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.
Highlights
All individuals with untreated obstructive sleep apnea experience chronic sleep disruption (CSD), and this feature of sleep apnea is considered an important source of impaired wakefulness [1, 2]
Chronic sleep disruption (CSD) Imparts Lasting Wake Impairments, Without Influencing Total Sleep Time There were no differences in total sleep time following CSD and Ctl conditions, t = 1.1, N.S
Mice exposed to CSD and allowed a 4-week recovery opportunity were assessed for sleep latencies at lights-on and lights-off
Summary
All individuals with untreated obstructive sleep apnea experience chronic sleep disruption (CSD), and this feature of sleep apnea is considered an important source of impaired wakefulness [1, 2]. While most patients successfully treated have marked improvements in hypersomnolence, many effectively treated individuals experience refractory or persistent wake impairments [3]. An alternative explanation for residual sleepiness in treated sleep apnea is that CSD might injure neurons responsible for optimal alertness sufficiently enough to manifest as lasting wake impairments. Potentially glia, influence sleep and wakefulness [4,5,6] Within this complex circuitry are subsets of neurons that are activated upon arousal and in turn modulate wakefulness. These wake-activated neurons (WAN) groups include the noradrenergic locus coeruleus (LC), orexinergic, histaminergic neurons, and specific cholinergic, serotoninergic, and dopaminergic
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