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.