Stimuli predicting high-calorie reward increase dopamine release and drive approach to food in the absence of homeostatic need.

Animals and humans are motivated to consume high-fat, high-calorie foods by cues predicting such foods. The neural mechanisms underlying this effect are not well understood.Objective: We tested the hypothesis that cues paired with a food reward, as compared to explicitly unpaired cues, increase rats' food-seeking behavior by potentiating dopamine release in the nucleus accumbens, and that this effect would be less evident under satiety.Methods: We used a simple discriminative stimulus task and electrochemical recordings of dopamine release in freely moving rats.Results: We found that both food-predictive cue and hunger increased conditioned approaches to the receptacle (food-seeking behavior indicated by movement to the food receptacle). In addition, we observed dopamine release when the food-predictive cue (but not the unpaired cue) was presented, independent of hunger or satiety. Finally, we found a positive correlation between dopamine release amplitude and the number of conditioned approaches to the food receptacle in the sated condition, but not in the hungry condition.Discussion: Our results suggest that dopamine could drive seeking behavior for calorie-dense food in absence of homeostatic need, a core aspect of binge eating disorders.

Limbic-motor integration by neural excitations and inhibitions in the nucleus accumbens.

The nucleus accumbens (NAc) has often been described as a "limbic-motor interface," implying that the NAc integrates the value of expected rewards with the motor planning required to obtain them. However, there is little direct evidence that the signaling of individual NAc neurons combines information about predicted reward and behavioral response. We report that cue-evoked neural responses in the NAc form a likely physiological substrate for its limbic-motor integration function. Across task contexts, individual NAc neurons in behaving rats robustly encode the reward-predictive qualities of a cue, as well as the probability of behavioral response to the cue, as coexisting components of the neural signal. In addition, cue-evoked activity encodes spatial and locomotor aspects of the behavioral response, including proximity to a reward-associated target and the latency and speed of approach to the target. Notably, there are important limits to the ability of NAc neurons to integrate motivational information into behavior: in particular, updating of predicted reward value appears to occur on a relatively long timescale, since NAc neurons fail to discriminate between cues with reward associations that change frequently. Overall, these findings suggest that NAc cue-evoked signals, including inhibition of firing (as noted here for the first time), provide a mechanism for linking reward prediction and other motivationally relevant factors, such as spatial proximity, to the probability and vigor of a reward-seeking behavioral response.NEW & NOTEWORTHY The nucleus accumbens (NAc) is thought to link expected rewards and action planning, but evidence for this idea remains sparse. We show that, across contexts, both excitatory and inhibitory cue-evoked activity in the NAc jointly encode reward prediction and probability of behavioral responding to the cue, as well as spatial and locomotor properties of the response. Interestingly, although spatial information in the NAc is updated quickly, fine-grained updating of reward value occurs over a longer timescale.

Reassessing wanting and liking in the study of mesolimbic influence on food intake.

Humans and animals such as rats and mice tend to overconsume calorie-dense foods, a phenomenon that likely contributes to obesity. One often-advanced explanation for why we preferentially consume sweet and fatty foods is that they are more "rewarding" than low-calorie foods. "Reward" has been subdivided into three interdependent psychological processes: hedonia (liking a food), reinforcement (formation of associations among stimuli, actions, and/or the food), and motivation (wanting the food). Research into these processes has focused on the mesolimbic system, which comprises both dopamine neurons in the ventral tegmental area and neurons in their major projection target, the nucleus accumbens. The mesolimbic system and closely connected structures are commonly referred to as the brain's "reward circuit." Implicit in this title is the assumption that "rewarding" experiences are generally the result of activity in this circuit. In this review, I argue that food intake and the preference for calorie-dense foods can be explained without reference to subjective emotions. Furthermore, the contribution of mesolimbic dopamine to food intake and preference may not be a general one of promoting or coordinating behaviors that result in the most reward or caloric intake but may instead be limited to the facilitation of a specific form of neural computation that results in conditioned approach behavior. Studies on the neural mechanisms of caloric intake regulation must address how sensory information about calorie intake affects not just the mesolimbic system but also many other forms of computation that govern other types of food-seeking and food-oriented behaviors.

Dopamine invigorates reward seeking by promoting cue-evoked excitation in the nucleus accumbens.

Approach to reward is a fundamental adaptive behavior, disruption of which is a core symptom of addiction and depression. Nucleus accumbens (NAc) dopamine is required for reward-predictive cues to activate vigorous reward seeking, but the underlying neural mechanism is unknown. Reward-predictive cues elicit both dopamine release in the NAc and excitations and inhibitions in NAc neurons. However, a direct link has not been established between dopamine receptor activation, NAc cue-evoked neuronal activity, and reward-seeking behavior. Here, we use a novel microelectrode array that enables simultaneous recording of neuronal firing and local dopamine receptor antagonist injection. We demonstrate that, in the NAc of rats performing a discriminative stimulus task for sucrose reward, blockade of either D1 or D2 receptors selectively attenuates excitation, but not inhibition, evoked by reward-predictive cues. Furthermore, we establish that this dopamine-dependent signal is necessary for reward-seeking behavior. These results demonstrate a neural mechanism by which NAc dopamine invigorates environmentally cued reward-seeking behavior.

Neurons in the nucleus accumbens promote selection bias for nearer objects.

Both animals and humans often prefer rewarding options that are nearby over those that are distant, but the neural mechanisms underlying this bias are unclear. Here we present evidence that a proximity signal encoded by neurons in the nucleus accumbens drives proximate reward bias by promoting impulsive approach to nearby reward-associated objects. On a novel decision-making task, rats chose the nearer option even when it resulted in greater effort expenditure and delay to reward; therefore, proximate reward bias was unlikely to be caused by effort or delay discounting. The activity of individual neurons in the nucleus accumbens did not consistently encode the reward or effort associated with specific alternatives, suggesting that it does not participate in weighing the values of options. In contrast, proximity encoding was consistent and did not depend on the subsequent choice, implying that accumbens activity drives approach to the nearest rewarding option regardless of its specific associated reward size or effort level.

Nucleus Accumbens Shell Neurons Encode the Kinematics of Reward Approach Locomotion.

The nucleus accumbens (NAc) is considered an interface between motivation and action, with NAc neurons playing an important role in promoting reward approach. However, the encoding by NAc neurons that contributes to this role remains unknown. We recorded 62 NAc neurons in male Wistar rats (n = 5) running towards rewarded locations in an 8-arm radial maze. Variables related to locomotor approach kinematics were the best predictors of the firing rate for most NAc neurons. Nearly 18% of the recorded neurons were inhibited during the entire approach run (locomotion-off cells), suggesting that reduction in firing of these neurons promotes initiation of locomotor approach. 27% of the neurons presented a peak of activity during acceleration followed by a valley during deceleration (acceleration-on cells). Together, these neurons accounted for most of the speed and acceleration encoding identified in our analysis. In contrast, a further 16% of neurons presented a valley during acceleration followed by a peak just prior to or after reaching reward (deceleration-on cells). These findings suggest that these three classes of NAc neurons influence the time course of speed changes during locomotor approach to reward.

Roles of nucleus accumbens core and shell in incentive-cue responding and behavioral inhibition.

The nucleus accumbens (NAc) is involved in many reward-related behaviors. The NAc has two major components, the core and the shell. These two areas have different inputs and outputs, suggesting that they contribute differentially to goal-directed behaviors. Using a discriminative stimulus (DS) task in rats and inactivating the NAc by blocking excitatory inputs with glutamate antagonists, we dissociated core and shell contributions to task performance. NAc core but not shell inactivation decreased responding to a reward-predictive cue. In contrast, inactivation of either subregion induced a general behavioral disinhibition. This reveals that the NAc actively suppresses actions inappropriate to the DS task. Importantly, selective inactivation of the shell but not core significantly increased responding to the nonrewarded cue. To determine whether the different contributions of the NAc core and shell depend on the information encoded in their constituent neurons, we performed electrophysiological recording in rats performing the DS task. Although there was no firing pattern unique to either core or shell, the reward-predictive cue elicited more frequent and larger magnitude responses in the NAc core than in the shell. Conversely, more NAc shell neurons selectively responded to the nonrewarded stimulus. These quantitative differences might account for the different behavioral patterns that require either core or shell. Neurons with similar firing patterns could also have different effects on behavior due to their distinct projection targets.

The Arousal-motor Hypothesis of Dopamine Function: Evidence that Dopamine Facilitates Reward Seeking in Part by Maintaining Arousal.

Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the accumbens reduces the proportion of reward-predictive cues to which rats respond with cued approach. Recent evidence indicates that accumbens dopamine also promotes wakefulness and arousal, but the relationship between dopamine's roles in arousal and reward seeking remains unexplored. Here, we show that the ability of systemic or intra-accumbens injections of the D1 antagonist SCH23390 to reduce cued approach to reward depends on the animal's state of arousal. Handling the animal, a manipulation known to increase arousal, was sufficient to reverse the behavioral effects of the antagonist. In addition, SCH23390 reduced spontaneous locomotion and increased time spent in sleep postures, both consistent with reduced arousal, but also increased time spent immobile in postures inconsistent with sleep. In contrast, the ability of the D2 antagonist haloperidol to reduce cued approach was not reversible by handling. Haloperidol reduced spontaneous locomotion but did not increase sleep postures, instead increasing immobility in non-sleep postures. We place these results in the context of the extensive literature on dopamine's contributions to behavior, and propose the arousal-motor hypothesis. This novel synthesis, which proposes that two main functions of dopamine are to promote arousal and facilitate motor behavior, accounts both for our findings and many previous behavioral observations that have led to disparate and conflicting conclusions.

Dips in dopamine say "no" to nicotine.

Nicotine has both rewarding and aversive effects. In this issue of Neuron, Liu et al. show that nicotine aversion depends on both desensitization of high-affinity nicotinic acetylcholine receptors (nAChRs) that activate midbrain dopamine neurons and activation of low-affinity nAChRs that inhibit dopamine neurons via the laterodorsal tegmental nucleus (LDT).

The flexible approach hypothesis: unification of effort and cue-responding hypotheses for the role of nucleus accumbens dopamine in the activation of reward-seeking behavior.

Dopamine released in the nucleus accumbens is thought to contribute to the decision to exert effort to seek reward. This hypothesis is supported by findings that performance of tasks requiring higher levels of effort is more susceptible to disruption by manipulations that reduce accumbens dopamine function than tasks that require less effort. However, performance of some low-effort cue-responding tasks is highly dependent on accumbens dopamine. To reconcile these disparate results, we made detailed behavioral observations of rats performing various operant tasks and determined how injection of dopamine receptor antagonists into the accumbens influenced specific aspects of the animals' behavior. Strikingly, once animals began a chain of operant responses, the antagonists did not affect the ability to continue the chain until reward delivery. Instead, when rats left the operandum, the antagonists severely impaired the ability to return. We show that this impairment is specific to situations in which the animal must determine a new set of approach actions on each approach occasion; this behavior is called "flexible approach." Both high-effort operant tasks and some low-effort cue-responding tasks require dopamine receptor activation in the accumbens because animals pause their responding and explore the chamber, and accumbens dopamine is required to terminate these pauses with flexible approach to the operandum. The flexible approach hypothesis provides a unified framework for understanding the contribution of the accumbens and its dopamine projection to reward-seeking behavior.

An inexpensive drivable cannulated microelectrode array for simultaneous unit recording and drug infusion in the same brain nucleus of behaving rats.

Neurons are functionally segregated into discrete populations that perform specific computations. These computations, mediated by neuron-neuron electrochemical signaling, form the neural basis of behavior. Thus fundamental to a brain-based understanding of behavior is the precise determination of the contribution made by specific neurotransmitters to behaviorally relevant neural activity. To facilitate this understanding, we have developed a cannulated microelectrode array for use in behaving rats that enables simultaneous neural ensemble recordings and local infusion of drugs in the same brain nucleus. The system is inexpensive, easy to use, and produces robust and quantitatively reproducible drug effects on recorded neurons.

Vigor Encoding in the Ventral Pallidum.

The ventral pallidum (VP) is the major downstream nucleus of the nucleus accumbens (NAc). Both VP and NAc neurons are responsive to reward-predictive stimuli and are critical drivers of reward-seeking behavior. The cue-evoked excitations and inhibitions of NAc neurons predict the vigor (latency and speed) of the cue-elicited locomotor approach response and encode the animal's proximity to the movement target, but do not encode more specific movement features such as turn direction. VP neurons also encode certain vigor parameters, but it remains unknown whether they also encode more specific movement features, and whether such encoding could account for vigor encoding. To address these questions, we recorded the firing of neurons in the VP of freely moving male rats performing a discriminative stimulus (DS) task. Similar to NAc neurons, VP neurons' cue-evoked excitations were correlated with the speed of the upcoming approach movement and the animal's proximity to the movement target at cue onset. Unlike NAc neurons, VP neurons' firing reflected the efficiency of the approach movement path but not the latency to initiate locomotion. VP cue-evoked excitations are unlikely to be directly influenced by NAc cue-evoked excitations because unilateral treatment of the NAc with a dopamine D1 receptor antagonist, a manipulation that reduces NAc neurons' cue-evoked excitations, did not alter ipsilateral VP cue-evoked excitations. These observations suggest that the two structures receive simultaneous activation by inputs conveying similar but not identical information, and work in parallel to set the vigor of the behavioral response.

Dorsomedial prefrontal cortex contribution to behavioral and nucleus accumbens neuronal responses to incentive cues.

Cue-elicited phasic changes in firing of nucleus accumbens (NAc) neurons can facilitate reward-seeking behavior. Here, we test the hypothesis that the medial prefrontal cortex (mPFC), which sends a dense glutamatergic projection to the NAc core, contributes to NAc neuronal firing responses to reward-predictive cues. Rats trained to perform an operant response to a cue for sucrose were implanted with recording electrodes in the core of the NAc and microinjection cannulas in the dorsal mPFC (dmPFC). The cue-evoked firing of NAc neurons was reduced by bilateral injection of GABA(A) and GABA(B) agonists into the dmPFC concomitant with loss of behavioral responding to the cue. In addition, unilateral dmPFC inactivation reduced ipsilateral cue excitations and contralateral cue inhibitions. These findings indicate that cue-evoked excitations and inhibitions of NAc core neurons depend on dmPFC projections to the NAc and that these phasic changes contribute to the behavioral response to reward-predictive cues.

NMDA receptor-dependent plasticity in the nucleus accumbens connects reward-predictive cues to approach responses.

Learning associations between environmental cues and rewards is a fundamental adaptive function. Via such learning, reward-predictive cues come to activate approach to locations where reward is available. The nucleus accumbens (NAc) is essential for cued approach behavior in trained subjects, and cue-evoked excitations in NAc neurons are critical for the expression of this behavior. Excitatory synapses within the NAc undergo synaptic plasticity that presumably contributes to cued approach acquisition, but a direct link between synaptic plasticity within the NAc and the development of cue-evoked neural activity during learning has not been established. Here we show that, with repeated cue-reward pairings, cue-evoked excitations in the NAc emerge and grow in the trials prior to the detectable expression of cued approach behavior. We demonstrate that the growth of these signals requires NMDA receptor-dependent plasticity within the NAc, revealing a neural mechanism by which the NAc participates in learning of conditioned reward-seeking behaviors.

A Working Hypothesis for the Role of the Cerebellum in Impulsivity and Compulsivity.

Growing evidence associates cerebellar abnormalities with several neuropsychiatric disorders in which compulsive symptomatology and impulsivity are part of the disease pattern. Symptomatology of autism, addiction, obsessive-compulsive (OCD), and attention deficit/hyperactivity (ADHD) disorders transcends the sphere of motor dysfunction and essentially entails integrative processes under control of prefrontal-thalamic-cerebellar loops. Patients with brain lesions affecting the cortico-striatum thalamic circuitry and the cerebellum indeed exhibit compulsive symptoms. Specifically, lesions of the posterior cerebellar vermis cause affective dysregulation and deficits in executive function. These deficits may be due to impairment of one of the main functions of the cerebellum, implementation of forward internal models of the environment. Actions that are independent of internal models may not be guided by predictive relationships or a mental representation of the goal. In this review article, we explain how this deficit might affect executive functions. Additionally, regionalized cerebellar lesions have been demonstrated to impair other brain functions such as the emergence of habits and behavioral inhibition, which are also altered in compulsive disorders. Similar to the infralimbic cortex, clinical studies and research in animal models suggest that the cerebellum is not required for learning goal-directed behaviors, but it is critical for habit formation. Despite this accumulating data, the role of the cerebellum in compulsive symptomatology and impulsivity is still a matter of discussion. Overall, findings point to a modulatory function of the cerebellum in terminating or initiating actions through regulation of the prefrontal cortices. Specifically, the cerebellum may be crucial for restraining ongoing actions when environmental conditions change by adjusting prefrontal activity in response to the new external and internal stimuli, thereby promoting flexible behavioral control. We elaborate on this explanatory framework and propose a working hypothesis for the involvement of the cerebellum in compulsive and impulsive endophenotypes.

Local µ-Opioid Receptor Antagonism Blunts Evoked Phasic Dopamine Release in the Nucleus Accumbens of Rats.

µ-opioid receptors (MORs) in the nucleus accumbens (NAc) can regulate reward-related behaviors that are dependent on mesolimbic dopamine, but the precise mechanism of this MOR regulation is unknown. We hypothesized that MORs within the NAc core regulate dopamine release. Specifically, we infused the MOR antagonist CTAP (d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2) into the NAc core while dopamine release was evoked by electrical stimulation of the ventral tegmental area and measured by fast-scan cyclic voltammetry. We report that CTAP dose-dependently inhibited evoked dopamine release, with full blockade achieved with the 8 µg infusion. In contrast, evoked dopamine release increased after nomifensine infusion and was unchanged after vehicle infusion. These findings demonstrate profound local control of dopamine release by MORs within the NAc core, which has implications for regulation of reward processing.

Endogenous opioids in the nucleus accumbens promote approach to high-fat food in the absence of caloric need.

When relatively sated, people (and rodents) are still easily tempted to consume calorie-dense foods, particularly those containing fat and sugar. Consumption of such foods while calorically replete likely contributes to obesity. The nucleus accumbens (NAc) opioid system has long been viewed as a critical substrate for this behavior, mainly via contributions to the neural control of consumption and palatability. Here, we test the hypothesis that endogenous NAc opioids also promote appetitive approach to calorie-dense food in states of relatively high satiety. We simultaneously recorded NAc neuronal firing and infused a µ-opioid receptor antagonist into the NAc while rats performed a cued approach task in which appetitive and consummatory phases were well separated. The results reveal elements of a neural mechanism by which NAc opioids promote approach to high-fat food despite the lack of caloric need, demonstrating a potential means by which the brain is biased towards overconsumption of palatable food.

The nucleus accumbens as part of a basal ganglia action selection circuit.

BACKGROUND: The nucleus accumbens is the ventral extent of the striatum, the main input nucleus of the basal ganglia. Recent hypotheses propose that the accumbens and its dopamine projection from the midbrain contribute to appetitive behaviors required to obtain reward. However, the specific nature of this contribution is unclear. In contrast, significant advances have been made in understanding the role of the dorsal striatum in action selection and decision making. OBJECTIVE: In order to develop a hypothesis of the role of nucleus accumbens dopamine in action selection, the physiology and behavioral pharmacology of the nucleus accumbens are compared to those of the dorsal striatum. HYPOTHESES: Three hypotheses concerning the role of dopamine in these structures are proposed: (1) that dopamine release in the dorsal striatum serves to facilitate the ability to respond appropriately to temporally predictable stimuli (that is, stimuli that are so predictable that animals engage in anticipatory behavior just prior to the stimulus); (2) that dopamine in the nucleus accumbens facilitates the ability to respond to temporally unpredictable stimuli (which require interruption of ongoing behavior); and (3) that accumbens neurons participate in action selection in response to such stimuli by virtue of their direct (monosynaptic inhibitory) and indirect (polysynaptic excitatory) projections to basal ganglia output nuclei.

Activation of Dopamine Receptors in the Nucleus Accumbens Promotes Sucrose-Reinforced Cued Approach Behavior.

Dopamine receptor activation in the nucleus accumbens (NAc) promotes vigorous environmentally-cued food-seeking in hungry rats. Rats fed ad libitum, however, respond to fewer food-predictive cues, particularly when the value of food reward is low. Here, we investigated whether this difference could be due to differences in the degree of dopamine receptor activation in the NAc. First, we observed that although rats given ad libitum access to chow in their home cages approached a food receptacle in response to reward-predictive cues, the number of such approaches declined as animals accumulated food rewards. Intriguingly, cued approach to food occurred in clusters, with several cued responses followed by successive non-responses. This pattern suggested that behavior was dictated by transitions between two states, responsive and non-responsive. Injection of D1 or D2 dopamine receptor agonists into the NAc dose-dependently increased cue responding by promoting transitions to the responsive state and by preventing transitions to the non-responsive state. In contrast, antagonists of either D1 or D2 receptors promoted long bouts of non-responding by inducing transitions to the non-responsive state and by preventing transitions to the responsive state. Moreover, locomotor behavior during the inter-trial interval was correlated with the responsive state, and was also increased by dopamine receptor agonists. These results suggest that activation of NAc dopamine receptors plays an important role in regulating the probability of approach to food under conditions of normative satiety.