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，但CSD损害觉醒的机制尚不清楚。清醒状态在一定程度上是由大脑中的神经元集合调节的，这些神经元在清醒状态下被激活，在睡眠状态下静止。我们认为，CSD诱导的唤醒激活神经元（WAN）在睡眠中的反复兴奋会对WAN代谢产生压力，WAN损伤和功能障碍会导致睡眠呼吸暂停的觉醒障碍。利用CSD的小鼠模型，我们证实CSD损害觉醒和唤醒反应，并且我们已经发现CSD显著降低蓝斑神经元（WAN的代表性组）中的神经元兴奋性。线粒体sirtuin type 3（SirT 3）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对WAN产生氧化和炎症应激，并且SirT 3在CSD中从WAN逐渐丢失。SirT 3的缺失诱导唤醒损伤和WAN损伤。我们假设CSD减少SirT 3和增强促炎反应决定WAN损伤和持久的觉醒障碍。该提案的目标是确定WAN SirT 3丢失在CSD WAN功能障碍和WAN退化中的相关性，并确定CSD炎症反应之间的WAN内串扰。阐明神经元线粒体代谢稳态异常是CSD导致觉醒受损和WAN退化的重要因素，将扩展我们在CSD条件下的睡眠/觉醒控制的基本模型，并将能够开发分子靶点以改善许多睡眠障碍（包括OSA）中的觉醒。

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.