Galanin-Expressing GABA Neurons in the Lateral Hypothalamus Modulate Food Reward and Noncompulsive Locomotion

Abstract

The lateral hypothalamus (LHA) integrates reward and appetitive behavior and is composed of many overlapping neuronal populations. Recent studies associated LHA GABAergic neurons (LHA ^GABA ), which densely innervate the ventral tegmental area (VTA), with modulation of food reward and consumption; yet, LHA ^GABA projections to the VTA exclusively modulated food consumption, not reward. We identified a subpopulation of LHA ^GABA neurons that coexpress the neuropeptide galanin (LHA ^Gal ). These LHA ^Gal neurons also modulate food reward, but lack direct VTA innervation. We hypothesized that LHA ^Gal neurons may represent a subpopulation of LHA ^GABA neurons that mediates food reward independent of direct VTA innervation. We used chemogenetic activation of LHA ^Gal or LHA ^GABA neurons in mice to compare their role in feeding behavior. We further analyzed locomotor behavior to understand how differential VTA connectivity and transmitter release in these LHA neurons influences this behavior. LHA ^Gal or LHA ^GABA neuronal activation both increased operant food-seeking behavior, but only activation of LHA ^GABA neurons increased overall chow consumption. Additionally, LHA ^Gal or LHA ^GABA neuronal activation similarly induced locomotor activity, but with striking differences in modality. Activation of LHA ^GABA neurons induced compulsive-like locomotor behavior; while LHA ^Gal neurons induced locomotor activity without compulsivity. Thus, LHA ^Gal neurons define a subpopulation of LHA ^GABA neurons without direct VTA innervation that mediate noncompulsive food-seeking behavior. We speculate that the striking difference in compulsive-like locomotor behavior is also based on differential VTA innervation. The downstream neural network responsible for this behavior and a potential role for galanin as neuromodulator remains to be identified.SIGNIFICANCE STATEMENT The lateral hypothalamus (LHA) regulates motivated feeding behavior via GABAergic LHA neurons. The molecular identity of LHA ^GABA neurons is heterogeneous and largely undefined. Here we introduce LHA ^Gal neurons as a subset of LHA ^GABA neurons that lack direct innervation of the ventral tegmental area (VTA). LHA ^Gal neurons are sufficient to drive motivated feeding and locomotor activity similar to LHA ^GABA neurons, but without inducing compulsive-like behaviors, which we propose to require direct VTA innervation. Our study integrates galanin-expressing LHA neurons into our current understanding of the neuronal circuits and molecular mechanisms of the LHA that contribute to motivated feeding behaviors.

Keywords: DREADD; compulsivity; energy expenditure; feeding; locomotor activity; marble-burying test.