Lateral hypothalamic LEPR neurons drive appetitive but not consummatory behaviors

Assigning behavioral roles to genetically defined neurons within the lateral hypothalamus (LH) is an ongoing challenge. We demonstrate that a subpopulation of LH GABAergic neurons expressing leptin receptors (LH(LEPR)) specifically drives appetitive behaviors in mice. Ablation of LH GABAergic neurons (LH(VGAT)) decreases weight gain and food intake, whereas LH(LEPR) ablation does not. Appetitive learning in a Pavlovian conditioning paradigm is delayed in LH(VGAT)-ablated mice but prevented entirely in LH(LEPR)-ablated mice. Both LH(VGAT) and LH(LEPR) neurons bidirectionally modulate reward-related behaviors, but only LH(VGAT) neurons affect feeding. In the Pavlovian paradigm, only LH(LEPR) activity discriminates between conditioned cues. Optogenetic activation or inhibition of either population in this task disrupts discrimination. However, manipulations of LH(LEPR)→VTA projections evoke divergent effects on responding. Unlike food-oriented learning, chemogenetic inhibition of LH(LEPR) neurons does not alter cocaine-conditioned place preference but attenuates cocaine sensitization. Thus, LH(LEPR) neurons may specifically regulate appetitive behaviors toward non-drug reinforcers.