title: Degeneration in Arousal Neurons in Chronic Sleep Disruption Modeling Sleep Apnea.
abstract: Chronic sleep disruption (CSD) is a cardinal feature of sleep apnea that predicts impaired wakefulness. Despite effective treatment of apneas and sleep disruption, patients with sleep apnea may have persistent somnolence. Lasting wake disturbances in treated sleep apnea raise the possibility that CSD may induce sufficient degeneration in wake-activated neurons (WAN) to cause irreversible wake impairments. Implementing a stereological approach in a murine model of CSD, we found reduced neuronal counts in representative WAN groups, locus coeruleus (LC) and orexinergic neurons, reduced by 50 and 25%, respectively. Mice exposed to CSD showed shortened sleep latencies lasting at least 4 weeks into recovery from CSD. As CSD results in frequent activation of WAN, we hypothesized that CSD promotes mitochondrial metabolic stress in WAN. In support, CSD increased lipofuscin within select WAN. Further, examining the LC as a representative WAN nucleus, we observed increased mitochondrial protein acetylation and down-regulation of anti-oxidant enzyme and brain-derived neurotrophic factor mRNA. Remarkably, CSD markedly increased tumor necrosis factor-alpha within WAN, and not in adjacent neurons or glia. Thus, CSD, as observed in sleep apnea, results in a composite of lasting wake impairments, loss of select neurons, a pro-inflammatory, pro-oxidative mitochondrial stress response in WAN, consistent with a degenerative process with behavioral consequences.
authors.affiliation: Center for Sleep and Circadian Neurobiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA , USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Center for Sleep and Circadian Neurobiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA , USA.
authors.forename: Polina
authors.initials: P
authors.lastname: Fenik
authors.affiliation: Center for Sleep and Circadian Neurobiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA , USA.
authors.forename: Guanxia
authors.initials: G
authors.lastname: Zhan
authors.affiliation: Center for Sleep and Circadian Neurobiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA , USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Xin
authors.affiliation: Center for Sleep and Circadian Neurobiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA , USA.
authors.forename: Sigrid C
authors.initials: SC
authors.lastname: Veasey
keywords: hypocretins/orexins; neurodegeneration and neural differentiation; norepinephrine; sleep fragmentation; wakefulness