Metabolic regulation of wakefulness

描述(申请人提供)：超过1700万美国人患有睡眠呼吸暂停和持续性睡眠过度。慢性睡眠中断(CSD)与睡眠呼吸暂停患者的残余嗜睡有关；然而，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各处的神经元集合调节的，这些神经元在清醒时被激活，在睡眠中处于静止状态。我们认为，CSD诱导的唤醒激活神经元(WAN)的重复兴奋跨越睡眠应激的广域代谢，并且广域的损伤和功能障碍参与了睡眠呼吸暂停中的觉醒损伤。利用CSD小鼠模型，我们证实了CSD对觉醒和觉醒反应的损害，我们发现CSD显著降低广泛性脑病的代表性群体蓝斑神经元的神经元兴奋性。线粒体sirtuin 3型(SirT3)在维持代谢稳态方面发挥着重要作用。在初步研究中，我们发现CSD在广域网上给予氧化和炎症应激，并且SirT3在CSD中逐渐从广域网上消失。SirT3的缺失会导致觉醒损伤和广域网损伤。我们假设，SirT3中CSD的减少和促炎反应的增加决定了广域网损伤和持久的觉醒损伤。该方案的目的是确定广域SirT3缺失在CSD广域网功能障碍和广域网变性中的相关性，并确定CSD炎症反应在广域网上的串扰。阐明神经元线粒体代谢紊乱是CSD引起觉醒受损和广域变性的重要因素，将扩展我们在CSD条件下睡眠/觉醒控制的基本模型，并将使包括OSA在内的许多睡眠障碍的分子靶点的开发能够改善觉醒。

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.