BLR&D Research Career Scientist Award

项目总结 失眠和睡眠障碍是情绪和焦虑症的常见症状。夜间活动 睡眠障碍是创伤性脑损伤(TBI)后的常见症状。以前的工作在 我的实验室已经在视前下丘脑中发现了GABA能神经元系统 具有关键的睡眠调节功能。正中视前核内的GABA能神经元 (MnPO)和腹外侧视前区(VLPO)在睡眠时被激活。腺苷是一种 关键的内源性睡眠调节因子，在动态平衡反应的表达中很重要 失眠。我们已经证明了A2A腺苷受体激活了MnPO/VLPO神经元 激动剂。我们最近证明了MnPO/VLPO神经元的放电是动态的 在睡眠剥夺和恢复睡眠期间，对内环境平衡睡眠动力的变化作出反应。我们 进一步表明，在发育过程中，MnPO/VLPO GABA能功能成熟 睡眠调节系统是睡眠动态平衡发展的基础。我们最重要的是 假说是由于视前功能障碍导致的失眠引起的动态平衡反应的破坏 下丘脑睡眠调节回路导致情绪和焦虑的睡眠障碍 精神障碍和脑外伤。我们将使用这些疾病的动物模型来检验这一假设。我们会 也扩大了我们对下丘脑和 正常和紊乱睡眠中的脑干唤醒状态调节回路。大脑中的水平 促肾上腺皮质激素释放因子(CRF)是HPA轴的关键神经肽调节因子。 在焦虑症和创伤后应激障碍(PTSD)中慢性升高。CRF有井 具有促进觉醒/扰乱睡眠的作用。我们假设CRF的激活 神经元对急性和慢性压力的反应会扰乱睡眠的稳态。我们 进一步假设CRF对睡眠稳态的影响是通过抑制 睡眠调节性GABA能神经元在视前、下丘脑和吻部的活动 延髓。我们将使用转基因CRF-cre小鼠和腺病毒载体来进行光遗传学和 化学遗传学操作大脑中的CRF信号，并确定对睡眠的影响 视前和延髓睡眠调节神经元群体的稳态和功能活动 以及急性和慢性应激源对睡眠的干扰作用。睡眠-觉醒障碍 继发的脑损伤包括日间困倦、夜间睡眠碎裂、失眠和改变 在睡眠脑电波中。先前的工作表明，在脑损伤的小鼠模型中，过度嗜睡 与食欲素神经元的激活减少有关。与同事在 波特兰退伍军人在脑损伤方面拥有专业知识，我们已经产生了与睡眠相关的初步发现 小鼠大脑皮质液压冲击伤后MnPO神经元的激活显著降低。 我们将继续研究这些初步发现，并检查GABA能睡眠的功能状态- 视前区的调节神经元和下丘脑外侧区的食欲素神经元 并将这些神经系统的功能活动与睡眠-觉醒相关 脑外伤后不同时间的表型。在NIH/NINDS支持的工作中，我们将 视前下丘脑和脑干内GABA能环路的相互作用 调节清醒、非快速眼动睡眠和快速眼动睡眠之间的切换。这些发现来自于 这些研究将为理解这些回路参与睡眠奠定基础。 伴随着精神和神经障碍的精神分裂。

PROJECT SUMMARY Insomnia and disturbed sleep are common symptoms in mood and anxiety disorders. Nocturnal sleep disruption is a frequent complaint following traumatic brain injury (TBI). Previous work in my laboratory has identified systems of GABAergic neurons in the preoptic hypothalamus that have critical sleep regulatory functions. GABAergic neurons in the median preoptic nucleus (MnPO) and the ventrolateral preoptic area (VLPO) are activated during sleep. Adenosine is a critical endogenous sleep regulatory factor, important in the expression of homeostatic responses to sleep loss. We have shown that MnPO/VLPO neurons are activated by A2A adenosine receptor agonists. We have recently demonstrated that discharge of MnPO/VLPO neurons is dynamically responsive to changing homeostatic sleep drive during sleep deprivation and recovery sleep. We have further shown that during development, functional maturation of MnPO/VLPO GABAergic sleep regulatory systems underlies the development of sleep homeostasis. Our overarching hypothesis is that disruption of homeostatic responses to sleep loss due to dysfunction of preoptic hypothalamic sleep regulatory circuits contributes to sleep disturbances in mood and anxiety disorders and TBI. We will test this hypothesis using animal models of these disorders. We will also expand our understanding of the fundamental interactions between hypothalamic and brainstem arousal state-regulatory circuits in normal and disordered sleep. Brain levels of corticotrophin-releasing factor (CRF), a critical neuropeptide regulator of the HPA axis, are chronically elevated in anxiety disorders and posttraumatic stress disorder (PTSD). CRF has well characterized wake-promoting/sleep-disruptive effects. We hypothesize that activation of CRF neurons occurring in response to acute and chronic stress 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 rostral medulla. We will use transgenic CRF-cre mice and adenoviral vectors to optogenetically and chemogenetically manipulate CRF-signaling in the brain, and determine the effects on sleep homeostasis, functional activity of preoptic and medullary sleep regulatory neuronal populations and the sleep disruptive effects of acute and chronic stressors. Sleep-wake disturbances following TBI include daytime sleepiness, nocturnal sleep fragmentation, insomnia and alterations in the sleep EEG. Previous work has shown that in mouse models of TBI, excessive sleepiness is associated with reduced activation of orexin neurons. In collaboration with colleagues at the Portland VA who have expertise in TBI, we have generated preliminary findings that sleep-related activation of MnPO neurons is dramatically reduced after cortical fluid percussion injury in mice. We will pursue these preliminary findings and examine the functional status of GABAergic sleep- regulatory neurons in the preoptic area and of orexin neurons in the lateral hypothalamus following TBI, and correlate the functional activity in these neuronal systems with the sleep-wake phenotype at different times after brain trauma. In work supported by NIH/NINDS, we will examine interactions between GABAergic circuits in the preoptic hypothalamus and brainstem that regulate the switching among waking, nonREM and REM sleep. The findings derived from these studies will be a foundation for understanding the involvement of these circuits in sleep disruption accompanying psychiatric and neurological disorders.