Diverse roles of pontine NPS-expressing neurons in sleep regulation

Neuropeptide S (NPS) was postulated to be a wake-promoting neuropeptide with unknown mechanism, and a mutation in its receptor (NPSR1) causes the short sleep duration trait in humans. We investigated the role of different NPS + nuclei in sleep/wake regulation. Loss-of-function and chemogenetic studies revealed that NPS + neurons in the parabrachial nucleus (PB) are wake-promoting, whereas peri-locus coeruleus (peri-LC) NPS + neurons are not important for sleep/wake modulation. Further, we found that a NPS + nucleus in the central gray of the pons (CGPn) strongly promotes sleep. Fiber photometry recordings showed that NPS + neurons are wake-active in the CGPn and wake/REM-sleep active in the PB and peri-LC. Blocking NPS–NPSR1 signaling or knockdown of Nps supported the function of the NPS–NPSR1 pathway in sleep/wake regulation. Together, these results reveal that NPS and NPS + neurons play dichotomous roles in sleep/wake regulation at both the molecular and circuit levels.