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 (LHA(Vglu)(t2)) 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 LHA(Vglu)(t2) populations, we systematically compared projections to the LHb and VTA using viral tracing, single-cell sequencing, electrophysiology, and in vivo calcium imaging. LHA(Vglu)(t2) 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 LHA(Vglu)(t2) neurons, suggesting that reward and aversion are differentially processed in divergent efferent pathways.

Automated summary

The lateral hypothalamic area (LHA) contains distinct populations of glutamatergic neurons that project to different brain regions, with neurons projecting to the lateral habenula (LHb) or ventral tegmental area (VTA) showing anatomical, transcriptional, electrophysiological, and functional differences. Neurons projecting to the LHb are particularly sensitive to satiety state and feeding hormones, indicating differential processing of reward and aversion stimuli in divergent efferent pathways.