It is widely agreed that the key event in the development of obstructive sleep apnea is a loss of upper airway dilator muscle activity in the transition from wakefulness to sleep. This produces pharyngeal airway closure resulting in hypoxia, hypercapnia and increasing respiratory effort. These consequences trigger a set of protective brainstem responses including cardiovascular reflexes and behavioral arousal resulting in restitution of pharyngeal dilator muscle activity, a return of airway patency, and a resumption of ventilation. When repeated many times over the course of the night this process leads to fragmented sleep and potentially adverse cardiovascular events. Our proposal consists of six Projects and four Cores all addressing various aspects of sleep, sleep apnea, or its consequences. Proj. 1 addresses the pathophysiology of sleep apnea examining upper airway muscle control and lung volume changes occurring during sleep in humans. Proj. 2 will assess the impact of both intermittent hypoxia and sleep interruption in rats on behavior, physiology, extracellular adenosine, and neural function. Proj. 3 addresses the mechanisms controlling extmcellular adenosine, focussing primarily on the role of nitric oxide in this process. Proj. 4 utilizes a stable model of rodent sleep fragmentation examining behavior, learning, physiology, and neurochemistry. Proj. 5 will assess the mechanisms by which orexin regulates sleep/wake in the mouse using novel molecular techniques. Proj. 6 addresses the anatomy and neuromodulation of upper airway reflexes in the rat again addressing the pathophysiology of sleep apnea. Core A, the Administrative Core, oversees the financial, statistical and scientific areas. Core B will handle all neuroanatomic studies for Projects 2, 3, 5, and 6. Core C, our Behavioral Core, will provide rodent behavioral assessment for Projects 2, 4, and 5. Finally, Core D is a slice Electrophysiology Core and will provide such testing to Projects 2, 3, 4, and 5. As should be evident from the Cores, this SCOR has a high integrated set of Projects that should substantially improve our understanding of sleep apnea and its consequences at a clinical and basic science level.
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