Neuromedin U Receptor 2 orchestrates sleep continuity and circadian entrainment

Neuromedin S signaling has recently been identified as a modulator of both sleep and circadian rhythms in the central nervous systems of mammals. Nevertheless, the involvement of its preferred receptor, NMUR2, in sleep and circadian regulation remains elusive. Here, employing its only selective antagonist R-PSOP, we demonstrate that NMUR2 function in the mouse brain is essential for physiological sleep architecture under baseline conditions, as well as for responses to homeostatic and circadian challenges. Using a combination of pharmacological, neuronal tagging, brain clearing and chemogenetic tools, we identified and functionally validated a group of PVH neurons as one of the targets mediating the effect of R-PSOP on sleep. These findings establish NMUR2 as a potential therapeutic target for the integral treatment of sleep and circadian neurological disorders. HIGHLIGHTSSelective NMUR2 antagonism via R-PSOP disrupts vigilance state continuity in a dose- and circadian phase-dependent manner R-PSOP administration delays circadian phase entrainment and hinders sleep homeostasis recovery PVH neurons are activated by R-PSOP and boost wake-to-NREM sleep transitions in the active period