Wake-activated neuronal populations that regulate sleep drive

Prolonged wakefulness increases sleep drive and is normally compensated for by increased sleep^1-3. This homeostatic regulation of sleep shapes our lives profoundly, 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. By comparing whole-brain responses to sleep deprivation, recovery sleep and circadian behaviour, we 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 increased sleep propensity usually observed during deprivation. Neurons in the median raphe that are responsive to sleep deprivation project to subcortical sleep-associated regions and act through the preoptic hypothalamus. These deprivation-sensitive cells include serotonergic neurons and 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 nearly 70%. Remarkably, most mice survive despite this marked reduction in sleep, without the compensatory increases in sleep drive or the behavioural deficits typically associated with severe sleep deprivation. Together, these results define neuronal populations that are activated during wakefulness and are crucial for sleep drive.