Intermittent Hypoxia: Mechanisms of Hypersomnolence

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DESCRIPTION (provided by applicant): Over 8 million adult Americans have obstructive sleep apnea syndrome. Many of these individuals will have persistent hypersomnolence despite therapy. We have found that exposure to long-term intermittent hypoxia (LTIH), modeling oxygenation in severe obstructive sleep apnea, in adult mice results in lasting hypersomnolence and oxidative injury to select wake-active neural groups. In preliminary studies, we are finding LTIH-induces apoptosis and loss of noradrenergic locus coeruleus neurons. We should now extend this to determine the nature and extent of LTIH injury in major wake-promoting groups: orexinergic, histaminergic and dopaminergic wake-active neurons, and we should determine if this injury is reversible with long-term recovery (Aim 1). We have recently shown that NADPH oxidase is a major source of oxidative injury in wake-active regions and that reduced NADPH oxidase throughout LTIH prevents hypersomnolence. It is now important to determine if NADPH oxidase is essential for the apoptosis and neural loss associated with LTIH injury. We propose to determine if NADPH oxidase activation in the above wake-active groups predicts susceptibility to LTIH neural loss, and we propose to use transgenic and pharmacological models of absent NADPH oxidase activation throughout LTIH to determine whether we can prevent apoptosis and neural loss in major groups of wake-control neurons (Aim 2). A next step is to determine the mechanism through which LTIH activates NADPH oxidase. Having found NADPH oxidase in neurons and having found that the neural groups with increased susceptibility are largely neurons with angiotensin 1A receptor (AT1A) immunoreactivity, we hypothesize that LTIH results in HIF-1a activated angiotensin synthesis, and that neurons with both AT1A receptors and NADPH oxidase (catecholaminergic wake neurons) will be the neurons most vulnerable to LTIH. We further hypothesize that transgenic absence and pharmacological inhibition of angiotensin will prevent NADPH oxidase activation and hypersomnolence and apoptosis and loss of wake-active neurons. To test this hypothesis, we propose to examine NADPH oxidase activation in wake-active groups in mice with transgenic and pharmacological inhibition of AT1A receptor function and we will determine if the hypersomnolence and neuron loss may be prevented, and reversed in the same models (Aim 3). Collectively, these studies will demonstrate major mechanisms through which LTIH modeling sleep apnea oxygenation injures neurons and at the same time, this work will unveil pharmacological avenues to test for the treatment and prevention of neurocognitive impairments in obstructive sleep apnea.