Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward

The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate the consumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloric intake and produced weight gain in mice that had access to a high-fat diet, while not altering general locomotor activity. Anterior LHA glutamatergic neurons send a functional glutamatergic projection to the LHb, a brain region involved in processing aversive stimuli and negative reward prediction outcomes. Pathway-specific, optogenetic stimulation of glutamatergic LHA-LHb circuit resulted in detectable glutamate-mediated EPSCs as well as GABA-mediated IPSCs, although the net effect of neurotransmitter release was to increase the firing of most LHb neurons. In vivo optogenetic inhibition of LHA-LHb glutamatergic fibers produced a real-time place preference, whereas optogenetic stimulation of LHA-LHb glutamatergic fibers had the opposite effect. Furthermore, optogenetic inhibition of LHA-LHb glutamatergic fibers acutely increased the consumption of a palatable liquid caloric reward. Collectively, these results demonstrate that L HA glutamatergic neurons are well situated to bidirectionally regulate feeding and potentially other behavioral states via their functional circuit connectivity with the LHb and potentially other brain regions.