Neural Injury in Sleep Apnea

Sleepiness has long been recognized as a presenting symptom in obstructive sleep apnea syndrome, but persistent neurocognitive injury from sleep apnea has been appreciated only recently. Although therapy for sleep apnea markedly improves daytime symptoms, cognitive impairments may persist despite long-term therapy with continuous positive airway pressure. We know now that certain groups of neurons, typically those that are more metabolically active, are more vulnerable to injury than others. Animal models of sleep apnea oxygenation patterns have been instrumental in elucidating mechanisms of injury. The hypoxia/reoxygenation events result in oxidative, inflammatory, and endoplasmic reticulum stress responses in susceptible neural groups. With molecular pathways being fleshed out in animal models, it is time to carefully and systematically examine neural injury in humans and test the applicability of findings from animal models. To succeed, however, we cannot view sleep apnea as an isolated process. Rather, injury in sleep apnea is more likely the consequence of overlapping injuries from comorbid conditions. The progress in elucidating mechanisms of neural injury is palpable, and it now seems we indeed are closer to developing therapies to prevent and treat neural injury in obstructive sleep apnea

Neural Consequences of Chronic Short Sleep: Reversible or Lasting?

Approximately one-third of adolescents and adults in developed countries regularly experience insufficient sleep across the school and/or work week interspersed with weekend catch up sleep. This common practice of weekend recovery sleep reduces subjective sleepiness, yet recent studies demonstrate that one weekend of recovery sleep may not be sufficient in all persons to fully reverse all neurobehavioral impairments observed with chronic sleep loss, particularly vigilance. Moreover, recent studies in animal models demonstrate persistent injury to and loss of specific neuron types in response to chronic short sleep (CSS) with lasting effects on sleep/wake patterns. Here, we provide a comprehensive review of the effects of chronic sleep disruption on neurobehavioral performance and injury to neurons, astrocytes, microglia, and oligodendrocytes and discuss what is known and what is not yet established for reversibility of neural injury. Recent neurobehavioral findings in humans are integrated with animal model research examining long-term consequences of sleep loss on neurobehavioral performance, brain development, neurogenesis, neurodegeneration, and connectivity. While it is now clear that recovery of vigilance following short sleep requires longer than one weekend, less is known of the impact of CSS on cognitive function, mood, and brain health long term. From work performed in animal models, CSS in the young adult and short-term sleep loss in critical developmental windows can have lasting detrimental effects on neurobehavioral performance

Inducible Nitric Oxide Synthase in Long-term Intermittent Hypoxia: Hypersomnolence and Brain Injury

Rationale: Long-term intermittent hypoxia (LTIH) exposure in adult mice, modeling oxygenation patterns of moderate–severe obstructive sleep apnea, results in lasting hypersomnolence and is associated with nitration and oxidation injuries in many brain regions, including wake-active regions. Objectives: We sought to determine if LTIH activates inducible nitric oxide synthase (iNOS) in sleep/wake regions, and if this source of NO contributes to the LTIH-induced proinflammatory gene response, oxidative injury, and wake impairments. Methods: Mice with genetic absence of iNOS activity and wild-type control animals were exposed to 6 weeks of long-term hypoxia/reoxygenation before behavioral state recordings, molecular and biochemical assays, and a pharmacologic intervention. Measurements and Main Results: Two weeks after recovery from hypoxia/reoxygenation exposures, wild-type mice showed increased iNOS activity in representative wake-active regions, increased sleep times, and shortened sleep latencies. Mutant mice, with higher baseline sleep times, showed no effect of long-term hypoxia/reoxygenation on sleep time latencies and were resistant to hypoxia/reoxygenation increases in lipid peroxidation and proinflammatory gene responses (tumor necrosis factor α and cyclooxygenase 2). Inhibition of iNOS after long-term hypoxia/reoxygenation in wild-type mice was effective in reversing the proinflammatory gene response. Conclusions: These data support a critical role for iNOS activity in the development of LTIH wake impairments, lipid peroxidation, and proinflammatory responses in wake-active brain regions, and suggest a potential role for inducible NO inhibition in protection from proinflammatory responses, oxidative injury, and residual hypersomnolence in obstructive sleep apnea

Degeneration in Arousal Neurons in Chronic Sleep Disruption Modeling Sleep Apnea

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 and orexinergic neurons, reduced by 50% and 25%, respectively. Mice exposed to CSD showed shortened sleep latencies lasting at least 4wk 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 locus coeruleus 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 proinflammatory, pro-oxidative mitochondrial stress response in WAN, consistent with a degenerative process with behavioral consequences