Lateral hypothalamic input engages a disinhibitory microcircuit in the dorsal raphe to promote behavior activation

Abstract

Behavioral activation involves coordination between hypothalamic and brainstem systems that regulate movement and internal state, but the circuit logic underlying this interaction remains poorly defined. The dorsal raphe nucleus (DRN), a major serotonergic hub, integrates diverse inputs to influence behavioral inhibition and activation, yet how hypothalamic signals shape its activity is unclear. Here, we identify a disinhibitory pathway through which the lateral hypothalamus (LHA) promotes behavioral activation via DRN. Using intersectional viral tracing, electrophysiology, and single-nucleus RNA sequencing, we show that LHA inputs preferentially target GABAergic DRN neurons that locally inhibit 5-HT neurons. Silencing these DRN neurons innervated by LHA increased locomotor and repetitive behaviors, decreased local inhibition, and enhanced cFos activity in serotonergic neurons, consistent with circuit-level disinhibition. Molecular profiling revealed distinct transmitter identities and transcriptional signatures of LHA-targeted versus LHA-projecting DRN populations. Together, these findings delineate a hypothalamic-raphe circuit that transforms hypothalamic drive into serotonergic activation, revealing a mechanism by which the lateral hypothalamus promotes behavioral activation through local inhibitory control. HIGHLIGHTSO_LILHA inputs preferentially target non-serotonergic, transcriptionally distinct DRN neurons C_LIO_LILHA-innervated DRN neurons form extensive local inhibition C_LIO_LISilencing LHA-innervated DRN neurons reduced local inhibitory tone and activate serotonin neurons C_LIO_LIDisrupting this circuit drives behavioral activation with repetitive motor pattern, not anxiety C_LI