Kyle S. Smith

Hedonic Hot Spots in the Brain

Hedonic “liking” for sensory pleasures is an important aspect of reward, and excessive ‘liking’ of particular rewards might contribute to excessive consumption and to disorders such as obesity. The present review aims to summarize recent advances in the identification of brain substrates for food ‘liking’ with a focus on opioid hot spots in the nucleus accumbens and ventral pallidum. Drug microinjection studies have shown that opioids in both areas amplify the ‘liking’ of sweet taste rewards. Modern neuroscience tools such as Fos plume mapping have further identified hedonic hot spots within the accumbens and pallidum, where opioids are especially tuned to magnify ‘liking’ of food rewards. Hedonic hot spots in different brain structures may interact with each other within the larger functional circuitry that interconnects them. Better understanding of how brain hedonic hot spots increase the positive affective impact of natural sensory pleasures will help characterize the neural mechanisms potentially involved in ‘liking’ for many rewards.

Opioid Limbic Circuit for Reward: Interaction between Hedonic Hotspots of Nucleus Accumbens and Ventral Pallidum

μ-Opioid stimulation of cubic millimeter hedonic hotspots in either the nucleus accumbens shell (NAc) or the ventral pallidum (VP) amplifies hedonic “liking” reactions to sweetness and appetitive “wanting” for food reward. How do these two NAc–VP hotspots interact? To probe their interaction and limbic circuit properties, we assessed whether opioid activation of one hotspot recruited the other hotspot (neurobiologically) and whether opioid hedonic and incentive motivational amplification by either opioid hotspot required permissive opioid coactivation in the other (behaviorally). We found that NAc and VP hotspots reciprocally modulated Fos expression in each other and that the two hotspots were needed together to enhance sucrose “liking” reactions, essentially cooperating within a single hedonic NAc–VP circuit. In contrast, the NAc hotspot dominated for opioid stimulation of eating and food intake (“wanting”), independent of VP activation. This pattern reveals differences between limbic opioid circuits that control reward “liking” and “wanting” functions.

Endocannabinoid Hedonic Hotspot for Sensory Pleasure: Anandamide in Nucleus Accumbens Shell Enhances ‘Liking’ of a Sweet Reward

Cannabinoid drugs such as Δ9-THC are euphoric and rewarding, and also stimulate food intake in humans and animals. Little is known about how naturally occurring endogenous brain cannabinoids mediate pleasure from food or other natural sensory rewards. The taste reactivity paradigm measures effects of brain manipulations on affective orofacial reactions to intraorally administered pleasant and unpleasant tastes. Here we tested if anandamide microinjection into medial nucleus accumbens shell enhances these affective reactions to sweet and bitter tastes in rats. Anandamide doubled the number of positive ‘liking’ reactions elicited by intraoral sucrose, without altering negative ‘disliking’ reactions to bitter quinine. Anandamide microinjections produced Fos plumes of approximately 0.02–1 mm3 volume. Plume-based maps, integrated with behavioral data, identified the medial shell of accumbens as the anatomical hotspot responsible for hedonic amplification. Anandamide produced especially intense hedonic enhancement in a roughly 1.6 mm3 ‘hedonic hotspot’ in dorsal medial shell, where anandamide also stimulated eating behavior. These results demonstrate that endocannabinoid signals within medial accumbens shell specifically amplify the positive hedonic impact of a natural reward (though identification of the receptor specificity of this effect will require future studies). Identification of an endocannabinoid hotspot for sensory pleasure gives insight into brain mechanisms of natural reward, and may be relevant to understanding the neural effects of cannabinoid drugs of abuse and therapeutic agents.

Disentangling pleasure from incentive salience and learning signals in brain reward circuitry

Multiple signals for reward—hedonic impact, motivation, and learned associative prediction—are funneled through brain mesocorticolimbic circuits involving the nucleus accumbens and ventral pallidum. Here, we show how the hedonic “liking” and motivation “wanting” signals for a sweet reward are distinctly modulated and tracked in this circuit separately from signals for Pavlovian predictions (learning). Animals first learned to associate a fixed sequence of Pavlovian cues with sucrose reward. Subsequent intraaccumbens microinjections of an opioid-stimulating drug increased the hedonic liking impact of sucrose in behavior and firing signals of ventral pallidum neurons, and likewise, they increased incentive salience signals in firing to the reward-proximal incentive cue (but did not alter firing signals to the learned prediction value of a reward-distal cue). Microinjection of a dopamine-stimulating drug instead enhanced only the motivation component but did not alter hedonic impact or learned prediction signals. Different dedicated neuronal subpopulations in the ventral pallidum tracked signal enhancements for hedonic impact vs. incentive salience, and a faster firing pattern also distinguished incentive signals from slower hedonic signals, even for a third overlapping population. These results reveal separate neural representations of wanting, liking, and prediction components of the same reward within the nucleus accumbens to ventral pallidum segment of mesocorticolimbic circuitry.

The Ventral Pallidum and Hedonic Reward: Neurochemical Maps of Sucrose “Liking” and Food Intake

How are natural reward functions such as sucrose hedonic impact and the motivation to eat generated within the ventral pallidum (VP)? Here, we used a novel microinjection and functional mapping procedure to neuroanatomically localize and neurochemically characterize substrates in the VP that mediate increases in eating behavior and enhancements in taste hedonic “liking” reactions. The μ-opioid agonist d-Ala2-N-Me-Phe4-Glycol5-enkephalin (DAMGO) caused increased hedonic “liking” reactions to sucrose only in the posterior VP but conversely suppressed “liking” reactions in the anterior and central VP. DAMGO similarly stimulated eating behavior in the posterior and central VP and suppressed eating in the anterior VP. In contrast, the GABAA antagonist bicuculline increased eating behavior at all VP sites, yet completely failed to enhance sucrose “liking” reactions at any site. These results reveal that VP generation of increased food reward and increased eating behavior is related but dissociable. Hedonic “liking” and eating are systematically mapped in a neuroanatomically and neurochemically interactive manner in the VP.

Corticostriatal Interactions during Learning, Memory Processing, and Decision Making

This mini-symposium aims to integrate recent insights from anatomy, behavior, and neurophysiology, highlighting the anatomical organization, behavioral significance, and information-processing mechanisms of corticostriatal interactions. In this summary of topics, which is not meant to provide a comprehensive survey, we will first review the anatomy of corticostriatal circuits, comparing different ways by which “loops” of cortical–basal ganglia circuits communicate. Next, we will address the causal importance and systems-neurophysiological mechanisms of corticostriatal interactions for memory, emphasizing the communication between hippocampus and ventral striatum during contextual conditioning. Furthermore, ensemble recording techniques have been applied to compare information processing in the dorsal and ventral striatum to predictions from reinforcement learning theory. We will next discuss how neural activity develops in corticostriatal areas when habits are learned. Finally, we will evaluate the role of GABAergic interneurons in dynamically transforming cortical inputs into striatal output during learning and decision making.

Reversible online control of habitual behavior by optogenetic perturbation of medial prefrontal cortex

Habits tend to form slowly but, once formed, can have great stability. We probed these temporal characteristics of habitual behaviors by intervening optogenetically in forebrain habit circuits as rats performed well-ingrained habitual runs in a T-maze. We trained rats to perform a maze habit, confirmed the habitual behavior by devaluation tests, and then, during the maze runs (ca. 3 s), we disrupted population activity in a small region in the medial prefrontal cortex, the infralimbic cortex. In accordance with evidence that this region is necessary for the expression of habits, we found that this cortical disruption blocked habitual behavior. Notably, however, this blockade of habitual performance occurred on line, within an average of three trials (ca. 9 s of inhibition), and as soon as during the first trial (<3 s). During subsequent weeks of training, the rats acquired a new behavioral pattern. When we again imposed the same cortical perturbation, the rats regained the suppressed maze-running that typified the original habit, and, simultaneously, the more recently acquired habit was blocked. These online changes occurred within an average of two trials (ca. 6 s of infralimbic inhibition). Measured changes in generalized performance ability and motivation to consume reward were unaffected. This immediate toggling between breaking old habits and returning to them demonstrates that even semiautomatic behaviors are under cortical control and that this control occurs online, second by second. These temporal characteristics define a framework for uncovering cellular transitions between fixed and flexible behaviors, and corresponding disturbances in pathologies.

Chemogenetic manipulation of ventral pallidal neurons impairs acquisition of sign-tracking in rats.

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.

Habit Formation Coincides with Shifts in Reinforcement Representations in the Sensorimotor Striatum

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.

An omission procedure reorganizes the microstructure of sign-tracking while preserving incentive salience

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.