Neuronal and homeostatic regulation of sleep and wake by corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus

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PROJECT SUMMARY Sleep is an evolutionarily conserved behavior that is widely observed across the animal kingdom. It is characterized by transitions between different vigilance states: wake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep. These transitions are controlled by interactions between different neuronal populations and are under the influence of homeostatic and circadian mechanisms. As sleep has many beneficial and restorative effects, good quality sleep is important for mental and physical health. It has been well-established that stress and sleep have a bidirectional relationship. Stress is known to be a major cause of disrupted sleep. Chronic sleep disruption can lead to an increased risk of developing psychiatric disorders. The paraventricular nucleus of the hypothalamus (PVN) contains corticotropin-releasing hormone (CRHPVN) neurons that have been shown to be activated by stress. Central and systemic administration of CRH has been found to induce wakefulness. Additional studies have found that central blockade of the CRH receptor 1 (CRHR1) reduces the wake-promoting effects of CRH injection, suggesting this receptor plays a key role in CRH-mediated arousal. However, the neural mechanisms by which CRH neurons regulate wakefulness are not very well understood. Tracing studies have revealed that CRHPVN neurons project to the preoptic area of the hypothalamus (POA), a well-known sleep center containing neurons that are crucial for sleep regulation. In situ hybridization studies have shown that CRHR1 is expressed in the POA. While CRH has been implicated as a regulator of wakefulness, the role that CRHPVN neurons and their projections to the POA (CRHPVN→POA) play in the sleep-wake cycle and sleep homeostasis has not been fully investigated. The central hypothesis of this proposal is that CRHPVN neurons control wakefulness and impair the homeostatic response to sleep pressure following chronic stress. To address this hypothesis, this proposal will use a genetic mouse model, CRH-Cre, to specifically label CRH neurons, in vivo calcium imaging, optogenetic manipulations, CRISPR-Cas9 gene editing techniques, and a chronic social defeat stress paradigm to manipulate these neurons and their projections. Aim 1 will determine the role of CRHPVN→POA projections in regulating sleep and wakefulness. Aim 2 will investigate the role of CRHPVN neurons and CRHPVN→POA projections in sleep homeostasis following chronic stress. Understanding how CRHPVN neurons promote wakefulness and regulate sleep homeostasis in response to chronic stress will further elucidate how the circuits controlling stress are interconnected with those regulating sleep and wakefulness.