Steven Tran, Jasmine Emtage, Chaodong Zhang, Xiaoyao Liu, Marina Lecoeuche, Andrey Andreev, Grigorios Oikonomou, Sujatha Narayan, Brianna Garcia, Tasha Cammidge, Cristina Gonzales, Hannah Hurley, Misha Yap, Shan Li, Feng Wang, Ting‐Yu Wang, Misha B. Ahrens, Tsui‐Fen Chou, Min Xu, Qinghua Liu, David A. Prober
ABSTRACT Sleep is regulated by a homeostatic process and associated with an increased arousal threshold, but the genetic and neuronal mechanisms that implement these essential features of sleep remain poorly understood. To address these fundamental questions, we performed a zebrafish genetic screen informed by human genome-wide association studies. We found that mutation of serine/threonine kinase 32a ( stk32a ) results in increased sleep and impaired sleep homeostasis in both zebrafish and mice, and that stk32a acts downstream of neurotensin signaling and the serotonergic raphe in zebrafish. stk32a mutation reduces phosphorylation of neurofilament proteins, which are co-expressed with stk32a in neurons that regulate motor activity and in lateral line hair cells that detect environmental stimuli, and ablating these cells phenocopies stk32a mutation. Neurotensin signaling inhibits specific sensory and motor populations, and blocks stimulus-evoked responses of neurons that relay sensory information from hair cells to the brain. Our work thus shows that stk32a is an evolutionarily conserved sleep regulator that links neuropeptidergic and neuromodulatory systems to homeostatic sleep drive and changes in arousal threshold, which are implemented through suppression of specific sensory and motor systems.