Neuro-orchestration of sleep and wakefulness.

Although considered an inactive state for centuries, sleep entails many active processes occurring at the cellular, circuit and organismal levels. Over the last decade, several key technological advances, including calcium imaging and optogenetic and chemogenetic manipulations, have facilitated a detailed understanding of the functions of different neuronal populations and circuits in sleep-wake regulation. Here, we present recent progress and summarize our current understanding of the circuitry underlying the initiation, maintenance and coordination of wakefulness, rapid eye movement sleep (REMS) and non-REMS (NREMS). We propose a de-arousal model for sleep initiation, in which the neuromodulatory milieu necessary for sleep initiation is achieved by engaging in repetitive pre-sleep behaviors that gradually reduce vigilance to the external environment and wake-promoting neuromodulatory tone. We also discuss how brain processes related to thermoregulation, hunger and fear intersect with sleep-wake circuits to control arousal. Lastly, we discuss controversies and lingering questions in the sleep field.