Lateral hypothalamic circuits for feeding and reward

Abstract

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.

Figure 1. Electrical stimulation of the LHA produces reinforcement

a. Animals will self-stimulate in many regions of the ventral forebrain, but only the LHA electrical self-stimulation is largely insatiable (b). c. Illustration showing that the forebrain and hypothalamus sites (shaded) that supports electrical self-stimulation. Adapted from.

Figure 2. The LHA contains a mixture of inhibitory and excitatory neurons

a. In situ hybridization image of LHA Vgat expression. b. Vgat targeted neurons in the Vgat-ires-Cre mouse line. c. In situ hybridization image of LHA Vglut2 expression. d. Vglut2-targeted neurons in the Vglut2-ires-Cre mouse line.

Figure 3. Vgat-targeted neurons are distinct from MCH and Orexin producing LHA neurons

a. YFP expressing Vgat neurons (green) and MCH immunopositive neurons (red) in the LHA. b. YFP expressing Vgat neurons (green) and Orexin immunopositive neurons (red) in the LHA. c. VGat target LHA neurons thus represent a distinct population of LHA cells that mediate feeding. Data adapted from.

Figure 4. Proposed neurocircuit-wiring diagram based on optogenetic studies

LHA GABAergic neurons inhibit VTA GABAergic neurons to disinhibit VTA dopamine neurons. Dopamine is release within the NAc where it excites D1R expressing MSNs and induces plasticity. These inhibitory signals then feedbacks to inhibit LHA GABAergic neurons to terminate feeding bouts. BNST GABAergic neurons preferentially inhibit LHA Glutamate neurons, some of which may project to the lateral habenula.