Impact of Corticotropin Releasing Factor on Sleep Regulation

失眠和睡眠障碍是情绪和焦虑症的常见症状。抑郁和抑郁 创伤后应激障碍与下丘脑-垂体-肾上腺(HPA)轴功能障碍有关。大脑中的水平 促肾上腺皮质激素释放因子(CRF)是HPA轴的重要神经肽调节因子。 在这些疾病中升高。CRF具有良好的促进觉醒/干扰睡眠的作用。 我们实验室和其他人之前的工作已经在视前区发现了GABA能神经元 下丘脑是睡眠开始、睡眠维持和睡眠动态平衡的关键调节器。在.期间 在之前的资助期间，我们证明了CRF的急剧升高会对睡眠产生干扰作用 部分地，通过对视前神经元的作用来调节。我们提供的初步数据表明，睡眠中断 慢性部分睡眠受限所致的动态平衡可被CRF逆转 受体拮抗剂。我们假设CRF神经元的激活是对压力的反应 长期睡眠限制会扰乱睡眠平衡。我们进一步假设CRF对睡眠有影响 脑内稳态是通过抑制睡眠调节性GABA能神经元的活动来实现的 视前部、下丘脑和延髓吻部。我们提出了四个具体目标来解决这些问题 假设。目标1将确定CRF是否扰乱视前和延髓睡眠调节神经元的活动 在大鼠的慢性睡眠限制期间。目标2将确定CRF神经元传入的起源核 下丘脑视前区和延髓嘴区GABA能睡眠调节神经元的相互作用 慢性肾功能衰竭大鼠下丘脑和杏仁核内靶向注射AAV-DIO-mCherry Cre基因敲入小鼠。目标3将确定负责负调节的CRF神经元群体 通道视紫红质-2和hM3Dq兴奋性设计受体的表达对睡眠稳态的影响 含CRH神经元的下丘脑和杏仁核延髓核团 不同CRF神经元群体的光诱导和化学激发对睡眠稳态的影响。 目标4将确定CRF神经元的化学沉默是否能恢复睡眠的动态平衡反应 长期睡眠受限期间的失眠。失眠和睡眠不足在精神疾病中很常见。 与生理或心理压力相关的和/或加剧的。我们建议 检查可能导致慢性轻症的负面影响的基本机制和回路 睡眠稳态调节的压力源，目标是确定关键的调节节点， 可以作为治疗的靶点。慢性睡眠障碍会导致不良适应压力，并可能 创伤后应激障碍、抑郁和其他疾病的不良精神和健康结果的可改变的风险因素。

Insomnia and disturbed sleep are common symptoms in mood and anxiety disorders. Depression and PTSD are associated with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. Brain levels of corticotrophin-releasing factor (CRF), a critical neuropeptide regulator of the HPA axis, are chronically elevated in these disorders. CRF has well characterized wake-promoting/sleep-disruptive effects. Previous work from our laboratory and others has identified GABAergic neurons in the preoptic hypothalamus as critical regulators of sleep onset, sleep maintenance and sleep homeostasis. During the previous funding period, we demonstrated that acute elevations of CRF has sleep disruptive effects mediated, in part, by actions on preoptic neurons. We provide preliminary data that the disruption of sleep homeostasis that accompanies chronic partial sleep restriction can be reversed by administration of CRF receptor antagonists. We hypothesize that activation of CRF neurons occurring in response to the stress of chronic sleep restriction disrupts sleep homeostasis. We further hypothesize that CRF effects on sleep homeostasis are mediated through suppression of the activity of sleep-regulatory GABAergic neurons in the preoptic hypothalamus and in the rostral medulla. We propose four specific aims to address these hypotheses. Aim 1 will determine if CRF disrupts preoptic and medullary sleep-regulatory neuronal activity during chronic sleep restriction in rats. Aim 2 will determine the nuclei of origin of CRF neuronal afferents to GABAergic sleep regulatory neurons in the preoptic hypothalamus and the rostral medulla through targeted microinjections in the hypothalamus and extended amygdala of AAV-DIO-mcherry in CRF-ires- CRE knock-in mice. Aim 3 will identify CRF neuronal populations responsible for the negative modulation of sleep homeostasis by expressing channel rhodopsin-2 and hM3Dq excitatory designer receptor in hypothalamic and extended amygdala nuclei that contain CRH neurons and determining the effects of light-induced and chemogenetic excitation of different CRF neuronal populations on sleep homeostasis. Aim 4 will determine if chemogenetic silencing of CRF neurons restores homeostatic responses to sleep loss during chronic sleep restriction. Insomnia and insufficient sleep are common in psychiatric disorders that are associated with and/or exacerbated by physiological or psychological stress. We propose to examine fundamental mechanisms and circuits that might underlie the negative impact of chronic mild stressors on the homeostatic regulation of sleep, with the goal of identifying critical regulatory nodes that can be targeted for therapy. Chronic sleep disturbance can contribute to maladaptive stress and may be a modifiable risk factor for poor psychiatric and health outcomes in PTSD, depression and other disorders.