This Program represents a renewal application to be a Special Center of Research for Cardiopulmonary Disorders in Sleep. An important goal of the basic science studies of the SCOR is to establish the neural mechanisms that lead to hypotonia of the upper airway during sleep. It is our view that pharmacological therapies for sleep apnea are most likely to come from elucidating these basic mechanisms. These neurobiological investigations involve complementary studies using electrophysiological techniques (Project 2), neuroanatomical approaches (Project 1),and studies in chronic, normally sleeping animals (Project 4). These studies are first addressing (Project 2) the overall hypothesis that disfacilitation is the major mechanism for reduction in motor activity in the upper airway during sleep. Attention is directed at the aminergic systems in the brainstem. Studies will be done to examine the role of the different relevant neurotransmitters. Such studies direct attention to complex neural systems such as the caudal raphe. In Project 1, the neurochemical and neuroanatomical organization of this system will be studied using a variety of techniques-tract tracing, double-labeling, immunohistochemistry, and receptor autoradiography. Apneas in REM sleep are associated with the phasic events of this state. In Project 4, we propose that an area in the rostral pons, the pedunculopontine tegmental nucleus (PPT), mediates these phasic respiratory phenomena and a series of studies are elucidated to test this postulate. These basic investigations lead to studies in the animal model of sleep apnea that we identified (Project 3), in which we will study neuromuscular adaptations to the presence of a chronically obstructed upper airway. This project is based on the premise that upper airway obstruction leads to an adaptive increase in activity of upper airway dilator muscles in wakefulness that prevents airway obstruction and results in secondary changes in the muscles themselves. As part of the studies being conducted in Project 3, novel imaging techniques, that we have pioneered, will be used. Efficacy of CPAP will be addressed in Project 5, but here the emphasis will be on patterns of use and impact on daytime sleepiness. Our previous studies have raised concerns that many patients prescribed CPAP are functioning at sub-optimal levels. The results of the studies proposed here are likely to have a major impact on how sleep apnea patients are managed. Thus, this is a comprehensive program incorporating both basic neurobiological and clinical research.
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