Effects of chronic intermittent hypoxia on cholinergic modulation at hypoglossal motoneurons

Project Summary/Abstract Exposure to chronic intermittent hypoxia (CIH) is a common consequence of obstructive sleep apnea (OSA) where patients experience repeated apneas and hypopneas throughout the night. Accumulating evidence indicates that CIH can lead to structural and functional changes in the brainstem neurons that control breathing.

Normally, activity of the tongue, innervated by hypoglossal motoneurons, stiffens the airway to keep it open, but this activity drops dramatically during sleep and contributes causally to OSA in susceptible individuals. During sleep, reduced hypoglossal motoneuron activity likely results from activation of sleep-specific muscarinic (i.e.

activation of muscarinic acetylcholine receptors) modulation at hypoglossal motoneurons. The specific effects of muscarinic modulation will depend on the muscarinic acetylcholine receptors present, where M1, M3, and M5 muscarinic receptors have canonically excitatory effects whereas the M2 muscarinic receptor subtype has a

canonically inhibitory effect, as well as the compliment of ion channels that are modulated by muscarinic receptors. This project will explore the hypothesis that CIH leads to significant changes in cholinergic synaptic inputs to, and cellular properties of, hypoglossal motoneurons resulting in an increased excitatory effect of

muscarinic modulation at hypoglossal motoneurons. This project uses powerful immunofluorescence methods in combination with in vitro electrophysiology to evaluate neuroanatomical as well as functional changes in cholinergic signaling at hypoglossal motoneurons in two specific aims. In Aim 1, the project will determine the

expression pattern of muscarinic acetylcholine receptor subtypes in neonatal and adult mice exposed to chronic intermittent hypoxia compared to mice naïve to chronic intermittent hypoxia. This aim will also explore changes in the cholinergic inputs to hypoglossal motoneurons in response to chronic intermittent hypoxia exposure. In

Aim 2, the project will use electrophysiology techniques to test in neonatal and adult mice the functional changes of muscarinic modulation at hypoglossal motoneurons in response to chronic intermittent hypoxia exposure. This aim will evaluate these effects both at the network level using the rhythmic slice preparation and also in individual

hypoglossal motoneurons using whole cell electrophysiology methods. These studies will contribute excellent training opportunities for graduate and professional students, thus providing scientific training to the next generation of clinicians. Furthermore, the expected outcomes will advance understanding of cellular and

synaptic cholinergic mechanisms that change in response to exposure to chronic intermittent hypoxia. This fundamental information will be essential to develop strategies to explore in vivo the cholinergic mechanisms that contribute to state-dependent reductions in airway tone and how those mechanisms change in response to

chronic intermittent hypoxia exposure. These data will contribute to the mission of the National Heart Lung, and Blood Institute of improving the health and quality of Americans suffering from sleep disordered breathing.