Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus (PSTN), a relatively unexplored population of neurons in the posterior hypothalamus, has been hypothesized to regulate appetite due to its connectivity with other anorexigenic neuronal populations and because these neurons express Fos, a marker of neuronal activation, following a meal. However, the individual cell types that make up the PSTN are not well characterized, nor are their functional roles in food intake behavior. Here, we identify and distinguish between two discrete PSTN subpopulations, those that express tachykinin-1 (PSTN^Tac1 neurons) and those that express corticotropin-releasing hormone (PSTN^CRH neurons), and use a panel of genetically encoded tools in mice to show that PSTN^Tac1 neurons play an important role in appetite suppression. Both subpopulations increase activity following a meal and in response to administration of the anorexigenic hormones amylin, cholecystokinin (CCK), and peptide YY (PYY). Interestingly, chemogenetic inhibition of PSTN^Tac1, but not PSTN^CRH neurons, reduces the appetite-suppressing effects of these hormones. Consistently, optogenetic and chemogenetic stimulation of PSTN^Tac1 neurons, but not PSTN^CRH neurons, reduces food intake in hungry mice. PSTN^Tac1 and PSTN^CRH neurons project to distinct downstream brain regions, and stimulation of PSTN^Tac1 projections to individual anorexigenic populations reduces food consumption. Taken together, these results reveal the functional properties and projection patterns of distinct PSTN cell types and demonstrate an anorexigenic role for PSTN^Tac1 neurons in the hormonal and central regulation of appetite.

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