Reward Loss Research Articles

Brain expression of pCREB in rats exposed to consummatory successive negative contrast

A 32-to-4% sucrose devaluation leads to suppression of consummatory behavior relative to unshifted 4% sucrose controls. This is accompanied by an emotional response inducing memory consolidation. Expression levels of phosphorylated cyclic adenosine monophosphate response element-binding protein (pCREB, a marker of synaptic plasticity) were higher after the first devaluation session than after the second in prelimbic cortex, anterior cingulate cortex, and dorso-medial striatum. The central nucleus of the amygdala showed a tendency to differential pCREB expression. This evidence contributes to identifying the brain circuit for one form of traumatic memory involving reward loss.

12. Left hemispheric “unbalance” (Alpha Band) and decisional bias in drug addiction – The role of the reward system

The current research explored the impact of cortical frontal asymmetry (left-lateralization effect of alpha frequency band) and Behavioral Activation System (BAS) on Substance Use Disorder (SUD) in decisional processes using the Iowa Gambling Task (IGT). Thus gambling behavior was considered in SUD. Forty SUD participants and forty-two controls (CG) were tested using the IGT. Behavioral responses (gain/loss options), BIS/BAS scores and lateralized alpha band modulation (LTA) were considered. The SUD group increased the tendency to opt in favor of the immediate reward (loss strategy) more than the long-term option (win strategy) compared to the CG. Secondly, higher reward-subscale scores were observed in SUD. Thirdly, SUD showed an increase in left-hemisphere activation in response to losing (with immediate reward) choices in comparison with the CG. An imbalanced left hemispheric effect related to higher BAS trait could explain this “reward bias,” because these components were found to affect (through the regression analysis) the main behavioral deficits. Lateralization effect and BAS may explain the gambling behavior in SUD.

Ambiguous Partially Observable Markov Decision Processes: Structural Results and Applications

Markov Decision Processes (MDPs) and their generalization, Partially Observable MDPs (POMDPs), have been widely studied and used as invaluable tools in dynamic stochastic decision-making. However, two major barriers have limited their application for problems arising in various practical settings: (a) computational challenges for problems with large state or action spaces, and (b) ambiguity in transition probabilities, which are typically hard to quantify. While several solutions for the first challenge, known as curse of dimensionality, have been proposed, the second challenge remains unsolved and even untouched in the case of POMDPs. We refer to the second challenge as the curse of ambiguity, and address it by developing a generalization of POMDPs termed Ambiguous POMDPs (APOMDPs). The proposed generalization not only allows the decision maker to take into account imperfect state information, but also tackles the inevitable ambiguity with respect to the correct probabilistic model. Importantly, this paper extends various structural results from POMDPs to APOMDPs. Such structural results can guide the decision maker to make robust decisions when facing model ambiguity. Robustness is achieved by using α-maximin expected utility (α -MEU), which (a) differentiates between ambiguity and ambiguity attitude, (b) avoids the over conservativeness of traditional maximin approaches widely used in robust optimization, and (c) is found to be suitable in laboratory experiments in various choice behaviors including those in portfolio selection. The structural results provided also help to handle the curse of dimensionality, since they significantly simplify the search for an optimal policy. Furthermore, we provide an analytical performance guarantee for the APOMDP approach by developing a bound for its maximum reward loss due to model ambiguity. To generate further insights into how APOMDPs can help to make better decisions, we also discuss specific applications of APOMDPs including machine replacement, medical decision-making, inventory control, revenue management, optimal search, sequential design of experiments, bandit problems, and dynamic principal-agent models.

Anti-anxiety self-medication in rats: Oral consumption of chlordiazepoxide and ethanol after reward devaluation

Rats increased preference for ethanol after sessions of appetitive extinction, but not after acquisition (reinforced) sessions (Manzo et al., 2014). Drinking was not influenced by appetitive extinction in control groups with postsession access to water, rather than ethanol. Because ethanol has anxiolytic properties in tasks involving reward loss, these results were interpreted as anti-anxiety self-medication. The present experiment tested the potential for self-medication with the prescription anxiolytic chlordiazepoxide, a benzodiazepine with an addictive profile used in the treatment of anxiety disorders. To test this hypothesis, Wistar rats exposed to a 32-to-4% sucrose devaluation received a two-bottle, 2-h preference test immediately after consummatory training. One bottle contained 1mg/kg of chlordiazepoxide, 2% ethanol, or water for different groups (the second bottle contained water for all groups). Three additional groups received the same postsession preference tests, but were exposed to 4% sucrose during consummatory training. Rats showed suppression of consummatory behavior after reward devaluation relative to unshifted controls. This effect was accompanied by a selective increase in preference for chlordiazepoxide and ethanol. Downshifted animals with access to water or unshifted controls with access to the anxiolytics failed to exhibit postsession changes in preference. Similar results were observed in terms of absolute consumption and consumption relative to body weight. This study shows for the first time that a prescription anxiolytic supports enhanced voluntary consumption during periods of emotional distress triggered by reward loss. Such anti-anxiety self-medication provides insights into the early stages of addictive behavior.

Identifying profiles of recovery from reward devaluation in rats

In humans and other mammals, the unexpected loss of a resource can lead to emotional conflict. Consummatory successive negative contrast (cSNC) is a laboratory model of reward devaluation meant to capture that conflict. In this paradigm, animals are exposed to a sharp reduction in the sucrose concentration of a solution after several days of access. This downshift in sucrose content leads to behavioral responses such as the suppression of consumption and physiologic responses including elevation of corticosterone levels. However, response heterogeneity in cSNC has yet to be explored and may be relevant for increasing the validity of this model, as humans demonstrate clinically meaningful heterogeneity in response to resource loss. The current analysis applied latent growth mixture modeling to test for and characterize heterogeneity in recovery from cSNC among rats (N=262). Although most animals exhibited recovery of consummatory behavior after a sharp drop in consumption in the first postshift trial (Recovery class; 83%), two additional classes were identified including animals that did not change their consumption levels after downshift (No Contrast class; 6%), and animals that exhibited an initial response similar to that of the Recovery class but did not recover to preshift consumption levels (No Recovery class; 11%). These results indicate heterogeneity in recovery from reward loss among rats, which may increase the translatability of this animal model to understand diverse responses to loss among humans.

Loss of Morphine Reward and Dependence in Mice Lacking G Protein–Coupled Receptor Kinase 5

The clinical benefits of opioid drugs are counteracted by the development of tolerance and addiction. We provide in vivo evidence for the involvement of G protein-coupled receptor kinases (GRKs) in opioid dependence in addition to their roles in agonist-selective mu-opioid receptor (MOR) phosphorylation. In vivo MOR phosphorylation was examined by immunoprecipitation and nanoflow liquid chromatography-tandem mass spectrometry analysis. Using the hot-plate and conditioned place preference test, we investigated opioid-related antinociception and reward effects in mice lacking GRK3 or GRK5. Etonitazene and fentanyl stimulated the in vivo phosphorylation of multiple carboxyl-terminal phosphate acceptor sites, including threonine 370, serine 375, and threonine 379, which was predominantly mediated by GRK3. By contrast, morphine promoted a selective phosphorylation of serine 375 that was predominantly mediated by GRK5. In contrast to GRK3 knockout mice, GRK5 knockout mice exhibited reduced antinociceptive responses after morphine administration and developed morphine tolerance similar to wild-type mice but fewer signs of physical dependence. Also, morphine was ineffective in inducing conditioned place preference in GRK5 knockout mice, whereas cocaine conditioned place preference was retained. However, the reward properties of morphine were evident in knock-in mice expressing a phosphorylation-deficient S375A mutation of the MOR. These findings show for the first time that MOR phosphorylation is regulated by agonist-selective recruitment of distinct GRK isoforms that influence different opioid-related behaviors. Modulation of GRK5 function could serve as a new approach for preventing addiction to opioids, while maintaining the analgesic properties of opioid drugs at an effective level.

Incentive Relativity: Gene-Environment Interactions

Reward loss experiences are among the main sources of emotional stress that humans face throughout their lives. In the animal laboratory, it has been repeatedly shown that the unexpected omission or devaluation of a reinforcer triggers a physiological, cognitive, and behavioral state called frustration. This state involves emotional mechanisms that resemble those unleashed by the presentation of other aversive stimuli, inducing similar stress responses through the activation of brain circuits involved in fear and anxiety. Although this hypothesis has been supported by behavioral, pharmacological, hormonal, and neurobiological evidence, only a few studies have focused on the neurogenetic basis of frustration in animals. This review focuses on the gene-environment interactions that determine the emotional response under conditions of reward loss. Behavioral and genetic correlates of frustration are reviewed in two strains of animals selected on the basis of extreme differences in active avoidance learning: inbred Roman High- (RHA-I) and Roman Low-Avoidance (RLA-I) rats. The review shows the usefulness of Roman strains for neurogenetic research and sets out unsolved questions regarding gene-environment interactions underlying behavior induced by incentive loss.

Introduction to Special Issue on Incentive Relativity

In 1996, Charles Flaherty opened the prologue of his book Incentive Relativity with these words: “We compare. Many of the pleasures and irritations of life are related to the match between an event and our expectancies. We compare meals, composers, presidents, books, performances, salaries, and many other events that have some interest or value” (Flaherty, 1996, p. 1). The capacity of organisms to acquire reward expectations based on prior experience and to contrast them with their immediate reality is referred as incentive relativity. Incentive relativity implies not only a mechanism for processing information, but also an emotional component resulting from such comparison. Our passions, feelings, and emotions are often based on a comparison of relative outcomes, and, when such comparison results in what is appraised as a significant loss, a state of stress, anxiety, aggression, depression, and substance abuse can follow, among other psychopathological states. Almost two decades after Flaherty’s words, the analysis of incentive relativity effects continues to engage specialists in behavior, cognition, clinical psychology, pharmacology, and neuroscience. Nonhuman animals also compare incentives and exhibit affective responses to the outcome of such comparisons. This characteristic allows researchers coming from different disciplines to approach the scientific study of incentive relativity using animal models of human behavior. We now know a large variety of paradoxical learning effects based on the presentation of different reward values (contrast effects) or reward contingencies (partial reinforcement and extinction). The behavioral, environmental, hormonal, pharmacological, neurobiological, and genetic characterizations of these phenomena are part of a field of basic research of great tradition and, simultaneously, of current importance given their clinical and applied implications. In this special issue, leading experts review incentive relativity from a multidisciplinary perspective. Research on different approaches is presented, including empirical articles and critical reviews. A key focus of the present special issue is to highlight the contribution of animal research to extend our knowledge of some basic principles of learning and their emotional correlates in a variety of organisms, including humans. The first paper by Bueno, Judice-Daher, and Deliberato (pp. 410-419) investigates a phenomenon related to reward loss: the reinforcement omission effect. Bueno and co-authors aim to clarify the relationship between reinforcement magnitude and the reinforcement omission effect manipulating the magnitude linked to discriminative stimuli in a partial reinforcement fixed interval schedule. The empirical and theoretical implications of the results are discussed.

BOUNDED-PARAMETER PARTIALLY OBSERVABLE MARKOV DECISION PROCESSES: FRAMEWORK AND ALGORITHM

Partially observable Markov decision processes (POMDPs) are powerful for planning under uncertainty. However, it is usually impractical to employ a POMDP with exact parameters to model the real-life situation precisely, due to various reasons such as limited data for learning the model, inability of exact POMDPs to model dynamic situations, etc. In this paper, assuming that the parameters of POMDPs are imprecise but bounded, we formulate the framework of bounded-parameter partially observable Markov decision processes (BPOMDPs). A modified value iteration is proposed as a basic strategy for tackling parameter imprecision in BPOMDPs. In addition, we design the UL-based value iteration algorithm, in which each value backup is based on two sets of vectors called U-set and L-set. We propose four strategies for computing U-set and L-set. We analyze theoretically the computational complexity and the reward loss of the algorithm. The effectiveness and robustness of the algorithm are shown empirically.

Measuring risk‐taking in mice: balancing the risk between seeking reward and danger

Assessing risk is an essential part of human behaviour and may be disrupted in a number of psychiatric conditions. Currently, in many animal experimental designs the basis of the potential 'risk' is loss or attenuation of reward, which fail to capture 'real-life' risky situations where there is a trade-off between a separate cost and reward. The development of rodent tasks where two separate and conflicting factors are traded against each other has begun to address this discrepancy. Here, we discuss the merits of these risk-taking tasks and describe the development of a novel test for mice - the 'predator-odour risk-taking' task. This paradigm encapsulates a naturalistic approach to measuring risk-taking behaviour where mice have to balance the benefit of gaining a food reward with the cost of exposure to a predator odour using a range of different odours (rat, cat and fox). We show that the 'predator-odour risk-taking' task was sensitive to the trade-off between cost and benefit by demonstrating reduced motivation to collect food reward in the presence of these different predator odours in two strains of mice and, also, if the value of the food reward was reduced. The 'predator-odour risk-taking' task therefore provides a strong platform for the investigation of the genetic substrates of risk-taking behaviour using mouse models, and adds a further dimension to other recently developed rodent tests.

Maternal Depression and Warmth During Childhood Predict Age 20 Neural Response to Reward

Early parenting experiences likely shape children's brain development, with consequences potentially extending into adulthood. Parents' affective disorders and expressions of positive affect could exert an influence on affect-related circuitry. The current study evaluated how maternal depression and maternal warmth assessed in early childhood and early adolescence were related to boys' reward function during early adulthood. Participants were 120 boys at socioeconomic risk for emotional problems. Mothers' history of depression during the child's lifetime was measured when boys were 42 months old and 10 and 11 years old. Maternal warmth was observed during mother-child interactions at 18 and 24 months and at 10 and 11 years. Maternal warmth during early childhood was associated with less activation in the medial prefrontal cortex (mPFC) when anticipating and experiencing reward loss. Maternal warmth during early adolescence was associated with less activation in the mPFC when winning rewards and greater activation in the caudate when experiencing loss. The association between maternal warmth during early childhood and early adolescence and reward function in the striatum and mPFC was stronger for boys exposed to maternal depression relative to boys who were not. The experience of warmth and affection from mothers may be a protective factor for reward function in boys exposed to maternal depression, possibly by engaging vulnerable neural reward systems through affiliation.

Deterministic Sequencing of Exploration and Exploitation for Multi-Armed Bandit Problems

In the Multi-Armed Bandit (MAB) problem, there is a given set of arms with unknown reward models. At each time, a player selects one arm to play, aiming to maximize the total expected reward over a horizon of length T. An approach based on a Deterministic Sequencing of Exploration and Exploitation (DSEE) is developed for constructing sequential arm selection policies. It is shown that for all light-tailed reward distributions, DSEE achieves the optimal logarithmic order of the regret, where regret is defined as the total expected reward loss against the ideal case with known reward models. For heavy-tailed reward distributions, DSEE achieves O(T1/p) regret when the moments of the reward distributions exist up to the pth order for and O(T1/(1+p/2)) for p > 2. With the knowledge of an upper bound on a finite moment of the heavy-tailed reward distributions, DSEE offers the optimal logarithmic regret order. The proposed DSEE approach complements existing work on MAB by providing corresponding results for general reward distributions. Furthermore, with a clearly defined tunable parameter-the cardinality of the exploration sequence, the DSEE approach is easily extendable to variations of MAB, including MAB with various objectives, decentralized MAB with multiple players and incomplete reward observations under collisions, restless MAB with unknown dynamics, and combinatorial MAB with dependent arms that often arise in network optimization problems such as the shortest path, the minimum spanning tree, and the dominating set problems under unknown random weights.

Remitted major depression is characterized by reduced prefrontal cortex reactivity to reward loss

BackgroundMajor depression (MDD) is characterized by anhedonia. Although a growing body of literature has linked anhedonia in MDD to reduced frontostriatal activity during reward gains, relatively few studies have examined neural responsivity to loss, and no studies to date have examined neural responses to loss in euthymic individuals with a history of MDD. Methods: An fMRI monetary incentive delay task was administered to 19 participants with remitted MDD (rMDD) and 19 never depressed controls. Analyses examined group activation differences in brain reward circuitry during monetary loss anticipation and outcomes. Secondary analyses examined the association between self-reported rumination and brain activation in the rMDD group. Results: Compared to controls, the rMDD group showed less superior frontal gyrus activation during loss anticipation and less inferior and superior frontal gyri activation during loss outcomes (cluster corrected p’s<.05). Ruminative Responses Scale scores were negatively correlated with superior frontal gyrus activation (r=−.68, p=.001) during loss outcomes in the rMDD group. Limitations: Replication with a larger sample is needed. Conclusions: Euthymic individuals with a history of MDD showed prefrontal cortex hypoactivation during loss anticipation and outcomes, and the degree of superior frontal gyrus hypoactivation was associated with rumination. Abnormal prefrontal cortex responses to loss may reflect a trait-like vulnerability to MDD, although future research is needed to evaluate the utility of this functional neural endophenotype as a prospective risk marker.

Robust Changes in Reward Circuitry During Reward Loss in Current and Former Cocaine Users During Performance of a Monetary Incentive Delay Task

Abnormal function in reward circuitry in cocaine addiction could predate drug use as a risk factor, follow drug use as a consequence of substance-induced alterations, or both. We used a functional magnetic resonance imaging monetary incentive delay task (MIDT) to investigate reward-loss neural response differences among 42 current cocaine users, 35 former cocaine users, and 47 healthy subjects who also completed psychological measures and tasks related to impulsivity and reward. We found various reward processing-related group differences in several MIDT phases. Across task phases we found a control > current user > former user activation pattern, except for loss outcome, where former compared with current cocaine users activated ventral tegmental area more robustly. We also found regional prefrontal activation differences during loss anticipation between cocaine-using groups. Both groups of cocaine users scored higher than control subjects on impulsivity, compulsivity and reward-punishment sensitivity factors. In addition, impulsivity-related factors correlated positively with activation in amygdala and negatively with anterior cingulate activation during loss anticipation. Compared with healthy subjects, both former and current users displayed abnormal brain activation patterns during MIDT performance. Both cocaine groups differed similarly from healthy subjects, but differences between former and current users were localized to the ventral tegmental area during loss outcome and to prefrontal regions during loss anticipation, suggesting that long-term cocaine abstinence does not normalize most reward circuit abnormalities. Elevated impulsivity-related factors that relate to loss processing in current and former users suggest that these tendencies and relationships may pre-exist cocaine addiction.

Perspective food addiction, caloric restriction, and dopaminergic neurotransmission

People attempt to change their lifestyle when obesity impairs their quality of life. The attempts often fail when multiple habits must be changed in unison. Here we explore relations among food addiction, the neurobiology of habits, and caloric restriction, when people seek to return to normal eating behaviour, with particular emphasis on the role of dopaminergic neurotransmission.Severely obese individuals have specific neurobiological characteristics in common with drug abusers, including low availability of dopamine receptors in the striatum, impaired neuronal responses to dopamine, and reduced activity in prefrontal regions of the cerebral cortex. The neurobiological characteristics suggest that obese people also have a pathological dependence in common with addicts, in the form of food addiction.Malnutrition and dieting both relate to binge eating, possibly as a compensation for a reduced cognitive reward condition. The combination of caloric restriction and food addiction imparts a high risk of relapse as a result of further reduction of dopaminergic neurotransmission and the subsequent loss of reward. As with drugs of abuse, ingestion of large quantities of sugar in circumstances of uncontrolled eating increases dopamine release in the nucleus accumbens. This and other evidence suggests that abuse of food is a habit learned by means of mechanisms centred in the basal ganglia, with an increased risk of relapse in the presence of associative amplifiers. This risk is predicted by the relationship between dopamine receptor availability in the striatum and sensation-seeking in the form of an inverted U, suggested by recent findings, consistent with two opposite states of hypodopaminergic and hyperdopaminergic neuromodulation.

Adaptive radio resource management for maximizing reward and balancing loads in 4G hybrid universal mobile telecommunications system and long term evolution communications

The universal mobile telecommunications system UMTS and long term evolution LTE/LTE-advanced specifications have been proposed to offer high data rate for the forwarding link under high-mobility wireless communications. The keys include supporting multi-modes of various coding schemes e.g., VSF-OFCDM, OFDM, OFDMA, multiple-input multiple-output, relay networks, and so on. To balance loads among different communication interfaces is one of the most important issues that should be addressed for achieving efficient radio resource allocations. In a shared packet service, the 3GPP UMTS adopts the VSF-OFCDM interface to allocate orthogonal codes of an OVSF code tree in two-dimension 2D spreading at the time and frequency domains. However, it easily leads to high packet loss rate and high bandwidth waste rate, because it does not consider interference and the adaptive modulation and coding scheme simultaneously. Conversely, although the LTE/LTE-advanced interface offers a high data rate, it suffers from unbalanced loads and moderate reward. This paper thus proposes an adaptive radio resource allocation for balancing loads between the UMTS and LTE/LTE-advanced interfaces according to various interference and mobility environments. In addition, an adaptive multi-code allocation is proposed for the UMTS to minimize the bandwidth waste rate while guaranteeing quality of service. Numerical results indicate that the proposed approach outperforms other approaches in fractional reward loss and system utilization. Copyright © 2013 John Wiley & Sons, Ltd.

Learning in a Changing World: Restless Multiarmed Bandit With Unknown Dynamics

We consider the restless multiarmed bandit problem with unknown dynamics in which a player chooses one out of <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">N</i> arms to play at each time. The reward state of each arm transits according to an unknown Markovian rule when it is played and evolves according to an arbitrary unknown random process when it is passive. The performance of an arm selection policy is measured by regret, defined as the reward loss with respect to the case where the player knows which arm is the most rewarding and always plays the best arm. We construct a policy with an interleaving exploration and exploitation epoch structure that achieves a regret with logarithmic order. We further extend the problem to a decentralized setting where multiple distributed players share the arms without information exchange. Under both an exogenous restless model and an endogenous restless model, we show that a decentralized extension of the proposed policy preserves the logarithmic regret order as in the centralized setting. The results apply to adaptive learning in various dynamic systems and communication networks, as well as financial investment.

Natural and Drug Rewards Act on Common Neural Plasticity Mechanisms with ΔFosB as a Key Mediator

Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. Recent evidence suggests that natural rewards may cause similar changes in the NAc, suggesting that drugs may activate mechanisms of plasticity shared with natural rewards, and allowing for unique interplay between natural and drug rewards. In this study, we demonstrate that sexual experience in male rats when followed by short or prolonged periods of loss of sex reward causes enhanced amphetamine reward, indicated by sensitized conditioned place preference for low-dose (0.5 mg/kg) amphetamine. Moreover, the onset, but not the longer-term expression, of enhanced amphetamine reward was correlated with a transient increase in dendritic spines in the NAc. Next, a critical role for the transcription factor ΔFosB in sex experience-induced enhanced amphetamine reward and associated increases in dendritic spines on NAc neurons was established using viral vector gene transfer of the dominant-negative binding partner ΔJunD. Moreover, it was demonstrated that sexual experience-induced enhanced drug reward, ΔFosB, and spinogenesis are dependent on mating-induced dopamine D1 receptor activation in the NAc. Pharmacological blockade of D1 receptor, but not D2 receptor, in the NAc during sexual behavior attenuated ΔFosB induction and prevented increased spinogenesis and sensitized amphetamine reward. Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets.

Don’t Get Your Hopes Up

We examine whether lower expectations for social reward selectively applied to high intimacy contexts may help avoidantly attached individuals minimize distress from reward loss. Studies 1, 2, and 4 demonstrated that avoidant attachment was negatively associated with perceived intimacy potential in relationships involving approach of closeness (current/future partners), but not for relationships less associated with approach of closeness (ex-partners). Studies 3 and 5 manipulated the potential for intimacy among dating prospects. Avoidant attachment was negatively associated with romantic interest in high intimacy targets but not low intimacy targets. This effect was mediated by perceived responsiveness. Studies 4 and 5 rule out perceived dissimilarity to responsive targets as a mechanism. Study 6 demonstrated that avoidants' lower expectations for connection are associated with less anticipated distress from reward loss. These results suggest that avoidant individuals may circumvent attachment system activation by perceiving lower opportunity for connection when there is potential for intimacy.

Risk-Responsive Orbitofrontal Neurons Track Acquired Salience

Decision making is impacted by uncertainty and risk (i.e., variance). Activity in the orbitofrontal cortex, an area implicated in decision making, covaries with these quantities. However, this activity could reflect the heightened salience of situations in which multiple outcomes-reward and reward omission-are expected. To resolve these accounts, rats were trained to respond to cues predicting 100%, 67%, 33%, or 0% reward. Consistent with prior reports, some orbitofrontal neurons fired differently in anticipation of uncertain (33% and 67%) versus certain (100% and 0%) reward. However, over 90% of these neurons also fired differently prior to 100% versus 0% reward (or baseline) or prior to 33% versus 67% reward. These responses are inconsistent with risk but fit well with the representation of acquired salience linked to the sum of cue-outcome and cue-no-outcome associative strengths. These results expand our understanding of how the orbitofrontal cortex might regulate learning and behavior.