The mammalian circadian pacemaker regulates wakefulness via CRF neurons in the paraventricular nucleus of the hypothalamus

In mammals, the daily rhythms of physiological functions are timed by the central circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Although the importance of the SCN for the regulation of sleep/wakefulness has been suggested, little is known about the neuronal projections from the SCN, which regulate sleep/wakefulness. Here, we show that corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus mediate circadian rhythms in the SCN and regulate wakefulness. Optogenetic activation of CRF neurons promoted wakefulness through orexin/hypocretin neurons in the lateral hypothalamus. In vivo Ca(2+) recording showed that CRF neurons were active at the initiation of wakefulness. Furthermore, chemogenetic suppression and ablation of CRF neurons decreased locomotor activity and time in wakefulness. Last, a combination of optical manipulation and Ca(2+) imaging revealed that neuronal activity of CRF neurons was negatively regulated by GABAergic neurons in the SCN. Our findings provide notable insights into circadian regulation of sleep/wakefulness in mammals.