The aims of this application are unified by their focus on brain cholinergic neurotransmission. Cholinergic neurons and their projections are anatomically poised to modulate many brain regions regulating sleep and breathing. This unique structure-function relationship will facilitate the long-term objective to evaluate the unifying, core hypothesis that cholinergic neurotransmission comprises a final common mechanism through which many molecules and brain regions modulate arousal and breathing. Four coherently related aims have been designed to address the core hypothesis relative to research goals encouraged by the National Sleep Disorders Research (NSDR) plan. The NSDR plan is the consensus of leading sleep researchers and provides a road map for efforts to solve major intellectual and public health problems related to sleep and breathing. The NSDR plan specifies brain cholinergic neurons as contributors to rapid eye movement (REM) sleep generation. The NSDR plan highlights prefrontal cortex as a brain region particularly vulnerable to sleep deprivation and intermittent hypoxia.
Aim 1 will use microdialysis and high performance liquid chromatography (HPLC) to test the hypothesis that acetylcholine release in prefrontal cortex varies as a function of arousal. Obstructive sleep apnea causes intermittent hypoxia and the NSDR plan notes the need for additional research regarding the effects of intermittent hypoxia on brain function.
Aim 2 will use [35S]GTPyS autoradiography to test the hypothesis that intermittent hypoxia decreases cholinergic activation of guanine nucleotide binding (G) proteins in prefrontal cortex, hippocampus, and pons. Mice provide unique insights into the genetic substrates of disease and the NSDR plan specifically encourages use of mice for studies of sleep and breathing.
Aim 3 will use microdialysis and HPLC to test the hypothesis that acetylcholine release in mouse pons is modulated by adenosine A2A receptors. The NSDR plan encourages bridging the gap between what is known about the neurochemistry of sleep and arousal-generating systems.
Aim 4 will use pontine and systemic drug administration to test the hypothesis that pontine cholinergic mechanisms modulate the ability of adenosine AI receptors to alter arousal and breathing.
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