Neuromedin U Receptor 2 orchestrates sleep continuity and circadian entrainment

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Abstract
Neuromedin S signaling has recently been identified as a modulator of both sleep and circadian rhythms within the mammalian central nervous system. However, the involvement of its preferred receptor, NMUR2, remains elusive. Following extensive profiling and refinement, we utilize R-PSOP, its only selective antagonist, to elucidate NMUR2 function in the mouse brain. We show that NMUR2 is essential for physiological sleep architecture under baseline conditions, as well as for responses to homeostatic and circadian challenges. We demonstrate that NMUR2 antagonism produces opposing effects on time spent asleep depending on the circadian phase of administration, while its effects on EEG spectral activity and locomotion persist across conditions. Combining pharmacological, neuronal-tagging, brain-clearing and chemogenetic tools, we functionally implicate a subset of PVH neurons whose activation unexpectedly promotes sleep. Together, our observations establish NMUR2 as a promising therapeutic target for the treatment of sleep and circadian neurological disorders.