ, HC) for the left and right OFC separately. Regression analyses between OFC functional connectivity and lifetime MJ use, age of first MJ use and impulsivity also were performed.	Increased OFC functional connectivity to frontal and motor regions was observed in heavy MJ users compared to HC. Earlier age of first MJ use was associated with increased functional connectivity of the right OFC to motor regions. High lifetime MJ use was associated with increased OFC functional connectivity to posterior brain regions in MJ youth.	Findings indicate atypical OFC functional connectivity patterns in attentional/executive, motor and reward networks in adolescents with heavy MJ use. These anomalies may be related to suboptimal decision making capacities and increased impulsivity. Results also suggest different OFC connectivity patterns may be present in adolescents with early onset of MJ use and high lifetime exposure to MJ.	
26295350	Although engaging in pleasant experiences following successful performance may be hedonically rewarding, in the present research we proposed that individuals might forego pleasant experiences when they have not yet completed a task. In Study 1 (N = 100), participants reported the extent to which they would like to engage in pleasant experiences in a hypothetical situation where their performance outcome on a task (successful vs. average) and task completion (task in progress vs. completed) were manipulated. In Study 2 (N = 115), participants were in a real situation in which they achieved either a successful or average performance outcome. Task completion was manipulated (task in progress vs. completed) and motivation to engage in a pleasant experience was assessed by a behavioral measure. Results of both studies provided support for our prediction by showing individuals to have a lower desire to engage in pleasant experiences following successful, but not average, performance when the task was in progress than when it was complete. These findings are discussed in light of the underlying mechanisms and consequences of the tendency to forego pleasant experiences. 
26295336	In alcohol-dependent patients craving is a difficult-to-treat phenomenon. It has been suggested that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) may have beneficial effects. However, exactly how this application exerts its effect on the underlying craving neurocircuit is currently unclear. In an effort to induce alcohol craving and to maximize detection of HF-rTMS effects to cue-induced alcohol craving, patients were exposed to a block and event-related alcohol cue-reactivity paradigm while being scanned with fMRI. Hence, we assessed the effect of right dorsolateral prefrontal cortex (DLPFC) stimulation on cue-induced and general alcohol craving, and the related craving neurocircuit. Twenty-six recently detoxified alcohol-dependent patients were included. First, we evaluated the impact of one sham-controlled stimulation session. Second, we examined the effect of accelerated right DLPFC HF-rTMS treatment: here patients received 15 sessions in an open label accelerated design, spread over 4 consecutive days. General craving significantly decreased after 15 active HF-rTMS sessions. However, cue-induced alcohol craving was not altered. Our brain imaging results did not show that the cue-exposure affected the underlying craving neurocircuit after both one and fifteen active HF-rTMS sessions. Yet, brain activation changes after one and 15 HF-rTMS sessions, respectively, were observed in regions associated with the extended reward system and the default mode network, but only during the presentation of the event-related paradigm. Our findings indicate that accelerated HF-rTMS applied to the right DLPFC does not manifestly affect the craving neurocircuit during an alcohol-related cue-exposure, but instead it may influence the attentional network. 
26294328	It is known that, on average, people adapt their choice of memory strategy to the subjective utility of interaction. What is not known is whether an individual's choices are boundedly optimal. Two experiments are reported that test the hypothesis that an individual's decisions about the distribution of remembering between internal and external resources are boundedly optimal where optimality is defined relative to experience, cognitive constraints, and reward. The theory makes predictions that are tested against data, not fitted to it. The experiments use a no-choice/choice utility learning paradigm where the no-choice phase is used to elicit a profile of each participant's performance across the strategy space and the choice phase is used to test predicted choices within this space. They show that the majority of individuals select strategies that are boundedly optimal. Further, individual differences in what people choose to do are successfully predicted by the analysis. Two issues are discussed: (a) the performance of the minority of participants who did not find boundedly optimal adaptations, and (b) the possibility that individuals anticipate what, with practice, will become a bounded optimal strategy, rather than what is boundedly optimal during training. 
26292268	Diet-induced obesity (DIO) causes ghrelin resistance in hypothalamic Agouti-related peptide (AgRP) neurons. However, ghrelin promotes feeding through actions at both the hypothalamus and mesolimbic dopamine reward pathways. Therefore, we hypothesized that DIO would also establish ghrelin resistance in the ventral tegmental area (VTA), a major site of dopaminergic cell bodies important in reward processing. We observed reduced sucrose and saccharin consumption in Ghrelin KO vs Ghrelin WT mice. Moreover, DIO reduced saccharin consumption relative to chow-fed controls. These data suggest that the deletion of ghrelin and high fat diet both cause anhedonia. To assess if these are causally related, we tested whether DIO caused ghrelin resistance in a classic model of drug reward, conditioned place preference (CPP). Chow or high fat diet (HFD) mice were conditioned with ghrelin (1mg/kg in 10ml/kg ip) in the presence or absence of food in the conditioning chamber. We observed a CPP to ghrelin in chow-fed mice but not in HFD-fed mice. HFD-fed mice still showed a CPP for cocaine (20mg/kg), indicating that they maintained the ability to develop conditioned behaviour. The absence of food availability during ghrelin conditioning sessions induced a conditioned place aversion, an effect that was still present in both chow and HFD mice. Bilateral intra-VTA ghrelin injection (0.33μg/μl in 0.5μl) robustly increased feeding in both chow-fed and high fat diet (HFD)-fed mice; however, this was correlated with body weight only in the chow-fed mice. Our results suggest that DIO causes ghrelin resistance albeit not directly in the VTA. We suggest there is impaired ghrelin sensitivity in upstream pathways regulating reward pathways, highlighting a functional role for ghrelin linking appropriate metabolic sensing with reward processing. 
26292189	Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug-abuse vulnerability, with HiS rats being more likely to consume sweets and cocaine than LoS rats. Still, the nature of these differences is poorly understood. This study examined whether the motivational consequences of cocaine exposure are differentially expressed in HiS and LoS rats by measuring intracranial self-stimulation (ICSS) thresholds following acute injections of cocaine (10 mg/kg). Reductions in ICSS thresholds following cocaine injection were greater in HiS rats than in LoS rats, suggesting that the reward-enhancing effects of cocaine are greater in the drug-vulnerable HiS than LoS rats. Higher cocaine-induced reward, indicated by lower ICSS thresholds, may explain the higher rates of drug consumption in sweet-preferring animal models, providing a clue to the etiology of cocaine addiction in vulnerable populations. 
26292186	Several recent studies have indicated the involvement of calcium-dependent mechanisms, in particular the abundant calcium-activated kinase, calcium/calmodulin-dependent kinase II (CaMKII), in behaviors associated with nicotine dependence in mice. Behavioral and biochemical studies have shown that CaMKII is involved in acute and chronic nicotine behaviors and nicotine withdrawal; however, evidence of a role for CaMKII in nicotine reward is lacking. Thus, the goal of the current study was to examine the role of CaMKII in nicotine reward. Using pharmacological and genetic tools, we tested nicotine conditioned place preference (CPP) in C57Bl/6 mice after administration of CaMKII antagonists and in α-CaMKII wild-type (+/+) and heterozygote (±) mice. CaMKII antagonists blocked expression of nicotine CPP, and the preference score was significantly reduced in α-CaMKII ± mice compared with their +/+ counterparts. Further, we assessed CaMKII activity in the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex, and hippocampus after nicotine CPP and found significant increases in CaMKII activity in the mouse VTA and NAc that were blocked by CaMKII antagonists. The findings from this study show that CaMKII mediates nicotine reward and suggest that increases in CaMKII activity in the VTA and NAc are relevant to nicotine reward behaviors. 
26290251	Reversal learning has been extensively studied across species as a task that indexes the ability to flexibly make and reverse deterministic stimulus-reward associations. Although various brain lesions have been found to affect performance on this task, the behavioral processes affected by these lesions have not yet been determined. This task includes at least two kinds of learning. First, subjects have to learn and reverse stimulus-reward associations in each block of trials. Second, subjects become more proficient at reversing choice preferences as they experience more reversals. We have developed a Bayesian approach to separately characterize these two learning processes. Reversal of choice behavior within each block is driven by a combination of evidence that a reversal has occurred, and a prior belief in reversals that evolves with experience across blocks. We applied the approach to behavior obtained from 89 macaques, comprising 12 lesion groups and a control group. We found that animals from all of the groups reversed more quickly as they experienced more reversals, and correspondingly they updated their prior beliefs about reversals at the same rate. However, the initial values of the priors that the various groups of animals brought to the task differed significantly, and it was these initial priors that led to the differences in behavior. Thus, by taking a Bayesian approach we find that variability in reversal-learning performance attributable to different neural systems is primarily driven by different prior beliefs about reversals that each group brings to the task.The ability to use prior knowledge to adapt choice behavior is critical for flexible decision making. Reversal learning is often studied as a form of flexible decision making. However, prior studies have not identified which brain regions are important for the formation and use of prior beliefs to guide choice behavior. Here we develop a Bayesian approach that formally characterizes learning set as a concept, and we show that, in macaque monkeys, the amygdala and medial prefrontal cortex have a role in establishing an initial belief about the stability of the reward environment.	
26290248	The posterior parietal cortex (PPC) has traditionally been considered important for awareness, spatial perception, and attention. However, recent findings provide evidence that the PPC also encodes information important for making decisions. These findings have initiated a running argument of whether the PPC is critically involved in decision making. To examine this issue, we reversibly inactivated the parietal reach region (PRR), the area of the PPC that is specialized for reaching movements, while two monkeys performed a memory-guided reaching or saccade task. The task included choices between two equally rewarded targets presented simultaneously in opposite visual fields. Free-choice trials were interleaved with instructed trials, in which a single cue presented in the peripheral visual field defined the reach and saccade target unequivocally. We found that PRR inactivation led to a strong reduction of contralesional choices, but only for reaches. On the other hand, saccade choices were not affected by PRR inactivation. Importantly, reaching and saccade movements to single instructed targets remained largely intact. These results cannot be explained as an effector-nonspecific deficit in spatial attention or awareness, since the temporary "lesion" had an impact only on reach choices. Hence, the PPR is a part of a network for reach decisions and not just reach planning.There has been an ongoing debate on whether the posterior parietal cortex (PPC) represents only spatial awareness, perception, and attention or whether it is also involved in decision making for actions. In this study we explore whether the parietal reach region (PRR), the region of the PPC that is specialized for reaches, is involved in the decision process. We inactivated the PRR while two monkeys performed reach and saccade choices between two targets presented simultaneously in both hemifields. We found that inactivation affected only the reach choices, while leaving saccade choices intact. These results cannot be explained as a deficit in attention, since the temporary lesion affected only the reach choices. Thus, PRR is a part of a network for making reach decisions.	
26290240	Addiction is thought to be a maladaptive form of learning and memory caused by drug-evoked aberrant synaptic plasticity. We previously showed that alcohol facilitates synaptic plasticity in the dorsomedial striatum (DMS), a brain region that drives goal-directed behaviors. The majority of DMS cells are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1Rs) or D2 receptors (D2Rs), which drive "Go" or "No-Go" behaviors, respectively. Here, we report that alcohol induces cell type-specific synaptic and structural plasticity in the DMS. Using mice that express a fluorescence marker to visualize D1R or D2R MSNs, we show that repeated cycles of systemic administration of alcohol or alcohol consumption induces a long-lasting increase in AMPAR activity specifically in DMS D1R but not in D2R MSNs. Importantly, we report that alcohol consumption increases the complexity of dendritic branching and the density of mature mushroom-shaped spines selectively in DMS D1R MSNs. Finally, we found that blockade of D1R but not D2R activity in the DMS attenuates alcohol consumption. Together, these data suggest that alcohol intake produces profound functional and structural plasticity events in a subpopulation of neurons in the DMS that control reinforcement-related learning.Alcohol addiction is considered maladaptive learning and memory processes. Here we unraveled a long-lasting cellular mechanism that may contribute to the memory of alcohol-seeking behaviors. Specifically, we found that alcohol consumption produces a long-lasting enhancement of channel activity and persistent alterations of neuronal morphology in a part of the brain (DMS) that controls alcohol-drinking behaviors. Furthermore, we show that these alterations occur only in a subpopulation of neurons that positively control reward and reinforcement of drugs of abuse. Finally, we report that blocking the activity of this neuronal population reduces alcohol intake. As such synaptic and structural changes are the cellular hallmarks of learning and memory, and these neuroadaptations may drive the development of pathological heavy alcohol consumption.	
26290234	Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shell DA release decreased predominantly during the TL. These release dynamics suggest parallel DA signals capable of supporting distinct theories of appetitive behavior.Dopamine signaling in the brain is important for a variety of cognitive functions, such as learning and motivation. Typically, it is assumed that a single dopamine signal is sufficient to support these cognitive functions, though competing theories disagree on how dopamine contributes to reward-based behaviors. Here, we have found that real-time dopamine release within the nucleus accumbens (a primary target of midbrain dopamine neurons) strikingly varies between core and shell subregions. In the core, dopamine dynamics are consistent with learning-based theories (such as reward prediction error) whereas in the shell, dopamine is consistent with motivation-based theories (e.g., incentive salience). These findings demonstrate that dopamine plays multiple and complementary roles based on discrete circuits that help animals optimize rewarding behaviors.	
26289464	It is well known that eye movement patterns are influenced by both goal- and salience-driven factors. Recent studies, however, have demonstrated that objects that are nonsalient and task irrelevant can still capture our eyes if moving our eyes to those objects has previously produced reward. Here we demonstrate that training such an association between eye movements to an object and delivery of reward is not needed. Instead, an object that merely signals the availability of reward captures the eyes even when it is physically nonsalient and never relevant for the task. Furthermore, we show that oculomotor capture by reward is more reliably observed in saccades with short latencies. We conclude that a stimulus signaling high reward has the ability to capture the eyes independently of bottom-up physical salience or top-down task relevance and that the effect of reward affects early selection processes. 
26287974	We previously suggested that abnormal sleep behaviors, i.e., as found in parasomnias, may often be the expression of increased activity of the reward system during sleep. Because nightmares and sleepwalking predominate during REM and NREM sleep respectively, we tested here whether exploratory excitability, a waking personality trait reflecting high activity within the mesolimbic dopaminergic (ML-DA) system, may be associated with specific changes in REM and NREM sleep patterns in these two sleep disorders.Twenty-four unmedicated patients with parasomnia (12 with chronic sleepwalking and 12 with idiopathic nightmares) and no psychiatric comorbidities were studied. Each patient spent one night of sleep monitored by polysomnography. The Temperament and Character Inventory (TCI) was administered to all patients and healthy controls from the Geneva population (n = 293).	Sleepwalkers were more anxious than patients with idiopathic nightmares (Spielberger Trait anxiety/STAI-T), but the patient groups did not differ on any personality dimension as estimated by the TCI. Compared to controls, parasomnia patients (sleepwalkers together with patients with idiopathic nightmares) scored higher on the Novelty Seeking (NS) TCI scale and in particular on the exploratory excitability/curiosity (NS1) subscale, and lower on the Self-directedness (SD) TCI scale, suggesting a general increase in reward sensitivity and impulsivity. Furthermore, parasomnia patients tended to worry about social separation persistently, as indicated by greater anticipatory worry (HA1) and dependence on social attachment (RD3). Moreover, exploratory excitability (NS1) correlated positively with the severity of parasomnia (i.e., the frequency of self-reported occurrences of nightmares and sleepwalking), and with time spent in REM sleep in patients with nightmares.	These results suggest that patients with parasomnia might share common waking personality traits associated to reward-related brain functions. They also provide further support to the notion that reward-seeking networks are active during human sleep.	

26287509	Symptoms of attention deficit hyperactivity disorder (ADHD) in children often persist into adulthood and can lead to severe antisocial behavior. However, to-date it remains unclear whether neuro-functional abnormalities cause ADHD, which in turn can then provide a marker of persistent ADHD. Using event-related functional magnetic resonance imaging (fMRI), we measured blood oxygenation level dependent (BOLD) signal changes in subjects during a reversal learning task in which choice of the correct stimulus led to a probabilistically determined 'monetary' reward or punishment. Participants were diagnosed with ADHD during their childhood (N=32) and were paired with age, gender, and education matched healthy controls (N=32). Reassessment of the ADHD group as adults resulted in a split between either persistent (persisters, N=17) or remitted ADHDs (remitters, N=15). All three groups showed significantly decreased activation in the medial prefrontal cortex (PFC) and the left striatum during punished correct responses, however only remitters and controls presented significant psycho-physiological interaction between these fronto-striatal reward and outcome valence networks. Comparing persisters to remitters and controls showed significantly inverted responses to punishment (P<0.05, family-wise error corrected) in left PFC region. Interestingly, the decreased activation shown after punishment was located in different areas of the PFC for remitters compared with controls, suggesting that remitters might have learned compensation strategies to overcome their ADHD symptoms. Thus, fMRI helps understanding the neuro-functional basis of ADHD related behavior differences and differentiates between persistent and remittent ADHD.
26286655	The dorsal raphe nucleus (DRN) represents one of the most sensitive reward sites in the brain. However, the exact relationship between DRN neuronal activity and reward signaling has been elusive. In this review, we will summarize anatomical, pharmacological, optogenetics, and electrophysiological studies on the functions and circuit mechanisms of DRN neurons in reward processing. The DRN is commonly associated with serotonin (5-hydroxytryptamine; 5-HT), but this nucleus also contains neurons of the neurotransmitter phenotypes of glutamate, GABA and dopamine. Pharmacological studies indicate that 5-HT might be involved in modulating reward- or punishment-related behaviors. Recent optogenetic stimulations demonstrate that transient activation of DRN neurons produces strong reinforcement signals that are carried out primarily by glutamate. Moreover, activation of DRN 5-HT neurons enhances reward waiting. Electrophysiological recordings reveal that the activity of DRN neurons exhibits diverse behavioral correlates in reward-related tasks. Studies so far thus demonstrate the strong power of DRN neurons in reward signaling and at the same time invite additional efforts to dissect the roles and mechanisms of different DRN neuron types in various processes of reward-related behaviors. 
26284529	The psychostimulant methamphetamine (METH) is an addictive drug of abuse. The neuropeptide oxytocin has been shown to modulate METH-related reward and METH-seeking behaviour. Recent findings implicated the subthalamic nucleus (STh) as a key brain region in oxytocin modulation of METH-induced reward. However, it is unclear if oxytocin acts in this region to attenuate relapse to METH-seeking behaviour, and if this action is through the oxytocin receptor. We aimed to determine whether oxytocin pretreatment administered into the STh would reduce reinstatement to METH use in rats experienced at METH self-administration, and if this could be reversed by the co-administration of the oxytocin receptor antagonist desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT. Male Sprague Dawley rats underwent surgery to implant an intravenous jugular vein catheter and bilateral microinjection cannulae into the STh under isoflourane anaesthesia. Rats were then trained to self-administer intravenous METH (0.1 mg/kg/infusion) by lever press during 2-hour sessions under a fixed ratio 1 schedule for 20 days. Following extinction of lever press activity, the effect of microinjecting saline, oxytocin (0.2 pmol, 0.6 pmol, 1.8 pmol, 3.6 pmol) or co-administration of oxytocin (3.6 pmol) and desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT (3 nmol) into the STh (200 nl/side) was examined on METH-primed reinstatement (1 mg/kg; i.p.). We found that local administration of the highest oxytocin dose (3.6 pmol) into the STh decreased METH-induced reinstatement and desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT had a non-specific effect on lever press activity. These findings highlight that oxytocin modulation of the STh is an important modulator of relapse to METH abuse. 
26284004	The eye movement system is sensitive to reward. However, whilst the eye movement system is extremely flexible, the extent to which changes to oculomotor behavior induced by reward paradigms persist beyond the training period or transfer to other oculomotor tasks is unclear. To address these issues we examined the effects of presenting feedback that represented small monetary rewards to spatial locations on the latency of saccadic eye movements, the time-course of learning and extinction of the effects of rewarding saccades on exogenous spatial attention and oculomotor inhibition of return. Reward feedback produced a relative facilitation of saccadic latency in a stimulus driven saccade task which persisted for three blocks of extinction trials. However, this hemifield-specific effect failed to transfer to peripheral cueing tasks. We conclude that rewarding specific spatial locations is unlikely to induce long-term, systemic changes to the human oculomotor or attention systems. 
26281947	Cognitive-behavioral therapy (CBT) is effective in reducing the frequency and intensity of chronic pain in adolescents. However, CBT seems not to be considered acceptable by all adolescents. The main aim of our study was therefore to evaluate the effects of guided Internet-delivered self-help for adolescents with chronic pain. Adolescents (N = 69) were assessed on the outcome measures of pain, coping, disability, catastrophizing, rewarding of pain behavior by parents, and quality of life. Measures were taken 7 weeks before treatment and at pretreatment, posttreatment, and 3-month follow-up. Multilevel modeling was used for longitudinal analysis of the data. Pain intensity, interference caused by pain, rewarding of pain behavior by parents, and sleep problems significantly decreased during the intervention. The quality-of-life scores for pain, general behavior, mental health, family activities, and health changes also significantly improved during the intervention. With regard to coping, only problem-focused avoidance behavior significantly increased. No significant differences were found for pain-related disability and pain catastrophizing. Contrary to expectations, guided Internet-delivered self-help for chronic pain is difficult to use in adolescents, resulting in treatment attrition and loss to follow-up.Dutch Trial Register NTR1926.	The results of this trial suggest that Internet-based self-management is effective in decreasing pain intensity in adolescents with chronic pain. Because the intervention is grounded in CBT, we expect the underlying mechanism to be a change in self-management skills and in the ability of challenging dysfunctional thoughts.	
26281715	The dopamine D2 receptor (D2R) has received much attention in obesity studies. Data indicate that D2R is reduced in obesity and that the TaqA1 D2R variant may be more prevalent among obese persons. It is often suggested that reduced D2R generates a reward deficiency and altered appetitive motivation that induces compulsive eating and contributes to obesity. Although dopamine is known to regulate physical activity, it is often neglected in these studies, leaving open the question of whether reduced D2R contributes to obesity through alterations in energy expenditure and activity.We generated a D2R knockdown (KD) mouse line and assessed both energy expenditure and appetitive motivation under conditions of diet-induced obesity.	The KD mice did not gain more weight or show increased appetitive motivation compared with wild-type mice in a standard environment; however, in an enriched environment with voluntary exercise opportunities, KD mice exhibited dramatically lower activity and became more obese than wild-type mice, obtaining no protective benefit from exercise opportunities.	These data suggest the primary contribution of altered D2R signaling to obesity lies in altered energy expenditure rather than the induction of compulsive overeating.	
26281285	Increasing rates of obesity and associated diseases and their consequences make the implementation of preventive and counteracting measures necessary. The aim of this study was the examination of the long-term effects of financial incentives on weight loss in obese patients and the identification of influencing factors.700 obese patients were randomly assigned to one of three study conditions: For reaching a pre-defined target weight within 4 months they were rewarded with Euro 150, Euro 300 or not at all. The effect of the incentives on weight loss in different subgroups was compared. After 18 months, other possible influences on weight loss were analyzed by comparing responders and non-responders.	Financial rewards led to significant weight loss in all subgroups, whereupon the height of the incentive only mattered in some. After 22 months, for several subgroups, the incentive's effect was still visible. Furthermore, responders showed more healthy behaviour, were better informed and reported more social support.	Especially for patient groups who do not lose weight in orthodox treatments alone, financial incentives can be an effective supplement. In addition it became clear that this kind of reward programme can be implemented area-wide.	
26280804	The goal of the present study was to examine the utility of a behavioral economic analysis to investigate the role of delay discounting in texting while driving. A sample of 147 college students completed a survey to assess how frequently they send and read text messages while driving. Based on this information, students were assigned to one of two groups: 19 students who frequently text while driving and 19 matched-control students who infrequently text while driving but were similar in gender, age, years of education, and years driving. The groups were compared on the extent to which they discounted, or devalued, delayed hypothetical monetary rewards using a delay-discounting task. In this task, students made repeated choices between $1000 available after a delay (ranging from 1 week to 10 years) and an equal or lesser amount of money available immediately. The results show that the students who frequently text while driving discounted delayed rewards at a greater rate than the matched control students. The study supports the conclusions that texting while driving is fundamentally an impulsive choice made by drivers, and that a behavioral economic approach may be a useful research tool for investigating the decision-making processes underlying risky behaviors. 
26280384	Older adults experience declines in deliberative decisional capacities, while their affective or experiential abilities tend to remain intact (Peters & Bruine de Bruin, 2012). The current study used this framework to investigate age differences in description-based and experience-based decision-making tasks. Description-based tasks emphasize deliberative processing by allowing decision makers to analyze explicit descriptions of choice-reward information. Experience-based tasks emphasize affective or experiential processing because they lack the explicit choice-reward information, forcing decision makers to rely on feelings and information derived from past experiences. This study used the Columbia Card Task (CCT) as a description-based task where probability information is provided and the Iowa Gambling Task (IGT) as an experience-based task, where it is not. As predicted, compared to younger adults (N = 65), older adults (N = 65) performed more poorly on the CCT but performed similarly on the IGT. Deliberative capacities (i.e., executive control and numeracy abilities) explained the relationship between age and performance on the CCT, suggesting that age-related differences in description-based decision-making tasks are related to declines in deliberative capacities. However, deliberative capacities were not associated with performance on the IGT for either older or younger adults. Nevertheless, on the IGT, older adults reported more use of affect-based strategies versus deliberative strategies, whereas younger adults reported similar use of these strategies. This finding offers partial support for the idea that decision-making tasks that rely on deliberate processing are more likely to demonstrate age effects than those that are more experiential.
26280299	Anticipatory and consummatory dissociation of hedonic experience may manifest as trait anhedonia in healthy and clinical populations. It is still unclear whether the underlying neural mechanisms of the monetary-based and affect-based incentive delay paradigms are distinct from each other. The present study aimed to examine the similarities and differences between the Affect Incentive Delay (AID) and the Monetary Incentive Delay (MID) imaging paradigms in relation to brain activations.We administered the AID and the MID imaging tasks to 28 adolescent participants. A cue signaling the type of forthcoming feedback (reward or punishment) was displayed to the participants, followed by a target-hit task with corresponding reward or punishment.	The striatal and limbic regions were activated during the anticipatory phase of MID, while there was no brain activation during the anticipatory phase of AID. In the consummatory phase, the MID task activated the medial frontal cortex, while the AID task activated the frontal and dorsal limbic regions. We further found that the anhedonic group exhibited significant hypoactivation than the nonanhedonic group at the left pulvinar, the left claustrum and the left insula to positive cues in the anticipatory phase of the AID task.	The results suggest that the AID and the MID tasks have unique activation patterns. Our findings also suggest that the AID task may be more sensitive in detecting anhedonia in people with trait anhedonia.	
26280134	A deficit in empathy has been suggested to underlie social behavioural atypicalities in autism. A parallel theoretical account proposes that reduced social motivation (i.e., low responsivity to social rewards) can account for the said atypicalities. Recent evidence suggests that autistic traits modulate the link between reward and proxy metrics related to empathy. Using an evaluative conditioning paradigm to associate high and low rewards with faces, a previous study has shown that individuals high in autistic traits show reduced spontaneous facial mimicry of faces associated with high vs. low reward. This observation raises the possibility that autistic traits modulate the magnitude of evaluative conditioning. To test this, we investigated (a) if autistic traits could modulate the ability to implicitly associate a reward value to a social stimulus (reward learning/conditioning, using the Implicit Association Task, IAT); (b) if the learned association could modulate participants' prosocial behaviour (i.e., social reciprocity, measured using the cyberball task); (c) if the strength of this modulation was influenced by autistic traits. In 43 neurotypical participants, we found that autistic traits moderated the relationship of social reward learning on prosocial behaviour but not reward learning itself. This evidence suggests that while autistic traits do not directly influence social reward learning, they modulate the relationship of social rewards with prosocial behaviour.
26279767	To further evolve in an evidence-based fashion, medical education needs to develop and evaluate new practices for teaching, learning, and assessment. However, educators face barriers in designing, conducting, and publishing education research.To explore the barriers medical educators face in formulating, conducting, and publishing high-quality medical education research, and to identify strategies for overcoming them.	A consensus workshop was held November 5, 2013, at the Association of American Medical Colleges annual meeting. A working group of education research experts and educators completed a preconference literature review focusing on barriers to education research. During the workshop, consensus-based and small group techniques were used to refine the broad themes into content categories. Attendees then ranked the most important barriers and strategies for overcoming them with the highest potential impact.	Barriers participants faced in conducting quality education research included lack of (1) expertise, (2) time, (3) funding, (4) mentorship, and (5) reward. The strategy considered most effective in overcoming these barriers involved building communities of education researchers for collaboration and networking, and advocating for education researchers' interests. Other suggestions included trying to secure increased funding opportunities, developing mentoring programs, and encouraging mechanisms to ensure protected time.	Barriers to education research productivity clearly exist. Many appear to result from feelings of isolation that may be overcome with systemic efforts to develop and enable communities of practice across institutions. Finally, the theme of "reward" is novel and complex and may have implications for education research productivity.	
26279138	Despite the existence of several treatment options for smoking cessation, the rate of relapse after treatment is very high. We and others have proposed that targeting the dopamine D3 receptor (DRD3) may be a good strategy for treatment of nicotine dependence. In human participants, reintroduction to an environment previously associated with drug-taking may induce relapse. In animals, such phenomenon can be studied using the context-induced reinstatement paradigm. As the role of DRD3 in context-induced reinstatement of nicotine-seeking has not yet been explored, we investigated the effects of different doses of the selective DRD3 antagonist SB-277011-A on this reinstatement. Sprague-Dawley adult rats were first trained to self-administer nicotine and subsequently underwent extinction in a second context for 5-7 days. We evaluated the effect of 1, 3 or 10mg/kg of SB-277011-A administered prior to the reintroduction to the training context. We used two different designs: 1) a between-subjects design with a unique reinstatement test; and 2) a counterbalanced within-subjects design, with 4 reinstatement tests. Our findings indicate that, in the within-subjects design, the magnitude of responding induced by the context-induced reinstatement of nicotine seeking was robust during the first reinstatement test, but significantly decreased with repeated testing. SB-277011-A (10mg/kg) blocked context-induced reinstatement of nicotine-seeking at first exposure to the context (between-subjects design), but not after repeated context exposure which produced weaker reinstatement over days. Our results support a role for DRD3 mediating context-induced reinstatement of nicotine seeking, but these effects may not be sustained over time. Further studies should explore this in human participants for validation.
26278401	The pervasive use of refined sugars in highly accessible, palatable foods and persistent exposure to reinforcing food-associated cues has contributed to overconsumption of sugar-rich diets and the current obesity epidemic in Western society. We have shown previously that brain relaxin-3 mRNA levels positively correlate with sucrose and alcohol intake, and that central antagonism of relaxin-3 receptors (RXFP3) attenuates alcohol self-administration and alcohol-seeking in rats, but food-seeking behaviour and palatable food consumption in mice. To further examine the relationship between motivated appetitive behaviours and relaxin-3/RXFP3 signalling, we investigated the effect of Rxfp3 gene deletion in C57BL/6J mice on sucrose and alcohol self-administration and cue-induced reinstatement (RNST) of sucrose- and alcohol-seeking. Acquisition and maintenance of sucrose and alcohol self-administration was assessed in male wild-type (WT) and Rxfp3 knockout (KO) (C57BL/6J(RXFP3TM1) (/) (DGen) ) littermate mice using fixed ratio (FR) schedules of reinforcement. Mice were subsequently challenged with a progressive ratio (PR) test to measure motivation and, following extinction training, re-exposed to reward-associated cues to evaluate RNST of active lever-responding. Wild-type and Rxfp3 KO mice displayed similar acquisition of FR1 sucrose self-administration, but Rxfp3 KO mice responded less when the instrumental requirement was increased to FR3. These mice also showed a lower breakpoint for sucrose and attenuated cue-induced RNST of sucrose-seeking. Notably, no marked genotype differences in alcohol-responding were observed. In mice, endogenous relaxin-3/RXFP3 signalling promotes self-administration of sucrose under high response requirements and cue-induced RNST of sucrose-seeking, but does not apparently regulate motivation to consume alcohol or alcohol-seeking behaviour. 
26278335	Reward-related feedback stimuli have been observed to elicit a burst of power in the beta frequency range over frontal areas of the human scalp. Recent discussions have suggested possible neural sources for this activity but there is a paucity of empirical evidence on the question. Here we recorded EEG from participants while they navigated a virtual T-maze to find monetary rewards. Consistent with previous studies, we found that the reward feedback stimuli elicited an increase in beta power (20-30 Hz) over a right-frontal area of the scalp. Source analysis indicated that this signal was produced in the right dorsolateral prefrontal cortex (DLPFC). These findings align with previous observations of reward-related beta oscillations in the DLPFC in non-human primates. We speculate that increased power in the beta frequency range following reward receipt reflects the activation of task-related neural assemblies that encode the stimulus-response mapping in working memory.
26277034	Despite similar emotional deficiencies, primary psychopathic individuals can be situated on a continuum that spans from controlled to disinhibited. The constructs on which primary psychopaths are found to diverge, such as self-control, cognitive flexibility, and executive functioning, are crucially regulated by dopamine (DA). As such, the goal of this review is to examine which specific alterations in the meso-cortico-limbic DA system and corresponding genes (e.g., TH, DAT, COMT, DRD2, DRD4) might bias development towards a more controlled or disinhibited expression of primary psychopathy. Based on empirical data, it is argued that primary psychopathy is generally related to a higher tonic and population activity of striatal DA neurons and lower levels of D2-type DA receptors in meso-cortico-limbic projections, which may boost motivational drive towards incentive-laden goals, dampen punishment sensitivity, and increase future reward-expectancy. However, increasingly higher levels of DA activity in the striatum (moderate versus pathological elevations), lower levels of DA functionality in the prefrontal cortex, and higher D1-to-D2-type receptor ratios in meso-cortico-limbic projections may lead to increasingly disinhibited and impetuous phenotypes of primary psychopathy. Finally, in order to provide a more coherent view on etiological mechanisms, we discuss interactions between DA and serotonin that are relevant for primary psychopathy. 
26276628	Advances in neuroscience identified addiction as a chronic brain disease with strong genetic, neurodevelopmental, and sociocultural components. We here discuss the circuit- and cell-level mechanisms of this condition and its co-option of pathways regulating reward, self-control, and affect. Drugs of abuse exert their initial reinforcing effects by triggering supraphysiologic surges of dopamine in the nucleus accumbens that activate the direct striatal pathway via D1 receptors and inhibit the indirect striato-cortical pathway via D2 receptors. Repeated drug administration triggers neuroplastic changes in glutamatergic inputs to the striatum and midbrain dopamine neurons, enhancing the brain's reactivity to drug cues, reducing the sensitivity to non-drug rewards, weakening self-regulation, and increasing the sensitivity to stressful stimuli and dysphoria. Drug-induced impairments are long lasting; thus, interventions designed to mitigate or even reverse them would be beneficial for the treatment of addiction. 
26276367	Operant behavior is typically organized into sequences of responses that eventually lead to a reinforcer. Response elements can be categorized as those that directly lead to reward consumption (i.e., a consumption response) and those that lead to the opportunity to make the consumption response (i.e., a procurement response). These responses often differ topographically and in terms of the discriminative stimuli that set the occasion for them. We have recently shown that extinction of the procurement response acts to weaken the specific associated consumption response, and that active inhibition of the procurement response is required for this effect. To expand the analysis of the associative structure of chains, in the present experiments we asked the reverse question: whether extinction of consumption behavior results in a decrease in the associated procurement response in a discriminated heterogeneous chain. In Experiment 1, extinction of consumption alone led to an attenuation of the associated procurement response only when rats were allowed to make the consumption response in extinction. Exposure to the consumption stimulus alone was not sufficient to produce weakened procurement responding. In Experiment 2, rats learned two distinct heterogeneous chains, and extinction of one consumption response specifically weakened the procurement response associated with it. The results add to the evidence suggesting that rats learn a highly specific associative structure in behavior chains, emphasizing the role of learning response inhibition in extinction. 
26276363	A cross-sectional survey was carried out among 275 and 760 randomly selected senior officers (SOs) and managerial assistants (MAs) aged between 30 and 60 years. Sum of scores of efforts, rewards, and overcommitment and effort-reward ratio assessed job stress. Blood pressure was measured and classified using JNC-7 guidelines. The response rates of SOs and MAs were 98.9% and 97.2%, respectively. The prevalence of job stress based on high effort-rewards imbalance among SOs and MAs was 74.6% and 80.5%, respectively. The prevalence of overcommitment among SOs and MAs was 35.3% and 29%, respectively. Statistically significant differences (P = .05) were observed between the prevalence of effort-reward imbalance and overcommitment among SOs and MAs. Multivariate analysis indicated effort-reward imbalance (odds ratio [OR] = 2.8; 95% confidence interval [CI] = 1.1-7.4), high efforts (OR = 2.5; 95% CI = 1.2-5.3), and overcommitment (OR = 2.5; 95% CI = 1.1-5.6) were significantly associated with hypertension among SOs. Similarly, effort-reward imbalance and high efforts increased the risk of hypertension by 2-fold (OR = 2.2; 95% CI = 1.1-4.2) and 3-fold (OR = 3.02; 95% CI = 1.9-4.8), respectively, among the MAs. A significant number of administrators are afflicted by job stress, and job stress was significantly associated with hypertension. 

26276036	Many brain areas are activated by the possibility and receipt of reward. Are all of these brain areas reporting the same information about reward? Or are these signals related to other functions that accompany reward-guided learning and decision-making? Through carefully controlled behavioral studies, it has been shown that reward-related activity can represent reward expectations related to future outcomes, errors in those expectations, motivation, and signals related to goal- and habit-driven behaviors. These dissociations have been accomplished by manipulating the predictability of positively and negatively valued events. Here, we review single neuron recordings in behaving animals that have addressed this issue. We describe data showing that several brain areas, including orbitofrontal cortex, anterior cingulate, and basolateral amygdala signal reward prediction. In addition, anterior cingulate, basolateral amygdala, and dopamine neurons also signal errors in reward prediction, but in different ways. For these areas, we will describe how unexpected manipulations of positive and negative value can dissociate signed from unsigned reward prediction errors. All of these signals feed into striatum to modify signals that motivate behavior in ventral striatum and guide responding via associative encoding in dorsolateral striatum. 
26275935	The consolidation of memories for places and events is thought to rely, at the network level, on the replay of spatially tuned neuronal firing patterns representing discrete places and spatial trajectories. This occurs in the hippocampal-entorhinal circuit during sharp wave ripple events (SWRs) that occur during sleep or rest. Here, we review theoretical models of lingering place cell excitability and behaviorally induced synaptic plasticity within cell assemblies to explain which sequences or places are replayed. We further provide new insights into how fluctuations in cholinergic tone during different behavioral states might shape the direction of replay and how dopaminergic release in response to novelty or reward can modulate which cell assemblies are replayed. 
26275785	Breaks in play represent a responsible gambling strategy designed to disrupt states of dissociation and enhance the likelihood of drawing attention to a player's session behaviour and expenditure with respect to time and money. The aim of the break in play is to motivate the player to modify or cease gambling so the activity remains within affordable levels. The aim of this study was to investigate whether imposed breaks in play in the absence of accompanying warning messages were effective in reducing cravings. Participants (141 university students) were randomly allocated to one of three conditions: 15 min computer simulated Black Jack play followed by no break, a 3 or 8 min break in play. Participants were administered a battery of measures to assess problem gambling card play, cravings, and dissociation to assess the effects of length of break on cravings. Results indicated that cravings increased rather than decreased with imposed breaks in play, and that the strength of cravings were higher following the eight- compared to 3-min break. It was concluded that breaks in play in isolation might produce counterproductive, unintended, and even perverse effects. The policy implications for responsible gambling strategies is that breaks in play ought to be accompanied with warning and/or personal appraisal messages if optimal effects in reducing within session gambling expenditure are to be achieved. 
26275360	Effective methods to prevent adolescent depressive symptoms could reduce suffering and burden across the lifespan. However, psychological interventions delivered to adolescents show efficacy only in symptomatic or high-risk youth. Targeting causal risk factors and assessing mechanistic change can help devise efficacious universal or classroom based prevention programs.A non-randomized longitudinal design was used to compare three classroom-based prevention programs for adolescent depression (Behavioral Activation with Reward Processing, "Thinking about Reward in Young People" (TRY); Cognitive Behavioral Therapy (CBT) and Mindfulness Based Cognitive Therapy (MBCT)), and determine cognitive mechanisms of change in these programs. Cognitive mechanisms examined were reward-seeking, negative self-beliefs (assessed with behavioral tasks) and over-general autobiographical memory. 256 healthy adolescents aged 13-14 participated with 236 (92%) and 227 (89%) completing the pre- and post-assessments.	TRY was the only intervention associated with a reduction in depressive symptoms at follow-up. Reward-seeking increased following TRY. In the other programs there were non-significant changes in cognitive mechanisms, with more reflective negative self-beliefs in CBT and fewer over-general autobiographical memories in MBCT In the TRY program, which focused on increasing sensitivity to rewarding activities, reward seeking increased and this was associated with decreased depressive symptoms.	Due to the infeasibility of a cluster randomized controlled trial, a non-randomized design was used.	Increased reward-seeking was associated with decreased depressive symptoms and may be a mechanism of depressive symptom change in the intervention with a focus on enhancing sensitivity and awareness of reward. This study provides preliminary evidence to suggest that incorporating activities to enhance reward sensitivity may be fruitful in randomized controlled trials of universal prevention programs for depression.	
26275334	Obese individuals show altered neural responses to high-calorie food cues. Individuals with binge eating [BE], who exhibit heightened impulsivity and emotionality, may show a related but distinct pattern of irregular neural responses. However, few neuroimaging studies have compared BE and non-BE groups. To examine neural responses to food cues in BE, 10 women with BE and 10 women without BE (non-BE) who were matched for obesity (5 obese and 5 lean in each group) underwent fMRI scanning during presentation of visual (picture) and auditory (spoken word) cues representing high energy density (ED) foods, low-ED foods, and non-foods. We then compared regional brain activation in BE vs. non-BE groups for high-ED vs. low-ED foods. To explore differences in functional connectivity, we also compared psychophysiologic interactions [PPI] with dorsal anterior cingulate cortex [dACC] for BE vs. non-BE groups. Region of interest (ROI) analyses revealed that the BE group showed more activation than the non-BE group in the dACC, with no activation differences in the striatum or orbitofrontal cortex [OFC]. Exploratory PPI analyses revealed a trend towards greater functional connectivity with dACC in the insula, cerebellum, and supramarginal gyrus in the BE vs. non-BE group. Our results suggest that women with BE show hyper-responsivity in the dACC as well as increased coupling with other brain regions when presented with high-ED cues. These differences are independent of body weight, and appear to be associated with the BE phenotype. 
26275165	Cognitive flexibility is a hallmark of prefrontal cortical (PFC) function yet little is known about downstream area involvement. The medial dorsal striatum (mDS) receives major projections from the PFC and is uniquely situated to perform the integration of responses with rule information. In this study, we use a novel rule shifting task in rats that mirrors non-human primate and human studies in its temporal precision and counterbalanced responses. We record activity from single neurons in the mDS while rats switch between different rules for reward. Additionally, we pharmacologically inactivate mDS by infusion of a baclofen/muscimol cocktail. Inactivation of mDS impaired the ability to shift to a new rule and increased the number of regressive errors. While recording in mDS, we identified neurons modulated by direction whose activity reflected the conflict between competing rule information. We show that a subset of these neurons was also rule selective, and that the conflict between competing rule cues was resolved as behavioural performance improved. Other neurons were modulated by rule, but not direction. These neurons became selective before behavioural performance accurately reflected the current rule. These data provide an additional locus for investigating the mechanisms underlying behavioural flexibility. Converging lines of evidence from multiple human psychiatric disorders have implicated dorsal striatum as an important and understudied neural substrate of flexible cognition. Our data confirm the importance of mDS, and suggest a mechanism by which mDS mediates abstract cognition functions. 
26273939	During laboratory gambling tasks participants are not typically allowed to wager their personal wealth. Instead, wealth is simulated by telling participants they have been endowed with game tokens that will be later exchanged for money. Past research indicates that participants undervalue game tokens following this procedure, which leads to elevated risk taking compared to procedures that add saliency or realism to the monetary payoff. A between-subjects experiment tested whether showing a picture of money during the endowment instructions and repeating token-money exchange information during the session influenced participants' preference for risky and riskless options. The results showed no effect of the money picture. However, repeated token-money exchange information significantly decreased risk taking. Together with past studies, this finding suggests that endowment procedures might establish greater value in game tokens, and therefore better simulate personal wealth, when the eventual exchange between game tokens and money is made more salient to participants. 
26272220	Rewards are defined by their behavioral functions in learning (positive reinforcement), approach behavior, economic choices, and emotions. Dopamine neurons respond to rewards with two components, similar to higher order sensory and cognitive neurons. The initial, rapid, unselective dopamine detection component reports all salient environmental events irrespective of their reward association. It is highly sensitive to factors related to reward and thus detects a maximal number of potential rewards. It also senses aversive stimuli but reports their physical impact rather than their aversiveness. The second response component processes reward value accurately and starts early enough to prevent confusion with unrewarded stimuli and objects. It codes reward value as a numeric, quantitative utility prediction error, consistent with formal concepts of economic decision theory. Thus, the dopamine reward signal is fast, highly sensitive and appropriate for driving and updating economic decisions.
26272038	The neurobiology of anorexia nervosa remains incompletely understood. Here we utilized PET imaging with the radiotracer [(11)C]raclopride to measure striatal dopamine type 2 (D2) receptor availability in patients with anorexia nervosa. 25 women with anorexia nervosa who were receiving treatment in an inpatient program participated, as well as 25 control subjects. Patients were scanned up to two times with the PET tracer [(11)C]raclopride: once while underweight, and once upon weight restoration. Control subjects underwent one PET scan. In the primary analyses, there were no significant differences between underweight patients (n=21) and control subjects (n=25) in striatal D2 receptor binding potential. Analysis of subregions (sensorimotor striatum, associative striatum, limbic striatum) did not reveal differences between groups. In patients completing both scans (n=15), there were no detectable changes in striatal D2 receptor binding potential after weight restoration. In this sample, there were no differences in striatal D2 receptor binding potential between patients with anorexia nervosa and control subjects. Weight restoration was not associated with a change in striatal D2 receptor binding. These findings suggest that disturbances in reward processing in this disorder are not attributable to abnormal D2 receptor characteristics, and that other reward-related neural targets may be of greater relevance. 
26269638	Adolescence is a critical developmental phase during which risk-taking behaviors increase across a variety of species, raising the importance of understanding how brain changes contribute to such behaviors. While the prefrontal cortex is thought to influence adolescent risk taking, the specific ways in which it functions are unclear. Using longitudinal functional magnetic resonance imaging in human adolescents, we found that ventrolateral prefrontal cortex (VLPFC) activation decreased during an experimental risk-taking task over time, with greater declines in VLPFC associated with greater declines in self-reported risky behavior. Furthermore, greater decreases in functional coupling between the medial prefrontal cortex (MPFC) and ventral striatum over time were associated with decreases in self-reported risky behavior. Thus, disparate roles of the VLPFC and MPFC modulate longitudinal declines in adolescent risk taking.Adolescence is a developmental period marked by steep increases in risk-taking behavior coupled with dramatic brain changes. Although theories propose that the prefrontal cortex (PFC) may influence adolescent risk taking, the specific ways in which it functions remain unclear. We report the first longitudinal functional magnetic resonance imaging study to examine how neural activation during risk taking changes over time and contributes to adolescents' real-life risk-taking behavior. We find that longitudinal declines in activation of the ventrolateral PFC are linked to declines in adolescent risk taking, whereas the medial PFC influences adolescent risk taking via its functional neural coupling with reward-related regions. This is the first study to identify the mechanism by which different regions of the PFC disparately contribute to declines in risk taking.	
26269633	Natural environments are complex, and a single choice can lead to multiple outcomes. Agents should learn which outcomes are due to their choices and therefore relevant for future decisions and which are stochastic in ways common to all choices and therefore irrelevant for future decisions between options. We designed an experiment in which human participants learned the varying reward and effort magnitudes of two options and repeatedly chose between them. The reward associated with a choice was randomly real or hypothetical (i.e., participants only sometimes received the reward magnitude associated with the chosen option). The real/hypothetical nature of the reward on any one trial was, however, irrelevant for learning the longer-term values of the choices, and participants ought to have only focused on the informational content of the outcome and disregarded whether it was a real or hypothetical reward. However, we found that participants showed an irrational choice bias, preferring choices that had previously led, by chance, to a real reward in the last trial. Amygdala and ventromedial prefrontal activity was related to the way in which participants' choices were biased by real reward receipt. By contrast, activity in dorsal anterior cingulate cortex, frontal operculum/anterior insula, and especially lateral anterior prefrontal cortex was related to the degree to which participants resisted this bias and chose effectively in a manner guided by aspects of outcomes that had real and more sustained relationships with particular choices, suppressing irrelevant reward information for more optimal learning and decision making.In complex natural environments, a single choice can lead to multiple outcomes. Human agents should only learn from outcomes that are due to their choices, not from outcomes without such a relationship. We designed an experiment to measure learning about reward and effort magnitudes in an environment in which other features of the outcome were random and had no relationship with choice. We found that, although people could learn about reward magnitudes, they nevertheless were irrationally biased toward repeating certain choices as a function of the presence or absence of random reward features. Activity in different brain regions in the prefrontal cortex either reflected the bias or reflected resistance to the bias.	
26269631	In decision making, dorsal and ventral medial prefrontal cortex show a sensitivity to key decision variables, such as reward prediction errors. It is unclear whether these signals reflect parallel processing of a common synchronous input to both regions, for example from mesocortical dopamine, or separate and consecutive stages in reward processing. These two perspectives make distinct predictions about the relative timing of feedback-related activity in each of these regions, a question we address here. To reconstruct the unique temporal contribution of dorsomedial (dmPFC) and ventromedial prefrontal cortex (vmPFC) to simultaneously measured EEG activity in human subjects, we developed a novel trialwise fMRI-informed EEG analysis that allows dissociating correlated and overlapping sources. We show that vmPFC uniquely contributes a sustained activation profile shortly after outcome presentation, whereas dmPFC contributes a later and more peaked activation pattern. This temporal dissociation is expressed mainly in the alpha band for a vmPFC signal, which contrasts with a theta based dmPFC signal. Thus, our data show reward-related vmPFC and dmPFC responses have distinct time courses and unique spectral profiles, findings that support distinct functional roles in a reward-processing network.Multiple subregions of the medial prefrontal cortex are known to be involved in decision making and learning, and expose similar response patterns in fMRI. Here, we used a novel approach to analyzing simultaneous EEG-fMRI that allows to dissociate the individual time courses of brain regions. We find that vmPFC and dmPFC have distinguishable time courses and time-frequency patterns.	
26268572	Deep brain stimulation (DBS) has become the preferred therapy for a growing number of treatment-resistant neuropsychiatric conditions, offering the benefit of being amenable to fine-tuning to enhance its efficacy. However, while some DBS parameters are routinely adjusted, the stimulation is almost always delivered in a continuous "tonic" pattern, which may be suboptimal at times. Our overall aim is to investigate the application of differing levels of rewarding DBS to the reconditioning of behavioral "trigger" and "non-trigger" stimuli in impulse-control disorders (including addiction). As a first step, we used a rat model of nucleus accumbens (NAc) DBS to rigorously compare the relative reward values of different stimulation paradigms. We hypothesized that delivering pulses in a more physiological pattern would prove more rewarding than delivering tonic stimulation.We implanted microelectrodes in the left NAc shell and trained rats to initiate and terminate DBS to demonstrate their "preference" between different brain stimulation reward (BSR) paradigms. We tested a range of BSR paradigms, including tonic, intermittent tonic, and burst paradigms. Two paradigms were compared at a time, and paired t-tests were used to determine whether the rats significantly "preferred" one paradigm over another.	The rats significantly preferred intermittent tonic BSR paradigms to continuous and burst paradigms, and generally preferred paradigms that delivered more pulses over the stimulation period.	These findings highlight that the standard approach of delivering tonic DBS is not optimal under all circumstances. Further research should investigate which DBS paradigms are best for different brain disorders.	

26266537	The frontal cortex controls behavioral adaptation in environments governed by complex rules. Many studies have established the relevance of firing rate modulation after informative events signaling whether and how to update the behavioral policy. However, whether the spatiotemporal features of these neuronal activities contribute to encoding imminent behavioral updates remains unclear. We investigated this issue in the dorsal anterior cingulate cortex (dACC) of monkeys while they adapted their behavior based on their memory of feedback from past choices. We analyzed spike trains of both single units and pairs of simultaneously recorded neurons using an algorithm that emulates different biologically plausible decoding circuits. This method permits the assessment of the performance of both spike-count and spike-timing sensitive decoders. In response to the feedback, single neurons emitted stereotypical spike trains whose temporal structure identified informative events with higher accuracy than mere spike count. The optimal decoding time scale was in the range of 70-200 ms, which is significantly shorter than the memory time scale required by the behavioral task. Importantly, the temporal spiking patterns of single units were predictive of the monkeys' behavioral response time. Furthermore, some features of these spiking patterns often varied between jointly recorded neurons. All together, our results suggest that dACC drives behavioral adaptation through complex spatiotemporal spike coding. They also indicate that downstream networks, which decode dACC feedback signals, are unlikely to act as mere neural integrators.
26265343	Incentives guide human behavior by altering the level of external motivation. We apply the idea of loss aversion from prospect theory (Kahneman & Tversky, 1979) to the point reward systems in soccer and investigate the controversial impact of the three-point rule on reducing the fraction of draws in this sport. Making use of the Poisson nature of goal scoring, we compared empirical results with theoretically deduced draw ratios from 24 countries encompassing 20 seasons each (N = 118.148 matches). The rule change yielded a slight reduction in the ratio of draws, but despite adverse incentives, still 18% more matches ended drawn than expected, t(23) = 11.04, p < .001, d = 2.25, consistent with prospect theory assertions. Alternative point systems that manipulated incentives for losses yielded reductions at or below statistical expectation. This provides support for the deduced concept of how arbitrary aims, such as the reduction of draws in the world's soccer leagues, could be more effectively accomplished than currently attempted. 
26265319	Participants show a perceptual bias favoring stimuli associated with the participants themselves over stimuli associated with other people. A major account of this self-bias effect is that self-related information is intrinsically rewarding, and that high-reward stimuli have enhanced perceptual processing. Here we used redundancy gains to examine the relations between self bias and reward, and whether self and reward biases modulate common levels of stimulus integration. We demonstrated that the self-association bias increases when more than one exemplar of the stimulus is presented (i.e., when participants are exposed to redundant stimuli). The larger self-bias effects for redundant than for single stimuli arose at both perceptual and conceptual levels of representation (respectively, for identical and nonidentical stimuli associated with the same category). In contrast, high-reward stimuli did not affect perceptual redundancy gains with identical shapes, but they did affect redundancy gains with nonidentical stimuli associated with the same category. The strong redundancy effects with self-related stimuli are consistent with self associations modulating stimulus integration at both perceptual and conceptual levels, whereas reward only modulated higher-level conceptual processes (with nonidentical stimuli). The data provide two novel theoretical advances, by showing that (i) self association modulates both early perceptual coding and higher-level conceptual coding, whereas reward only affects the higher-level process, and (ii) self bias can not be reduced simply to differential effects of reward. 
26262941	This study presents an application of the theoretical domains framework (TDF; Michie et al., 2005), an integrative framework drawing on behavior-change theories, to speech-language pathology.A multistep procedure was used to identify barriers affecting caregivers' implementation of shared-reading interventions with their children with language impairment (LI). The authors examined caregiver-level data corresponding to implementation issues from two randomized controlled trials and mapped these to domains in the TDF as well as empirically validated behavior-change techniques.	Four barriers to implementation were identified as potentially affecting caregivers' implementation: time pressures, reading difficulties, discomfort with reading, and lack of awareness of benefits. These were mapped to 3 TDF domains: intentions, beliefs about capabilities, and skills. In turn, 4 behavior-change techniques were identified as potential vehicles for affecting these domains: reward, feedback, model, and encourage. An ongoing study is described that is determining the effects of these techniques for improving caregivers' implementation of a shared-reading intervention.	A description of the steps to identifying barriers to implementation, in conjunction with an ongoing experiment that will explicitly determine whether behavior-change techniques affect these barriers, provides a model for how implementation science can be used to identify and overcome implementation barriers in the treatment of communication disorders.	
26260431	Dopamine and opioid neurotransmitter systems share many functions such as regulation of reward and pleasure. μ-Opioid receptors (MOR) modulate the mesolimbic dopamine system in ventral tegmental area and striatum, key areas implicated in reward. We hypothesized that dopamine and opioid receptor availabilities correlate in vivo and that this correlation is altered in obesity, a disease with altered reward processing. Twenty lean females (mean BMI 22) and 25 non-binge eating morbidly obese females (mean BMI 41) underwent two positron emission tomography scans with [(11)C]carfentanil and [(11)C]raclopride to measure the MOR and dopamine D2 receptor (DRD2) availability, respectively. In lean subjects, the MOR and DRD2 availabilities were positively associated in the ventral striatum (r=0.62, p=0.003) and dorsal caudate nucleus (r=0.62, p=0.004). Moreover, DRD2 availability in the ventral striatum was associated with MOR availability in other regions of the reward circuitry, particularly in the ventral tegmental area. In morbidly obese subjects, this receptor interaction was significantly weaker in ventral striatum but unaltered in the caudate nucleus. Finally, the association between DRD2 availability in the ventral striatum and MOR availability in the ventral tegmental area was abolished in the morbidly obese. The study demonstrates a link between DRD2 and MOR availabilities in living human brain. This interaction is selectively disrupted in mesolimbic dopamine system in morbid obesity. We propose that interaction between the dopamine and opioid systems is a prerequisite for normal reward processing and that disrupted cross-talk may underlie altered reward processing in obesity. 

26258191	Chronic inflammation may play an important role in linking job stress to atherosclerosis. We sought to investigate the relationship between job stress and high-sensitivity C-reactive protein (hs-CRP) among Chinese workers.A total of 731 subjects (506 men and 225 women) were analyzed. Job stress was evaluated by effort-reward imbalance (ERI) model.	Among men, after adjustment for confounders, effort, overcommitment, and ERI were significantly positively correlated with hs-CRP; and reward was significantly inversely related with hs-CRP; high level of effort, overcommitment, or ERI, respectively, significantly increased the odds of high hs-CRP with ORs of 2.0, 3.5, and 3.3 (all P<0.001), compared with the corresponding low level groups. Among women, high overcommitment or ERI also increased risk of high hs-CRP with ORs of 2.8, and 4.1 (P<0.05).	High effort, overcommmitment, and ERI were positively associated with hs-CRP. Inflammation indicated by hs-CRP may be one of important mediators linking job stress and atherosclerosis.	
26258159	Anhedonia - diminished pleasure and/or decreased reactivity to pleasurable stimuli - is a core feature of depression that frequently persists after treatment. As a result, extensive effort has been directed towards characterizing the psychological and biological processes that mediate dysfunctional reward processing in depression. Reward processing can be parsed into sub-components that include motivation, reinforcement learning, and hedonic capacity, which, according to preclinical and neuroimaging evidence, involve partially dissociable brain systems. In line with this, recent findings indicate that behavioral impairments and neural abnormalities in depression vary across distinct reward-related constructs. Ultimately, improved understanding of precise reward-related dysfunctions in depression promises to improve diagnostic and therapeutic efforts in depression.
26257691	Increasing evidence suggests that the prefrontal cortex (PFC) is influenced by sex steroids and that some cognitive functions dependent on the PFC may be sexually differentiated in humans. Past work has identified a male advantage on certain complex reinforcement learning tasks, but it is unclear which latent task components are important to elicit the sex difference. The objective of the current study was to investigate whether there are sex differences on measures of response inhibition and valenced feedback processing, elements that are shared by previously studied reinforcement learning tasks. Healthy young adults (90 males, 86 females) matched in general intelligence completed the Probabilistic Selection Task (PST), a Simon task, and the Stop-Signal task. On the PST, females were more accurate than males in learning from positive (but not negative) feedback. On the Simon task, males were faster than females, especially in the face of incongruent stimuli. No sex difference was observed in Stop-Signal reaction time. The current findings provide preliminary support for a sex difference in the processing of valenced feedback and in interference inhibition. 
26257639	Neurorobots enable researchers to study how behaviors are produced by neural mechanisms in an uncertain, noisy, real-world environment. To investigate how the somatosensory system processes noisy, real-world touch inputs, we introduce a neurorobot called CARL-SJR, which has a full-body tactile sensory area. The design of CARL-SJR is such that it encourages people to communicate with it through gentle touch. CARL-SJR provides feedback to users by displaying bright colors on its surface. In the present study, we show that CARL-SJR is capable of learning associations between conditioned stimuli (CS; a color pattern on its surface) and unconditioned stimuli (US; a preferred touch pattern) by applying a spiking neural network (SNN) with neurobiologically inspired plasticity. Specifically, we modeled the primary somatosensory cortex, prefrontal cortex, striatum, and the insular cortex, which is important for hedonic touch, to process noisy data generated directly from CARL-SJR's tactile sensory area. To facilitate learning, we applied dopamine-modulated Spike Timing Dependent Plasticity (STDP) to our simulated prefrontal cortex, striatum, and insular cortex. To cope with noisy, varying inputs, the SNN was tuned to produce traveling waves of activity that carried spatiotemporal information. Despite the noisy tactile sensors, spike trains, and variations in subject hand swipes, the learning was quite robust. Further, insular cortex activities in the incremental pathway of dopaminergic reward system allowed us to control CARL-SJR's preference for touch direction without heavily pre-processed inputs. The emerged behaviors we found in this model match animal's behaviors wherein they prefer touch in particular areas and directions. Thus, the results in this paper could serve as an explanation on the underlying neural mechanisms for developing tactile preferences and hedonic touch. 
26257616	Previous research has shown that trial ordering affects cognitive performance, but this has not been tested using category-learning tasks that differentiate learning from reward and punishment. Here, we tested two groups of healthy young adults using a probabilistic category learning task of reward and punishment in which there are two types of trials (reward, punishment) and three possible outcomes: (1) positive feedback for correct responses in reward trials; (2) negative feedback for incorrect responses in punishment trials; and (3) no feedback for incorrect answers in reward trials and correct answers in punishment trials. Hence, trials without feedback are ambiguous, and may represent either successful avoidance of punishment or failure to obtain reward. In Experiment 1, the first group of subjects received an intermixed task in which reward and punishment trials were presented in the same block, as a standard baseline task. In Experiment 2, a second group completed the separated task, in which reward and punishment trials were presented in separate blocks. Additionally, in order to understand the mechanisms underlying performance in the experimental conditions, we fit individual data using a Q-learning model. Results from Experiment 1 show that subjects who completed the intermixed task paradoxically valued the no-feedback outcome as a reinforcer when it occurred on reinforcement-based trials, and as a punisher when it occurred on punishment-based trials. This is supported by patterns of empirical responding, where subjects showed more win-stay behavior following an explicit reward than following an omission of punishment, and more lose-shift behavior following an explicit punisher than following an omission of reward. In Experiment 2, results showed similar performance whether subjects received reward-based or punishment-based trials first. However, when the Q-learning model was applied to these data, there were differences between subjects in the reward-first and punishment-first conditions on the relative weighting of neutral feedback. Specifically, early training on reward-based trials led to omission of reward being treated as similar to punishment, but prior training on punishment-based trials led to omission of reward being treated more neutrally. This suggests that early training on one type of trials, specifically reward-based trials, can create a bias in how neutral feedback is processed, relative to those receiving early punishment-based training or training that mixes positive and negative outcomes. 
26257243	Observed impairment in reciprocal social interaction is a diagnostic hallmark of autism spectrum disorders. There is no effective medical treatment for these problems. Psychological treatments remain costly, time intensive, and developmentally sensitive for efficacy. In this review, we explore the potential of oxytocin-based therapies for social impairments in autism. Evidence shows that acute oxytocin administration improves numerous markers critical to the social circuitry underlying social deficits in autism. Oxytocin may optimize these circuits and enhance reward, motivation, and learning to improve therapeutic outcomes. Despite this, the current evidence of therapeutic benefit from extended oxytocin treatment remains very limited. We highlight complexity in crossing from the laboratory to the autism clinical setting in evaluation of this therapeutic. We discuss a clinical trial approach that provides optimal opportunity for therapeutic response by using personalized methods that better target specific circuitry to define who will obtain benefit, at what stage of development, and the optimal delivery approach for circuitry manipulation. For the autism field, the therapeutic challenges will be resolved by a range of treatment strategies, including greater focus on specific interventions, such as oxytocin, that have a strong basis in the fundamental neurobiology of social behavior. More sophisticated and targeted clinical trials utilizing such approaches are now required, placing oxytocin into the autism context. 

26255975	Recent research demonstrated structural overlap between reward and self processing, but the functional relationship that explains how self processing influences reward processing remains unclear. The present study used an experimentally constrained reflection task to investigate whether individuals' outcome evaluations in a gambling task are modulated by task-unrelated self- and other-reflection processes. The self- and other-reflection task contained descriptions of the self or others, and brain event-related potentials (ERPs) were recorded while 16 normal adults performed a gambling task. The ERP analysis focused on the feedback-related negativity (FRN) component. We found that the difference wave of FRN increased in the self-reflection condition compared with the other-reflection condition. The present findings provide direct evidence that self processing can influence reward processing. 
26255603	When it is not possible to distribute resources equitably to everyone, people look for an equitable or just procedure. In the current study, we investigated young children's sense of procedural justice. We tested 32 triads of 5-year-olds in a new resource allocation game. Triads were confronted with three unequal reward packages and then agreed on a procedure to allocate them among themselves. To allocate the rewards, they needed to use a "wheel of fortune." Half of the groups played with a fair wheel (where each child had an equal chance of obtaining each reward package), and the other half played with an unfair wheel. We analyzed children's interactions when using the wheel and conducted an interview with each child after the game was over. Children using the unfair wheel often decided to change the rules of the game, and they also rated it as an unfair procedure in the interview. In contrast, children who played with the fair wheel were mostly accepting of both the outcome and the procedure. Overall, we found that children as young as preschool age are already sensitive not only to distributive justice but to procedural justice as well. 
26255593	This article reviews the anatomical connections of the paraventricular nucleus of the thalamus (PVT) and discusses some of the connections by which the PVT could influence behavior. The PVT receives neurochemically diverse projections from the brainstem and hypothalamus with an especially strong innervation from peptide producing neurons. Anatomical evidence is also presented which suggests that the PVT relays information from neurons involved in visceral or homeostatic functions. In turn, the PVT is a major source of projections to the nucleus accumbens, the bed nucleus of the stria terminalis and the central nucleus of the amygdala as well as the cortical areas associated with these subcortical regions. The PVT is activated by conditions and cues that produce states of arousal including those with appetitive or aversive emotional valences. The paper focuses on the potential contribution of the PVT to circadian rhythms, fear, anxiety, food intake and drug-seeking. The information in this paper highlights the potential importance of the PVT as being a component of the brain circuits that regulate reward and defensive behavior with the hope of generating more research in this relatively understudied region of the brain. 

26255152	The present experiments examined the effects of adolescent nicotine pre-exposure on the rewarding and aversive effects of cocaine and on cocaine self-administration in adult male rats. In Experiment 1, adolescent Sprague-Dawley rats (postnatal days 28-43) were given once daily injections of nicotine (0.6mg/kg) or vehicle and then tested for the aversive and rewarding effects of cocaine in a combined conditioned taste avoidance (CTA)/conditioned place preference (CPP) procedure in adulthood. In Experiment 2, adolescent Sprague-Dawley rats were pre-exposed to nicotine then tested for cocaine self-administration (0.25 or 0.75mg/kg), progressive ratio (PR) responding, extinction and cue-induced reinstatement in adulthood. In Experiment 1, rats showed significant dose-dependent cocaine-induced taste avoidance with cocaine-injected subjects consuming less saccharin over trials, but no effect of nicotine pre-exposure. For place preferences, cocaine induced significant place preferences with cocaine injected subjects spending significantly more time on the cocaine-paired side, but again there was no effect of nicotine history. All rats in Experiment 2 showed clear, dose-dependent responding during cocaine acquisition, PR testing, extinction and reinstatement with no effect of nicotine pre-exposure. These studies demonstrate that adolescent nicotine pre-exposure does not have an impact on cocaine's affective properties or its self-administration at least with the specific parametric conditions under which these effects were tested. 
26254588	Human actions are driven by the pursuit of goals, especially when achieving these goals entails a reward. Accordingly, recent work showed that anticipating a reward in a motor task influences the motor system, boosting motor excitability and increasing overall readiness. Attaining a reward typically requires some mental or physical effort. Recent neuroimaging evidence suggested that both reward expectation and effort requirements are encoded by a partially overlapping brain network. Moreover, reward and effort information are combined in an integrative value signal. However, whether and how mental effort is integrated with reward at the motor level during task preparation remains unclear. To address these issues, we implemented a mental effort task where reward expectation and effort requirements were manipulated. During task preparation, TMS was delivered on the motor cortex and motor-evoked potentials (MEPs) were recorded on the right hand muscles to probe motor excitability. The results showed an interaction of effort and reward in modulating the motor system, reflecting an unsigned value prediction-error signal. Crucially, this was observed in the motor system in absence of a value-based decision or value-driven action selection. This suggests a high-level cognitive factor such as unsigned value prediction-error can modulate the motor system. Interestingly, effort-related motor excitability was also modulated by individual differences in tendency to engage in (and enjoy) mental effort, as measured by the Need for Cognition questionnaire, underlining a role of subjective effort experience in value-driven preparation for action. 
26254587	Behavioral responses to, and the neural processing of, rewards change dramatically during adolescence and may contribute to observed increases in risk-taking during this developmental period. Functional MRI (fMRI) studies suggest differences between adolescents and adults in neural activation during reward processing, but findings are contradictory, and effects have been found in non-predicted directions. The current study uses an activation likelihood estimation (ALE) approach for quantitative meta-analysis of functional neuroimaging studies to: (1) confirm the network of brain regions involved in adolescents' reward processing, (2) identify regions involved in specific stages (anticipation, outcome) and valence (positive, negative) of reward processing, and (3) identify differences in activation likelihood between adolescent and adult reward-related brain activation. Results reveal a subcortical network of brain regions involved in adolescent reward processing similar to that found in adults with major hubs including the ventral and dorsal striatum, insula, and posterior cingulate cortex (PCC). Contrast analyses find that adolescents exhibit greater likelihood of activation in the insula while processing anticipation relative to outcome and greater likelihood of activation in the putamen and amygdala during outcome relative to anticipation. While processing positive compared to negative valence, adolescents show increased likelihood for activation in the posterior cingulate cortex (PCC) and ventral striatum. Contrasting adolescent reward processing with the existing ALE of adult reward processing reveals increased likelihood for activation in limbic, frontolimbic, and striatal regions in adolescents compared with adults. Unlike adolescents, adults also activate executive control regions of the frontal and parietal lobes. These findings support hypothesized elevations in motivated activity during adolescence. 
28491381	A 7-month-old, entire female, domestic shorthair cat was referred to our behavioural service owing to soiling in the house and a play-related problem. The owners' complaints were that the cat had never used the litter tray, and it did not know how to play. After reviewing the behavioural history, a problem of substrate preferences acquisition was suspected with regard to the elimination problem. During the consultation, the physical examination was unremarkable, but the neurological examination revealed a moderate and hypermetric ataxic gait, and a bilateral lack of menace response. Some degree of visual impairment was suspected. The problem was located in the central nervous system (CNS); specifically, an intracranial and multifocal problem was diagnosed. After a complete work-up (complete ophthalmological examination, complete blood count and a complete biochemistry panel, feline immunodeficiency virus/feline leukaemia virus test, thorax radiographs, abdominal ultrasound, brain magnetic resonance imaging [0.2 T], cerebrospinal fluid analysis and a urinary metabolic screen test), a degenerative CNS problem was suspected. No treatment was prescribed for the neurological problem. Regarding the problem of soiling in the house, reward-based training with a clicker was used, and the cat partially improved in a few weeks. Three months later, the cat was referred to the neurology service in status epilepticus. A symptomatic treatment was prescribed, with a mild response. After 2 years of treatment and a progressive worsening, the cat was euthanased. Necropsy revealed spongiform polioencephalomyelopathy. In order to rule out prion aetiology a PrPsc inmunohistochemistry assay was performed, and the results were negative. Congenital spongiform polioencephalomyelopathy (CSP) was diagnosed. We strongly suggest that the cat's behavioural clinical signs were caused by the CSP, causing learning impairment. To the best of our knowledge, this would be the first case in which a congenital degenerative disease affected a cat's capability to learn, leading to behavioural signs as the main complaint of the owners, even before neurological signs are detected by the owners.
26254032	Control rules are parental practices that use food, especially those high in fat or sugar, as an instrumental reinforcer to encourage children to behave in a normative manner in non-food domains. Past laboratory experiments show that repeatedly presenting snacks as a reward or associated with adults' attention, increases children's preference for the presented food. This field study aims to examine whether control rules are associated with children's increased everyday intake of food high in sugar/fat, and whether this effect is moderated by individual differences in neurobehavioral sensitivity to reward and in gender.207 six- to twelve-year-old children's parents reported the children's everyday dietary intake through a food frequency questionnaire and provided information regarding the children's sensitivity to rewards as well as the frequency of enforcing control rules.	Children who lived in families with a high frequency of using control rules exhibited more daily fat, carbohydrate, and total energy intake than did children whose parents use control rules less often. Furthermore, the effect of control rules on dietary pattern was particularly strong for children with high reward sensitivity, especially boys.	Control rules have adverse consequences on children's nutrition. The moderating effects of sensitivity to reward and gender are consistent to a reinforcement learning process--associating the high-fat/sugar food consumption with social-affective pleasure resulting from performing behavior desired by parents--through which parental control rules contribute to children's maladaptive dietary patterns.	
26253218	Cues associated with food can stimulate food anticipation, procurement, and consumption, independently of hunger. These and other behaviors driven by learned cues are persistent and can reappear after extinction, because the original learned associations continue to exist. Renewal, or reinstatement, of extinguished conditioned behavior may explain the inability to change maladaptive eating habits driven by food cues, similar to the mechanisms of drug use relapse. Here, we investigated sex differences in context-induced renewal of responding to food cues, and the role of estradiol in females in a Pavlovian conditioning preparation. We compared adult male and female rats because there is evidence for sex differences in learning and memory and in the control of feeding. Context-induced renewal involves conditioning and extinction in different contexts and the renewal of conditioned behavior is induced by return to the conditioning context ("ABA renewal"; experimental groups). Control groups remain in the same context during conditioning, extinction, and test. In Experiment 1, male and female rats were trained to associate a tone with food pellets during acquisition, and after extinction with tone only presentations, were tested for renewal of responding to the tone. Learning was assessed through the expression of the conditioned response, which included approach and activity directed at food receptacle (food cup behavior). Males and females learned the acquisition and extinction of tone-food associations similarly, but there were sex differences during renewal of the conditioned responses to the food cue. Males showed robust renewal of responding, while renewal in intact females was inconsistent. Males in the experimental group had significantly higher food cup behavior compared to males in the control group, while females in both groups showed similar levels of food cup behavior during the tone. In Experiment 2, we examined a potential role of estradiol in renewal, by comparing intact females with ovariectomized females with, and without, estradiol replacement. Rats in all groups acquired and extinguished tone-food associations similarly. During the test for renewal, the ovariectomized rats with estradiol replacement in the experimental group showed renewal of responding, evidenced by significantly higher food cup behavior compared to the control group. Intact and ovariectomized rats in the experimental groups had similar rates of food cup behavior as their corresponding control groups. These results provide novel evidence for sex differences and relevance of estradiol in renewal of responding to food cues and more broadly in contextual processing and appetitive associative learning, potentially relevant to maladaptive eating habits and eating disorders. 
26251999	This study investigated whether deciding to either stay with or leave a social relationship partner, based on a sequence of collaborative social interactions, is impacted by (1) observed and (2) anticipated gains and losses associated with the collaboration; and, importantly, (3) whether these effects differ between social and nonsocial contexts. In the social context, participants played an iterated collaborative economic game in which they were dependent on the successes and failures of a game partner in order to increase their monetary payoff, and in which they were free to stop collaborating with this partner whenever they chose. In Study 1, we manipulated the actual success rate of partners, and demonstrated that participants decided to stay longer with 'better' partners. In Study 2, we induced prior expectations about specific partners, while keeping the objective performance of all partners equal, and found that participants decided to stay longer with partners whom they expected to be 'better' than others, irrespective of actual performance. Importantly, both Study 1 and 2 included a nonsocial control condition that was probabilistically identical to the social conditions. All findings were replicated in nonsocial context, but results demonstrated that the effect of prior beliefs on stay/leave decision-making was much less pronounced in a social than a nonsocial context. 
26250442	Around half the inmates in prison institutions have antisocial personality disorder (ASPD). A recent theory has proposed that a dysfunction of the endogenous opioid system (EOS) underlies the neurobiology of borderline personality disorder (BPD). In the present theoretical paper, based on a comprehensive database and hand search of the relevant literature, this hypothesis is extended to ASPD, which may be the predominant expression of EOS dysfunction in men, while the same pathology underlies BPD in women. According to evidence from human and animal studies, the problematic behaviours of persons with antisocial, callous, or psychopathic traits may be seen as desperate, unconscious attempts to stimulate their deficient EOS, which plays a key role in brain reward circuits. If the needs of this system are not being met, the affected persons experience dysphoric mood, discomfort, or irritability, and strive to increase binding of endogenous opioids to receptors by using the rewarding effects of aggression by exertion of physical or manipulative power on others, by abusing alcohol or substances that have the reward system as target, by creating an "endorphin rush" by self-harm, by increasing the frequency of their sexual contacts, or by impulsive actions and sensation seeking. Symptoms associated with ASPD can be treated with opioid antagonists like naltrexone, naloxone, or nalmefene.
26250147	Anhedonia, a core symptom of Major Depressive Disorder (MDD), is predictive of antidepressant non-response. In contrast to the definition of anhedonia as a "loss of pleasure", neuropsychological studies provide evidence for multiple facets of hedonic function. The aim of the current study was to develop and validate the Dimensional Anhedonia Rating Scale (DARS), a dynamic scale that measures desire, motivation, effort and consummatory pleasure across hedonic domains. Following item selection procedures and reliability testing using data from community participants (N=229) (Study 1), the 17-item scale was validated in an online study with community participants (N=150) (Study 2). The DARS was also validated in unipolar or bipolar depressed patients (n=52) and controls (n=50) (Study 3). Principal components analysis of the 17-item DARS revealed a 4-component structure mapping onto the domains of anhedonia: hobbies, food/drink, social activities, and sensory experience. Reliability of the DARS subscales was high across studies (Cronbach's α=0.75-0.92). The DARS also demonstrated good convergent and divergent validity. Hierarchical regression analysis revealed the DARS showed additional utility over the Snaith-Hamilton Pleasure Scale (SHAPS) in predicting reward function and distinguishing MDD subgroups. These studies provide support for the reliability and validity of the DARS. 

26248901	Highly palatable foods behave as appetitive reinforcers and tend to be consumed compulsively. Nevertheless, the motivation for this kind of diets in experimental diet-induced obesity models has not been well established. Our hypothesis is that obesity caused by a regular consumption of high-fat diet (HFD) occurs concomitantly with the inhibition of food reward. The ultimate goal of our study was to further analyze the extent to which the perception of food as an appetitive reinforcer is a necessary condition for obesity.We have evaluated the influence of HFD on operant food self-administration (FSA) during a whole light-dark (12-12-h) cycle in mice that consumed HFD either during 1, 4 or 8 weeks. The study has been complemented by a two-bottle free-choice assay between tap water and sweetened drinks.	These data show that both 4- and 8-week HFD treatments induced a significant decrease in operant FSA rate. Moreover, HFD impaired the sweetened-conditioned flavor preference in the two-bottle choice assay.	Our results, showing a reduction in how hard an animal is willing to work for food reinforcers, provide evidence that chronic consumption of HFD negatively contributes to the incentive motivation to acquire food/drink reinforcers. We demonstrate that energy homeostasis imbalance triggered by HFD is associated with the inhibition of hedonic feeding.	
26248279	The memories that are formed between rewarding and drug-associated contextual cues have been suggested to contribute to drug addiction relapse. Recent evidence has indicated that the ventrolateral orbital cortex (VLO) plays important roles in reward-based learning and reversal learning. However, whether the VLO is required for methamphetamine-induced contextual memory formation is not well understood. In the present study, a three-phase methamphetamine-induced conditioned place preference (CPP) model was used to investigate the effects of VLO lesions on the formation of drug-associated contextual memories in rats. We found that the VLO lesions themselves elicited no observable effects on place preferences. However, the VLO lesions delayed the acquisition and extinction phases of CPP without affecting the expression level. Furthermore, the VLO lesions did not have an obvious influence on CPP reinstatement. These results indicate that electrolytic lesions of the bilateral ventrolateral orbital cortex can inhibit the formation of methamphetamine-induced contextual memories in rats. Moreover, VLO may not be critically involved in memory storage and retrieval. 
26247393	Female rats alternately approach and avoid the male rat during copulation, potentially reflecting appetitive and aversive aspects of mating, respectively. We developed a novel classical conditioning procedure, conditioned object preference (COP), to test whether female rats show increased approach toward a conditioned stimulus associated directly with receipt of sexual stimulation. During conditioning, one scented object was paired with an appetitive stimulus and a different object plus scent was paired with a control stimulus on a separate day. After conditioning, preference for each object was evaluated with a choice task. Experiment 1 was conducted to verify the procedure. Rats exhibited a significant COP for 1mg/kg amphetamine, indicating that the conditioned object preference procedure is an effective tool for evaluating the rewarding nature of a treatment. In Experiment 2, paced mating to one ejaculation and experimenter-delivered artificial vaginocervical stimulation (aVCS) each induced a COP. The robust COPs for paced mating and aVCS support the notion that female rats experience a reward state during receipt of sexual stimulation. Moreover, the data suggest that any aversive aspects of receipt of sexual stimulation do not overshadow the appetitive effects. 
26246915	Corticobasal ganglia networks coursing through the striatum are key structures for reward-guided behaviors. The ventral striatum (nucleus accumbens (nAc)) and its reciprocal connection with the ventral tegmental area (VTA) represent a primary component of the reward system, but reward-guided learning also involves the dorsal striatum and dopaminergic inputs from the substantia nigra. The majority of neurons in the striatum (>90%) are GABAergic medium spiny neurons (MSNs), but both the input to and the output from these neurons are dynamically controlled by striatal interneurons. Dopamine is a key neurotransmitter in reward and reward-guided learning, and the physiological activity of GABAergic and cholinergic interneurons is regulated by dopaminergic transmission in a complex manner. Here we review the role of striatal interneurons in modulating striatal output during drug reward, with special emphasis on alcohol. 
26246443	Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and an evocative images task, using selective antagonists for µ-opioid, dopamine D3 receptor (DRD3) and neurokinin 1 (NK1) receptors (naltrexone, GSK598809, vofopitant/aprepitant), in a placebo-controlled, randomised, crossover design. In two years, 609 scans were performed, with 155 individuals scanned at baseline. Attrition was low and the majority of individuals were sufficiently motivated to complete all five sessions (n=87). We describe herein the study design, main aims, recruitment numbers, sample characteristics, and explain the test hypotheses and anticipated study outputs. 
26246438	In this paper, we study the potential involvement of monkey amygdala in the evaluation of value encoding of visual and auditive stimuli associated with reward or no reward. We recorded the activity of 93 extracellular neurons from the monkey right amygdala, while performing a multisensory operant task. The activity of 78 task-related neurons was studied. Of these, 13 neurons (16%) responded to the value of visual stimuli, 22 neurons (28%) responded after the presentation of visual stimuli, 22 neurons (28%) showed an inhibition around the lever-pressing and were classified as action related neurons and 22 neurons (28%) responded after reward delivery. These findings suggest that neurons in the amygdala play a role in encoding value and processing visual information, participate in motor regulation and are sensitive to reward. The activity of these neurons did not change in the evaluation of auditive stimuli. These data support the hypothesis that amygdala neurons are specific to each sensory modality and that different groups of amygdala neurons process visual and auditive information. 
26245974	Context plays a pivotal role in many decision-making scenarios, including social interactions wherein the identities and strategies of other decision makers often shape our behaviors. However, the neural mechanisms for tracking such contextual information are poorly understood. Here, we investigated how opponent identity affects human reinforcement learning during a simulated competitive game against two independent computerized opponents. We found that strategies of participants were affected preferentially by the outcomes of the previous interactions with the same opponent. In addition, reinforcement signals from the previous trial were less discriminable throughout the brain after the opponent changed, compared with when the same opponent was repeated. These opponent-selective reinforcement signals were particularly robust in right rostral anterior cingulate and right lingual regions, where opponent-selective reinforcement signals correlated with a behavioral measure of opponent-selective reinforcement learning. Therefore, when choices involve multiple contextual frames, such as different opponents in a game, decision making and its neural correlates are influenced by multithreaded histories of reinforcement. Overall, our findings are consistent with the availability of temporally overlapping, context-specific reinforcement signals.In real-world decision making, context plays a strong role in determining the value of an action. Similar choices take on different values depending on setting. We examined the contextual dependence of reward-based learning and reinforcement signals using a simple two-choice matching-pennies game played by humans against two independent computer opponents that were randomly interleaved. We found that human subjects' strategies were highly dependent on opponent context in this game, a fact that was reflected in select brain regions' activity (rostral anterior cingulate and lingual cortex). These results indicate that human reinforcement histories are highly dependent on contextual factors, a fact that is reflected in neural correlates of reinforcement signals.	
26245962	We used electroencephalography (EEG) and behavior to examine the role of payoff bias in a difficult two-alternative perceptual decision under deadline pressure in humans. The findings suggest that a fast guess process, biased by payoff and triggered by stimulus onset, occurred on a subset of trials and raced with an evidence accumulation process informed by stimulus information. On each trial, the participant judged whether a rectangle was shifted to the right or left and responded by squeezing a right- or left-hand dynamometer. The payoff for each alternative (which could be biased or unbiased) was signaled 1.5 s before stimulus onset. The choice response was assigned to the first hand reaching a squeeze force criterion and reaction time was defined as time to criterion. Consistent with a fast guess account, fast responses were strongly biased toward the higher-paying alternative and the EEG exhibited an abrupt rise in the lateralized readiness potential (LRP) on a subset of biased payoff trials contralateral to the higher-paying alternative ∼ 150 ms after stimulus onset and 50 ms before stimulus information influenced the LRP. This rise was associated with poststimulus dynamometer activity favoring the higher-paying alternative and predicted choice and response time. Quantitative modeling supported the fast guess account over accounts of payoff effects supported in other studies. Our findings, taken with previous studies, support the idea that payoff and prior probability manipulations produce flexible adaptations to task structure and do not reflect a fixed policy for the integration of payoff and stimulus information.Humans and other animals often face situations in which they must make choices based on uncertain sensory information together with information about expected outcomes (gains or losses) about each choice. We investigated how differences in payoffs between available alternatives affect neural activity, overt choice, and the timing of choice responses. In our experiment, in which participants were under strong time pressure, neural and behavioral findings together with model fitting suggested that our human participants often made a fast guess toward the higher reward rather than integrating stimulus and payoff information. Our findings, taken with findings from other studies, support the idea that payoff and prior probability manipulations produce flexible adaptations to task structure and do not reflect a fixed policy.	
26245838	We investigated the effect of reward expectation on the processing of emotional words in two experiments using event-related potentials (ERPs). A cue indicating the reward condition of each trial (incentive vs non-incentive) was followed by the presentation of a negative or neutral word, the target. Participants were asked to discriminate the emotional content of the target word in Experiment 1 and to discriminate the color of the target word in Experiment 2, rendering the emotionality of the target word task-relevant in Experiment 1, but task-irrelevant in Experiment 2. The negative bias effect, in terms of the amplitude difference between ERPs for negative and neutral targets, was modulated by the task-set. In Experiment 1, P31 and early posterior negativity revealed a larger negative bias effect in the incentive condition than that in the non-incentive condition. However, in Experiment 2, P31 revealed a diminished negative bias effect in the incentive condition compared with that in the non-incentive condition. These results indicate that reward expectation improves top-down attentional concentration to task-relevant information, with enhanced sensitivity to the emotional content of target words when emotionality is task-relevant, but with reduced differential brain responses to emotional words when their content is task-irrelevant. 
26245498	Mood disorders are twice as frequent in women than in men. Risk mechanisms for major depression include adverse responses to acute changes in sex-steroid hormone levels, eg, postpartum in women. Such adverse responses may involve an altered processing of rewards. Here, we examine how women's vulnerability for mood disorders is linked to sex-steroid dynamics by investigating the effects of a pharmacologically induced fluctuation in ovarian sex steroids on the brain response to monetary rewards. In a double-blinded placebo controlled study, healthy women were randomized to receive either placebo or the gonadotropin-releasing hormone agonist (GnRHa) goserelin, which causes a net decrease in sex-steroid levels. Fifty-eight women performed a gambling task while undergoing functional MRI at baseline, during the mid-follicular phase, and again following the intervention. The gambling task enabled us to map regional brain activity related to the magnitude of risk during choice and to monetary reward. The GnRHa intervention caused a net reduction in ovarian sex steroids (estradiol and testosterone) and increased depression symptoms. Compared with placebo, GnRHa reduced amygdala's reactivity to high monetary rewards. There was a positive association between the individual changes in testosterone and changes in bilateral insula response to monetary rewards. Our data provide evidence for the involvement of sex-steroid hormones in reward processing. A blunted amygdala response to rewarding stimuli following a rapid decline in sex-steroid hormones may reflect a reduced engagement in positive experiences. Abnormal reward processing may constitute a neurobiological mechanism by which sex-steroid fluctuations provoke mood disorders in susceptible women. 
26245262	Numerous tree species' seeds contain an 'elaiosome' that acts as a food reward for ants and thus induces dispersal of the seeds. Many stick and leaf insect species appear to have evolved a convergent adaptation for dispersal whereby the egg 'capitulum' serves to induce ants to pick up and carry their eggs. Here, we investigated whether the capitulum facilitates egg dispersal by ants in the Australian stick insect Eurycnema goliath. The total fatty acid composition of E. goliath egg capsules and egg capitula were characterized to identify potential signaling compounds. Removing capitula from E. goliath eggs significantly reduced the likelihood of eggs being carried into the nests of Rhytidoponera metallica ants. Furthermore, attaching capitula to inert objects (polystyrene balls) resulted in these objects being carried into nests by R. metallica. Several fatty acids were present on the egg capsule surface in only trace amounts, whereas they made up over 10% of the dry weight of egg capitula. The fatty acid composition of egg capitula consisted mostly of palmitic acid (C16:0), linoleic acid (C18: 2n6c), oleic acid (C18:1n9c), linolenic acid (C18:3n3), and stearic acid (C18:0). Previously reported research has found that a diglyceride lipid species of oleic acid induces carrying behavior in R. metallica when added to inert artificial stimuli. Therefore, we propose that the dispersal mechanism of E. goliath eggs has converged upon the same chemical signaling pathway used by plants to exploit ant behavior.
26244335	The emotional state can influence decision-making under ambiguity. Cognitive bias tests (CBT) proved to be a promising indicator of the affective valence of animals in a context of farm animal welfare. Although it is well-known that humans can influence the intensity of fear and reactions of animals, research on cognitive bias often focusses on housing and management conditions and neglects the role of humans on emotional states of animals. The present study aimed at investigating whether humans can modulate the emotional state of weaned piglets. Fifty-four piglets received a chronic experience with humans: gentle (GEN), rough (ROU) or minimal contact (MIN). Simultaneously, they were individually trained on a go/no-go task to discriminate a positive auditory cue, associated with food reward in a trough, from a negative one, associated with punishments (e.g. water spray). Independently of the treatment (P = 0.82), 59% of piglets completed the training. Successfully trained piglets were then subjected to CBT, including ambiguous cues in presence or absence of a human observer. As hypothesized, GEN piglets showed a positive judgement bias, as shown by their higher percentage of go responses following an ambiguous cue compared to ROU (P = 0.03) and MIN (P = 0.02) piglets, whereas ROU and MIN piglets did not differ (P > 0.10). The presence of an observer during CBT did not modulate the percentage of go responses following an ambiguous cue (P > 0.10). However, regardless of the treatment, piglets spent less time in contact with the trough following positive cues during CBT in which the observer was present than absent (P < 0.0001). This study originally demonstrates that the nature of a chronic experience with humans can induce a judgement bias indicating that the emotional state of farm animals such as piglets can be affected by the way humans interact with them. 
26244278	While impairments in memory recall are apparent in aging, older adults show a remarkably preserved ability to selectively remember information deemed valuable. Here, we use fMRI to compare brain activation in healthy older and younger adults during encoding of high and low value words to determine whether there are differences in how older adults achieve value-directed memory selectivity. We find that memory selectivity in older adults is associated with value-related changes in activation during word presentation in left hemisphere regions that are involved in semantic processing, similar to young adults. However, highly selective young adults show a relatively greater increase in semantic network activity during encoding of high-value items, whereas highly selective older adults show relatively diminished activity during encoding of low-value items. Additionally, only younger adults showed value-related increases in activity in semantic and reward processing regions during presentation of the value cue preceding each to-be-remembered word. Young adults therefore respond to cue value more proactively than do older adults, yet the magnitude of value-related differences in cue period brain activity did not predict individual differences in memory selectivity. Thus, our data also show that age-related reductions in prestimulus activity do not always lead to inefficient performance.
26243825	Constructing interaction network from biomedical texts is a very important and interesting work. The authors take advantage of text mining and reinforcement learning approaches to establish protein interaction network. Considering the high computational efficiency of co-occurrence-based interaction extraction approaches and high precision of linguistic patterns approaches, the authors propose an interaction extracting algorithm where they utilise frequently used linguistic patterns to extract the interactions from texts and then find out interactions from extended unprocessed texts under the basic idea of co-occurrence approach, meanwhile they discount the interaction extracted from extended texts. They put forward a reinforcement learning-based algorithm to establish a protein interaction network, where nodes represent proteins and edges denote interactions. During the evolutionary process, a node selects another node and the attained reward determines which predicted interaction should be reinforced. The topology of the network is updated by the agent until an optimal network is formed. They used texts downloaded from PubMed to construct a prostate cancer protein interaction network by the proposed methods. The results show that their method brought out pretty good matching rate. Network topology analysis results also demonstrate that the curves of node degree distribution, node degree probability and probability distribution of constructed network accord with those of the scale-free network well. 
26243270	Cocaine is habit-forming because of its ability to enhance dopaminergic neurotransmission in the forebrain. In addition to neuronal inputs, forebrain dopamine circuits are modulated by hormonal influences; one of these is leptin, an adipose-derived hormone that attenuates the rewarding effects of food- and hunger-associated brain stimulation reward. Here we report reciprocal inhibition between the reward-related effects of leptin and the reward-related effects of cocaine in rats. First, we report that cocaine and the expectancy of cocaine each depresses plasma leptin levels. Second, we report that exogenous leptin, given systemically or directly into the ventral tegmental area, attenuates the ability of cocaine to elevate dopamine levels in the nucleus accumbens, the ability of cocaine to establish a conditioned place preference, and the ability of cocaine-predictive stimuli to prolong responding in extinction of cocaine-seeking. Thus, whereas leptin represents an endogenous antagonist of the habit-forming and habit-sustaining effects of cocaine, this antagonism is attenuated by cocaine and comes to be attenuated by the expectancy of cocaine. 
26241341	Adolescence is often portrayed as a period of enhanced sensitivity to reward, with long-lasting neurobiological changes upon reward exposure. However, we previously found that time-dependent increases in cue-induced sucrose seeking were more pronounced in rats trained to self-administer sucrose as adults than as adolescents. In addition, adult, but not adolescent sucrose self-administration led to a decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-Methyl-D-aspartate (AMPA/NMDA) ratio in the nucleus accumbens core, suggesting that long-lasting changes in glutamatergic transmission may affect adult processing of natural rewards. Here we tested whether altering glutamatergic transmission in the nucleus accumbens core via local injection of an mGluR2/3 agonist and antagonist affects cue-induced sucrose seeking following abstinence and whether this is different in the two age groups. Rats began oral sucrose self-administration training (10 days) on postnatal day (P) 35 (adolescents) or P70 (adults). Following 21 days of abstinence, rats received microinjections of the mGluR2/3 agonist LY379268 (0.3 or 1.0 μg/side) or vehicle into the nucleus accumbens core, and 15 min later cue-induced sucrose seeking was assessed. An additional group of rats trained as adults received nucleus accumbens core microinjections of the mGluR2/3 antagonist (RS)-α-Methyl-4-phosphonophenylglycine (MPPG) (0.12 or 0.5 μg/side). Confirming our previous results, adult rats earned more sucrose reinforcers, while sucrose intake per body weight was similar across ages. On abstinence day 22, local injection of the mGluR2/3 agonist LY379268 increased cue-induced sucrose seeking only in adult rats, and had no effect in adolescents. Local injections of the mGluR2/3 antagonist MPPG had no effect on sucrose seeking in adult rats. These data suggest an important developmental difference in the neural substrates of natural reward, specifically a difference in glutamatergic transmission in the accumbens in cue-induced responding for sucrose between adolescent and adult rats.
26240425	Tying complex psychological processes to precisely defined neural circuits is a major goal of systems and behavioural neuroscience. This is critical for understanding adaptive behaviour, and also how neural systems are altered in states of psychopathology, such as addiction. Efforts to relate psychological processes relevant to addiction to activity within defined neural circuits have been complicated by neural heterogeneity. Recent advances in technology allow for manipulation and mapping of genetically and anatomically defined neurons, which when used in concert with sophisticated behavioural models, have the potential to provide great insight into neural circuit bases of behaviour. Here we discuss contemporary approaches for understanding reward and addiction, with a focus on midbrain dopamine and cortico-striato-pallidal circuits. 
26240415	Brain reward systems play a central role in the cognitive and hedonic behaviors of mammals. Multiple neuron types and brain regions are involved in reward processing, posing fascinating scientific questions, and major experimental challenges. Using diverse approaches including genetics, electrophysiology, imaging, and behavioral analysis, a large body of research has focused on both normal functioning of the reward circuitry and on its potential significance in neuropsychiatric diseases. In this introduction, we illustrate a real-world application of optogenetics to mammalian behavior and physiology, delineating procedures and technologies for optogenetic control of individual components of the reward circuitry. We describe the experimental setup and protocol for integrating optogenetic modulation of dopamine neurons with fast-scan cyclic voltammetry, conditioned place preference, and operant conditioning to assess the causal role of well-defined electrical and biochemical signals in reward-related behavior. 
26239766	Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine's reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine. 
26239494	Negative affective states can increase the rewarding value of drugs of abuse and promote drug taking. Chronic cocaine exposure increases levels of the neuropeptide dynorphin, an endogenous ligand at kappa opioid receptors (KOR) that suppresses dopamine release in the nucleus accumbens (NAc) and elicits negative affective states upon drug withdrawal. However, there is evidence that the effects of KOR activation on affective state are biphasic: immediate aversive effects are followed by delayed increases in reward. The impact of KOR-induced affective states on reward-related effects of cocaine over time is not known. We hypothesize that the initial aversive effects of KOR activation increase, whereas the delayed rewarding effects decrease, the net effects of cocaine on reward and dopamine release. We treated rats with cocaine at various times (15 min to 48 h) after administration of the selective KOR agonist salvinorin A (salvA). Using intracranial self-stimulation and fast scan cyclic voltammetry, we found that cocaine-induced increases in brain stimulation reward and evoked dopamine release in the NAc core were potentiated when cocaine was administered within 1 h of salvA, but attenuated when administered 24 h after salvA. Quantitative real-time PCR was used to show that KOR and prodynorphin mRNA levels were decreased in the NAc, whereas tyrosine hydroxylase and dopamine transporter mRNA levels and tissue dopamine content were increased in the ventral tegmental area 24 h post-salvA. These findings raise the possibility that KOR activation-as occurs upon withdrawal from chronic cocaine-modulates vulnerability to cocaine in a time-dependent manner.
26239424	Burnout is a significant problem among healthcare professionals working within the oncology setting. This study aimed to investigate predictors of emotional exhaustion (EE) and depersonalisation (DP) in psychosocial oncologists, through the application of the effort-reward imbalance (ERI) model with an additional focus on the role of meaningful work in the burnout process.Psychosocial oncology clinicians (n = 417) in direct patient contact who were proficient in English were recruited from 10 international psychosocial oncology societies. Participants completed an online questionnaire, which included measures of demographic and work characteristics, EE and DP subscales of the Maslach Burnout Inventory-Human Services Survey, the Short Version ERI Questionnaire and the Work and Meaning Inventory.	Higher effort and lower reward were both significantly associated with greater EE, although not DP. The interaction of higher effort and lower reward did not predict greater EE or DP. Overcommitment predicted both EE and DP but did not moderate the impact of effort and reward on burnout. Overall, the ERI model accounted for 33% of the variance in EE. Meaningful work significantly predicted both EE and DP but accounted for only 2% more of the variance in EE above and beyond the ERI model.	The ERI was only partially supported as a useful framework for investigating burnout in psychosocial oncology professionals. Meaningful work may be a viable extension of the ERI model. Burnout among health professionals may be reduced by interventions aimed at increasing self-efficacy and changes to the supportive work environment.	
26239291	Memories associated with drug use increase vulnerability to relapse in substance use disorder (SUD), and there are no pharmacotherapies for the prevention of relapse. Previously, we reported a promising finding that storage of memories associated with methamphetamine (METH), but not memories for fear or food reward, is vulnerable to disruption by actin depolymerization in the basolateral amygdala complex (BLC). However, actin is not a viable therapeutic target because of its numerous functions throughout the body. Here we report the discovery of a viable therapeutic target, nonmuscle myosin IIB (NMIIB), a molecular motor that supports memory by directly driving synaptic actin polymerization. A single intra-BLC treatment with Blebbistatin (Blebb), a small-molecule inhibitor of class II myosin isoforms, including NMIIB, produced a long-lasting disruption of context-induced drug seeking (at least 30 days). Further, postconsolidation genetic knockdown of Myh10, the heavy chain of the most highly expressed NMII in the BLC, was sufficient to produce METH-associated memory loss. Blebb was found to be highly brain penetrant. A single systemic injection of the compound selectively disrupted the storage of METH-associated memory and reversed the accompanying increase in BLC spine density. This effect was specific to METH-associated memory, as it had no effect on an auditory fear memory. The effect was also independent of retrieval, as METH-associated memory was disrupted 24 h after a single systemic injection of Blebb delivered in the home cage. Together, these results argue for the further development of small-molecule inhibitors of NMII as potential therapeutics for the prevention of SUD relapse triggered by drug associations. 
26239290	Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse. 
26238384	With the wide and rapid expansion of computers and smartphones, Internet use has become an essential part of life and an important tool that serves various purposes. Despite the advantages of Internet use, psychological and behavioral problems, including Internet addiction, have been reported. In response to growing concern, researchers have focused on the characteristics of Internet addicts. However, relatively little is known about the behavioral and neural mechanisms that underlie Internet addiction, especially with respect to risky decision making, which is an important domain frequently reported in other types of addictions.To examine the neural characteristics of decision making in Internet addicts, Internet addicts and healthy controls were scanned while they performed a financial decision-making task.	Relative to healthy controls, Internet addicts showed (1) more frequent risky decision making; (2) greater activation in the dorsal anterior cingulate cortex and the left caudate nucleus, which are brain regions involved in conflict monitoring and reward, respectively; and (3) less activation in the ventrolateral prefrontal cortex, an area associated with cognitive control/regulation.	These findings suggest that risky decision making may be an important behavioral characteristic of Internet addiction and that altered brain function in regions associated with conflict monitoring, reward and cognitive control/regulation might be critical biological risk factors for Internet addiction.	
26238300	To examine the impact of satisfaction with psychological rewards (received from the head nurse and from physicians) and with pay on Chinese nurses' work attitudes.We conducted a cross-sectional survey in China. A total of 413 nurses completed our survey. We examined the effect of satisfactions with psychological rewards and pay on work attitudes by performing a series of hierarchical regression analyses.	We found that both satisfaction with pay and satisfaction with psychological rewards from the head nurse significantly predicted work attitudes, whereas satisfaction with psychological rewards from physicians did not.	Our results illustrate that when nurses feel satisfied with their pay and the psychological rewards received from the head nurse they exhibit more positive work attitudes.	
26237619	There is much evidence that the prospect of reward modulates cognitive control in terms of more stable behavior. Increases in expected reward magnitude, however, have been suggested to increase flexible behavior as evidenced by reduced switch costs. In a series of experiments, the authors provide evidence that this increased cognitive flexibility following increases in reward magnitude also promotes deliberate task switching. A modified task switching paradigm with forced- and free-choice trials and varying reward prospects was used. In Experiments 1-3 the prospect of a reward increase as compared to unchanged high reward increased voluntary switching rate (VSR). Experiment 4 showed that the prospect of a reward decrease did not alter VSR as compared to unchanged low reward. Experiment 5 used a standard voluntary task switching procedure and confirmed VSR effects found in Experiments 1-4. These findings are strong evidence for a mechanism that biases the cognitive system either toward stability or flexibility depending on changing reward expectation. Results are discussed within the framework of the adaptive gain theory.
26237363	Humans learn about people and objects through positive and negative experiences, yet they can also look beyond the immediate reward of an interaction to encode trait-level attributes. We found that perceivers encoded both reward and trait-level information through feedback in an instrumental learning task, but relied more heavily on trait representations in cross-context decisions. Both learning types implicated ventral striatum, but trait learning also recruited a network associated with social impression formation. 
26237323	Men and women differ dramatically in their rates of alcohol use disorder (AUD), and researchers have long been interested in identifying mechanisms underlying male vulnerability to problem drinking. Surveys suggest that social processes underlie sex differences in drinking patterns, with men reporting greater social enhancement from alcohol than women, and all-male social drinking contexts being associated with particularly high rates of hazardous drinking. But experimental evidence for sex differences in social-emotional response to alcohol has heretofore been lacking. Research using larger sample sizes, a social context, and more sensitive measures of alcohol's rewarding effects may be necessary to better understand sex differences in the etiology of AUD. This study explored the acute effects of alcohol during social exchange on speech volume--an objective measure of social-emotional experience that was reliably captured at the group level. Social drinkers (360 male; 360 female) consumed alcohol (.82 g/kg males; .74 g/kg females), placebo, or a no-alcohol control beverage in groups of 3 over 36-min. Within each of the 3 beverage conditions, equal numbers of groups consisted of all males, all females, 2 females and 1 male, and 1 female and 2 males. Speech volume was monitored continuously throughout the drink period, and group volume emerged as a robust correlate of self-report and facial indexes of social reward. Notably, alcohol-related increases in group volume were observed selectively in all-male groups but not in groups containing any females. Results point to social enhancement as a promising direction for research exploring factors underlying sex differences in problem drinking.
26237322	Sex--a marker of biological and social individual differences--matters for drug use, particularly for cigarette smoking, which is the leading cause of preventable death in the United States. More men than women smoke, but women are less likely than men to quit. Resting state brain function, or intrinsic brain activity that occurs in the absence of a goal-directed task, is important for understanding cigarette smoking, as it has been shown to differentiate between smokers and nonsmokers. But, it is unclear whether and how sex influences the link between resting state brain function and smoking behavior. In this study, the authors demonstrate that sex is indeed associated with resting state connectivity in cigarette smokers, and that sex moderates the link between resting state connectivity and self-reported nicotine dependence. Using functional MRI and behavioral data from 50 adult daily smokers (23 women), the authors found that women had greater connectivity than men within the default mode network, and that increased connectivity within the reward network was related to increased nicotine tolerance in women but to decreased nicotine tolerance in men. Findings highlight the importance of sex-related individual differences reflected in resting state connectivity for understanding the etiology and treatment of substance use problems.
26237321	Preclinical and clinical research indicates that there are sex differences in how men and women initiate, progress, respond to, and withdraw from cannabis use; however, neurophysiological differences, such as neural responses to cannabis cues, are not well understood. Using functional MRI and an event-related blood oxygen level-dependent backward-masking task, we compared neural responses to backward-masked cannabis cues to neutral cues in treatment-seeking, cannabis-dependent adults (N = 44; 27 males) and examined whether sex differences exist. In addition, functional MRI findings were correlated with cannabis craving. Backward-masked cannabis cues elicited greater neural responses than neutral cues in reward-related brain regions, including the striatum, hippocampus/amygdala, insula, anterior cingulate cortex, and lateral orbitofrontal cortex, p < .01, k > 121 voxels. Although no significant sex differences in neural responses to cannabis cues emerged, women showed a positive correlation between neural responses to cannabis cues in the bilateral insula and cannabis craving and an inverse correlation between neural responses to cannabis cues in the left lateral orbitofrontal cortex and cannabis craving. Men, however, showed a positive correlation between neural responses to cannabis cues in the striatum and cannabis craving. Given that cues and craving are important triggers and the focus on many behavioral treatment approaches, these findings suggest that treatment-seeking, cannabis-dependent men and women may benefit from sex-specific and tailored cannabis use disorder treatments.
26237317	Interaction with social peers may increase rates of drug self-administration, but a recent study from our laboratory showed that social interaction may serve as a type of alternative reward that competes with drug taking in adolescent male rats. Based on those previous results, the current study examined sex differences in preference for social interaction compared with amphetamine (AMPH) in adolescent rats using the conditioned place preference (CPP) paradigm. Similar to previous results with males, females showed AMPH CPP regardless of whether they were individual- or pair-housed. In contrast to males, however, females failed to show social CPP, and they did not prefer a peer-associated compartment over an AMPH-associated compartment in a free-choice test. In separate experiments, dopamine (DA) and serotonin (5-HT) metabolite levels were measured in adolescent males and females that were exposed acutely to peer interaction, no peer interaction, AMPH, or saline. In amygdala, levels of the DA metabolite dihydroxyphenylacetic acid (DOPAC) were altered more in response to peer interaction in males than females; in contrast, there was a greater amygdala DOPAC response to AMPH in females. Furthermore, there were greater changes in the 5-HT metabolite hydroxyindoleacetic acid (5-HIAA) in females than in males following social interaction. These results indicate that the ability of peer interactions to reduce drug reward is greater in adolescent males than females, perhaps due to a greater ability of social cues to activate limbic reward mechanisms in males or a greater ability of AMPH cues to activate limbic reward mechanisms in females.
26236266	In a complex and uncertain world, how do we select appropriate behavior? One possibility is that we choose actions that are highly reinforced by their probabilistic consequences (model-free processing). However, we may instead plan actions prior to their actual execution by predicting their consequences (model-based processing). It has been suggested that the brain contains multiple yet distinct systems involved in reward prediction. Several studies have tried to allocate model-free and model-based systems to the striatum and the lateral prefrontal cortex (LPFC), respectively. Although there is much support for this hypothesis, recent research has revealed discrepancies. To understand the nature of the reward prediction systems in the LPFC and the striatum, a series of single-unit recording experiments were conducted. LPFC neurons were found to infer the reward associated with the stimuli even when the monkeys had not yet learned the stimulus-reward (SR) associations directly. Striatal neurons seemed to predict the reward for each stimulus only after directly experiencing the SR contingency. However, the one exception was "Exclusive Or" situations in which striatal neurons could predict the reward without direct experience. Previous single-unit studies in monkeys have reported that neurons in the LPFC encode category information, and represent reward information specific to a group of stimuli. Here, as an extension of these, we review recent evidence that a group of LPFC neurons can predict reward specific to a category of visual stimuli defined by relevant behavioral responses. We suggest that the functional difference in reward prediction between the LPFC and the striatum is that while LPFC neurons can utilize abstract code, striatal neurons can code individual associations between stimuli and reward but cannot utilize abstract code. 
26235331	Individuals vary in the extent to which they attribute incentive salience to a discrete cue (conditioned stimulus; CS) that predicts reward delivery (unconditioned stimulus; US), which results in some individuals approaching and interacting with the CS (sign-trackers; STs) more than others (goal-trackers; GTs). Here we asked how periods of non-reinforcement influence conditioned responding in STs vs. GTs, in both Pavlovian and instrumental tasks. After classifying rats as STs or GTs by pairing a retractable lever (the CS) with the delivery of a food pellet (US), we introduced periods of non-reinforcement, first by simply withholding the US (i.e., extinction training; experiment 1), then by signaling alternating periods of reward (R) and non-reward (NR) within the same session (experiments 2 and 3). We also examined how alternating R and NR periods influenced instrumental responding for food (experiment 4). STs and GTs did not differ in their ability to discriminate between R and NR periods in the instrumental task. However, in Pavlovian settings STs and GTs responded to periods of non-reward very differently. Relative to STs, GTs very rapidly modified their behavior in response to periods of non-reward, showing much faster extinction and better and faster discrimination between R and NR conditions. These results highlight differences between Pavlovian and instrumental extinction learning, and suggest that if a Pavlovian CS is strongly attributed with incentive salience, as in STs, it may continue to bias attention toward it, and to facilitate persistent and relatively inflexible responding, even when it is no longer followed by reward. 
26235329	The frequency or intensity of behavior is often facilitated by the presence of others. This social facilitation has been reported in a variety of animals, including birds and humans. Based on Zajonc's "drive theory," we hypothesized that facilitation and drive have shared neural mechanisms, and that dopaminergic projections from the midbrain to striatum are involved. As the ascending dopaminergic projections include the mesolimbic and nigrostriatal pathways, we targeted our lesions at the medial striatum (MSt) and substantia nigra (SN). We found that a bilateral electrolytic lesion of the MSt suppressed baseline foraging effort, but social facilitation was intact. Conversely, an electrolytic lesion targeted at the unilateral SN (on the right side) partially suppressed social facilitation, while baseline foraging effort remained unaffected. However, selective depletion of catecholaminergic (thyrosine hydroxylase immunoreactive) terminals by micro-infusion of 6-hydroxydopamine (6-OHDA) to bilateral MSt had no significant effects on foraging behavior, whereas it impaired formation of the association memory reinforced by water reward. Neurochemical assay by high-perfromance liquid chromatography also revealed a significant decrease in the dopamine and noradrenaline contents in MSt after 6-OHDA micro-infusion compared with intact control chicks. Thus, we conclude that the neural substrate of social facilitation can be dissociated from that responsible for reward-based foraging effort, and that ascending dopaminergic pathways do not appear to contribute to social facilitation. Based on our detailed analysis of the lesion areas, we discuss fiber tracts or neural components of the midbrain tegmental area that may be responsible for social facilitation. 
26234537	All organisms continuously have to adapt their behavior according to changes in the environment in order to survive. Experience-driven changes in behavior are usually mediated and maintained by modifications in signaling within defined brain circuits. Given the simplicity of the larval brain of Drosophila and its experimental accessibility on the genetic and behavioral level, we analyzed if Drosophila neuropeptide F (dNPF) neurons are involved in classical olfactory conditioning. dNPF is an ortholog of the mammalian neuropeptide Y, a highly conserved neuromodulator that stimulates food-seeking behavior. We provide a comprehensive anatomical analysis of the dNPF neurons on the single-cell level. We demonstrate that artificial activation of dNPF neurons inhibits appetitive olfactory learning by modulating the sugar reward signal during acquisition. No effect is detectable for the retrieval of an established appetitive olfactory memory. The modulatory effect is based on the joint action of three distinct cell types that, if tested on the single-cell level, inhibit and invert the conditioned behavior. Taken together, our work describes anatomically and functionally a new part of the sugar reinforcement signaling pathway for classical olfactory conditioning in Drosophila larvae.
26234210	Mutualistic interactions typically involve the exchange of different commodities between species. Nutritious secretions are produced by a number of insects and plants in exchange for services such as defense. These rewards are valuable metabolically and can be used to reinforce the behavior of symbiotic partners that can learn and remember them effectively. We show here novel effects of insect exocrine secretions produced by caterpillars in modulating the behavior of attendant ants in the food-for-defense interaction between lycaenid butterflies and ants. Reward secretions from the dorsal nectary organ (DNO) of Narathura japonica caterpillars function to reduce the locomotory activities of their attendant ants, Pristomyrmex punctatus workers. Moreover, workers that feed from caterpillar secretions are significantly more likely to show aggressive responses to eversion of the tentacle organs of the caterpillars. Analysis of the neurogenic amines in the brains of workers that consumed caterpillar secretions showed a significant decrease in levels of dopamine compared with controls. Experimental treatments in which reserpine, a known inhibitor of dopamine in Drosophila, was fed to workers similarly reduced their locomotory activity. We conclude that DNO secretions of lycaenid caterpillars can manipulate attendant ant behavior by altering dopaminergic regulation and increasing partner fidelity. Unless manipulated ants also receive a net nutritional benefit from DNO secretions, this suggests that similar reward-for-defense interactions that have been traditionally considered to be mutualisms may in fact be parasitic in nature.
26233728	It is widely agreed upon that hippocampal function is linked to episodic-like and spatial memory across various species, for example, rodents. However, the interplay between hippocampal function and other types of learning and memory, like procedural stimulus-response or sequential learning, is less clear. Recently (Eckart et al. in Hippocampus 22:1202-1214, 2012), we showed that excitotoxic hippocampal lesions, which mainly affected its dorsal part, led not only to the expected deficits in a spatial and episodic-like memory task, namely the object place recognition test, but also to substantial improvements in terms of speed and accuracy in a rat adaption of the human sequential reaction time task (SRTT). The design of that experiment, however, which included fixed test durations per training day, led to the fact that lesioned animals gained more instrumental experience, which may partly have accounted for their enhanced performance. In order to rule out such a potential confound, we performed the present experiment on rats with similar ibotenic lesions aiming at the dorsal hippocampus, but we now kept the amount of correct instrumental responses and reinforcements on the same level as in controls. Our data revealed that lesioned animals were still able to complete the SRTT in a substantially smaller amount of time, when compared to control and sham-operated animals, although no differences were observable in terms of speed or accuracy. Also, the animals with lesions showed impaired extinction in a subsequent test where rewards were omitted. The former effect can primarily be attributed to shorter post-reinforcement pauses in the lesioned animals, and the possible mechanisms of this and the extinction effect will be addressed in the discussion. 
26233645	This paper summarizes the degree to which different forms of legal gambling contribute to Problem and Pathological Gambling (PPG) in Canada. Legal gambling activities were compared using meta-analysis of publicly available data concerning Canada's legal gambling industry. The majority of revenues in the decade spanning 2002-2012 were drawn from Video Lottery Terminals and casino slot machines. Population surveys indicated that three quarters of Canadians reported some form of past-year gambling participation, but most did not play Electronic Gambling Machines. Annual revenues divided by estimated numbers of participants in various gambling activities showed that Video Lottery players spent more money on average than did participants in other forms of gambling. The relative risk of PPG was higher among Video Lottery players than it was for other common forms of gambling. Results from a community study of frequent Video Lottery players showed that the risk of frequent players reporting symptoms of PPG was elevated if they reported playing weekly, spending $50 or more per session, or playing for more than an hour per session. These studies provide converging evidence that Video Lottery is more hazardous to consumers than other forms of gambling that are commonly practised in Canada. 
26233484	Dysfunctional reward processing leading to the undervaluation of non-drug rewards is hypothesized to play a crucial role in nicotine dependence. However, it is unclear if blunted reward responsivity and the desire to use nicotine are directly linked after a brief period of abstinence. Such an association would suggest that individuals with reduced reward responsivity may be at increased risk to experience nicotine craving.Reward function was evaluated with a probabilistic reward task (PRT), which measures reward responsivity to monetary incentives. To identify whether smoking status influenced reward function, PRT performance was compared between non-depressed, nicotine-dependent smokers and non-smokers. Within smokers, correlations were conducted to determine if blunted reward responsivity on the PRT was associated with increased nicotine craving. Time since last nicotine exposure was standardized to 4h for all smokers.	Smokers and non-smokers did not differ in reward responsivity on the PRT. However, within smokers, a significant negative correlation was found between reward responsivity and intensity of nicotine craving.	The current findings show that, among smokers, the intensity of nicotine craving is linked to lower sensitivity to non-drug rewards. This finding is in line with prior theories that suggest reward dysfunction in some clinical populations (e.g., depressive disorders, schizophrenia) may facilitate nicotine use. The current study expands on such theories by indicating that sub-clinical variations in reward function are related to motivation for nicotine use. Identifying smokers who show blunted sensitivity to non-drug rewards may help guide treatments aimed at mitigating the motivation to smoke.	
26233323	Adolescent depression and suicide are pressing public health concerns, and identifying key differences among suicide ideators and attempters is critical. The goal of the current study is to test whether depressed adolescent suicide attempters report greater anhedonia severity and exhibit aberrant effort-cost computations in the face of uncertainty.Depressed adolescents (n=101) ages 13-19 years were administered structured clinical interviews to assess current mental health disorders and a history of suicidality (suicide ideators=55, suicide attempters=46). Then, participants completed self-report instruments assessing symptoms of suicidal ideation, depression, anhedonia, and anxiety as well as a computerized effort-cost computation task.	Compared with depressed adolescent suicide ideators, attempters report greater anhedonia severity, even after concurrently controlling for symptoms of suicidal ideation, depression, and anxiety. Additionally, when completing the effort-cost computation task, suicide attempters are less likely to pursue the difficult, high value option when outcomes are uncertain. Follow-up, trial-level analyses of effort-cost computations suggest that receipt of reward does not influence future decision-making among suicide attempters, however, suicide ideators exhibit a win-stay approach when receiving rewards on previous trials.	Findings should be considered in light of limitations including a modest sample size, which limits generalizability, and the cross-sectional design.	Depressed adolescent suicide attempters are characterized by greater anhedonia severity, which may impair the ability to integrate previous rewarding experiences to inform future decisions. Taken together, this may generate a feeling of powerlessness that contributes to increased suicidality and a needless loss of life.	
26232868	Sex hormones impact reward processing, which is dysfunctional in schizophrenia; however, the degree to which testosterone levels relate to reward-related brain activity in healthy men and the extent to which this relationship may be altered in men with schizophrenia has not been determined. We used functional magnetic resonance imaging (fMRI) to measure neural responses in the striatum during reward prediction-errors and hormone assays to measure testosterone and prolactin in serum. To determine if testosterone can have a direct effect on dopamine neurons, we also localized and measured androgen receptors in human midbrain with immunohistochemistry and quantitative PCR. We found correlations between testosterone and prediction-error related activity in the ventral striatum of healthy men, but not in men with schizophrenia, such that testosterone increased the size of positive and negative prediction-error related activity in a valence-specific manner. We also identified midbrain dopamine neurons that were androgen receptor immunoreactive, and found that androgen receptor (AR) mRNA was positively correlated with tyrosine hydroxylase (TH) mRNA in human male substantia nigra. The results suggest that sex steroid receptors can potentially influence midbrain dopamine biosynthesis, and higher levels of serum testosterone are linked to better discrimination of motivationally-relevant signals in the ventral striatum, putatively by modulation of the dopamine biosynthesis pathway via AR ligand binding. However, the normal relationship between serum testosterone and ventral striatum activity during reward learning appears to be disrupted in schizophrenia. 
26232229	Recent progress in understanding the diversity of midbrain dopamine neurons has highlighted the importance--and the challenges--of defining mammalian neuronal cell types. Although neurons may be best categorized using inclusive criteria spanning biophysical properties, wiring of inputs, wiring of outputs, and activity during behavior, linking all of these measurements to cell types within the intact brains of living mammals has been difficult. Here, using an array of intact-brain circuit interrogation tools, including CLARITY, COLM, optogenetics, viral tracing, and fiber photometry, we explore the diversity of dopamine neurons within the substantia nigra pars compacta (SNc). We identify two parallel nigrostriatal dopamine neuron subpopulations differing in biophysical properties, input wiring, output wiring to dorsomedial striatum (DMS) versus dorsolateral striatum (DLS), and natural activity patterns during free behavior. Our results reveal independently operating nigrostriatal information streams, with implications for understanding the logic of dopaminergic feedback circuits and the diversity of mammalian neuronal cell types.
26231324	Among chronic hemodialysis patients, hyperphosphatemia is common and associated with mortality. Behavioral economics and complementary behavior-change theories may offer valuable approaches to achieving phosphorus (PO4) control. The aim was to determine feasibility of implementing financial incentives and structured coaching to improve PO4 in the hemodialysis setting.This pilot randomized controlled trial was conducted in 3 urban dialysis units for 10 weeks among 36 adults with elevated serum PO4 (median >5.5 mg/dL over 3 months).	Twelve participants each were randomized to: (1) financial incentives for lowering PO4, (2) coaching about dietary and medication adherence, or (3) usual care. PO4 was measured during routine clinic operations. Each incentives arm participant received the equivalent of $1.50/day if the PO4 was ≤5.5 mg/dL or >5.5 mg/dL but decreased ≥0.5 mg/dL since the prior measurement. The coach was instructed to contact coaching arm participants at least 3 times per week.	The outcome measures included: (1) enrollment rate, (2) dropout rate, and (3) change in PO4 from beginning to end of 10-week intervention period.	Of 66 eligible patients, 36 (55%) enrolled. Median age was 53 years, 83% were black race, and 78% were male. Median baseline PO4 was 6.0 (interquartile range 5.6, 7.5). Using stratified generalized estimation equation analyses, the monthly decline in PO4 was -0.32 mg/dL (95% CI -0.60, -0.04) in the incentives arm, -0.40 mg/dL (-0.60, -0.20) in the coaching arm, and -0.24 mg/dL (-0.60, 0.08) in the usual care arm. No patients dropped out. All intervention arm participants expressed interest in receiving similar support in the future.	This pilot trial demonstrated good feasibility in enrollment and implementation of novel behavioral health strategies to reduce PO4 in dialysis patients.	
26230746	Drivers' risk-taking is a key issue of road safety. This study explored individual differences in drivers' decision-making, linking external behaviours to internal neural activity, to reveal the cognitive mechanisms of risky driving. Twenty-four male drivers were split into two groups (risky vs. safe drivers) via the Drivier Behaviour Questionnaire-violation. The risky drivers demonstrated higher preference for the risky choices in the paradigms of Iowa Gambling Task and Balloon Analogue Risk Task. More importantly, the risky drivers showed lower amplitudes of feedback-related negativity (FRN) and loss-minus-gain FRN in both paradigms, which indicated their neural processing of error-detection. A significant difference of P300 amplitudes was also reported between groups, which indicated their neural processing of reward-evaluation and were modified by specific paradigm and feedback. These results suggested that the neural basis of risky driving was the decision patterns less revised by losses and more motivated by rewards.Risk-taking on the road is largely determined by inherent cognitive mechanisms, which can be indicated by the behavioural and neural patterns of decision-making. In this regard, it is feasible to quantize drivers’ riskiness in the cognitive stage before actual risky driving or accidents, and intervene accordingly.	
26230643	More than 100 years ago, Karl von Frisch showed that honeybee workers learn and discriminate colors. Since then, many studies confirmed the color learning capabilities of females from various hymenopteran species. Yet, little is known about visual learning and memory in males despite the fact that in most bee species males must take care of their own needs and must find rewarding flowers to obtain food. Here we used the proboscis extension response (PER) paradigm to study the color learning capacities of workers and drones of the bumblebee, Bombus terrestris. Light stimuli were paired with sucrose reward delivered to the insects' antennae and inducing a reflexive extension of the proboscis. We evaluated color learning (i.e. conditioned PER to color stimuli) in absolute and differential conditioning protocols and mid-term memory retention was measured two hours after conditioning. Different monochromatic light stimuli in combination with neutral density filters were used to ensure that the bumblebees could only use chromatic and not achromatic (e.g. brightness) information. Furthermore, we tested if bees were able to transfer the learned information from the PER conditioning to a novel discrimination task in a Y-maze. Both workers and drones were capable of learning and discriminating between monochromatic light stimuli and retrieved the learned stimulus after two hours. Drones performed as well as workers during conditioning and in the memory test, but failed in the transfer test in contrast to workers. Our data clearly show that bumblebees can learn to associate a color stimulus with a sugar reward in PER conditioning and that both workers and drones reach similar acquisition and mid-term retention performances. Additionally, we provide evidence that only workers transfer the learned information from a Pavlovian to an operant situation. 
26228683	Recently, evidence has emerged suggesting a role for the paraventricular nucleus of the thalamus (PVT) in the processing of reward-associated cues. However, the specific role of the PVT in these processes has yet to be elucidated. Here we use an animal model that captures individual variation in response to discrete reward-associated cues to further assess the role of the PVT in stimulus-reward learning. When rats are exposed to a Pavlovian conditioning paradigm, wherein a discrete cue predicts food reward, two distinct conditioned responses emerge. Some rats, termed sign-trackers, approach and manipulate the cue, whereas others, termed goal-trackers, approach the location of reward delivery upon cue presentation. For both sign- and goal-trackers the cue is a predictor, but only for sign-trackers is it also an incentive stimulus. We investigated the role of the PVT in the acquisition and expression of these conditioned responses using an excitotoxic lesion. Results indicate that PVT lesions prior to acquisition amplify the differences between phenotypes - increasing sign-tracking and attenuating goal-tracking behavior. Lesions of the PVT after rats had acquired their respective conditioned responses also attenuated the expression of the goal-tracking response, and increased the sign-tracking response, but did so selectively in goal-trackers. These results suggest that the PVT acts to suppress the attribution of incentive salience to reward cues, as disruption of the functional activity within this structure enhances the tendency to sign-track. 
26228461	The metabolic controls of eating are embedded in a neural system that permits an interaction with the environment. The result is an integrated adaptive response that coordinates the internal milieu with the prevailing environment. Securing adequate amounts of fat and optimizing its storage and use has an evolutionary basis. By generating neuronal and endocrine feedback signals, behavior and metabolism could then adapt to fluctuations in food availability. However, in modern society, foods that appeal to the palate are neither in shortage nor are they difficult to procure. These foods can activate brain reward circuitry beyond their evolved 'survival advantage' limits. Many foods high in fat invoke an undeniably pleasurable sensation and could excessively stimulate the brain's reward pathways leading to overeating. However, the high appeal and potential for being eaten in excess notwithstanding, fat has the added distinction of inducing powerful signals in the gut that are transduced to the brain and result in the regulation of appetite. Fatty acids are sensed by G-protein-coupled receptors on enteroendocrine cells which trigger the release of peptides involved in appetite regulation. Lipid sensing may also occur through the fatty acid translocase, CD-36, on enterocytes. Additionally, fat can activate dopaminergic systems affecting reward, to promote an inhibition over eating. Prolonging the presence of fats in the gastrointestinal lumen permits the activation of signaling mechanisms. Thylakoids, found within the chloroplasts of plants, are flattened disc-like membranous vesicles in which the light-dependent reactions of photosynthesis occur. By interacting with lipids and delaying fat digestion, thylakoid membranes promote the release of peptides involved in appetite regulation and may influence the reward system. This review explores gut lipid sensing and signaling in the context of appetite regulation. The effects of thylakoid membranes on eating behavior are also reviewed. 
26227627	Parkinson's Disease (PD) is a neurodegenerative disease characterized by motor symptoms, but in which behavioral and cognitive disturbances are also common. Trust, due to its pervasiveness in society, has become a major research topic in several scientific disciplines. However, empirical evidence for trust behavior in neurological patients, and specifically for movement disorders such as PD, is missing. Evidence from healthy subjects, however, indicates that three brain regions are involved in trust perceptions and behavior, namely the limbic system, basal ganglia, and frontal cortex. PD affects all these brain regions. Therefore, we hypothesized that PD patients and healthy controls show differences in trust behavior.We conducted an experiment using the trust game, an established paradigm to investigate trust behavior in both patient and healthy populations alike, controlling for risky decision making. Twenty patients suffering from PD diagnosed according to UK PDS Brain Bank criteria and twenty healthy controls (matched for age, gender, education, and income) were recruited. We excluded those suffering from clinically relevant neuropsychiatric comorbidities.	We found that PD patients exhibit significantly lower levels of trust than do healthy controls. Importantly, our results cannot be explained by lower levels of risk-taking. Moreover, our results indicate that the trust deficit is independent of medication, disease duration, and severity of motor symptoms.	Application of a standard procedure for measuring trust behavior revealed that PD patients exhibit lower levels of trust in other humans than do healthy controls. Against this background we make a call for further research to determine the underlying pathophysiology of reduced trust in PD.	
26224779	Multimodal GABA-immunoreactive feedback neurons in the honeybee brain connecting the output region of the mushroom body with its input are expected to tune the input to the mushroom body in an experience-dependent way. These neurons are known to change their rate responses to learned olfactory stimuli. In this work we ask whether these neurons also transmit learned attentional effects during multisensory integration. We find that a visual context and an olfactory cue change the rate responses of these neurons after learning according to the associated values of both context and cue. The learned visual context promotes attentional response selection by enhancing olfactory stimulus valuation at both the behavioral and the neural level. During a rewarded visual context, bees reacted faster and more reliably to a rewarded odor. We interpreted this as the result of the observed enhanced neural discharge toward the odor. An unrewarded context reduced already low rate responses to the unrewarded odor. In addition to stimulus valuation, these feedback neurons generate a neural error signal after an incorrect behavioral response. This might act as a learning signal in feedback neurons. All of these effects were exclusively found in trials in which the animal prepares for a motor response that happens during attentional stimulus selection. We discuss possible implications of the results for the feedback connections of the mushroom body. 
26224774	The prefronto-striatal network is involved in many cognitive functions, including perceptual decision making and reward-modulated behaviors. For well-trained subjects, neural responses frequently show similar patterns in the prefrontal cortex and striatum, making it difficult to tease apart distinct regional contributions. Here I show that, despite similar mean firing rate patterns, prefrontal and striatal responses differ in other temporal dynamics for both perceptual and reward-based tasks. Compared with simulation results, the temporal dynamics of prefrontal activity are consistent with an accumulation of sensory evidence used to solve a perceptual task but not with an accumulation of reward context-related information used for the development of a reward bias. In contrast, the dynamics of striatal activity is consistent with an accumulation of reward context-related information and with an accumulation of sensory evidence during early stimulus viewing. These results suggest that prefrontal and striatal neurons may have specialized functions for different tasks even with similar average activity. 
26224444	A model system capable of providing clinically relevant analgesic doses with minimal trauma has been elusive in laboratory animal medicine. Our laboratory has developed an orofacial operant pain system that effectively discriminates between non-noxious and noxious thermal stimuli in rats and mice. Male and female rats (Crl:SD) and mice (Crl:SKR-HR(hr)) were trained to perform a task (placing their face through an opening and having their cheeks stay in contact with thermodes) to receive a reward (a solution of sweetened condensed milk). Currently accepted doses of buprenorphine were tested by using a crossover design. Pain was induced in both species by sensitizing the depilated skin over both cheeks with capsaicin cream or by creating a surgical incision (rats only) and then allowing the animals to contact a temperature-regulated thermode while obtaining a reward. Optimal antinociceptive doses included 0.05 and 0.1 mg/kg in male mice but only 0.05 mg/kg in female mice. In rats, optimal antinociceptive doses included 0.03 and 0.05 mg/kg for male rats but only 0.03 mg/kg for female rats. The 2 pain-induction models in rats (capsaicin cream and surgical incision) did not differ. Our orofacial operant pain assay can determine clinically relevant analgesic doses for rodents in a preclinical assay. The automated, investigator-independent nature of the assay, in conjunction with its high sensitivity, makes this method an improvement over traditional noninvasive methods, providing better data for developing optimal analgesic recommendations for rats and mice.
26223494	Compulsive behavior, which is a hallmark of psychiatric disorders such as addiction and obsessive-compulsive disorder, engages corticostriatal circuits. Previous studies indicate a role for corticostriatal N-methyl-D-aspartate receptors (NMDARs) in mediating compulsive-like responding for drugs of abuse, but the specific receptor subunits controlling reward-seeking in the face of punishment remain unclear.The current study assessed the involvement of corticostriatal GluN2B-containing NMDARs in measures of persistent and punished food reward-seeking.	Mice with genetic deletion of GluN2B in one of three distinct neuronal populations, cortical principal neurons, forebrain interneurons, or striatal medium spiny neurons, were tested for (1) sustained food reward-seeking when reward was absent, (2) reward-seeking under a progressive ratio schedule of reinforcement, and (3) persistent reward-seeking after a footshock punishment.	Mutant mice with genetic deletion of GluN2B in cortical principal neurons demonstrated attenuated suppression of reward-seeking during punishment. These mice performed normally on other behavioral measures, including an assay for pain sensitivity. Mutants with interneuronal or striatal GluN2B deletions were normal on all behavioral assays.	Current findings offer novel evidence that loss of GluN2B-containing NMDARs expressed on principal neurons in the cortex results in reduced punished food reward-seeking. These data support the involvement of GluN2B subunit in cortical circuits regulating cognitive flexibility in a variety of settings, with implications for understanding the basis of inflexible behavior in neuropsychiatric disorders including obsessive-compulsive disorders (OCD) and addictions.	
26223291	The monetary incentive delay (MID) task has been widely used in fMRI studies to investigate the neural networks involved in anticipatory and consummatory reward processing. Previous efforts to adapt the MID task for use with ERPs, however, have had limited success. Here, we sought to further decompose reward dynamics using a comprehensive set of anticipatory (cue-N2, cue-P3, contingent negative variation [CNV]) and consummatory ERPs (feedback negativity [FN], feedback P3 [fb-P3]). ERP data was recorded during adapted versions of the MID task across two experiments. Unlike previous studies, monetary incentive cues modulated the cue-N2, cue-P3, and CNV; however, cue-related ERPs and the CNV were uncorrelated with one another, indicating distinct anticipatory subprocesses. With regard to consummatory processing, FN amplitude primarily tracked outcome valence (reward vs. nonreward), whereas fb-P3 amplitude primarily tracked outcome salience (uncertain vs. certain). Independent modulation of the cue-P3 and fb-P3 was observed, indicating that these two P3 responses may uniquely capture the allocation of attention during anticipatory and consummatory reward processing, respectively. Overall, across two samples, consistent evidence of both anticipatory and consummatory ERP activity was observed on an adapted version of the MID paradigm, demonstrating for the first time how these ERP components may be integrated with one another to more fully characterize the time course of reward processing. This ERP-MID paradigm is well suited to parsing reward dynamics, and can be applied to both healthy and clinical populations. 
26222550	This study on competition in human groups was performed within the context of the competitive outcome interdependence concept: the degree to which personal outcomes among group members are affected by the consequences of task performance of others, e.g. when one group member gains a high reward for a task, this lowers the available reward for other group members. Our computer-based multi-participant game empirically assessed how competitive versus neutral conditions influenced the reward-maximising behaviour of 200 undergraduate students functioning in ten-person groups - each playing two games (1 neutral and 1 competitive), their perceived pay satisfaction as well as perceived stress levels and sense of calmness within the games' task to search for coins. Participants were represented by black dots moving on a virtual playground. Results showed that competition led to reward-maximising but fellow group member disadvantaging behaviour, and all participants experienced lower pay satisfaction, higher stress levels and less calmness. We conclude that short-term behavioural consequences of positive individual competitive behaviour were gained at the above-mentioned potential long-term negative costs for all group members. This implies group paradigms aimed at sustainability should avoid introducing competitive factors that at best result in short-lived gains and at worst cause widespread dissatisfaction, stress and a pervasive lack of calmness. 
26222257	Pleiotrophin (PTN) is a neurotrophic factor with important functions in addiction and neurodegenerative disorders. Morphine administration induces an increase in the expression of PTN and Midkine (MK), the only other member of this family of cytokines, in brain areas related with the addictive effects of drug of abuse, like the Ventral Tegmental Area or the hippocampus. In spite of previous studies showing that PTN modulates amphetamine and ethanol rewarding effects, and that PTN is involved in morphine-induced analgesia, it was still unknown if the rewarding effects of morphine may be regulated by endogenous PTN. Thus, we aim to study the role of PTN in the reward and physical dependence induced by morphine. We used the Conditioned Place Preference (CPP) paradigm in PTN genetically deficient (PTN-/-) and wild type (WT) mice to assess the rewarding effects of morphine in absence of endogenous PTN. Second, to study if PTN may be involved in morphine physical dependence, naloxone-precipitated withdrawal syndrome was induced in PTN-/- and WT morphine dependent mice. Although the increase in the time spent in the morphine-paired compartment after conditioning tended to be more pronounced in PTN-/- mice, statistical significance was not achieved. The data suggest that PTN does not exert an important role in morphine reward. However, our results clearly indicate that PTN-/- mice develop a more severe withdrawal syndrome than WT mice, characterized as a significant increase in the time standing and in the total incidences of forepaw licking, forepaw tremors, wet dog shake and writhing. The data presented here suggest that PTN is a novel genetic factor that plays a role in morphine withdrawal syndrome. 
26221832	Impaired social interaction is a hallmark symptom of many psychiatric disorders. In substance use disorders, impaired social interaction is triply harmful (a) because addicts increasingly prefer the drug of abuse to the natural reward of drug-free social interaction, thus worsening the progression of the disease by increasing their drug consumption, (b) because treatment adherence and, consequently, treatment success itself depends on the ability of the recovering addict to maintain social interaction and adhere to treatment, and (c) because socially interacting with an individual suffering from a substance use disorder may be harmful for others. Helping the addict reorient his/her behavior away from the drug of abuse toward social interaction would therefore be of considerable therapeutic benefit. This article reviews our work on the neural basis of such a reorientation from cocaine, as a prototypical drug of abuse, toward dyadic (i.e. one-to-one) social interaction and compares our findings with the effects of other potentially beneficial interventions, that is, environmental enrichment or paired housing, on the activation of the accumbens and other brain regions involved in behavior motivated by drugs of abuse or nondrug stimuli. Our experimental models are based on the conditioned place preference paradigm. As the therapeutically most promising finding, only four 15 min episodes of dyadic social interaction were able to inhibit both the subsequent reacquisition/re-expression of preference for cocaine and the neural activation associated with this behavior, that is, an increase in the expression of the immediate early gene Early Growth Response protein 1 (EGR1, Zif268) in the nucleus accumbens, basolateral and central amygdala, and the ventral tegmental area. The time spent in the cocaine-associated conditioning compartment was correlated with the density of EGR1-activated neurons not only in the medial core (AcbCm) and medial shell (AcbShm) of the nucleus accumbens, but was observed in all regions medial to the anterior commissure ('accumbens corridor'), including (from medial to lateral), the vertical limb of the diagonal band and the medial septum (VDB+MS), the major island of Calleja and the intermediate nucleus of the lateral septum (ICjM+LSI), the AcbShm, and the AcbCm. All effects were limited to GABAergic projection neurons (called 'medium spiny neurons', in the accumbens), encompassing both dopamine D1 receptor-expressing and D2 receptor-expressing medium spiny neuron subtypes. Our EGR1 expression findings were mirrored in multielectrode array recordings. Finally, we have validated our paradigm in C57BL/6 mice to make use of the plethora of transgenic models available in this genus.
26221767	Oxytocin (OT) plays a crucial role in parental-infant bonding and attachment. Recent functional imaging studies reveal specific attachment and reward related brain regions in individuals or within the parent-child dyad. However, the time course and functional stage of modulatory effects of OT on attachment-related processing, especially in fathers, are poorly understood. To elucidate the functional and neural mechanisms underlying the role of OT in paternal-child attachment, we performed an event-related potential study in 24 healthy fathers who received intranasal OT in a double-blind, placebo-controlled, within-subject experimental design. Participants passively viewed pictures of their own child (oC), a familiar (fC) and an unfamiliar child (ufC) while event-related potentials were recorded. Familiarity of the child's face modulated a broad negativity at occipital and temporo-parietal electrodes within a time window of 300-400ms, presumably reflecting a modulation of the N250 and N300 ERP components. The oC condition elicited a more negative potential compared to the other familiarity conditions suggesting different activation of perceptual memory representations and assignment of emotional valence. Most importantly, this familiarity effect was only observed under placebo (PL) and was abolished under OT, in particular at left temporo-parietal electrodes. This OT induced attenuation of ERP responses was related to habitual attachment representations in fathers. In summary, our results demonstrate an OT-specific effect at later stages of attachment-related face processing presumably reflecting both activation of perceptual memory representations and assignment of emotional value. 
26220740	The ability to learn associations between stimuli, responses and rewards is a prerequisite for survival. Models of reinforcement learning suggest that the striatum, a basal ganglia input nucleus, vitally contributes to these learning processes. Our recently presented computational model predicts, first, that not only the striatum, but also the globus pallidus contributes to the learning (i.e., exploration) of stimulus-response associations based on rewards. Secondly, it predicts that the stable execution (i.e., exploitation) of well-learned associations involves further learning in the thalamus. To test these predictions, we postoperatively recorded local field potentials (LFPs) from patients that had undergone surgery for deep brain stimulation to treat severe movement disorders. Macroelectrodes were placed either in the globus pallidus or in the ventral thalamus. During recordings, patients performed a reward-based stimulus-response learning task that comprised periods of exploration and exploitation. We analyzed correlations between patients' LFP amplitudes and model-based estimates of their reward expectations and reward prediction errors. In line with our first prediction, pallidal LFP amplitudes during the presentation of rewards and reward omissions correlated with patients' reward prediction errors, suggesting pallidal access to reward-based teaching signals. Unexpectedly, the same was true for the thalamus. In further support of this prediction, pallidal LFP amplitudes during stimulus presentation correlated with patients' reward expectations during phases of low reward certainty - suggesting pallidal participation in the learning of stimulus-response associations. In line with our second prediction, correlations between thalamic stimulus-related LFP amplitudes and patients' reward expectations were significant within phases of already high reward certainty, suggesting thalamic participation in exploitation. 
26219923	Imagining future events while performing an intertemporal choice task can attenuate the devaluation of future rewards. Here, we investigated whether this effect and its neural basis depend on the degree of personal prior experience associated with the simulated future scenarios. Functional magnetic resonance imaging was combined with a modified intertemporal choice task in which the delayed options were either purely monetary, or linked with a social event. Subject-specific events differed regarding familiarity, that is, meeting a close, familiar person or a celebrity in a café. In line with recent hypotheses on episodic construction, the simulation of future familiar and unfamiliar events equally attenuated delay discounting behavior in comparison with the control condition and both were imagined with similar richness. Imaging data, however, indicate that these results rely on differential neural activation patterns. The hippocampus was particularly involved in the simulation of unfamiliar future scenarios, probably reflecting enhanced construction processes when personal experience with similar past events is lacking. Consequently, functional coupling of the hippocampus with neural valuation signals in the anterior cingulate cortex predicted the subjective value only of rewards offered in the unfamiliar context. In contrast, valuation of rewards in a familiar context was predicted by activation in key nodes of emotional and autobiographical memory retrieval and dynamically modulated by frontal-striatal connectivity. The present data emphasize that the mechanisms underlying neural valuation of prospective rewards largely depend on the pre-experience with the context in which they are offered.
26219396	The self-positivity bias, which is inherent to healthy people, is known to be blunted in depression. The lack of positive or excessive negative self-reference is considered to be a potential mechanism underlying depressive rumination. However, the motivational factors that drive people to approach and avoid emotional self-related materials are still unclear. Therefore, we measured intrinsic motivation that is associated with emotional self-references by using a reward-based decision-making task (pay-per-view paradigm). Forty-nine undergraduates completed two tasks in which they were asked to choose between negative vs. positive references (Task 1) and self vs. other references (Task 2) for variable monetary rewards. Participants with lower levels of depressive symptoms showed a self-positivity bias, sacrificing rewards for the opportunity to engage in positive self-reference, whereas those with higher levels of depressive symptoms had no specific preference for either negative or positive self-reference (Task 1). However, all participants sacrificed monetary rewards for the opportunity for self-reference versus other reference, regardless of the symptom level or the primed valence (Task 2). Together, these findings suggest that depressive cognition could be characterised by the lack of intrinsic motivation for positive self-reference, which is attributable to the biased valence selection, but not to self-other preferences.
26219213	Nicotine exposure causes the release of dopamine from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). We have previously shown that maternal exposure to nicotine during lactation causes hyperleptinemia in dams and pups, and leptin is known to decrease dopamine release from the VTA. Here we evaluated whether maternal exposure to nicotine during lactation causes changes in dopamine and leptin signaling pathways at the end of exposure and after 5days of withdrawal in the: VTA, NAc, arcuate nucleus (ARC) and dorsal striatum (DS). On postnatal day (PN) 2, lactating Wistar rats were implanted with minipumps releasing nicotine (NIC; 6mg/kg/day, s.c.) or saline (C) for 14days. Offspring were tested in the elevated plus maze (EPM) and open field on PN14 or PN20, and euthanized on PN15 or PN21. Entries into the open arms and head dips in the EPM were reduced in NIC pups at P20. At weaning (PN21), NIC dams had: lower tyrosine hydroxylase (TH), higher OBRb and SOCS3 contents in VTA; lower TH, higher D1R, D2R and DAT contents in NAc; higher TH content in DS; and higher D2R and SOCS3 contents in ARC. On PN15, NIC offspring had higher D1R, D2R and lower DAT contents in NAc, while on PN21, they had lower DAT in DS, and lower pSTAT3 content in ARC. We evidenced that postnatal nicotine exposure induces relevant changes in the brain reward system of dams and pups, possibly associated with changes in leptinemia and increased offspring anxiety-like behavior. 
26218584	Neurodevelopmental evidence suggests that children's main decision-making strategy is to avoid options likely to induce punishment. However, the cognitive and affective factors contributing to children's avoidance to high punishment frequency remain unknown. The present study explored psychophysiological, cognitive, and metacognitive processes associated with sensitivity to punishment frequency. We evaluated 54 participants (between 8 and 15 years old) with a modified Iowa Gambling Task for children (IGT-C) which included options with varying long-term profit and punishment frequencies. Skin conductance responses (SCRs) were recorded during this task. Additionally, we assessed IGT-C metacognitive knowledge, fluid intelligence, and executive functions. Participants exhibited behavioral avoidance and high anticipatory SCRs to options with high frequency of punishment. Moreover, age, IGT-C metacognitive knowledge, and inhibitory control were associated with individual differences in sensitivity to punishment frequency. Our results suggest that children's preference for infrequently punished decisions is partially explained by psychophysiological signals as well as task complexity and development of cognitive control. 
26218424	Irritability is an aspect of the negative affectivity domain of temperament, but in severe and dysregulated forms is a symptom of a range of psychopathologies. Better understanding of the neural underpinnings of irritability, outside the context of specific disorders, can help to understand normative variation but also characterize its clinical salience in psychopathology diagnosis. This study assessed brain activation during reward and frustration, domains of behavioral deficits in childhood irritability. Children (age 6-9) presenting in mental health clinics for extreme and impairing irritability (n = 26) were compared to healthy children (n = 28). Using developmentally sensitive methods, neural activation was measured via a negative mood induction paradigm during fMRI scanning. The clinical group displayed more activation of the anterior cingulate and middle frontal gyrus during reward, but less activation during frustration, than healthy comparison children. The opposite pattern was found in the posterior cingulate. Further, in clinical subjects, parent report of irritability was dimensionally related to decreased activation of the anterior cingulate and striatum during frustration. The results of this study indicate neural dysfunction within brain regions related to reward processing, error monitoring, and emotion regulation underlying clinically impairing irritability. Results are discussed in the context of a growing field of neuroimaging research investigating irritable children.
26216520	The striatum has an essential role in neural control of instrumental behaviors by reinforcement learning. Adenosine A(2A) receptors (A(2A)Rs) are highly enriched in the striatopallidal neurons and are implicated in instrumental behavior control. However, the temporal importance of the A(2A)R signaling in relation to the reward and specific contributions of the striatopallidal A(2A)Rs in the dorsolateral striatum (DLS) and the dorsomedial striatum (DMS) to the control of instrumental learning are not defined. Here, we addressed temporal relationship and sufficiency of transient activation of optoA(2A)R signaling precisely at the time of the reward to the control of instrumental learning, using our newly developed rhodopsin-A2AR chimeras (optoA(2A)R). We demonstrated that transient light activation of optoA(2A)R signaling in the striatopallidal neurons in 'time-locked' manner with the reward delivery (but not random optoA(2A)R activation) was sufficient to change the animal's sensitivity to outcome devaluation without affecting the acquisition or extinction phases of instrumental learning. We further demonstrated that optogenetic activation of striatopallidal A(2A)R signaling in the DMS suppressed goal-directed behaviors, as focally genetic knockdown of striatopallidal A(2A)Rs in the DMS enhanced goal-directed behavior by the devaluation test. By contrast, optogenetic activation or focal AAV-Cre-mediated knockdown of striatopallidal A(2A)R in the DLS had relatively limited effects on instrumental learning. Thus, the striatopallidal A(2A)R signaling in the DMS exerts inhibitory and predominant control of goal-directed behavior by acting precisely at the time of reward, and may represent a therapeutic target to reverse abnormal habit formation that is associated with compulsive obsessive disorder and drug addiction.
26216231	Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the "endocannabinoid (eCB) system", a rather complex ensemble of lipid signals ("endocannabinoids"), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.
26215921	Circadian clocks drive daily rhythms in physiology and behavior which allow organisms to anticipate predictable daily changes in the environment. In most mammals, circadian rhythms result in nocturnal activity patterns although plasticity of the circadian system allows activity patterns to shift to different times of day. Such plasticity is seen when food access is restricted to a few hours during the resting (light) phase resulting in food anticipatory activity (FAA) in the hours preceding food availability. The mechanisms underlying FAA are unknown but data suggest the involvement of the reward system and homeostatic regulation of metabolism. We previously demonstrated the isolated effect of metabolism by inducing diurnality in response to energetic challenges. Here the importance of reward timing in inducing daytime activity is assessed. The daily activity distribution of mice earning palatable chocolate at their preferred time by working in a running wheel was compared with that of mice receiving a timed palatable meal at noon. Mice working for chocolate (WFC) without being energetically challenged increased their total daily activity but this did not result in a shift to diurnality. Providing a chocolate meal at noon each day increased daytime activity, identifying food timing as a factor capable of altering the daily distribution of activity and rest. These results show that timing of food reward and energetic challenges are both independently sufficient to induce diurnality in nocturnal mammals. FAA observed following timed food restriction is likely the result of an additive effect of distinct regulatory pathways activated by energetic challenges and food reward. 
26215506	Negative symptoms and motivational deficits are prevalent features of schizophrenia, and represent robust predictors of real-world functional outcomes. The standard for assessment of these symptoms is clinical interview and severity ratings on standardized rating scales. In the present study we examined the psychometric properties of a performance-based measure of motivational deficits in patients with schizophrenia.Ninety-seven patients with schizophrenia were included in this investigation. Patients' willingness to expend effort for reward (i.e., motivation) was evaluated using an effort-based decision making paradigm where participants chose over a series of trials whether to expend a greater amount of effort for a larger monetary reward versus less effort for a smaller reward. Effort performance was evaluated twice, separated by a two-week interval.	Patients with schizophrenia opted to expend greater effort for trials with higher reward value and greater likelihood of reward receipt. Patients did not find the task overly difficult and reported being motivated to perform well, underscoring the tolerability of the task for patients. Test-retest consistency was good and there was only minimal change in scores over time. Effort performance was not related to sociodemographic or clinical variables (e.g., positive symptoms); however, deficit syndrome patients exerted effort for reward at a significantly lower rate than nondeficit patients.	The effort-based decision making task used in the present study represents an objective paradigm that can be used to evaluate motivational impairments in patients with schizophrenia. Such performance-based measures of motivation may also serve as viable endpoints in clinical trials.	
26215473	Early adolescent onset of substance use is a robust predictor of future substance use disorders. We examined the relation between age of substance use initiation and resting state functional connectivity (RSFC) of the core reward processing (nucleus accumbens; NAcc) to cognitive control (prefrontal cortex; PFC) brain networks.Adolescents in a longitudinal study of Mexican-origin youth reported their substance use annually from ages 10 to 16 years. At age 16, 69 adolescents participated in a resting state functional magnetic resonance imaging scan. Seed-based correlational analyses were conducted using regions of interest in bilateral NAcc.	The earlier that adolescents initiated substance use, the stronger the connectivity between bilateral NAcc and right dorsolateral PFC, right dorsomedial PFC, right pre-supplementary motor area, right inferior parietal lobule, and left medial temporal gyrus.	The regions that demonstrated significant positive linear relationships between the number of adolescent years using substances and connectivity with NAcc are nodes in the right frontoparietal network, which is central to cognitive control. The coupling of reward and cognitive control networks may be a mechanism through which earlier onset of substance use is related to brain function over time, a trajectory that may be implicated in subsequent substance use disorders.	
26214708	Depressive disorders are associated with significant economic and public health burdens as well as increased morbidity. Yet, perhaps due to the heterogeneous nature of the disease, prevention and intervention efforts are only moderately efficacious. A better understanding of core mechanisms of depressive disorders might aid in the development of more targeted intervention, and perhaps help identify individuals at risk. One mechanism that may be particularly important to depressive phenotypes is reward insensitivity. Examination of neurobiological correlates of reward-processing, which should relate more directly to the neuropathology of depression, may be helpful in identifying liability for the disorder. To that end, we used a family study design to examine whether a neural response to rewards is a familial risk factor for depression in a sample of probands with a wide range of internalizing psychopathology, as well as their biological siblings. Event-related potentials were recorded during a simple forced-choice gambling paradigm, in which participants could either win or lose small amounts of money. Lower levels of positive affect in probands predicted a reduced neural response to rewards in siblings, even over and above the sibling's own level of positive and negative affect. Additionally, the neural response to rewards was familial (i.e., correlated among siblings). Combined, these analyses suggest that a blunted neural response to rewards may be useful in identifying individuals vulnerable to depressive illnesses.
26214660	Previous studies have reported deficits in decision making under ambiguity for patients with mesial temporal lobe epilepsy (mTLE). It is unknown whether mTLE is also associated with alterations at a predecisional stage. This study aimed to gain insight into predecisional processing of patients with mTLE.We compared performance of patients with mTLE (n = 25) with that of healthy controls (n = 75) on the information sampling task (IST), a task assessing reflection-impulsivity and predecisional information sampling.	Patients and healthy controls showed a similar performance pattern in both conditions of the IST as indicated by the amount of information gathered, the degree of uncertainty tolerated, and the number of decision errors made. They both also demonstrated a significant sensitivity to the different reward characteristics of the task. For the patient group, we found no significant effects on performance on the IST of epilepsy lateralization, abnormality side, structural abnormality (hippocampus vs. amygdala), and medication (monotherapy vs. polytherapy).	Reflection processes and predecisional information sampling as tested by the IST are intact in mTLE. Patients collect as much information as healthy individuals and adapt their behavior according to the changing reward conditions. Our findings indicate that in well-defined risk situations, where memory demands are sufficiently minimized, patients with mTLE should be able to gather sufficient information, weight risks and benefits, and make advantageous decisions.	
26214215	We investigated the role of the septo-hippocampal cholinergic projection in anxiety, spatial novelty preference, and differential reward for low rates of responding (DRL) performance. Cholinergic neurons of the rat medial septum (MS) and the vertical limb of the diagonal band of Broca (VDB) were lesioned using the selective immunotoxin, 192 IgG-saporin. Rats were then tested on several behavioral tests previously shown to be sensitive to either (a) hippocampal lesions or (b) nonselective MS/VDB lesions which target both cholinergic and γ-aminobutyric acid (GABA)-ergic projections, or both. Saporin lesions substantially reduced hippocampal cholinergic innervation, resulting in an absence of acetyl cholinesterase staining and markedly reduced choline acetyltransferase activity (mean reduction: 80 ± 5%; range: 50-97%). However, the saporin-lesioned rats did not differ from control rats in any of the behavioral tests. Thus we found no evidence from these lesion studies that the septo-hippocampal cholinergic projection plays an essential role in anxiety, spatial novelty preference, or DRL.
26214209	Prolonged morphine treatment in neonatal pediatric populations is associated with a high incidence of opioid tolerance and dependence. Despite the clinical relevance of this problem, our knowledge of long-term consequences is sparse. The main objective of this study was to investigate whether prolonged morphine administration in a neonatal rat is associated with long-term behavioral changes in adulthood. Newborn animals received either morphine (10 mg/kg) or equal volume of saline subcutaneously twice daily for the first 2 weeks of life. Morphine-treated animals underwent 10 days of morphine weaning to reduce the potential for observable physical signs of withdrawal. Animals were subjected to nonstressful testing (locomotor activity recording and a novel-object recognition test) at a young age (Postnatal Days [PDs] 27-31) or later in adulthood (PDs 55-56), as well as stressful testing (calibrated forceps test, hot plate test, and forced swim test) only in adulthood. Analysis revealed that prolonged neonatal morphine exposure resulted in decreased thermal but not mechanical threshold. Importantly, no differences were found for total locomotor activity (proxy of drug reward/reinforcement behavior), individual forced swim test behaviors (proxy of affective processing), or novel-object recognition test. Performance on the novel-object recognition test was compromised in the morphine-treated group at the young age, but the effect disappeared in adulthood. These novel results provide insight into the long-term consequences of opioid treatment during an early developmental period and suggest long-term neuroplastic differences in sensory processing related to thermal stimuli.
26214208	The central amygdala (CeA) has been shown to play an important role in mediating several attentional processes, including selective and sustained attention. Emerging evidence suggests that the connections between the CeA and the midbrain dopamine areas are important for attentional processing. However, little is known about the role of dopaminergic input into the CeA in mediating attentional processes. To investigate how dopamine activity in the CeA modulates attentional processing, CeA D1 and D2 receptors were temporarily inactivated during testing in a 5-choice task. In this task, rats were trained to detect 1 of 5 recessed ports that briefly illuminated in order to receive a food reward, therefore requiring the rats to successfully sustain their attention to monitor all 5 ports and selectively attend to the lit port. Then, rats were tested in several altered versions of the task to increase attentional load (e.g., variable ready period). In 2 experiments, the D1 antagonist CH 23390 or the D2 antagonist raclopride were infused into the bilateral CeA preceding the test sessions. D1, but not D2, inactivation reduced performance in the more demanding versions of the 5-choice task. Therefore, CeA D1 receptors might mediate attentional functions important for visual cue detection in a 5-choice task.
26214033	Delay of gratification, the ability to forgo an immediate reward to gain either better quality or quantity, has been used as a metric for temporal discounting, self-control, and the ability to plan for the future in both humans (particularly children) and nonhumans. The task involved can be parsed in several ways, such that the subjects can be required to wait, not only for a better or a larger reward, but also such that the rewards can either be in view or hidden during the delay interval. We have demonstrated that a Grey parrot (Psittacus erithacus) trained in the use of English speech could respond to the label "wait" for up to 15 min, in a task that has many similarities to those used with young children, to receive a better quality reward, whether or not the better quality reward or the experimenter was in view.

26213335	The present study examined neural circuit activity in a working memory (WM) task under conditions of approach and avoidance motivation. Eighteen participants were scanned with functional MRI while they performed a 3-back WM task under three conditions: in an avoidance condition incorrect responses were punished with monetary loss; in an approach condition correct responses were rewarded with monetary gain; in a neutral control condition there was no monetary incentive. Compared with the control condition, activation in fronto-parietal areas - which are associated with WM processing - was increased in both the approach and avoidance conditions. The results suggest that both approach and avoidance motivation increase task-related cognitive activation. 
26212791	Previous electrophysiological studies have confirmed impaired reward processing in patients with BPD. However, it is not clear which aspects of reward processing are affected and which brain regions are involved. The present study investigated both evoked and induced event-related oscillations (EROs) to feedback events (thought to represent different aspects of feedback processing), and used source localization (sLORETA) to assess activity in two areas known to contribute to reward processing, the dorsomedial prefrontal/anterior cingulate cortex (dmPFC/ACC) and the orbitofrontal cortex (OFC).Eighteen patients with BPD and 22 healthy controls performed a gambling task, while 64-channel electroencephalographic activity was recorded. Evoked and induced theta and high-beta band EROs as well as activity in the two regions of interest were investigated depending on the valence and magnitude of feedback events.	Theta-band responses to negative feedback were reduced in BPD, an effect that involved only evoked responses and the dmPFC/ ACC region, and was associated with trait impulsivity in patients. sLORETA analyses revealed disturbed evoked responses depending on feedback magnitude in the theta (OFC) and high-beta (dmPFC/ACC and OFC) frequency range.	The results indicate multiple dysfunctions of feedback processing in patients with BPD, implicating several distinct subsets of reward-processing mechanisms.	
26212790	Environmental stimuli have the ability to generate specific representations of the rewards they predict and in so doing alter the selection and performance of reward-seeking actions. The basolateral amygdala participates in this process, but precisely how is unknown. To rectify this, we monitored, in near-real time, basolateral amygdala glutamate concentration changes during a test of the ability of reward-predictive cues to influence reward-seeking actions (Pavlovian-instrumental transfer). Glutamate concentration was found to be transiently elevated around instrumental reward seeking. During the Pavlovian-instrumental transfer test these glutamate transients were time-locked to and correlated with only those actions invigorated by outcome-specific motivational information provided by the reward-predictive stimulus (i.e., actions earning the same specific outcome as predicted by the presented CS). In addition, basolateral amygdala AMPA, but not NMDA glutamate receptor inactivation abolished the selective excitatory influence of reward-predictive cues over reward seeking. These data support [corrected] the hypothesis that transient glutamate release in the BLA can encode the outcome-specific motivational information provided by reward-predictive stimuli.
26212413	This study was conducted to evaluate the impact of job stress on absence from work caused by illnesses and accidents through a prospective research design. A total of 2,349 manual workers were included in this analysis. In the first survey, job stress was determined using the Korean Occupational Stress Scale-Short Form. In the second survey, information on absence due to accidents or illnesses during the past one year was obtained through a questionnaire. The relationship was analyzed using a logistic regression model with multiple imputation. After adjusting for confounding variables for males, absence due to accidents was statistically associated with high job demand, insufficient job control, inadequate social support, and organizational injustice. In addition, high job demands and organizational injustice were related to increased absence due to illnesses in both genders. A lack of reward was associated with increased absence due to illnesses among female workers. We found that job stress was associated with a higher risk of absence caused by accidents or illnesses of manual workers. 
26212270	Cognitive models of eating disorders propose that attentional biases for disorder-relevant stimuli contribute to eating disorder pathology. Empirical evidence of a contribution of attentional biases for binge eating disorder (BED) is still scarce. The aim of the present study was to assess attention engagement towards, and disengagement from, food stimuli in overweight females with BED (n = 25) and a group of overweight and obese women without BED (OW; n = 30). Participants completed a rapid serial visual presentation (RSVP) paradigm with food and neutral words as target stimuli. This task can be used to decompose an attentional bias for food stimuli into its stimulus engagement and stimulus disengagement components. Findings indicate that facilitated stimulus engagement for food stimuli over neutral stimuli was more pronounced in the BED group compared to the OW group. Conversely, there were no substantial disengagement effects in either group. Thereby, results support the idea that early attentional processes are biased in BED.
26211731	Unconditioned rewarding stimuli evoke phasic increases in dopamine concentration in the nucleus accumbens (NAc) while discrete aversive stimuli elicit pauses in dopamine neuron firing and reductions in NAc dopamine concentration. The unconditioned effects of more prolonged aversive states on dopamine release dynamics are not well understood and are investigated here using the malaise-inducing agent lithium chloride (LiCl). We used fast-scan cyclic voltammetry to measure phasic increases in NAc dopamine resulting from electrical stimulation of dopamine cell bodies in the ventral tegmental area (VTA). Systemic LiCl injection reduced electrically evoked dopamine release in the NAc of both anesthetized and awake rats. As some behavioral effects of LiCl appear to be mediated through glucagon-like peptide-1 receptor (GLP-1R) activation, we hypothesized that the suppression of phasic dopamine by LiCl is GLP-1R dependent. Indeed, peripheral pretreatment with the GLP-1R antagonist exendin-9 (Ex-9) potently attenuated the LiCl-induced suppression of dopamine. Pretreatment with Ex-9 did not, however, affect the suppression of phasic dopamine release by the kappa-opioid receptor agonist, salvinorin A, supporting a selective effect of GLP-1R stimulation in LiCl-induced dopamine suppression. By delivering Ex-9 to either the lateral or fourth ventricle, we highlight a population of central GLP-1 receptors rostral to the hindbrain that are involved in the LiCl-mediated suppression of NAc dopamine release. 
26210948	Nicotine can activate dopaminergic neurons within the ventral tegmental area (VTA). However, there is no evidence about complete inhibition of VTA on nicotine reinforcement.in the present study, we used conditioned-place preference (CPP) method to study the effect of transient inhibition of left and/or right side of the VTA by lidocaine on nicotine reward properties. Male Wistar rats seven days after recovery from surgery and cannulation were conditioned to nicotine (1.5 mg/kg) in an unbiased designed CPP apparatus. Five min before each nicotine injection in conditioning phase, lidocaine (2%) was administered either uni- or bi-laterally into the VTA (0.5µl/rat).	results revealed that lidocaine administration into the left but not right side of the VTA reduced nicotine CPP significantly. The reduction was potentiated when lidocaine injected in to both sides of the VTA. In addition, the number of compartment crossing was reduced when lidocaine injected in both side of VTA as well as left side. On the other hand, rearing was reduced when lidocaine injected to the right but not left side of VTA. At last, sniffing was reduced only in the group in which received lidocaine in both side of VTA. Sniffing and rearing increased in the group in which received lidocaine in right side.	It is concluded that the right and left side of VTA play different role in nicotine-induced activity and reward.	
26210606	Alcohol consumption is a potential risk factor for being overweight. We aimed to investigate the effects of an alcohol priming dose and an alcohol-related environment on snacking behaviour. One hundred and fourteen social drinkers completed one of four experimental sessions either receiving a priming dose of alcohol (.6 g/kg) or soft drink in a bar-lab or a sterile lab. Participants provided ratings of appetite, snack urge, and alcohol urge before and after consuming their drinks. Participants completed an ad libitum snack taste test of savoury and sweet, healthy and unhealthy foods before completing the self-reports a final time. Appetite and snack urge increased more following alcohol consumption, and decreased to a lesser extent following the taste test relative to the soft drink. Total calories (including drink calories) consumed were significantly higher in the alcohol groups. There was a marginal effect of environment; those in the bar-lab consumed a higher proportion of unhealthy foods. These effects were more pronounced in those who were disinhibited. While alcohol may not increase food consumption per se, alcohol may acutely disrupt appetite signals, perhaps via processes of reward and inhibitory control, resulting in overall greater calorie intake. Individuals who are generally disinhibited may be more vulnerable to the effects of alcohol and drinking environments on eating behaviour.

26210333	Reduced reward responsiveness and altered response to loss of reward are observed in adults with major depressive disorder (MDD) and adolescents at increased risk for MDD based on family history. However, it is unclear whether altered behavioral responsiveness to reward/loss is a lifelong marker of MDD risk, which is evident before the normative adolescent increase in incentive responding.Healthy 7- to 10-year-old children of mothers with MDD (high risk: n = 27) or without MDD (low risk: n = 42) performed 2 signal detection tasks assessing response bias toward reward (approach) and away from loss (avoidance). Differences in approach/avoidance were related to MDD risk, child general depressive symptoms (maternal report), child-reported anhedonic symptoms, and child-reported negative mood symptoms via repeated-measures analysis of variance.	MDD risk did not significantly relate to gain approach or loss avoidance. However, within high-risk children, higher numbers of maternal depressive episodes predicted blunted loss avoidance. Blunted gain approach was related to elevated anhedonic symptoms, whereas enhanced loss avoidance was related to elevated negative mood. Elevated negative mood was further related to blunted gain approach in high-risk children but related to enhanced gain approach in low-risk children.	In children, individual differences in specific depressive symptoms and recurrence of maternal depression significantly predicted gain approach/loss avoidance, but the presence/absence of maternal MDD did not. Child depressive symptoms characterized by low positive affect (anhedonia) were related to blunted gain responsiveness, whereas elevated depressed/negative mood was related to enhanced loss responsiveness. Findings suggest that relations between gain approach and negative mood may be an important distinction between those at high versus low risk for MDD.	
26209857	Preclinical and emerging clinical evidence indicates that varenicline, a nicotinic partial agonist approved for smoking cessation, attenuates alcohol seeking and consumption. Reductions of alcohol craving have been observed under varenicline treatment and suggest effects of the medication on alcohol reward processing, but this hypothesis remains untested.In this double-blind, placebo-controlled randomized experimental medicine study, 29 heavy drinkers underwent a functional magnetic resonance imaging scan after 2 weeks of varenicline (2mg/d) or placebo administration. During functional magnetic resonance imaging, participants performed the Alcohol-Food Incentive Delay task, where they could earn points for snacks or alcohol. At baseline and after 3 weeks of medication, participants underwent intravenous alcohol self-administration sessions in the laboratory.	During the functional magnetic resonance imaging scan, participants in the varenicline group (N=17) reported lower feelings of happiness and excitement on subjective mood scales when anticipating alcohol reward compared with the placebo group (N=12). Linear mixed effects analysis revealed that anticipation of alcohol reward was associated with significant blood oxygen level dependent activation of the ventral striatum, amygdala, and posterior insula in the placebo group; this activation was attenuated in the varenicline group. The varenicline group showed no difference in intravenous alcohol self-administration relative to the placebo group for either session. Participants with higher insula activation when anticipating alcohol reward showed higher alcohol self-administration behavior across groups.	Our findings suggest that varenicline decreases blood oxygen level dependent activation in striato-cortico-limbic regions associated with motivation and incentive salience of alcohol in heavy drinkers. This mechanism may underlie the clinical effectiveness of varenicline in reducing alcohol intake and indicates its potential utility as a pharmacotherapy for alcohol use disorders.	
26209851	Smoking topography (ST) devices are an important methodological tool for quantifying puffing behavior (eg, puff volume, puff velocity) as well as identifying puffing differences across individuals and situations. Available ST devices are designed such that the smoker's mouth and hands have direct contact with the device rather than the cigarette itself. Given the importance of the sensorimotor aspects of cigarette smoking in smoking reward, it is possible that ST devices may interfere with the acute rewarding effects of smoking. Despite the methodological importance of this issue, few studies have directly compared subjective reactions to smoking through a topography device to naturalistic smoking.Smokers (N = 58; 38% female) smoked their preferred brand of cigarettes one time through a portable topography device and one time naturalistically, in counterbalanced order across two laboratory sessions. Smoking behavior (eg, number of puffs) and subjective effects (eg, urge reduction, affect, smoking satisfaction) were assessed.	Negative affect reduction was greater in the natural smoking condition relative to the topography condition, but differences were not significant on measures of urge, withdrawal, or positive affect. Self-reported smoking satisfaction, enjoyment of respiratory tract sensations, psychological reward, craving reduction, and other rewarding effects of smoking were also significantly greater in the naturalistic smoking condition.	The effects of using a ST device on the smoking experience should be considered when it is used in research as it may diminish some of the rewarding effects of smoking.	When considering the inclusion of a smoking topography device in one's research, it is important to know if use of that device will alter the smoker's experience. This study assessed affective and subjective reactions to smoking through a topography device compared to naturalistic smoking. We found that smoking satisfaction, psychological reward, enjoyment of respiratory tract sensations and other rewarding effects were all diminished when smoking through the topography device. The effects of using a smoking topography device on the smoking experience should be considered when it is used in future research.	
26209546	Effort-based decision making has strong conceptual links to the motivational disturbances that define a key subdomain of negative symptoms. However, the extent to which effort-based decision-making performance relates to negative symptoms, and other clinical and functionally important variables has yet to be systematically investigated. In 94 clinically stable outpatients with schizophrenia, we examined the external validity of 5 effort-based paradigms, including the Effort Expenditure for Rewards, Balloon Effort, Grip Strength Effort, Deck Choice Effort, and Perceptual Effort tasks. These tasks covered 3 types of effort: physical, cognitive, and perceptual. Correlations between effort related performance and 6 classes of variables were examined, including: (1) negative symptoms, (2) clinically rated motivation and community role functioning, (3) self-reported motivational traits, (4) neurocognition, (5) other psychiatric symptoms and clinical/demographic characteristics, and (6) subjective valuation of monetary rewards. Effort paradigms showed small to medium relationships to clinical ratings of negative symptoms, motivation, and functioning, with the pattern more consistent for some measures than others. They also showed small to medium relations with neurocognitive functioning, but were generally unrelated to other psychiatric symptoms, self-reported traits, antipsychotic medications, side effects, and subjective valuation of money. There were relatively strong interrelationships among the effort measures. In conjunction with findings from a companion psychometric article, all the paradigms warrant further consideration and development, and 2 show the strongest potential for clinical trial use at this juncture. 
26209529	In the current studies, we addressed the development of effort-based object valuation. Four- and 6-year-olds invested either great or little effort in order to obtain attractive or unattractive rewards. Children were allowed to allocate these rewards to an unfamiliar recipient (dictator game). Investing great effort to obtain attractive rewards (a consonant situation) led 6-year-olds, but not 4-year-olds, to enhance the value of the rewards and thus distribute fewer of them to others. After investing effort to attain unattractive rewards (a dissonant situation), 6-year-olds cognitively reduced the dissonance between effort and reward quality by reappraising the value of the rewards and thus distributing fewer of them. In contrast, 4-year-olds reduced the dissonance behaviorally by discarding the rewards. These findings provide evidence for the emergence of an effort-value link and underline possible mechanisms underlying the primacy of cognitive versus behavioral solutions to dissonance reduction. 
26208783	Nicotine addiction is highly prevalent in current society and is often comorbid with other diseases. In the central nervous system, nicotine acts as an agonist for nicotinic acetylcholine receptors (nAChRs) and its effects depend on location and receptor composition. Although nicotinic receptors are found in most brain regions, many studies on addiction have focused on the mesolimbic system and its reported behavioral correlates such as reward processing and reinforcement learning. Profound modulatory cholinergic input from the pedunculopontine and laterodorsal tegmentum to dopaminergic midbrain nuclei as well as local cholinergic interneuron projections to dopamine neuron axons in the striatum may play a major role in the effects of nicotine. Moreover, an indirect mesocorticolimbic feedback loop involving the medial prefrontal cortex may be involved in behavioral characteristics of nicotine addiction. Therefore, this review will highlight current understanding of the effects of nicotine on the function of mesolimbic and mesocortical dopamine projections in the mesocorticolimbic circuit. 
26206173	Previous studies indicate that many people perceive themselves to be addicted to food. However, little is known about how the concept of 'food addiction' is defined amongst members of the lay public. The current study examined beliefs about the cognitive and behavioural manifestations of food addiction. Participants (N = 210) completed an internet-delivered questionnaire in which they indicated whether or not they perceived themselves to be a food addict and provided a brief explanation for their response. Over a quarter of participants (28%) perceived themselves to be food addicts and self-diagnosis was predicted by increased BMI and younger age, but not by gender. Thematic analysis was conducted to explore the causal attributions provided by self-perceived food addicts and non-addicts. Six characteristics were identified: 1) Reward-driven eating (i.e. eating for psychological rather than physiological reasons), 2) A functional or psychological preoccupation with food, 3) A perceived lack of self-control around food, 4) Frequent food cravings, 5) Increased weight or an unhealthy diet, and 6) A problem with a specific type of food. The emergent themes, and their frequency, did not differ between self-perceived food addicts and non-addicts. However, self-perceived food addicts and non-addicts reported divergent cognitions, behaviours and attitudes within each common theme. This study is the first to provide qualitative insight into beliefs about food addiction in both self-perceived food addicts and non-addicts. The findings appear to reflect a view of food addiction that is identifiable through several core behaviours.
26205210	Previous studies suggest dopamine (DA) D2-like receptor involvement in the reinforcing effects of food. To determine contributions of the three D2-like receptor subtypes, knockout (KO) mice completely lacking DA D2, D3, or D4 receptors (D2R, D3R, or D4R KO mice) and their wild-type (WT) littermates were exposed to a series of fixed-ratio (FR) food-reinforcement schedules in two contexts: an open economy with additional food provided outside the experimental setting and a closed economy with all food earned within the experimental setting. A behavioral economic model was used to quantify reinforcer effectiveness with food pellets obtained as a function of price (FR schedule value) plotted to assess elasticity of demand. Under both economies, as price increased, food pellets obtained decreased more rapidly (ie, food demand was more elastic) in DA D2R KO mice compared with WT littermates. Extinction of responding was studied in two contexts: by eliminating food deliveries and by delivering food independently of responding. A hyperbolic model quantified rates of extinction. Extinction in DA D2R KO mice occurred less rapidly compared with WT mice in both contexts. Elasticity of food demand was higher in DA D4R KO than WT mice in the open, but not closed, economy. Extinction of responding in DA D4R KO mice was not different from that in WT littermates in either context. No differences in elasticity of food demand or extinction rate were obtained in D3R KO mice and WT littermates. These results indicate that the D2R is the primary DA D2-like receptor subtype mediating the reinforcing effectiveness of food. 
26204232	Feedback and monetary reward can enhance motor skill learning, suggesting reward system involvement. Continuous theta burst (cTBS) transcranial magnetic stimulation (TMS) of the primary motor area (M1) disrupts processing, reduces excitability and impairs motor learning. To see whether feedback and reward can overcome the learning impairment associated with M1 cTBS, we delivered real or sham stimulation to two groups of participants before they performed a motor sequence learning task with and without feedback. Participants were trained on two intermixed sequences, one occurring 85% of the time (the "probable" sequence) and the other 15% of the time (the "improbable" sequence). We measured sequence learning as the difference in reaction time (RT) and error rate between probable and improbable trials (RT and error difference scores). Participants were also tested for sequence recall with the same indices of learning 60 min after cTBS. Real stimulation impaired initial sequence learning and sequence knowledge recall as measured by error difference scores and impaired sequence knowledge recall as measured by RT difference score. Relative to non-feedback learning, the introduction of feedback during sequence learning improved subsequent sequence knowledge recall indexed by RT difference score, in both real and sham stimulation groups and feedback reversed the RT difference score based sequence knowledge recall impairment from real cTBS that we observed in the non-feedback learning condition. Only the real cTBS group in the non-feedback condition showed no evidence of explicit sequence knowledge when tested at the end of the study. Feedback improves recall of implicit and explicit motor sequence knowledge and can protect sequence knowledge against the effect of M1 inhibition. Adding feedback and monetary reward/punishment to motor skill learning may help overcome retention impairments or accelerate training in clinical and other settings. 
26204172	Thirty-five healthy adult women offspring of alcohol-dependent probands (AWOA) were compared with 63 healthy controls to test whether personality dimensions on the Temperament and Character Inventory questionnaire were associated with the brain-derived neurotrophic factor Val66Met polymorphism in offspring. We found a significantly lower reward dependence score in AWOA compared with the controls. The brain-derived neurotrophic factor Val66Met polymorphism may be involved in this difference as the lower reward dependence score was found only in AWOA carrying the Val allele. 
26204110	Harassment bribes, paid by citizens to corrupt officers for services the former are legally entitled to, constitute one of the most widespread forms of corruption in many countries. Nation states have adopted different policies to address this form of corruption. While some countries make both the bribe giver and the bribe taker equally liable for the crime, others impose a larger penalty on corrupt officers. We examine the consequences of asymmetric and symmetric penalties by developing deterministic and stochastic evolutionary game-theoretic models of bribery. We find that the asymmetric penalty scheme can lead to a reduction in incidents of bribery. However, the extent of reduction depends on how the players update their strategies over time. If the interacting members change their strategies with a probability proportional to the payoff of the alternative strategy option, the reduction in incidents of bribery is less pronounced. Our results indicate that changing from a symmetric to an asymmetric penalty scheme may not suffice in achieving significant reductions in incidents of harassment bribery. 
26204099	Poor weight management may relate to a reduction in neurobehavioural control over food intake and heightened reactivity of the brain's neural reward pathways. Here we explore the neurophysiology of food-related visual cue processing in weight reduced and weight relapsed women by assessing differences in cortical arousal and attentional processing using a food-Stroop paradigm.51 women were recruited into 4 groups: reduced-weight participants (RED, n=14) compared to BMI matched low-weight controls (LW-CTL, n=18); and weight relapsed participants (REL, n=10) compared to BMI matched high-weight controls (HW-CTL, n=9). Eating behaviour and body image questionnaires were completed. Two Stroop tasks (one containing food images, the other containing neutral images) were completed with record of electroencephalography (EEG).	Differences in cortical arousal were found in RED versus LW-CTL women, and were seen during food task execution only. Compared to their controls, RED women exhibited lower relative delta band power (p=0.01) and higher relative beta band power (p=0.01) over the right frontal cortex (F4). Within the RED group, delta band oscillations correlated positively with self-reported habitual fat intake and with body shape dissatisfaction.	As compared to women matched for phenotype but with no history of weight reduction, reduced-overweight/obese women show increased neurobehavioural control over external food cues and the inhibition of reward-orientated feeding responses. Insight into these self-regulatory mechanisms which attenuate food cue saliency may aid in the development of cognitive remediation therapies which facilitate long-term weight loss.	
26203152	An odor induces food-seeking behaviors when humans and animals learned to associate the odor with food, whereas the same odor elicits aversive behaviors following odor-danger association learning. It is poorly understood how central olfactory circuits transform the learned odor cue information into appropriate motivated behaviors. The olfactory tubercle (OT) is an intriguing area of the olfactory cortex in that it contains medium spiny neurons as principal neurons and constitutes a part of the ventral striatum. The OT is therefore a candidate area for participation in odor-induced motivated behaviors. Here we mapped c-Fos activation of medium spiny neurons in different domains of the mouse OT following exposure to learned odor cues. Mice were trained to associate odor cues to a sugar reward or foot shock punishment to induce odor-guided approach behaviors or aversive behaviors. Regardless of odorant types, the anteromedial domain of the OT was activated by learned odor cues that induced approach behaviors, whereas the lateral domain was activated by learned odor cues that induced aversive behaviors. In each domain, a larger number of dopamine receptor D1 type neurons were activated than D2 type neurons. These results indicate that specific domains of the OT represent odor-induced distinct motivated behaviors rather than odor stimuli, and raise the possibility that neuronal type-specific activation in individual domains of the OT plays crucial roles in mediating the appropriate learned odor-induced motivated behaviors. Significance statement: Although animals learn to associate odor cues with various motivated behaviors, the underlying circuit mechanisms are poorly understood. The olfactory tubercle (OT), a subarea of the olfactory cortex, also constitutes the ventral striatum. Here, we trained mice to associate odors with either reward or punishment and mapped odor-induced c-Fos activation in the OT. Regardless of odorant types, the anteromedial domain was activated by approach behavior-inducing odors, whereas the lateral domain was activated by aversive behavior-inducing odors. In each domain, dopamine receptor D1 neurons were preferentially activated over D2 neurons. The results indicate that specific OT domains represent odor-induced distinct motivated behaviors rather than odor types, and suggest the importance of neuronal type-specific activation in individual domains in mediating appropriate behaviors.
26203145	Failure to sustain positive affect over time is a hallmark of depression and other psychopathologies, but the mechanisms supporting the ability to sustain positive emotional responses are poorly understood. Here, we investigated the neural correlates associated with the persistence of positive affect in the real world by conducting two experiments in humans: an fMRI task of reward responses and an experience-sampling task measuring emotional responses to a reward obtained in the field. The magnitude of DLPFC engagement to rewards administered in the laboratory predicted reactivity of real-world positive emotion following a reward administered in the field. Sustained ventral striatum engagement in the laboratory positively predicted the duration of real-world positive emotional responses. These results suggest that common pathways are associated with the unfolding of neural processes over seconds and with the dynamics of emotions experienced over minutes. Examining such dynamics may facilitate a better understanding of the brain-behavior associations underlying emotion. Significance statement: How real-world emotion, experienced over seconds, minutes, and hours, is instantiated in the brain over the course of milliseconds and seconds is unknown. We combined a novel, real-world experience-sampling task with fMRI to examine how individual differences in real-world emotion, experienced over minutes and hours, is subserved by affective neurodynamics of brain activity over the course of seconds. When winning money in the real world, individuals sustaining positive emotion the longest were those with the most prolonged ventral striatal activity. These results suggest that common pathways are associated with the unfolding of neural processes over seconds and with the dynamics of emotions experienced over minutes. Examining such dynamics may facilitate a better understanding of the brain-behavior associations underlying emotion.
26203140	Midbrain dopamine (DA) neurons are thought to be a critical node in the circuitry that mediates reward learning. DA neurons receive diverse inputs from regions distributed throughout the neuraxis from frontal neocortex to the mesencephalon. While a great deal is known about changes in the activity of individual DA neurons during learning, much less is known about the functional changes in the microcircuits in which DA neurons are embedded. Here we used local field potentials recorded from the midbrain of behaving mice to show that the midbrain evoked potential (mEP) faithfully reflects the temporal and spatial structure of the phasic response of midbrain neuron populations during conditioning. By comparing the mEP to simultaneously recorded single units, we identified specific components of the mEP that corresponded to phasic DA and non-DA responses to salient stimuli. The DA component of the mEP emerged with the acquisition of a conditioned stimulus, was extinguished following changes in reinforcement contingency, and could be inhibited by pharmacological manipulations that attenuate the phasic responses of DA neurons. In contrast to single-unit recordings, the mEP permitted relatively dense sampling of the midbrain circuit during conditioning and thus could be used to reveal the spatiotemporal structure of multiple intermingled midbrain circuits. Finally, the mEP response was stable for months and thus provides a new approach to study long-term changes in the organization of ventral midbrain microcircuits during learning. Significance statement: Neurons that synthesize and release the neurotransmitter dopamine play a critical role in voluntary reward-seeking behavior. Much of our insight into the function of dopamine neurons comes from recordings of individual cells in behaving animals; however, it is notoriously difficult to record from dopamine neurons due to their sparsity and depth, as well as the presence of intermingled non-dopaminergic neurons. Here we show that much of the information that can be learned from recordings of individual dopamine and non-dopamine neurons is also revealed by changes in specific components of the local field potential. This technique provides an accessible measurement that could prove critical to our burgeoning understanding of the molecular, functional, and anatomical diversity of neuron populations in the midbrain.

26203061	To evaluate the effectiveness of monetary reinforcement to increase the frequency of self-monitoring blood glucose (SMBG).Ten adolescents with poorly controlled diabetes enrolled in a 12-week program in which they earned monetary reinforcers based on SMBG frequency ($0.10 per test, with bonuses for ≥4 tests per day, and $251.40 maximum).	SMBG increased from 1.8 ± 1.0 to 4.9 ± 1.0 tests per day (P < 0.001) with 90% completing four or more tests per day. Mean A1C fell from 9.3 ± 0.9% to 8.4 ± 1.5% (P = 0.05). Adolescents and parents reported high satisfaction with procedures.	Reinforcing adolescents for SMBG may increase testing and improve A1C.	
26202104	Opioid dependence is accompanied by neuroplastic changes in reward circuitry leading to a negative affective state contributing to addictive behaviors and risk of relapse. The current study presents a neuroimmune mechanism through which chronic opioids disrupt the ventral tegmental area (VTA) dopaminergic circuitry that contributes to impaired reward behavior. Opioid dependence was induced in rodents by treatment with escalating doses of morphine. Microglial activation was observed in the VTA following spontaneous withdrawal from chronic morphine treatment. Opioid-induced microglial activation resulted in an increase in brain-derived neurotrophic factor (BDNF) expression and a reduction in the expression and function of the K(+)Cl(-) co-transporter KCC2 within VTA GABAergic neurons. Inhibition of microglial activation or interfering with BDNF signaling prevented the loss of Cl(-) extrusion capacity and restored the rewarding effects of cocaine in opioid-dependent animals. Consistent with a microglial-derived BDNF-induced disruption of reward, intra-VTA injection of BDNF or a KCC2 inhibitor resulted in a loss of cocaine-induced place preference in opioid-naïve animals. The loss of the extracellular Cl(-) gradient undermines GABAA-mediated inhibition, and represents a mechanism by which chronic opioid treatments can result in blunted reward circuitry. This study directly implicates microglial-derived BDNF as a negative regulator of reward in opioid-dependent states, identifying new therapeutic targets for opiate addictive behaviors. 
26201761	Despite small- and wide-scale prevention efforts to curb obesity, the percentage of children classified as overweight and obese has remained relatively consistent in the last decade. As school personnel are increasingly pressured to enhance student performance, many educators use food as a reward to motivate and reinforce positive behavior and high achievement. Yet, many educators have missed the link between student health and academic achievement.Based on a review of the literature, this article explores the link between childhood obesity and adverse mental and physical health, learning, and behavior outcomes. The role in providing children with food as a reward in the relationship between obesity and detrimental health and performance outcomes are examined.	The use of food as a reward is pervasive in school classrooms. Although there is a paucity of research in this area, the few studies published in this area show detrimental outcomes for children in the areas of physical health, learning, and behavior.	It is imperative that educators understand the adverse outcomes associated with using food as a reward for good behavior and achievement. This study provides alternatives to using food as a reward and outlines future directions for research.	
26199415	Sensory stimuli not only activate specific populations of cortical neurons but can also silence other populations. However, it remains unclear whether neuronal silencing per se leads to memory formation and behavioral expression. Here we show that mice can report optogenetic inactivation of auditory neuron ensembles by exhibiting fear responses or seeking a reward. Mice receiving pairings of footshock and silencing of a neuronal ensemble exhibited a fear response selectively to the subsequent silencing of the same ensemble. The valence of the neuronal silencing was preserved for at least 30 d and was susceptible to extinction training. When we silenced an ensemble in one side of auditory cortex for conditioning, silencing of an ensemble in another side induced no fear response. We also found that mice can find a reward based on the presence or absence of the silencing. Neuronal silencing was stored as working memory. Taken together, we propose that neuronal silencing without explicit activation in the cerebral cortex is enough to elicit a cognitive behavior. 
26198691	Although small-scale navigation is well studied in a wide range of species, much of what is known about landmark use by vertebrates is based on laboratory experiments. To investigate how vertebrates in the wild use landmarks, we trained wild male rufous hummingbirds to feed from a flower that was placed in a constant spatial relationship with two artificial landmarks. In the first experiment, the landmarks and flower were 0.25, 0.5 or 1 m apart and we always moved them 3-4 m after each visit by the bird. In the second experiment, the landmarks and flower were always 0.25 m apart and we moved them either 1 or 0.25 m between trials. In tests, in which we removed the flower, the hummingbirds stopped closer to the predicted flower location when the landmarks had been closer to the flower during training. However, while the distance that the birds stopped from the landmarks and predicted flower location was unaffected by the distance that the landmarks moved between trials, the birds directed their search nearer to the predicted direction of the flower, relative to the landmarks, when the landmarks and flower were more stable in the environment. In the field, then, landmarks alone were sufficient for the birds to determine the distance of a reward but not its direction. 
26197051	Patients with anorexia nervosa (AN) display impaired social interactions, implicated in the development and prognosis of the disorder. Importantly, social behavior is modulated by reward-based processes, and dysfunctional at-brain-level reward responses have been involved in AN neurobiological models. However, no prior evidence exists of whether these neural alterations would be equally present in social contexts. In this study, we conducted a cross-sectional social-judgment functional magnetic resonance imaging (fMRI) study of 20 restrictive-subtype AN patients and 20 matched healthy controls. Brain activity during acceptance and rejection was investigated and correlated with severity measures (Eating Disorder Inventory -EDI-2) and with personality traits of interest known to modulate social behavior (The Sensitivity to Punishment and Sensitivity to Reward Questionnaire). Patients showed hypoactivation of the dorsomedial prefrontal cortex (DMPFC) during social acceptance and hyperactivation of visual areas during social rejection. Ventral striatum activation during rejection was positively correlated in patients with clinical severity scores. During acceptance, activation of the frontal opercula-anterior insula and dorsomedial/dorsolateral prefrontal cortices was differentially associated with reward sensitivity between groups. These results suggest an abnormal motivational drive for social stimuli, and involve overlapping social cognition and reward systems leading to a disruption of adaptive responses in the processing of social reward. The specific association of reward-related regions with clinical and psychometric measures suggests the putative involvement of reward structures in the maintenance of pathological behaviors in AN.
26196954	The orienting attention network is responsible for prioritizing sensory input through overt or covert shifts of attention among targets. The ability to disengage attention is essential for the proper functioning of this network. In addition to its importance for proper orienting, deficits in disengagement have been recently implicated in autism disorders. Despite its importance, the neural mechanisms underlying disengagement processing are still poorly understood. In this study, the involvement of the superior colliculus (SC) in disengagement was investigated in unrestrained rats that had been trained in a two-alternative light-guided spatial choice task. At each trial, the rats had to choose one of two paths, leading either to a large or a small reward, based on 1 (single-cue) or 2 (double-cue) lights. The task consisted of serial trials with single- and/or double-cue lights, and rats could acquire a large reward if the rats chose infrequent lights when infrequent cue lights were presented after preceding frequent cue lights. Experiment 1 included trials with either single- or double-cue lights, and infrequent trials with double-cue lights required both attentional disengagement and shift of attention from preceding frequent single-cue lights, while experiment 2 included only trials with single-cue lights requiring shifts of attention but not attentional disengagement. The results indicated that temporary inactivation of the SC by muscimol injections selectively impaired performance on trials requiring disengagement. No impairment was observed on the other trials, in which attention disengagement was not required. The results provide the first evidence that the SC is necessary for attentional disengagement. 
26196899	Although mental fatigue is a complex, multi-facetted state that involves changes in motivation, cognition, and mood, one of its main characteristics is reduced task engagement. Despite its relevance for performance and safety, knowledge about the underlying neurocognitive processes in mental fatigue is still limited. Inspired by the idea that central norepinephrine plays an important role in regulating task engagement, we test a set of predictions that have been derived from recent studies that relate pupil dynamics to the levels of norepinephrine in the brain. Participants worked on a 2-back task for 2h while we used pupil measures to further explore the link between task engagement and the effects of mental fatigue. We hypothesized that baseline pupil diameter and stimulus-evoked pupil dilations decrease with increasing fatigue. Also, because previous studies have shown that the effects of fatigue are reversible by increasing the task rewards, we hypothesized that increasing the task rewards after 2h on the task would restore these pupil measures to pre-fatigue levels. While we did not find a decrease in baseline pupil diameter, we found that increasing mental fatigue coincided with diminished stimulus-evoked pupil dilation. Also, we confirmed that when sufficient rewards were presented to a fatigued individual, the pupil dilations could be restored. This supports the view that motivational factors are important in predicting engagement versus disengagement during fatigue. 
26196667	Models of reinforcement learning represent reward and punishment in terms of reward prediction errors (RPEs), quantitative signed terms describing the degree to which outcomes are better than expected (positive RPEs) or worse (negative RPEs). An electrophysiological component known as feedback related negativity (FRN) occurs at frontocentral sites 240-340ms after feedback on whether a reward or punishment is obtained, and has been claimed to neurally encode an RPE. An outstanding question however, is whether the FRN is sensitive to the size of both positive RPEs and negative RPEs. Previous attempts to answer this question have examined the simple effects of RPE size for positive RPEs and negative RPEs separately. However, this methodology can be compromised by overlap from components coding for unsigned prediction error size, or "salience", which are sensitive to the absolute size of a prediction error but not its valence. In our study, positive and negative RPEs were parametrically modulated using both reward likelihood and magnitude, with principal components analysis used to separate out overlying components. This revealed a single RPE encoding component responsive to the size of positive RPEs, peaking at ~330ms, and occupying the delta frequency band. Other components responsive to unsigned prediction error size were shown, but no component sensitive to negative RPE size was found.
26194891	Amotivation and reward-processing deficits have long been described in patients with schizophrenia and considered large contributors to patients' inability to integrate well in society. No effective treatments exist for these symptoms, partly because the neuromechanisms mediating such symptoms are poorly understood. Here, we propose a translational neuroscientific approach that can be used to assess reward/motivational deficits related to the negative symptoms of schizophrenia using behavioral paradigms that can also be conducted in experimental animals. By designing and using objective laboratory behavioral tools that are parallel in their parameters in rodents and humans, the neuromechanisms underlying behaviors with relevance to these symptoms of schizophrenia can be investigated. We describe tasks that measure the motivation of rodents to expend physical and cognitive effort to gain rewards, as well as probabilistic learning tasks that assess both reward learning and feedback-based decision making. The latter tasks are relevant because of demonstrated links of performance deficits correlating with negative symptoms in patients with schizophrenia. These tasks utilize operant techniques in order to investigate neural circuits targeting a specific domain across species. These tasks therefore enable the development of insights into altered mechanisms leading to negative symptom-relevant behaviors in patients with schizophrenia. Such findings will then enable the development of targeted treatments for these altered neuromechanisms and behaviors seen in schizophrenia. 
26192817	Anhedonia, the loss of interest or pleasure in reward processing, is a hallmark feature of major depressive disorder (MDD), but its underlying neurobiological mechanism is largely unknown. The present study aimed to examine the underlying neural mechanism of reward-related decision-making in patients with MDD.We examined behavioral and neural responses to rewards in patients with first-episode MDD (N=25) and healthy controls (N=25) using the Effort-Expenditure for Rewards Task (EEfRT). The task involved choices about possible rewards of varying magnitude and probability. We tested the hypothesis that individuals with MDD would exhibit a reduced neural response in reward-related brain structures involved in cost-benefit decision-making.	Compared with healthy controls, patients with MDD showed significantly weaker responses in the left caudate nucleus when contrasting the 'high reward'-'low reward' condition, and blunted responses in the left superior temporal gyrus and the right caudate nucleus when contrasting high and low probabilities. In addition, hard tasks chosen during high probability trials were negatively correlated with superior temporal gyrus activity in MDD patients, while the same choices were negatively correlated with caudate nucleus activity in healthy controls.	These results indicate that reduced caudate nucleus and superior temporal gyrus activation may underpin abnormal cost-benefit decision-making in MDD.	
26192710	The reward comparison hypothesis suggests that drugs of abuse-induced conditioned saccharin suppression intake is due to the reward value of drugs of abuse that outweighs that of a saccharin solution dissociating from the aversive LiCl-induced conditioned taste aversion (CTA). Huang and Hsiao (2008) provided some conflict data to challenge the reward comparison hypothesis. Whether the rewarding drugs of abuse-induced conditioned suppression and the aversive LiCl-induced CTA resulted from aversion or reward should be addressed. The present study investigated how gender and footshock affect aversive LiCl- and rewarding morphine- and methamphetamine (MAMPH)-induced conditioned suppression to re-examine the reward comparison hypothesis. The results indicated that gender and footshock did not directly influence the aversive LiCl-induced CTA or rewarding morphine- and MAMPH-induced conditioned suppression. The gender effect interacted with the drug effect in the aversive LiCl- and rewarding MAMPH-induced conditioned suppression but did not interact with the drug effect in the rewarding morphine-induced conditioned suppression. Footshock interacted with the drug effect in rewarding morphine- and MAMPH-induced conditioned suppression, but footshock did not interact with the drug effect in the aversive LiCl-induced CTA. Therefore, the gender and footshock effects might play a modulatory (but not a mediating) role with the drug effect. The present data indicated that footshock modulates drugs of abuse-induced conditioned suppression, which is consistent with the reward comparison hypothesis, but our findings with regard to the modulatory role of the gender effect and the drug effect do not support this hypothesis. The reward comparison hypothesis should be discussed and possibly reconsidered. 
26192187	Animal research finds that insulin regulates dopamine signaling and reward behavior, but similar research in humans is lacking. We investigated whether individual differences in body mass index, percent body fat, pancreatic β-cell function, and dopamine D2 receptor binding were related to reward discounting in obese and non-obese adult men and women. Obese (n = 27; body mass index>30) and non-obese (n = 20; body mass index<30) adults were assessed for percent body fat with dual-energy X-ray absorptiometry and for β-cell function using disposition index. Choice of larger, but delayed or less certain, monetary rewards relative to immediate, certain smaller monetary rewards was measured using delayed and probabilistic reward discounting tasks. Positron emission tomography using a non-displaceable D2-specific radioligand, [11C](N-methyl)benperidol quantified striatal D2 receptor binding. Groups differed in body mass index, percent body fat, and disposition index, but not in striatal D2 receptor specific binding or reward discounting. Higher percent body fat in non-obese women related to preference for a smaller, certain reward over a larger, less likely one (greater probabilistic discounting). Lower β-cell function in the total sample and lower insulin sensitivity in obese related to stronger preference for an immediate and smaller monetary reward over delayed receipt of a larger one (greater delay discounting). In obese adults, higher striatal D2 receptor binding related to greater delay discounting. Interestingly, striatal D2 receptor binding was not significantly related to body mass index, percent body fat, or β-cell function in either group. Our findings indicate that individual differences in percent body fat, β-cell function, and striatal D2 receptor binding may each contribute to altered reward discounting behavior in non-obese and obese individuals. These results raise interesting questions about whether and how striatal D2 receptor binding and metabolic factors, including β-cell function, interact to affect reward discounting in humans. 
26191947	A recent study demonstrated that a single 50-min supplemental session that targeted the behavioral economic mechanisms of substance-free reinforcement and delayed reward discounting (Substance-Free Activity Session: SFAS) enhanced the efficacy of a standard alcohol brief motivational intervention (BMI) for college drinkers. The purpose of the current study was to conduct a randomized controlled trial intended to replicate and extend the aforementioned study by focusing on both drug and alcohol misuse and reducing session length in order to enhance dissemination potential. Participants were 97 college students (58.8% women; 59.8% White/Caucasian, and 30.9% African American; M age = 20.01, SD = 2.23) who reported at least 1 heavy drinking episode in the past month (M = 4.01 episodes). Most participants (62%) reported recent marijuana use (M = 12.22 days of past-month use). After completing a baseline assessment and an individual 30-min alcohol-focused BMI, participants were randomized to either the 30-min SFAS session or an education control session. A series of mixed model intent-to-treat analyses revealed that both groups reported drinking reductions and that participants in the BMI + SFAS group reported fewer days using marijuana at the 6-month follow-up. These results do not support the incremental efficacy of the briefer SFAS for reducing drinking but suggest that it may improve marijuana outcomes. Future research is needed to identify the ideal length and timing of the SFAS supplement to BMIs.
26191637	Bulimia nervosa (BN) is a serious eating disorder that can persist for years and contribute to medical complications and increased mortality, underscoring the need to better understand factors maintaining this disorder. Higher levels of weight suppression (WS) have been found to predict both the onset and maintenance of BN; however, no studies have examined mechanisms that may account for the effects of WS on BN. We hypothesized that high WS would lead to reduced leptin levels, which may increase risk of binge eating by modulating reward responses to food. The current study examined the relationship between WS, leptin levels, and the reinforcing value of food in women with BN (n = 32) and noneating disorder controls (n = 30). Participants provided information on WS, completed a fasting blood draw to obtain serum leptin, and completed a progressive ratio task to measure the reinforcing value of food. Individuals with BN had greater WS (p < .01) and reinforcing food value (p < .05) compared with controls. Additionally, higher WS was associated with both lower leptin (p < .05) and increased reinforcing value of food (p < .05). Contrary to hypotheses, BN and control participants did not differ on leptin levels, and leptin levels were not significantly associated with the reinforcing value of food. Findings support that efforts to conform to the thin ideal may alter drive to consume rewarding foods and leave women vulnerable to binge episodes. However, mechanisms through which WS contributes to food reward and binge eating remain unknown.
26190995	Neurofeedback training of Motor imagery (MI)-related brain-states with brain-computer/brain-machine interfaces (BCI/BMI) is currently being explored as an experimental intervention prior to standard physiotherapy to improve the motor outcome of stroke rehabilitation. The use of BCI/BMI technology increases the adherence to MI training more efficiently than interventions with sham or no feedback. Moreover, pilot studies suggest that such a priming intervention before physiotherapy might-like some brain stimulation techniques-increase the responsiveness of the brain to the subsequent physiotherapy, thereby improving the general clinical outcome. However, there is little evidence up to now that these BCI/BMI-based interventions have achieved operate conditioning of specific brain states that facilitate task-specific functional gains beyond the practice of primed physiotherapy. In this context, we argue that BCI/BMI technology provides a valuable neurofeedback tool for rehabilitation but needs to aim at physiological features relevant for the targeted behavioral gain. Moreover, this therapeutic intervention has to be informed by concepts of reinforcement learning to develop its full potential. Such a refined neurofeedback approach would need to address the following issues: (1) Defining a physiological feedback target specific to the intended behavioral gain, e.g., β-band oscillations for cortico-muscular communication. This targeted brain state could well be different from the brain state optimal for the neurofeedback task, e.g., α-band oscillations for differentiating MI from rest; (2) Selecting a BCI/BMI classification and thresholding approach on the basis of learning principles, i.e., balancing challenge and reward of the neurofeedback task instead of maximizing the classification accuracy of the difficulty level device; and (3) Adjusting the difficulty level in the course of the training period to account for the cognitive load and the learning experience of the participant. Here, we propose a comprehensive neurofeedback strategy for motor restoration after stroke that addresses these aspects, and provide evidence for the feasibility of the suggested approach by demonstrating that dynamic threshold adaptation based on reinforcement learning may lead to frequency-specific operant conditioning of β-band oscillations paralleled by task-specific motor improvement; a proposal that requires investigation in a larger cohort of stroke patients. 
26190983	Whether the opioid system plays a role in the ability to flexibly adapt behavior is still unclear. We used fMRI to investigate the effect of a nucleotide tandem repeat (68-bp VNTR) functional polymorphism of the prodynorphin (PDYN) gene on cerebral activation during a reversal learning task in which participants had to flexibly adapt stimulus-response associations. Past studies suggested that alleles with 3 or 4 repeats (HH genotype) of this polymorphism are associated with higher levels of dynorphin peptides than alleles with 1 or 2 repeats (LL genotype). On the behavioral level, the HH group made more perseverative errors than the LL group. On the neural level, the HH group demonstrated less engagement of left orbitofrontal cortex (lOFC) and cortico-striatal circuitry, and lower effective connectivity of lOFC with anterior midcingulate cortex and anterior insula/ventrolateral prefrontal cortex during reversal learning and processing negative feedback. This points to a lower ability of the HH genotype to monitor or adapt to changes in reward contingencies. These findings provide first evidence that dynorphins may contribute to individual differences in reversal learning, and that considering the opioid system may shed new light on the neurochemical correlates of decision-making and behavioral regulation. 
26190979	The hippocampus is an important structure for learning and memory processes, and has strong rhythmic activity. Although a large amount of research has been dedicated toward understanding the rhythmic activity in the hippocampus during exploratory behaviors, specifically in the theta (5-10 Hz) frequency range, few studies have examined the temporal interplay of theta and other frequencies during the presentation of meaningful cues. We obtained in vivo electrophysiological recordings of local field potentials (LFP) in the dentate gyrus (DG) of the hippocampus as rats performed three different associative learning tasks. In each task, cue presentations elicited pronounced decrements in theta amplitude in conjunction with increases in beta (15-30 Hz) amplitude. These changes were often transient but were sustained from the onset of cue encounters until the occurrence of a reward outcome. This oscillatory profile shifted in time to precede cue encounters over the course of the session, and was not present during similar behaviors in the absence of task relevant stimuli. The observed decreases in theta amplitude and increases in beta amplitude in the DG may thus reflect a shift in processing state that occurs when encountering meaningful cues. 
26190832	The mechanisms for pattern completion and pattern separation are described in the context of a theory of hippocampal function in which the hippocampal CA3 system operates as a single attractor or autoassociation network to enable rapid, one-trial, associations between any spatial location (place in rodents, or spatial view in primates) and an object or reward, and to provide for completion of the whole memory during recall from any part. The factors important in the pattern completion in CA3 and also a large number of independent memories stored in CA3 include: a sparse distributed representation, representations that are independent due to the randomizing effect of the mossy fibres, heterosynaptic long-term depression as well as long-term potentiation in the recurrent collateral synapses, and diluted connectivity to minimize the number of multiple synapses between any pair of CA3 neurons which otherwise distort the basins of attraction. Recall of information from CA3 is implemented by the entorhinal cortex perforant path synapses to CA3 cells, which in acting as a pattern associator allow some pattern generalization. Pattern separation is performed in the dentate granule cells using competitive learning to convert grid-like entorhinal cortex firing to place-like fields, and in the dentate to CA3 connections that have diluted connectivity. Recall to the neocortex is achieved by a reverse hierarchical series of pattern association networks implemented by the hippocampo-cortical backprojections, each one of which performs some pattern generalization, to retrieve a complete pattern of cortical firing in higher-order cortical areas. New results on competitive networks show which factors contribute to their ability to perform pattern separation, pattern clustering, and pattern categorisation, and how these apply in different hippocampal and neocortical systems. 
26190276	Due to ongoing development, adolescence may be a period of heightened vulnerability to the neurotoxic effects of alcohol. Binge drinking may alter reward-driven behavior and neurocircuitry, thereby increasing risk for escalating alcohol use. Therefore, we compared reward processing in adolescents with and without a history of recent binge drinking. At their baseline study visit, all participants (age=14.86 ± 0.88) were free of heavy alcohol use and completed a modified version of the Wheel of Fortune (WOF) functional magnetic resonance imaging task. Following this visit, 17 youth reported binge drinking on ≥3 occasions within a 90 day period and were matched to 17 youth who remained alcohol and substance-naïve. All participants repeated the WOF task during a second visit (age=16.83 ± 1.22). No significant effects were found in a region of interest analysis of the ventral striatum, but whole-brain analyses showed significant group differences in reward response at the second study visit in the left cerebellum, controlling for baseline visit brain activity (p/α<0.05), which was negatively correlated with mean number of drinks consumed/drinking day in the last 90 days. These findings suggest that binge drinking during adolescence may alter brain activity during reward processing in a dose-dependent manner.
26189112	Until now, Machiavellianism has mainly been studied in personality and social psychological framework, and little attention has been paid to the underlying cognitive and neural equipment. In light of recent findings, Machiavellian social skills are not limited to emotion regulation and "cold-mindedness" as many authors have recently stated, but linked to specific cognitive abilities. Although Machiavellians appear to have a relatively poor mindreading ability and emotional intelligence, they can efficiently exploit others which is likely to come from their flexible problem solving processes in changing environmental circumstances. The author proposed that Machiavellians have specialized cognitive domains of decision making, such as monitoring others' behavior, task orientation, reward seeking, inhibition of cooperative feelings, and choosing victims. He related the relevant aspects of cognitive functions to their neurological substrates, and argued why they make Machiavellians so successful in interpersonal relationships. 

26188262	Reward availability is known to facilitate various cognitive operations, which is usually studied in cue-based paradigms that allow for enhanced preparation in reward-related trials. However, recent research using tasks that signal reward availability via task-relevant stimuli suggests that reward can also rapidly promote performance independent of global strategic preparation. Notably, this effect was also observed in a reward-related stop-signal task, in which behavioral measures of inhibition speed were found to be shorter in trials signaling reward. Corresponding fMRI results implied that this effect relies on boosted reactive control as indicated by increased activity in the 'inhibition-related network' in the reward-related condition. Here, we used EEG to better characterize transient modulations of attentional processes likely preceding this ultimate implementation of response inhibition. Importantly, such modulations would probably reflect enhanced proactive control in the form of more top-down attention to reward-related features. Counter to the notion that behavioral benefits would rely purely on reactive control, we found increased stop-evoked attentional processing (larger N1 component) on reward-related trials. This effect was accompanied by enhanced frontal P3 amplitudes reflecting successful stopping, and earlier and larger ERP differences between successful and failed stop trials in the reward-related condition. Finally, more global proactive control processes in the form of a reward context modulation of reward-unrelated trials did not have an effect on stopping performance but did influence attentional processing of go stimuli. Together, these results suggest that proactive and reactive processes can interact to bring about stimulus-specific reward benefits when the task precludes differential global preparation. 
26188154	Psychopathy has been associated with behavioral adaptation deficits, which might be associated with problems in feedback and reward processing. In the present study, we examined the relation between psychopathic traits and reward processing in a passive gambling task. A total of 39 male participants who scored high (HP) and 39 male participants who scored low (LP) on the Triarchic Psychopathy Measure (TriPM), total score were tested. Feedback-related Event-Related Potentials (ERPs; i.e., P2, FRN, and P3) on predicted and unpredicted rewards and reward omissions were compared between both groups. It was found that in HP individuals, the P2 was enhanced for predicted rewards and reward omissions, but not for unpredicted stimuli. Moreover, HP individuals as compared to the LP individuals demonstrated a generally reduced P3 amplitude. The FRN amplitude, however, did not differ between the two groups. In addition, HP individuals showed enhanced reward sensitivity on the self-report level. Taken together, these findings suggest that HP individuals show enhanced sensitivity to early and reduced sensitivity to later markers of processing reinforcement learning signals, which points in the direction of compromised behavioral adaptation. 
26187757	Drug addiction and reward learning both involve mechanisms in which reinforcing neuromodulators participate in changing synaptic strength. For example, dopamine receptor activation modulates corticostriatal plasticity through a mechanism involving the induction of the immediate early gene Homer 1a, the phosphorylation of metabotropic glutamate receptor 5 (mGluR5)'s Homer ligand, and the enhancement of an NMDA receptor-dependent current. Inspired by hypotheses that Homer 1a functions selectively in recently-active synapses, we propose that Homer 1a is recruited by a synaptic tag to functionally discriminate between synapses that predict reward and those that do not. The involvement of Homer 1a in this mechanism further suggests that decaminutes-old firing patterns can define which synapses encode new information.
26187394	Adolescence marks a critical time when the brain is highly susceptible to pathological insult yet also uniquely amenable to therapeutic intervention. It is during adolescence that the onset of the majority of psychiatric disorders, including substance use disorder (SUDs), occurs. It has been well established that stress, particularly during early development, can contribute to the pathological changes which contribute to the development of SUDs. Glutamate as the main excitatory neurotransmitter in the mammalian CNS plays a key role in various physiological processes, including reward function, and in mediating the effects of psychological stress. We hypothesised impairing glutamatergic signalling during the key adolescent period would attenuate early-life stress induced impaired reward function. To test this, we induced early-life stress in male rats using the maternal-separation procedure. During the critical adolescent period (PND25-46) animals were treated with the glutamate transporter activator, riluzole, or the NMDA receptor antagonist, memantine. Adult reward function was assessed using voluntary cocaine intake measured via intravenous self-administration. We found that early-life stress in the form of maternal-separation impaired reward function, reducing the number of successful cocaine-infusions achieved during the intravenous self-administration procedure as well impairing drug-induced reinstatement of cocaine-taking behaviour. Interestingly, riluzole and memantine treatment reversed this stress-induced impairment. These data suggest that reducing glutamatergic signalling may be a viable therapeutic strategy for treating vulnerable individuals at risk of developing SUDs including certain adolescent populations, particularly those which may have experienced trauma during early-life. 
26187003	The combination of alcohol with an energy drink (ED) is believed to contribute to risky alcohol-drinking behaviors, such as binge drinking. However, the long-term effects on cognition and reward function that are caused by the repeated binge-like ingestion of alcohol and EDs are still poorly known. The present study examined the effects of a history of repeated exposure to alcohol and/or an ED on short-term memory and alcohol-seeking behavior. Male Wistar rats were given daily intragastric administration of alcohol (3.4g/kg) combined or not with an ED (10.71ml/kg) for 6 consecutive days. The rats were tested for locomotion 15min after the first intragastric treatment. Short-term memory was assessed in the novel object recognition and social discrimination tests 2-3days after the last intragastric administration. The rewarding effect of alcohol was tested 1-3weeks following the last intragastric administration in a conditioned place preference paradigm. The acute binge-like ingestion of alcohol decreased locomotor activity, whereas the combination of alcohol and an ED increased locomotion in the first minutes of assessment. Alcohol exposure produced cognitive deficits in both the object recognition and social discrimination tests, and adding the ED to the alcohol solution did not modify these effects. The combination of alcohol and the ED increased alcohol-induced conditioned place preference. Thus, a history of binge-like alcohol exposure combined with the ED caused subsequent cognitive deficits and increased alcohol seeking behavior, and such behavioral effects might contribute to the progression to alcohol abuse disorders. 
26185892	Anhedonia is one of the core negative symptoms of schizophrenia that affect the ultimate outcome of this disorder. It is unclear whether the motivational or the hedonic component of anhedonia is impaired in patients with schizophrenia. This study examined the deficits in motivation and hedonic capacity in patients with schizophrenia using an Effort-based pleasure experience task (E-pet). Twenty-two schizophrenia patients with prominent negative symptoms, 18 schizophrenia patients without prominent negative symptoms and 29 healthy controls participated in the present study. All of them were administered the E-pet task, which required the participants to make decisions on whether to choose a hard or easy task based on probability and reward magnitude. When making the grip effort allocation decision, schizophrenia patients with prominent negative symptoms were significantly less likely to choose a hard task than healthy controls. As the reward magnitude and the estimated reward value increased, unlike healthy controls, schizophrenia patients with prominent negative symptoms did not increase their hard task choices. They were also significantly less likely to choose a hard task than healthy controls in medium and high probability conditions. When anticipating potential rewards, these patients reported significantly less anticipatory pleasure than healthy controls, even when reward probability and magnitude increased. The pleasure experience rating after obtaining the actual reward was positively correlated with two pleasure experience scales in schizophrenia patients. In conclusion, patients with schizophrenia, especially those with prominent negative symptoms, showed deficits in both reward motivation and anticipatory pleasure experience. 
26183698	Anhedonia, disrupted reward processing, is a core symptom of major depressive disorder. Recent findings demonstrate altered reward-related ventral striatal reactivity in depressed individuals, but the extent to which this is specific to anhedonia remains poorly understood. The authors examined the effect of anhedonia on reward expectancy (expected outcome value) and prediction error- (discrepancy between expected and actual outcome) related ventral striatal reactivity, as well as the relationship between these measures.A total of 148 unmedicated individuals with major depressive disorder and 31 healthy comparison individuals recruited for the multisite EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study underwent functional MRI during a well-validated reward task. Region of interest and whole-brain data were examined in the first- (N=78) and second- (N=70) recruited cohorts, as well as the total sample, of depressed individuals, and in healthy individuals.	Healthy, but not depressed, individuals showed a significant inverse relationship between reward expectancy and prediction error-related right ventral striatal reactivity. Across all participants, and in depressed individuals only, greater anhedonia severity was associated with a reduced reward expectancy-prediction error inverse relationship, even after controlling for other symptoms.	The normal reward expectancy and prediction error-related ventral striatal reactivity inverse relationship concords with conditioning models, predicting a shift in ventral striatal responding from reward outcomes to reward cues. This study shows, for the first time, an absence of this relationship in two cohorts of unmedicated depressed individuals and a moderation of this relationship by anhedonia, suggesting reduced reward-contingency learning with greater anhedonia. These findings help elucidate neural mechanisms of anhedonia, as a step toward identifying potential biosignatures of treatment response.	
26183405	The rewarding value of palatable foods contributes to overconsumption, even in satiated subjects. Midbrain dopaminergic activity in response to reward-predicting environmental stimuli drives reward-seeking and motivated behavior for food rewards. This mesolimbic dopamine (DA) system is sensitive to changes in energy balance, yet it has thus far not been established whether reward signaling of DA neurons in vivo is under control of hormones that signal appetite and energy balance such as ghrelin and leptin.We trained rats (n=11) on an operant task in which they could earn two different food rewards. We then implanted recording electrodes in the ventral tegmental area (VTA), and recorded from DA neurons during behavior. Subsequently, we assessed the effects of mild food restriction and pretreatment with the adipose tissue-derived anorexigenic hormone leptin or the orexigenic hormone ghrelin on VTA DA reward signaling.	Animals showed an increase in performance following mild food restriction (P=0.002). Importantly, food-cue induced DA firing increased when animals were food restricted (P=0.02), but was significantly attenuated after leptin pretreatment (P=0.00). While ghrelin did affect baseline DA activity (P=0.025), it did not affect cue-induced firing (P⩾0.353).	Metabolic signals, such as leptin, affect food seeking, a process that is dependent on the formation of cue-reward outcomes and involves midbrain DA signaling. These data show that food restriction engages the encoding of food cues by VTA DA neurons at a millisecond level and leptin suppresses this activity. This suggests that leptin is a key in linking metabolic information to reward signaling.	
26183338	Intensive rehabilitation interventions have been shown to be efficacious in improving upper extremity function in children with unilateral spastic cerebral palsy (USCP). These interventions are based on motor learning principles and engage children in skillful movements. Improvements in upper extremity function are believed to be associated with neuroplastic changes. However, these neuroplastic changes have not been well-described in children with cerebral palsy, likely due to challenges in defining and implementing the optimal tools and tests in children. Here we documented the implementation of three different neurological assessments (diffusion tensor imaging-DTI, transcranial magnetic stimulation-TMS and functional magnetic resonance imaging-fMRI) before and after a bimanual intensive treatment (HABIT-ILE) in two children with USCP presenting differential corticospinal developmental reorganization (ipsilateral and contralateral). The aim of the study was to capture neurophysiological changes and to document the complementary relationship between these measures, the potential measurable changes and the feasibility of applying these techniques in children with USCP. Independent of cortical reorganization, both children showed increases in activation and size of the motor areas controlling the affected hand, quantified with different techniques. In addition, fMRI provided additional unexpected changes in the reward circuit while using the affected hand.
26183088	Varazzani and colleagues explored how noradrenergic and dopaminergic neural activity relates to cost/benefit decisions involving effort. They show these systems may play complementary roles in resolving these decisions; dopamine encodes cost-discounted values of rewards, whereas noradrenergic cells modify activity in relation to the amount of effort required to obtain them. 
26182424	We propose a neurocomputational model of altruistic choice and test it using behavioral and fMRI data from a task in which subjects make choices between real monetary prizes for themselves and another. We show that a multi-attribute drift-diffusion model, in which choice results from accumulation of a relative value signal that linearly weights payoffs for self and other, captures key patterns of choice, reaction time, and neural response in ventral striatum, temporoparietal junction, and ventromedial prefrontal cortex. The model generates several novel insights into the nature of altruism. It explains when and why generous choices are slower or faster than selfish choices, and why they produce greater response in TPJ and vmPFC, without invoking competition between automatic and deliberative processes or reward value for generosity. It also predicts that when one's own payoffs are valued more than others', some generous acts may reflect mistakes rather than genuinely pro-social preferences.
26181801	Serious games may be effective in promoting sexual health behavior. Their confidential nature may encourage users to discuss sensitive sexuality topics. Furthermore, they can tailor messages to the individual's needs and may be intrinsically motivating. This meta-analysis investigates the effectiveness of interventions for sexual health promotion that use serious games.A database search was conducted in PubMed, Web of Science, CINAHL, and PsycINFO for publications before the end of July 2013. Serious digital games studies measuring effects on behavior or its determinants, using a control condition, allowing the calculation of an effect size (Hedges' g, random-effects model) were included.	Seven game studies for sexual health promotion were included. These showed positive effects on determinants (g=0.242; 95 percent confidence interval, 0.129, 0.356), albeit of small effect size. The effects on behavior, measured in only two studies, were not significant (g=0.456; 95 percent confidence interval, -0.649, 1.561). Most games did not use many game features that are considered to be immersive or enhancing flow. Instead, there was a strong reliance on pure gamification features, such as rewards and feedback.	The effectiveness of the next generation of games may be enhanced by building on the behavioral change and educational gaming literatures (e.g., using role-play and simulation game formats, individual tailoring, offering adaptation in the difficulty of the challenge, and amount and timing of the feedback). There is a need for studies with rigorous evaluations of game effectiveness, longer-term follow-up, and using measures of behavior rather than merely their determinants.	
26181675	This article reviews theoretical and empirical evidence related to three mechanisms for encouraging enjoyment during exergame play: Feedback, challenge, and rewards.A literature search and narrative review were conducted.	Feedback is found in nearly all exergames, and richer, more in-depth feedback is associated with increased activity. Challenge is a vital component of any videogame, and exergames include physical as well as cognitive challenges. Flow states have traditionally been conceptualized as occurring when an optimal match between player skills and game challenge occurs. However, failure and retrial are necessary for feelings of overall satisfaction and fun, despite not necessarily being ideally fun or satisfying themselves. Rewards are a more complicated issue, with significant theoretical and empirical evidence suggesting positive and negative effects of reward systems. How rewards are integrated into the mechanics and storyline of the game likely impacts how they are perceived and, thus, their effectiveness. Finally, integration of these mechanisms into exergames requires specific attention to both cognitive and physical implementations. Movements that are not themselves enjoyable or engaging may lead to cheating and lower energy expenditure.	Feedback, challenge, and rewards are promising mechanisms by which exergames could become more enjoyable. How these concepts are operationalized can affect physical and psychological reactions to exergames. Attention to these concepts in future exergame development and implementation would benefit theory, research, and practice.	
26180206	Because no large prospective study has investigated neural vulnerability factors that predict future weight gain, we tested whether neural response to receipt and anticipated receipt of palatable food and monetary reward predicted body fat gain over a 3-year follow-up in healthy-weight adolescent humans and whether the TaqIA polymorphism moderates these relations. A total of 153 adolescents completed fMRI paradigms assessing response to these events; body fat was assessed annually over follow-up. Elevated orbitofrontal cortex response to cues signaling impending milkshake receipt predicted future body fat gain (r = 0.32), which is a novel finding that provides support for the incentive sensitization theory of obesity. Neural response to receipt and anticipated receipt of monetary reward did not predict body fat gain, which has not been tested previously. Replicating an earlier finding (Stice et al., 2008a), elevated caudate response to milkshake receipt predicted body fat gain for adolescents with a genetic propensity for greater dopamine signaling by virtue of possessing the TaqIA A2/A2 allele, but lower caudate response predicted body fat gain for adolescents with a genetic propensity for less dopamine signaling by virtue of possessing a TaqIA A1 allele, though this interaction was only marginal [p-value <0.05 corrected using voxel-level familywise error rate (pFWE) = 0.06]. Parental obesity, which correlated with TaqIA allele status (odds ratio = 2.7), similarly moderated the relation of caudate response to milkshake receipt to future body fat gain, which is another novel finding. The former interaction implies that too much or too little dopamine signaling and reward region responsivity increases risk for overeating, suggesting qualitatively distinct reward surfeit and reward deficit pathways to obesity.Because no large prospective study has investigated neural vulnerability factors that predict future weight gain we tested whether neural response to receipt and anticipated receipt of palatable food and monetary reward predicted body fat gain over 3-year follow-up in healthy-weight adolescent humans and whether the TaqIA polymorphism moderates these relations. Elevated reward activation in response to food cues predicted future body fat gain. Elevated reward response to food receipt predicted body fat gain for adolescents with a TaqIA A2/A2 allele and lower reward response predicted body fat gain for those with a TaqIA A1 allele. Results imply that too much or too little dopamine signaling and reward region responsivity increases risk for overeating.	
26180188	The striatum is known to play a key role in reinforcement learning, specifically in the encoding of teaching signals such as reward prediction errors (RPEs). It has been proposed that aberrant salience attribution is associated with impaired coding of RPE and heightened dopamine turnover in the striatum, and might be linked to the development of psychotic symptoms. However, the relationship of aberrant salience attribution, RPE coding, and dopamine synthesis capacity has not been directly investigated. Here we assessed the association between a behavioral measure of aberrant salience attribution, the salience attribution test, to neural correlates of RPEs measured via functional magnetic resonance imaging while healthy participants (n = 58) performed an instrumental learning task. A subset of participants (n = 27) also underwent positron emission tomography with the radiotracer [(18)F]fluoro-l-DOPA to quantify striatal presynaptic dopamine synthesis capacity. Individual variability in aberrant salience measures related negatively to ventral striatal and prefrontal RPE signals and in an exploratory analysis was found to be positively associated with ventral striatal presynaptic dopamine levels. These data provide the first evidence for a specific link between the constructs of aberrant salience attribution, reduced RPE processing, and potentially increased presynaptic dopamine function. 
26180123	Effective error-driven learning requires individuals to adapt learning to environmental reward variability. The adaptive mechanism may involve decays in learning rate across subsequent trials, as shown previously, and rescaling of reward prediction errors. The present study investigated the influence of prediction error scaling and, in particular, the consequences for learning performance. Participants explicitly predicted reward magnitudes that were drawn from different probability distributions with specific standard deviations. By fitting the data with reinforcement learning models, we found scaling of prediction errors, in addition to the learning rate decay shown previously. Importantly, the prediction error scaling was closely related to learning performance, defined as accuracy in predicting the mean of reward distributions, across individual participants. In addition, participants who scaled prediction errors relative to standard deviation also presented with more similar performance for different standard deviations, indicating that increases in standard deviation did not substantially decrease "adapters'" accuracy in predicting the means of reward distributions. However, exaggerated scaling beyond the standard deviation resulted in impaired performance. Thus efficient adaptation makes learning more robust to changing variability. 
26180121	Chronic stress is thought to impart risk for depression via alterations in brain structure and function, but contributions of specific mediators in generating these changes remain unclear. We test the hypothesis that stress-induced increases in corticosterone (CORT), the primary rodent glucocorticoid, are the key mediator of stress-induced depressive-like behavioral changes and synaptic dysfunction in the rat hippocampus. In rats, we correlated changes in cognitive and affective behavioral tasks (spatial memory consolidation, anhedonia, and neohypophagia) with impaired excitatory strength at temporoammonic-CA1 (TA-CA1) synapses, an archetypical stress-sensitive excitatory synapse. We tested whether elevated CORT was sufficient and necessary to generate a depressive-like behavioral phenotype and decreased excitatory signaling observed at TA-CA1 after chronic unpredictable stress (CUS). Chronic CORT administration induced an anhedonia-like behavioral state and neohypophagic behavior. Like CUS, chronic, but not acute, CORT generated an impaired synaptic phenotype characterized by reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptor-mediated excitation at TA-CA1 synapses, decreased AMPA-type glutamate receptor subunit 1 protein expression, and altered serotonin-1B receptor-mediated potentiation. Repeatedly blunting stress-induced increases of CORT during CUS with the CORT synthesis inhibitor metyrapone (MET) prevented these stress-induced neurobehavioral changes. MET also prevented the CUS-induced impairment of spatial memory consolidation. We conclude that corticosterone is sufficient and necessary to mediate glutamatergic dysfunction underlying stress-induced synaptic and behavioral phenotypes. Our results indicate that chronic excessive glucocorticoids cause specific synaptic deficits in the hippocampus, a major center for cognitive and emotional processing, that accompany stress-induced behavioral dysfunction. Maintaining excitatory strength at stress-sensitive synapses at key loci throughout corticomesolimbic reward circuitry appears critical for maintaining normal cognitive and emotional behavior. 
26180069	The competition for resources among cells, individuals or species is a fundamental characteristic of evolution. Biological all-pay auctions have been used to model situations where multiple individuals compete for a single resource. However, in many situations multiple resources with various values exist and single reward auctions are not applicable. We generalize the model to multiple rewards and study the evolution of strategies. In biological all-pay auctions the bid of an individual corresponds to its strategy and is equivalent to its payment in the auction. The decreasingly ordered rewards are distributed according to the decreasingly ordered bids of the participating individuals. The reproductive success of an individual is proportional to its fitness given by the sum of the rewards won minus its payments. Hence, successful bidding strategies spread in the population. We find that the results for the multiple reward case are very different from the single reward case. While the mixed strategy equilibrium in the single reward case with more than two players consists of mostly low-bidding individuals, we show that the equilibrium can convert to many high-bidding individuals and a few low-bidding individuals in the multiple reward case. Some reward values lead to a specialization among the individuals where one subpopulation competes for the rewards and the other subpopulation largely avoids costly competitions. Whether the mixed strategy equilibrium is an evolutionarily stable strategy (ESS) depends on the specific values of the rewards. 
26179859	We frequently encounter decisions where we have to determine whether to wait for a certain reward delayed for an uncertain duration or to move on. The appropriate decision depends upon the underlying temporal distribution of the delay. With some distributions it is best to be completely persistent, whereas in others it is more appropriate to abandon waiting after a certain period of time. The current study examined whether the ability to form temporal expectations and adjust persistence accordingly is compromised by sleep deprivation. Participants performed a willingness-to-wait task either in a well-rested state or after a night of total sleep deprivation. Participants had to decide either to wait for a larger reward or to abandon waiting in favour of a smaller immediate reward. Delays were drawn from either a uniform distribution, where being persistent yields maximal returns, or from a heavy-tailed distribution, where occasional long delays render full persistence suboptimal. In spite of increased sleepiness and decreased vigilance, sleep-deprived participants were able to adjust waiting time appropriate to the experienced timing distribution. Additionally, sleep deprivation did not affect the foreperiod effect, indicating intact perception of conditional probability of temporal events and ability to adjust preparation accordingly. 

26178858	The traditional distinction between exogenous and endogenous attentional control has recently been enriched with an additional mode of control, termed "selection history." Recent findings have indicated, for instance, that previously rewarded or punished stimuli capture more attention than their physical attributes would predict. As such, the value that is associated with certain stimuli modulates attentional capture. This particular influence has also been shown for endogenous attention. Although recent leads have emerged, elucidating the influences of reward on exogenous and endogenous attention, it remains unclear to what extent exogenous attention is modulated by reward when endogenous attention is already deployed. We used a Posner cueing task in which exogenous and endogenous cues were presented to guide attention. Crucially, the exogenous cue also indicated the reward value. That is, the color of the exogenous cue indicated how much reward could be obtained on a given trial. The results showed main effects of endogenous and exogenous attention (i.e., speeded reaction times when either cue was valid, as compared to when it was invalid). Crucially, an interaction between exogenous cue validity and reward level was observed, indicating that reward-based associative-learning processes rapidly influence attentional capture, even when endogenous attention has been actively deployed. 
26178189	Intranasal oxytocin (OT) can modulate social-emotional functioning and related brain activity in humans. Consequently, OT has been discussed as a potential treatment for psychiatric disorders involving social behavioral deficits. However, OT effects are often heterogeneous across individuals. Here we explore individual differences in OT effects on the neural response to social cooperation as a function of the rs53576 polymorphism of the oxytocin receptor gene (OXTR). Previously, we conducted a double-blind, placebo-controlled study in which healthy men and women were randomized to treatment with intranasal OT or placebo. Afterwards, they were imaged with functional magnetic resonance imaging while playing an iterated Prisoner's Dilemma Game with same-sex partners. Within the left ventral caudate nucleus, intranasal OT treatment increased activation to reciprocated cooperation in men, but tended to decrease activation in women. Here, we show that these sex differences in OT effects are specific to individuals with the rs53576 GG genotype, and are not found for other genotypes (rs53576 AA/AG). Thus, OT may increase the reward or salience of positive social interactions for male GG homozygotes, while decreasing those processes for female GG homozygotes. These results suggest that rs53576 genotype is an important variable to consider in future investigations of the clinical efficacy of intranasal OT treatment. 
26178031	With the rising prevalence of obesity, hedonic eating has become an important theme in obesity research. Hedonic eating is thought to be that driven by the reward of food consumption and not metabolic need, and this has focused attention on the brain reward system and how its dysregulation may cause overeating and obesity. Here, we begin by examining the brain reward system and the evidence for its dysregulation in human obesity. We then consider the issue of how individuals are able to control their hedonic eating in the present obesogenic environment and compare 2 contrasting perspectives on the control of hedonic eating, specifically, enhanced control of intake via higher cognitive control and loss of control over intake as captured by the food addiction model. We conclude by considering what these perspectives offer in terms of directions for future research and for potential interventions to improve control over food intake at the population and the individual levels. 
26177527	The problem of poor mental health in residency is well established. Burnout, depression, and suicidal ideation are prevalent among resident physicians, and these problems appear to persist into practice. Leaders in graduate medical education such as policy makers at the Accreditation Council for Graduate Medical Education (ACGME) and directors of individual programs and institutions should acknowledge these important issues and take steps to address them. The ACGME's Clinical Learning Environment Review (CLER) Program currently outlines an expectation that institutions both educate residents about burnout and measure burnout annually. The CLER Program could go further by expecting institutions to create quality initiatives to enhance resident wellness and increase resident engagement. The ACGME should also call for and support research in this area. Leaders or directors of individual programs and institutions should consider wellness initiatives that both (1) identify and address suboptimal aspects of the learning environment and (2) train residents in resilience skills. Efforts to improve the residency learning environment could be guided by the work of Maslach and Leiter, who describe six categories of work stress that can contribute to burnout: (1) workload, (2) control, (3) balance between effort and reward, (4) community, (5) fairness, and (6) values.
26174598	We focus on exploratory decisions across disorders of compulsivity, a potential dimensional construct for the classification of mental disorders. Behaviors associated with the pathological use of alcohol or food, in alcohol use disorders (AUD) or binge-eating disorder (BED), suggest a disturbance in explore-exploit decision-making, whereby strategic exploratory decisions in an attempt to improve long-term outcomes may diminish in favor of more repetitive or exploitatory choices. We compare exploration vs exploitation across disorders of natural (obesity with and without BED) and drug rewards (AUD). We separately acquired resting state functional MRI data using a novel multi-echo planar imaging sequence and independent components analysis from healthy individuals to assess the neural correlates underlying exploration. Participants with AUD showed reduced exploratory behavior across gain and loss environments, leading to lower-yielding exploitatory choices. Obese subjects with and without BED did not differ from healthy volunteers but when compared with each other or to AUD subjects, BED had enhanced exploratory behaviors particularly in the loss domain. All subject groups had decreased exploration or greater uncertainty avoidance to losses compared with rewards. More exploratory decisions in the context of reward were associated with frontal polar and ventral striatal connectivity. For losses, exploration was associated with frontal polar and precuneus connectivity. We further implicate the relevance and dimensionality of constructs of compulsivity across disorders of both natural and drug rewards. 
26174594	The mammalian basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) comprise a functionally interconnected circuit that is critical for processing opiate-related associative memories. In the opiate-naïve state, reward memory formation in the BLA involves a functional link between dopamine (DA) D1 receptor (D1R) and extracellular signal-related kinase 1/2 (ERK1/2) signaling substrates, but switches to a DA D2 (D2R)/Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα)-dependent memory substrate following chronic opiate exposure and spontaneous withdrawal. Using conditioned place preference (CPP) in rats paired with molecular analyses, we examined the role of intra-mPFC CaMKII, ERK and DAergic activity during the formation of opiate associative memories, and how opiate exposure state may regulate the functions of these molecular memory pathways. We report that the role of CaMKIIα signaling is functionally reversed within the BLA-mPFC pathway depending on opiate exposure state. Thus, in the opiate-naïve state, intra-mPFC but not intra-BLA blockade of CaMKII signaling prevents formation of opiate reward memory. However, following chronic opiate exposure and spontaneous withdrawal, the role of CaMKII signaling in the BLA-mPFC is functionally reversed. This behavioral memory switch corresponds to a selective increase in the expression of D2R and CaMKIIα, but not other calcium/calmodulin-related molecules, nor D1R expression levels within the mPFC. 

26173174	The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects. 
26171719	Overconsumption of dietary fat is increasingly linked with motivational and emotional impairments. Human and animal studies demonstrate associations between obesity and blunted reward function at the behavioral and neural level, but it is unclear to what degree such changes are a consequence of an obese state and whether they are contingent on dietary lipid class. We sought to determine the impact of prolonged ad libitum intake of diets rich in saturated or monounsaturated fat, separate from metabolic signals associated with increased adiposity, on dopamine (DA)-dependent behaviors and to identify pertinent signaling changes in the nucleus accumbens (NAc). Male rats fed a saturated (palm oil), but not an isocaloric monounsaturated (olive oil), high-fat diet exhibited decreased sensitivity to the rewarding (place preference) and locomotor-sensitizing effects of amphetamine as compared with low-fat diet controls. Blunted amphetamine action by saturated high-fat feeding was entirely independent of caloric intake, weight gain, and plasma levels of leptin, insulin, and glucose and was accompanied by biochemical and behavioral evidence of reduced D1R signaling in the NAc. Saturated high-fat feeding was also tied to protein markers of increased AMPA receptor-mediated plasticity and decreased DA transporter expression in the NAc but not to alterations in DA turnover and biosynthesis. Collectively, the results suggest that intake of saturated lipids can suppress DA signaling apart from increases in body weight and adiposity-related signals known to affect mesolimbic DA function, in part by diminishing D1 receptor signaling, and that equivalent intake of monounsaturated dietary fat protects against such changes. 
26171607	The CUB and sushi multiple domains 1 (CSMD1) gene harbors signals provided by clusters of nearby SNPs with 10-2 > p > 10-8 associations in genome wide association (GWAS) studies of addiction-related phenotypes. A CSMD1 intron 3 SNP displays p < 10-8 association with schizophrenia and more modest associations with individual differences in performance on tests of cognitive abilities. CSDM1 encodes a cell adhesion molecule likely to influence development, connections and plasticity of brain circuits in which it is expressed. We tested association between CSMD1 genotypes and expression of its mRNA in postmortem human brains (n = 181). Expression of CSMD1 mRNA in human postmortem cerebral cortical samples differs 15-25%, in individuals with different alleles of simple sequence length and SNP polymorphisms located in the gene's third/fifth introns, providing nominal though not Bonferroni-corrected significance. These data support mice with altered CSMD1 expression as models for common human CSMD1 allelic variation. We tested baseline and/or cocaine-evoked addiction, emotion, motor and memory-related behaviors in +/- and -/- csmd1 knockout mice on mixed and on C57-backcrossed genetic backgrounds. Initial csmd1 knockout mice on mixed genetic backgrounds displayed a variety of coat colors and sizable individual differences in responses during behavioral testing. Backcrossed mice displayed uniform black coat colors. Cocaine conditioned place preference testing revealed significant influences of genotype (p = 0.02). Homozygote knockouts displayed poorer performance on aspects of the Morris water maze task. They displayed increased locomotion in some, though not all, environments. The combined data thus support roles for common level-of-expression CSMD1 variation in a drug reward phenotype relevant to addiction and in cognitive differences that might be relevant to schizophrenia. Mouse model results can complement data from human association findings of modest magnitude that identify likely polygenic influences. 
26170333	The prefrontal cortex (PFC) guides execution and inhibition of behavior based on contextual demands. In rodents, the dorsal/prelimbic (PL) medial PFC (mPFC) is frequently considered essential for execution of goal-directed behavior ("go") whereas ventral/infralimbic (IL) mPFC is thought to control behavioral suppression ("stop"). This dichotomy is commonly seen for fear-related behaviors, and for some behaviors related to cocaine seeking. Overall, however, data for reward-directed behaviors are ambiguous, and few recordings of PL/IL activity have been performed to demonstrate single-neuron correlates. We recorded neuronal activity in PL and IL during discriminative stimulus driven sucrose seeking followed by multiple days of extinction of the reward-predicting stimulus. Contrary to a generalized PL-go/IL-stop hypothesis, we found cue-evoked activity in PL and IL during reward seeking and extinction. Upon analyzing this activity based on resultant behavior (lever press or withhold), we found that neurons in both areas encoded contextually appropriate behavioral initiation (during reward seeking) and withholding (during extinction), where context was dictated by response-outcome contingencies. Our results demonstrate that PL and IL signal contextual information for regulation of behavior, irrespective of whether that involves initiation or suppression of behavioral responses, rather than topographically encoding go vs. stop behaviors. The use of context to optimize behavior likely plays an important role in maximizing utility-promoting exertion of activity when behaviors are rewarded and conservation of energy when not. 
26169527	Executive processes consist of at least two sets of functions: one concerned with cognitive control and the other with reward-related decision making. Abnormal performance in both sets occurs in late-life depression. This study tested the hypothesis that only abnormal performance in cognitive control tasks predicts poor outcomes of late-life depression treated with escitalopram.We studied older subjects with major depression (N = 53) and non-depressed subjects (N = 30). Executive functions were tested with the Iowa Gambling Test (IGT), Stroop Color-Word Test, Tower of London (ToL), and Dementia Rating Scale - Initiation/Perseveration domain (DRS-IP). After a 2-week placebo washout, depressed subjects received escitalopram (target daily dose: 20 mg) for 12 weeks.	There were no significant differences between depressed and non-depressed subjects on executive function tests. Hierarchical cluster analysis of depressed subjects identified a Cognitive Control cluster (abnormal Stroop, ToL, DRS-IP), a Reward-Related cluster (IGT), and an Executively Unimpaired cluster. Decline in depression was greater in the Executively Unimpaired (t = -2.09, df = 331, p = 0.0375) and the Reward-Related (t = -2.33, df = 331, p = 0.0202) clusters than the Cognitive Control cluster. The Executively Unimpaired cluster (t = 2.17, df = 331, p = 0.03) and the Reward-Related cluster (t = 2.03, df = 331, p = 0.0433) had a higher probability of remission than the Cognitive Control cluster.	Dysfunction of cognitive control functions, but not reward-related decision making, may influence the decline of symptoms and the probability of remission of late-life depression treated with escitalopram. If replicated, simple to administer cognitive control tests may be used to select depressed older patients at risk for poor outcomes to selective serotonin reuptake inhibitors who may require structured psychotherapy.	
26169446	It has become clear that histamine H3 receptors (H3R) have been implicated in modulating ethanol intake and preference in laboratory animals. The novel non-imidazole H3R antagonist DL77 with excellent selectivity profile shows high in-vivo potency as well as in-vitro antagonist affinity with ED50 of 2.1 ± 0.2 mg/kg and pKi=8.08, respectively. In the present study, and applying an unlimited access two-bottle choice procedure, the anti-alcohol effects of the H3R antagonist, DL77 (0, 3, 10 and 30 mg/kg; i.p.), were investigated in adult mice. In this C57BL/6 line, effects of DL77 on voluntary alcohol intake and preference, as well as on total fluid intake were evaluated. Results have shown that DL77, dose-dependently, reduced both ethanol intake and preference. These effects were very selective as both saccharin and quinine, used to control for taste sensitivity, and intakes were not affected following DL77 pre-application. More importantly, systemic administration of DL77 (10 mg/kg) during acquisition inhibited ethanol-induced conditioned-place preference (EtOH-CPP) as measured using an unbiased protocol. The anti-alcohol activity observed for DL77 was abrogated when mice were pretreated with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10 mg/kg), or with the CNS penetrant H1R antagonist pyrilamine (PYR) (10mg/kg). These results suggest that DL77 has a predominant role in two in vivo effects of ethanol. Therefore, signaling via H3R is essential for ethanol-related consumption and conditioned reward and may represent a novel therapeutic pharmacological target to tackle ethanol abuse and alcoholism.

26167945	The present study attempted to determine whether behavioral economic indices of elevated alcohol reward value, measured before and immediately after a brief alcohol intervention, predict treatment response.Participants were 133 heavy drinking college students (49.6% female, 51.4% male; 64.3% Caucasian, 29.5% African American) who were randomized to 1 of 3 conditions: motivational interviewing plus personalized feedback (brief motivational interventions; BMI), computerized personalized feedback intervention (electronic check-up to go; e-CHUG), and assessment only.	Baseline level of alcohol demand intensity (maximum consumption) significantly predicted drinks per week and alcohol problems at 1-month follow-up and baseline relative discretionary expenditures on alcohol significantly predicted drinks per week and alcohol problems at 6-month follow-up. BMI and e-CHUG were associated with an immediate postsession reduction in alcohol demand (p < .001, ηp2 = .29) that persisted at the 1-month follow-up, with greater postsession reductions in the BMI condition (p = .02, ηp2 = .06). Reductions in demand intensity and Omax (maximum expenditure) immediately postintervention significantly predicted drinking reductions at 1-month follow up (p = .04, ΔR2 = .02, and p = .01, ΔR2 = .03, respectively). Reductions in relative discretionary expenditures on alcohol at 1-month significantly predicted drinking (p = .002, ΔR2 = .06,) and alcohol problem (p < .001, ΔR2 = .13) reductions at the 6-month follow-up.	These results suggest that behavioral economic reward value indices may function as risk factors for poor intervention response and as clinically relevant markers of change in heavy drinkers.	
26167716	Marijuana produces acute increases in positive subjective effects and decreased reactivity to negative affective stimuli, though may also acutely induce anxiety. Implicit attentional and evaluative processes may explicate marijuana's ability to acutely increase positive and negative emotions. This within-subjects study examined whether smoked marijuana with 2.7-3.0% delta-9-tetrahydrocannabinol (THC), relative to placebo, acutely changed attentional processing of rewarding and negative affective stimuli as well as marijuana-specific stimuli. On 2 separate days, regular marijuana users (N = 89) smoked placebo or active THC cigarette and completed subjective ratings of mood, intoxication, urge to smoke marijuana, and 2 experimental tasks: pleasantness rating (response latency and perceived pleasantness of affective and marijuana-related stimuli) and emotional Stroop (attentional bias to affective stimuli). On the pleasantness rating task, active marijuana increased response latency to negatively valenced and marijuana-related (vs. neutral) visual stimuli, beyond a general slowing of response. Active marijuana also increased pleasantness ratings of marijuana images, although to a lesser extent than placebo due to reduced marijuana urge after smoking. Overall, active marijuana did not acutely change processing of positive emotional stimuli. There was no evidence of attentional bias to affective word stimuli on the emotional Stroop task with the exception of attentional bias to positive word stimuli in the subgroup of marijuana users with cannabis dependence. Marijuana may increase allocation of attentional resources toward marijuana-specific and negatively valenced visual stimuli without altering processing of positively valenced stimuli. Marijuana-specific cues may be more attractive with higher levels of marijuana craving and less wanted with low craving levels.
26167715	Environmental enrichment has previously been shown to alter sensitivity to psychostimulants and opiates in various preclinical models. However, little research has been conducted studying the effects of environmental enrichment on the more commonly abused drug, nicotine. The current study raised male rats in either enriched conditions (EC) or isolated conditions (IC) and tested the animals' sensitivity to acquisition, extinction and reinstatement of nicotine conditioned place preference (CPP). Using a 3-chamber CPP apparatus, male Sprague-Dawley rats were conditioned with 1 of 3 doses of nicotine (0.4, 0.6, and 0.8 mg/kg) or saline on alternating days across 8 conditioning trials, followed by a test day for a nicotine-induced CPP response. Next, the animals had 5 extinction sessions followed by a nicotine-primed reinstatement session. EC rats displayed nicotine CPP at all 3 doses, whereas IC rats failed to show significant nicotine CPP relative to saline controls. EC rats also showed extinction of the nicotine-induced CPP response by the fifth extinction session for all 3 nicotine doses tested. However, only the 2 highest doses of the nicotine prime reinstated a CPP response in EC rats relative to saline controls. Taken together, these findings suggest that environmental enrichment may increase sensitivity to the rewarding effects of nicotine.
26166678	The tobacco epidemic disproportionately affects low-income populations, and telehealth is an evidence-based strategy for extending tobacco cessation services to underserved populations. A public health priority is to establish incentive-based interventions at the population level in order to promote long-term smoking cessation in low-income populations. Yet randomized clinical trials show that financial incentives tend to encourage only short-term steps of cessation, not continuous smoking abstinence. One potential mechanism for increasing long-term cessation is interpersonal communication (IPC) in response to population-level interventions. However, more research is needed on IPC and its influence on health behavior change, particularly in the context of incentive-based, population-level programs. This study used survey data gathered after a population-level telehealth intervention that offered $20 incentives to low-income smokers for being connected to Minnesota's free quitline in order to examine how perceived incentive importance and IPC about the incentive-based program relate to both short-term and long-term health behavior change. Results showed that IPC was strongly associated with initial quitline utilization and continuous smoking abstinence as measured by 30-day point prevalence rates at 7-month follow-up. Perceived incentive importance had weak associations with both measures of cessation, and all associations were nonsignificant in models adjusting for IPC. These results were found in descriptive analyses, logistic regression models, and Heckman probit models that adjusted for participant recruitment. In sum, a behavioral telehealth intervention targeting low-income smokers that offered a financial incentive inspired IPC, and this social response was strongly related to utilization of intervention services as well as continuous smoking abstinence.