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. Circadian rhythms and homeostatic pressure set the baseline dynamics of the sleep–wake cycle, but affective inputs can tip this balance [1, 2].
Under acute stress conditions, rapid sleep-to-wake switching, prolonged wakefulness durations, and elevated arousal levels enable adaptive behavioral responses [3,4,5,6]. Chronic stress exposure, however, induces maladaptive changes that contribute to the development of psychiatric disorders, including anxiety, addiction, and social dysfunction [7, 8]. These stress-related psychiatric disorders often present with sleep disturbances, particularly insomnia [8,9,10].
Positive affect, whether derived from incentive motivation or consummatory reward, biases the system toward wakefulness and can transiently override both circadian timing signals and homeostatic sleep pressure [1, 11, 12]. Thus, both negative and positive emotionally salient stimuli influence sleep–wake dynamics by increasing wakefulness. Despite this, the underlying neuronal mechanisms through which emotional systems act upon sleep–wake regulatory circuits remain poorly understood.
The bed nucleus of the stria terminalis (BNST) is a limbic forebrain nucleus embedded within the extended amygdala [1], where it serves as a key node linking stress- and reward-related neural systems [13]. The BNST exhibits high sensitivity to stress and serves a pivotal role in mediating anxiety-like behaviors [8, 14,15,16,17,18,19,20,21]. It is also critically involved in sustained threat monitoring and avoidance behaviors [22,23,24], reward and aversion [17, 25, 26], social preference [27, 28], as well as the withdrawal and relapse stages of addiction [7, 29].
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