WAKE-ACTIVATED NEURONAL POPULATIONS THAT REGULATE SLEEP DRIVE

Prolonged wakefulness increases sleep drive and is normally compensated by increased sleep. This homeostatic regulation of sleep profoundly shapes our lives, but the underlying neural circuit mechanisms remain poorly understood. Here, we identify wake-activated neurons that regulate sleep drive in mice, using whole-brain activity mapping, targeted neuronal manipulations, and electrophysiology. Comparison of whole-brain responses to sleep deprivation, recovery sleep, and circadian behavior identify the anterior medial preoptic area and the median raphe as candidate regions that encode sleep deficit. Activating sleep deprivation-responsive cells in these regions induces increases in sleep duration and intensity that resemble recovery sleep. Conversely, inhibiting deprivation-responsive cells reduces sleep and abolishes the elevated sleep propensity normally observed during deprivation. Sleep deprivation-responsive neurons in the median raphe project to subcortical sleep-associated regions and act through the preoptic hypothalamus. These deprivation-sensitive cells include serotonergic neurons plus a distinct population of GABAergic neurons, whose intrinsic excitability increases during sleep deprivation. Co-activation of GABAergic and serotonergic neurons synergistically promotes sleep, whereas co-inhibition chronically decreases sleep by ~70%. Remarkably, this profound reduction in sleep does not elicit compensatory increases in sleep drive or the behavioral deficits typically associated with severe sleep deprivation. Together, these results define novel neuronal populations that are activated during wakefulness to regulate sleep drive.