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

下丘脑室旁核中促肾上腺皮质激素释放激素神经元对睡眠和觉醒的神经元和稳态调节

• 批准号: 10464942
• 负责人: ALYSSA N WIEST
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464942
• 关键词: Address; Animals; Arousal; Attention; Axon; Behavior; Brain region; CRH gene; CRISPR/Cas technology; Calcium; Cell Nucleus; Chronic; Chronic stress; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Emotional; Genes; Genetic; Health; Homeostasis; Hypothalamic structure; Image; Impairment; In Situ Hybridization; Injections; Label; Lead; Mediating; Mental Health; Mental disorders; Metabolic; Monitor; Neurons; Patients; Pituitary Gland; Play; Population; Preoptic Areas; REM Sleep; Risk; Role; Short-Term Memory; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Stress; Stressful Event; Techniques; Wakefulness; Waste Products; circadian; cognitive function; emotional functioning; improved; in vivo; in vivo calcium imaging; in vivo monitoring; insight; mouse model; neural circuit; neuromechanism; new therapeutic target; non rapid eye movement; optogenetics; paraventricular nucleus; physical conditioning; pressure; receptor; relating to nervous system; response; sleep quality; sleep regulation; social defeat; vigilance

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.

项目摘要 睡眠是一种进化上保守的行为，在动物王国中被广泛观察到。是 以不同警觉状态之间的转换为特征：清醒，快速眼动（REM）睡眠，以及 非快速眼动睡眠（NREM）这些转换是由不同神经元群体之间的相互作用控制的 并且受到体内平衡和昼夜节律机制的影响。因为睡眠有很多好处， 恢复效果，良好的睡眠质量是重要的精神和身体健康。这是公认的 压力和睡眠是双向的众所周知，压力是睡眠中断的主要原因。 长期睡眠中断会导致患精神疾病的风险增加。脑室旁 下丘脑核（PVN）含有促肾上腺皮质激素释放激素（CRHPVN）神经元，这些神经元已被 被压力激活已发现CRH的中枢和全身给药可诱导 清醒另外的研究发现，CRH受体1（CRHR 1）的中枢阻断降低了 促醒作用的CRH注射，这表明该受体在CRH介导的觉醒中起着关键作用。 然而，CRH神经元调节觉醒的神经机制还不是很清楚。 追踪研究表明，CRHPVN神经元投射到下丘脑视前区（POA）， 众所周知的睡眠中心，包含对睡眠调节至关重要的神经元。原位杂交研究 已经证明CRHR 1在POA中表达。虽然CRH被认为是清醒的调节器， CRHPVN神经元及其向POA的投射（CRHPVN→POA）在睡眠-觉醒周期中的作用， 睡眠内稳态尚未得到充分研究。该建议的中心假设是CRHPVN 神经元控制觉醒，并损害慢性压力后对睡眠压力的稳态反应。 为了解决这一假设，该提案将使用一种遗传小鼠模型CRH-Cre来特异性标记CRH 神经元，体内钙成像，光遗传学操作，CRISPR-Cas9基因编辑技术，以及 慢性社会失败压力范式来操纵这些神经元及其投射。目标1将决定 CRHPVN→POA投射在调节睡眠和觉醒中的作用目的2：探讨CRHPVN的作用 神经元和CRHPVN→POA投射在慢性应激后睡眠稳态中的作用了解CRHPVN如何 神经元促进觉醒和调节睡眠稳态对慢性应激的反应将进一步阐明 控制压力的神经回路与调节睡眠和清醒的神经回路是如何相互联系的。