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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.

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