A Subcircuit in the Suprachiasmatic Nucleus Generates Wakefulness

The daily cycles of sleep and arousal are among the most prominent biological rhythms under circadian control. While the role of the suprachiasmatic nucleus (SCN) as the master circadian pacemaker is well-established, the molecular and circuit mechanisms by which it regulates the rhythms of sleep and arousal remain poorly understood. It has previously shown that the Drosophila clock-output molecule Wide Awake (WAKE) and its mammalian homolog mWAKE are expressed in fly clock neurons and dorsomedial hypothalamus neurons that promote arousal. Here, it is investigated whether mWAKE labels an arousal-promoting SCN subcircuit in mice. Broad chemogenetic activation and inhibition of mWAKE+ cells lead to a marked increase in wakefulness and a stupor-like phenotype, respectively. Optogenetic activation specifically of mWAKE-expressing neurons in the SCN (SCNmWAKE neurons) promotes arousal, while genetic knockout of mWAKE or impairment of CLOCK function in these neurons enhances wakefulness selectively at night. The latter phenotype corresponds to a specific increase in nighttime spiking of SCNmWAKE neurons in mWake mutants. At the circuit level, SCNmWAKE neuron signaling to the subparaventricular zone (SPZ) yields a stronger arousal phenotype. Together, these findings suggest that the genetic mechanisms regulating circadian control of sleep and arousal are evolutionarily conserved and define a clock-regulated neural network important for rhythmic arousal.