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Effects of chronic intermittent hypoxia on cholinergic modulation at hypoglossal motoneurons

Award Number: R15HL175526
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $421,800 )
2024	2024	MIDWESTERN UNIVERSITY	19555 N. 59TH AVE ADMINISTRATION BUILDING	GLENDALE	AZ	85308	MARICOPA	USA	National Center on Sleep Disorders Research	000	1	8/19/2024	NEW	$421,800
														Subtotal = $421,800

Grand Total All Awards = $421,800

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Effects of chronic intermittent hypoxia on cholinergic modulation at hypoglossal motoneurons

Award Number: R15HL175526

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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