Metabolic regulation of wakefulness

描述（由申请人提供）：超过1700万美国人患有睡眠呼吸暂停和持续性嗜睡。慢性睡眠中断（CSD）与睡眠呼吸暂停的残余嗜睡有关；然而，CSD损害清醒的机制尚不清楚。清醒状态在一定程度上是由大脑中神经元的集合来调节的，这些神经元在清醒时被激活，在睡眠时处于静止状态。我们认为，csd诱导的觉醒激活神经元（WAN）在睡眠应激WAN代谢过程中的重复兴奋，WAN损伤和功能障碍导致睡眠呼吸暂停的觉醒障碍。利用小鼠CSD模型，我们证实了CSD损害清醒和觉醒反应，我们发现CSD显著降低蓝斑神经元的神经元兴奋性，蓝斑神经元是WAN的代表群。线粒体sirtuin 3型（SirT3）在保护代谢稳态中起着重要作用。在初步研究中，我们发现CSD给WAN带来氧化和炎症应激，并且SirT3在CSD中逐渐从WAN丢失。SirT3的缺失会导致清醒损伤和WAN损伤。我们假设CSD中SirT3的减少和促炎反应的增强决定了WAN损伤和持续的尾流损伤。本提案的目的是确定WAN SirT3缺失与CSD WAN功能障碍和WAN变性的相关性，并确定CSD炎症反应之间WAN内部的串扰。阐明神经元线粒体代谢失衡是导致睡眠障碍和WAN变性的重要因素，将扩展我们在睡眠障碍条件下睡眠/觉醒控制的基本模型，并将促进开发分子靶点来改善包括OSA在内的许多睡眠障碍的觉醒。

DESCRIPTION (provided by applicant): Over 17 million Americans have sleep apnea and have persistent hypersomnolence. Chronic sleep disruption (CSD) is implicated in residual sleepiness in sleep apnea; yet the mechanisms by which CSD impairs wakefulness are not known. Wakefulness is modulated, in part, by collections of neurons throughout the brain that are activated in wakefulness and quiescent in sleep. We propose that CSD-induced repeated excitation of wake-activated neurons (WAN) across sleep stresses WAN metabolics, and that WAN injury and dysfunction contribute to wake impairments in sleep apnea. Utilizing a mouse model of CSD, we confirmed that CSD impairs wakefulness and arousal responses, and we have discovered that CSD markedly reduces neuronal excitability in locus coeruleus neurons, a representative group of WAN. Mitochondrial sirtuin type 3 (SirT3) plays several crucial roles in protecting metabolic homeostasis. In preliminary studies, we find that CSD imparts oxidative and inflammatory stress on WAN and that SirT3 is progressively lost from WAN across CSD. Loss of SirT3 induces wake impairments and WAN injury. We hypothesize that CSD reductions in SirT3 and augmentations in a pro-inflammatory response determine both WAN injury and lasting wake impairments. The goals of this proposal are to determine the relevance of WAN SirT3 loss in CSD WAN dysfunction and WAN degeneration and to identify the within WAN crosstalk between the CSD inflammatory response. Elucidation of neuronal mitochondrial metabolic dyshomeostasis as an important contributor to impaired wakefulness and WAN degeneration from CSD will extend our fundamental model of sleep/wake control under conditions of CSD and will enable development of molecular targets to improve wakefulness in many sleep disorders, including OSA.