Intermittent hypoxia and cognitive function: implications from chronic animal models.

Obstructive sleep apnea syndrome (OSAS) is a frequent sleep disorder in which the upper airway collapses repeatedly during sleep, resulting in intermittent hypoxia (IH) and asphyxia, and leading also to sleep fragmentation due to the recurrent nocturnal arousals necessary to relieve the upper airway obstruction. In addition to cardiovascular and metabolic morbidities, OSAS also causes serious neurocognitive daytime dysfunction and is associated with regional alterations in brain morphology in humans. These findings suggest that the anatomical brain lesions may underlie the behavioral deficits associated with the disease. In rodents, chronic exposure to intermittent hypoxia (IH) during sleep, which model the hypoxia/re-oxygenation patterns observed in moderate to severe OSAS patients, replicates many of the neurocognitive features of OSAS in humans, such as learning and memory deficits and impaired vigilance. Exposure to experimentally-induced IH in the rodent is also associated with age- and time-related neurodegenerative changes in addition to alterations in brain regions and neurotransmitter systems involved in learning and memory, attention, and locomotor activity. Multiple pathophysiological processes appear to be involved in the mechanistic aspects of the behavioral and neuronal susceptibility to IH during sleep, and include pathways leading to increased oxidative stress and inflammation, altered gene regulation, and decreases in the cellular and molecular substrates of synaptic plasticity. In addition, both environmental and genetic factors modulate the end-organ susceptibility to IH-induced cognitive dysfunction in rodents. Collectively, the available data indicate that exposure to IH during sleep is associated with adverse behavioral and neuronal consequences in the rodent. Improved understanding of the determinants of IH-related susceptibility may help explain the phenotypic variance in OSAS-associated morbidities, and enable improved therapeutic approaches in the future.