An excitatory peri-tegmental reticular nucleus circuit for wake maintenance.

Sleep is a necessity for our survival, but its regulation remains incompletely understood. Here, we used a human sleep duration gene to identify a population of cells in the peri-tegmental reticular nucleus (pTRN) that regulate sleep-wake, uncovering a role for a poorly understood brain area. Although initial ablation in mice led to increased wakefulness, further validation revealed that pTRN neuron stimulation strongly promotes wakefulness, even after stimulation offset. Using combinatorial genetics, we found that excitatory pTRN neurons promote wakefulness. pTRN neurons can be characterized as anterior- or posterior-projecting neurons based on multiplexed analysis of projections by sequencing (MAPseq) analysis. Finally, we found that pTRN neurons promote wakefulness, in part, through projections to the lateral hypothalamus. Thus, human genetic information from a human sleep trait allowed us to identify a role for the pTRN in sleep-wake regulation.