Obstructive sleep apnea is a common disorder characterized by recurrent pharyngeal collapse during sleep leading to sleep disruption and potentially adverse cardiovascular consequences. Despite the well- established links between sleep onset and pharyngeal collapse in afflicted individuals, how the neurobiologic processes required to generate sleep lead to apneas has been minimally investigated. It is our intent, in this proposal, to better define several of the basic neural mechanisms driving sleep and the relationship between these mechanisms (plus other established sleep neural processes) and the control of the pharyngeal muscles responsible for maintaining airway patency. The influence of airway obstruction on circulatory control will also be studied. Therefore, a more complete understanding of the neurobiologic events leading to sleep and apnea should emerge. Our proposal consists of five projects and two core units with each project addressing one components of the cascade from sleep onset to airway collapse to the consequences of apnea. Project #1 addresses the control of the pharyngeal musculature in man and the influence of sleep on the chemical, neural reflex, hormonal, and neuromodulatory factors controls these muscles. Project #2 will study the control of extracellular adenosine at the sleep-sensitive cholinergic nuclei (LDT/PPT) with a particular focus on cyclic AMP as in importance source of sleep-inducing adenosine at this site. Project #3 will also address adenosine but will focus on the mechanisms by which rising extracellular adenosine at this site. Project #3 will also address adenosine but will focus on the mechanisms by which rising extracellular adenosine leads to disinhibition of VLPO neurons. These VLPO neurons have recently been reported to become active during sleep and likely influence a variety of other neural systems important in sleep onset. Project #4 will investigate, in the brain stem slice, the electrophysiology of cholinergic influences on hypoglossal (XII) motor neuron activity and how cholinergic systems may interact with serotonergic and noradrenergic systems to control this important upper airway motor system. Finally, Project #5 will address, in a pig model, the relationship between airway occlusion, arousal from sleep, and the activation of patterned cardiovascular response. In addition to these projects, two Cores are planned. Core A will be an administrative/statistical one to assure the ongoing quality of the science to maintain efficient financial controls and provide statistical consultations. The second (B) will be a Neuroanatomic Core in which all neuroanatomic studies (in situ histochemistry, EM, etc.) will be conducted for Projects 2, 3, and 4. These studies, taken together should substantially advance our understanding not only of the pathogenesis of sleep apnea, but of the neurobiology of sleep as well.
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