Lateral hypothalamus, nucleus accumbens, and ventral pallidum roles in eating and hunger: interactions between homeostatic and reward circuitry

Abstract

The study of the neural bases of eating behavior, hunger, and reward has consistently implicated the lateral hypothalamus (LH) and its interactions with mesocorticolimbic circuitry, such as mesolimbic dopamine projections to nucleus accumbens (NAc) and ventral pallidum (VP), in controlling motivation to eat. The NAc and VP play special roles in mediating the hedonic impact ("liking") and motivational incentive salience ("wanting") of food rewards, and their interactions with LH help permit regulatory hunger/satiety modulation of food motivation and reward. Here, we review some progress that has been made regarding this circuitry and its functions: the identification of localized anatomical hedonic hotspots within NAc and VP for enhancing hedonic impact; interactions of NAc/VP hedonic hotspots with specific LH signals such as orexin; an anterior-posterior gradient of sites in NAc shell for producing intense appetitive eating vs. intense fearful reactions; and anatomically distributed appetitive functions of dopamine and mu opioid signals in NAc shell and related structures. Such findings help improve our understanding of NAc, VP, and LH interactions in mediating affective and motivation functions, including "liking" and "wanting" for food rewards.

Keywords: lateral hypothalamus; motivation; nucleus accumbens; reward; ventral pallidum.

Figure 1

Hedonic hotspots in nucleus accumbens (NAc) and ventral pallidum (VP). Top: Sagittal views of NAc medial shell showing functional maps of opioid-stimulated hedonic enhancements, as measured by taste reactivity to sucrose. Microinjections that stimulated mu (left), delta (middle) or kappa (right) opioid receptors in the rostrodorsal quadrant of NAc medial shell increased hedonic “liking” reactions to sucrose, compared to vehicle baselines in the same rats. A single map showing shared opioid hotspot includes any site where agonist microinjection increased hedonic reactions by at least 250% compared to baseline (overlapping sites shown adjacently). Mu effects are depicted in red, delta in orange, and kappa in yellow (Modified from Castro and Berridge, 2014). Bottom: Horizontal maps of VP similarly show sites where mu opioid (left) or orexin stimulation increased hedonic reactions. A shared hedonic hotspot is revealed in posterior VP, where either mu opioid or orexin stimulation increased hedonic reactions by at least 150% compared to vehicle baseline in the same rats. Mu is colored red, and orexin is colored yellow (Modified from Ho and Berridge, 2013).

Figure 2

NAc rostrocaudal differences in glutamate and GABA mediation of desire and dread. Top: Sagittal view showing maps of DNQX- or muscimol-generated appetitive eating vs. fearful or defensive behaviors, and effects of adding local dopamine blockade to the same microinjection. Appetitive eating and defensive reactions elicited by DNQX (top left) both require D1 receptor function (top middle), but defensive reactions additionally require D2 receptor function (top right) (figure is adapted from Richard and Berridge, 2011). By contrast, GABAergic muscimol-generated eating and defensive behaviors (bottom left) are unaffected by dopamine blockade (bottom right) (adapted from Richard et al., 2013). Bottom: Environmental ambience retunes the motivation function of NAc sites. Testing in home environments abolished almost all defensive reactions, and promoted appetitive eating, elicited by DNQX microinjections in NAc shell (top left). By contrast, a stressfully loud and bright environment expanded DNQX-generated defensive behaviors into rostral regions of NAc shell, and suppressed fearful reactions (top right), relative to standard laboratory conditions (top middle). Muscimol microinjections in NAc shell generated eating and fear at similar sites to DNQX, but was not shifted by environmental ambience of home (bottom left), standard (bottom middle), or stressful test conditions (bottom right). Sites are colored as producing appetitive behavior (green sites), defensive behavior (red sites), or mixtures of both behaviors (yellow). Green symbols represent at least a 200% increase in food intake, red symbols represent at least a 500% increase in defensive treading or another defensive reaction (distress vocalization, escape attempt or biting when rat was touched), and yellow symbols represent a combination of the eating and defensive criteria (adapted from Richard et al., 2013).

Figure 3

Mesocorticolimbic-hypothalamic circuitry and functions. Sagittal view depicts structures and circuitry underlying “liking”, “wanting”, and “fear” functions discussed in text. The NAc medial shell contains a hedonic hotspot in the rostral half, where opioid and related stimulation increases “liking” reactions to sucrose taste. Conversely, NAc shell contains a caudal hedonic coldspot, where opioid stimulation suppresses “liking” reactions to sweetness. These functional sites overlap with the NAc shell motivational keyboard for GABAergic/glutamatergic microinjections, in which rostral sites produce desire (e.g., eating, place preference, etc.), caudal sites produce fear (e.g., antipredator reactions, distress calls and bites, and place avoidance). Furthermore, NAc glutamatergic generation of appetitive behavior by DNQX microinjection requires endogenous dopamine stimulation of D1 receptors on direct path neurons that project directly to ventral tegmental area (VTA). Optogenetic stimulation of NAc D1-expressing neurons also supports appetitive self-stimulation behavior throughout the entire medial shell. By contrast, NAc glutamatergic generation of fearful behaviors requires additional dopamine stimulation of D2-receptors, implicating indirect path neurons that project to the VP and lateral hypothalamus (LH). The posterior half of VP contains an opioid hedonic hotspot, whereas the rostral half of VP contains a coldspot where mu opioid stimulation suppresses “liking” reactions to sucrose taste. Optogenetic stimulation of the VP hotspot, or of its lateral hypothalamic inputs, may produce enhanced “liking” and “wanting”. Colors denote implication in “wanting” (green), fear (red), mixed “wanting” and fear (yellow), suppression of “wanting” or “fear” (gray), “liking” (orange), or suppression of “liking” (blue). All data from sources described in text.