authors contributed equally to this work.One-sentence summaries: A human Neuropeptide S Receptor 1 (NPSR1) mutation found in natural short sleepers renders mutant mice to be short sleepers with more resilience to memory deficits caused by sleep deprivation.Abstract: Sleep is a crucial physiological process for our survival and cognitive performance, yet the factors controlling human sleep regulation remain poorly understood. Here we identified a missense mutation in a G-protein coupled Neuropeptide S Receptor 1 (NPSR1) that is associated with a natural short sleep phenotype in humans. Mice carrying the homologous mutation exhibit less sleep time despite increased sleep pressure. They are also resistant to contextual memory deficits associated with sleep deprivation. In vivo, the mutant receptors are more sensitive to Neuropeptide S ligand treatment. These results highlight an important role for the NPS/NPSR1 pathway in human sleep duration regulation and in the connection between sleep homeostasis and memory consolidation.

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Sleep deprivation can generate inflammatory responses in the central nervous system. In turn, this inflammation increases sleep drive, leading to a rebound in sleep duration. Microglia, the innate immune cells found exclusively in the CNS, have previously been found to release inflammatory signals and exhibit altered characteristics in response to sleep deprivation. Together, this suggests that microglia may be partially responsible for the brain's response to sleep deprivation through their inflammatory activity. In this study, we ablated microglia from the mouse brain and assessed resulting sleep, circadian, and sleep deprivation phenotypes. We find that microglia are dispensable for both homeostatic sleep and circadian function and the sleep rebound response to sleep deprivation. However, we uncover a phenomenon by which microglia appear to be essential for the protection of fear-conditioning memories formed during the recovery sleep period following a period of sleep deprivation. This phenomenon occurs potentially through the upregulation of synaptic-homeostasis related genes to protect nascent dendritic spines that may be otherwise removed or downscaled during recovery sleep. These findings further expand the list of known functions for microglia in synaptic modulation.

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