Metabolic regulation of wakefulness

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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.