Corticotropin-releasing hormone neurons in the bed nucleus of the stria terminalis control wakefulness in physiological and stressful conditions in mice

Stressful and emotionally salient stimuli often trigger heightened wakefulness that can predispose to sleep disorders such as insomnia. The bed nucleus of the stria terminalis (BNST), a center for emotional information processing and anxiety-related behaviors, contains diverse neuropeptide-enriched neuronal subpopulations that may respond to and drive opposing emotional states. Although recently implicated in arousal regulation, the mechanisms by which BNST neuronal subpopulations control sleep–wake states remain unclear. Here, we show that optogenetic activation of corticotropin-releasing hormone (CRH)-expressing neurons, but not cholecystokinin- or somatostatin-expressing neurons, in the BNST triggers a rapid shift from non-rapid eye movement sleep to wakefulness in male mice. BNST CRH neurons are active during both wakefulness and rapid eye movement (REM) sleep, and their optogenetic activation also triggers wakefulness from REM sleep. Chemogenetic activation of BNST CRH neurons significantly increases the amount and alpha (8–13 Hz) power of wakefulness, whereas their inhibition decreases wakefulness. Moreover, inhibition of BNST CRH neurons alleviates stress-induced heightened wakefulness. These results identify BNST CRH neurons as key regulators of wakefulness under physiological and stressful conditions and suggest them as potential targets for stress-induced heightened wakefulness and insomnia.