Obstructive sleep apnea (OSA) patients have specific cognitive deficits and symptoms of depression, but the neurological basis of these abnormalities is unknown. Reduced hippocampal gray matter volume was recently detected in OSA patients and in major depression. Suppression of neurogenesis could account for a critical part of these hippocampal volume changes. Adult neurogenesis, the proliferation of new cells in the hippocampus and their differentiation into functional neurons, was found to be required for acquisition of complex spatially- and temporally-structured learning tasks in adult animals. Cognitive deficits of this type are found in OSA patients. We propose that OSA patients have impaired hippocampal neurogenesis. We will use the chronic intermittent hypoxia (CIH) model of OSA in rats to assess the hypotheses that CIH inhibits neurogenesis, and that sleep deprivation (SD) associated with CIH further inhibits neurogenesis. We will show that the inhibition of neurogenesis predicts cognitive performance in a hippocampal-dependent spatial learning paradigm, the Barnes maze. Measurement of cell proliferation and neurogenesis will be based on 5-bromo-2-deoxyuridine-5-monophosphate (BrdU) immunostaining, combined with neuronal and glial markers and will use stereological technique to assess cell counts. Brain temperature (Tbr) is normally down-regulated during hypoxia as well as during sleep, but changes during CIH and CIH-coincident sleep are unknown. Tbr is a primary determinant of the extent of focal or global ischemic brain damage, but its role in the pathological changes following CIH has not been examined. A second objective of our proposal is to determine how CIH and SD affect Tbr and if Tbr modulates the inhibition of neurogenesis by SD and CIH. Serotonergic neurotransmission is strongly modulated during CIH and is also known to control neurogenesis. A third goal of our proposal is to determine if augmentation of serotonergic neurotransmission reduces the inhibition of neurogenesis by IH. Glucocorticoids and stress inhibit neurogenesis. We will determine if changes in glucocorticoid secretion account for inhibition of neurogenesis by IH. These studies will provide evidence about the basis of cognitive deficits in OSA, including 1) regulation of neurogenesis in the CIH model of OSA, 2) the modulating effects of sleep deprivation, temperature, and other variables, and 3) interventions to aid in recovery from deficits.
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