Hypoglossal motor neurons (XIImn) innervating the upper airway muscles are essential to the maintenance of a patent airway. Obstructive sleep apneas is associated with a state-dependent decrease in the activity of these muscles caused by a state-dependent decrease in the excitability of XIImn's. These neurons receive neuromodulatory input from brainstem monoaminergic and cholinergic neurons whose activity is also state dependent and thus, many contribute to alterations of XIImn excitability across behavioral states. However, little is known about the electrophysiological effects of the cholinergic input nor of possible interactions between monoaminergic and cholinergic input that may account for the changes in XIImn excitability. It is hypothesized that activation of nicotinic receptors in the XII nucleus increases XIImn excitability. Based on preliminary work, the mechanism of this increase is suggested to be through an enhancement of the release of excitatory monoaminergic transmitters such that the most prominent effect would occur during waking when both monoaminergic and cholinergic activity is high and a reduced or absent during slow wave sleep or REM when monoaminergic activity is low or absent. To test this hypothesis an electrophysiological examination and analysis of XIImn responses to nicotinic activating using whole cell voltage clamp techniques in the in vitro slice preparation is proposed. The analysis will include an examination of potential nicotinic pre-synaptic effects on fast ionotropic and monoaminergic-mediated transmission. A morphological characterization of the synaptic input to XIImn's in correlation with the electrophysiological characterizations using biocytin intracellular staining will be pursued at the light and EM level. An understanding of the cellular mechanisms responsible for the change in XIImn excitability leading to an apneic episode in patients suffering from obstructive sleep apnea will suggest potential therapeutic approaches. In particularly, specific, testable predictions about the pharmacological manipulation of monoaminergic and/or cholinergic neuromodulatory systems on XIImn across behavior states may evolve from this proposal.
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