The obstructive sleep apnea syndrome (OSA) affects 3-5% of adults. The disorder is manifest by recurring episodes of upper airway narrowing and obstruction that occur exclusively during sleep. Underlying the disorder is altered anatomy of the upper airway that allows the soft tissues surrounding the airway lumen to collapse under the centripetal force of the negative inspiratory pressure, which leads to airway obstruction. OSA subjects adapt to this anatomical vulnerability by generating a higher level of activity in their upper airway dilating muscles than that in healthy subjects, but the cellular and systemic mechanisms underlying this adaptation are unknown and cannot be determined due to lack of a suitable animal model. The goal of this project is to develop and conduct initial characterization of what may prove to be the first rodent model of compromised upper airway in which, like in OSA patients, the animal adapts to weakened muscular support of the upper airway by increasing its upper airway motor tone. Our preliminary experiments show that severing the attachment of the geniohyoid and hyoglossus (GH/GH) muscles to the hyoid (H) bone makes less negative the critical pressure at which the airway collapses and increases the level of activity in the genioglossus (GG), the main muscle that protects the airway from collapse in humans. Based on these encouraging initial results, we propose a study with the following two Specific Aims. (1) Determine whether, in chronically instrumented, behaving rats, surgically weakened support of the upper airway leads to a compensatory increase in GG muscle activity. We shall quantify the tonic, phasic-inspiratory and total GG activity in rats that will have different degrees of permanent detachment of the GH/HG from the H-bone and those in which a re-attachment will be allowed to occur. In parallel acute experiments, we will determine the impact of the same surgical intervention on airway resistance and collapsibility. (2) Determine whether surgically weakened support of the upper airway in rats that exhibit increased upper airway motor tone is associated with increased density of noradrenergic and serotonergic innervation of hypoglossal (XII) motoneurons that control the GG and/or increased expression of excitatory aminergic receptors (type 2 serotonergic and 11 adrenergic) that were previously identified as playing a key role in mediating state-dependent excitatory drive to XII motoneurons. The project will characterize a novel, rodent-based, model of upper airway control that mimics the adaptive processes that may be similar to those in OSA patients. This should offer new means of investigating the mechanisms underlying the adaptive increase in upper airway motor tone in OSA patients.

Public Health Relevance

Obstructive sleep apnea syndrome (OSA) is a debilitating disorder affecting 3-5% of adult Americans. To maintain adequate breathing during wakefulness, OSA patients adapt to the compromised anatomy of their upper airway, but the mechanisms underlying this adaptation are unknown. Our goal is to establish a novel rodent model of compromised upper airway in which, like in OSA patients, upper airway motor tone is increased in response to a surgical intervention that weakens the muscular support of the airway. We will characterize the model and determine whether the adaptation is associated with changes in the central control of the motor neurons that innervate the genioglossus, an important muscle that protects the airway from collapse. The study will provide a new tool with which to investigate the pathophysiological mechanisms of OSA.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Laposky, Aaron D
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University of Pennsylvania
Veterinary Sciences
Schools of Veterinary Medicine
United States
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