Transcriptional and functional divergence in lateral hypothalamic glutamate neurons projecting to the lateral habenula and ventral tegmental area

The lateral hypothalamic area (LHA) regulates feeding- and reward-related behavior, but because of its molecular and anatomical heterogeneity, the functions of defined neuronal populations are largely unclear. Glutamatergic neurons within the LHA (LHAVglut2) negatively regulate feeding and appetitive behavior. However, this population comprises transcriptionally distinct and functionally diverse neurons that project to diverse brain regions, including the lateral habenula (LHb) and ventral tegmental area (VTA). To resolve the function of distinct LHAVglut2 populations, we systematically compared projections to the LHb and VTA using viral tracing, single-cell sequencing, electrophysiology, and in vivo calcium imaging. LHAVglut2 neurons projecting to the LHb or VTA are anatomically, transcriptionally, electrophysiologically, and functionally distinct. While both populations encode appetitive and aversive stimuli, LHb projecting neurons are especially sensitive to satiety state and feeding hormones. These data illuminate the functional heterogeneity of LHAVglut2 neurons, suggesting that reward and aversion are differentially processed in divergent efferent pathways. [Display omitted] •LHA glutamate projections to LHb and VTA are anatomically and molecularly distinct•LHb projectors are more active and excitable than VTA projectors•LHb and VTA projections discern appetitive and aversive tastes and satiety states•Leptin and Ghrelin differentially influence LHb and VTA projection reward encoding Rossi et al. systematically compare lateral hypothalamic glutamatergic neurons projecting to LHb and VTA using viral tracing, single-cell sequencing, electrophysiology, and in vivo calcium imaging. The two populations are anatomically, transcriptionally, and functionally distinct. In vivo dynamics are modified by stimulus valance, satiety, and the feeding hormones leptin and ghrelin.