Quantification of the State-Dependent Inputs to Hypoglossal Motoneurons

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DESCRIPTION (provided by applicant): Obstructive Sleep Apnea (OSA) affects about 4% of men and 2% of women of adult population. It is caused by partial or complete airway obstruction in individuals with anatomically compromised airways due to a decrease in upper airway muscle (including genioglossus muscle innervated by hypoglossal motoneurons) tone during sleep and especially during its rapid eye movement (REM) phase. The resulting hypopnea/apnea episodes cause recurrent decreases in hemoglobin oxygen saturation, accumulation of CO2, and frequent awakenings which results in chronic sleep deprivation and fragmentation. OSA patients suffer from excessive daytime sleepiness and diminished quality of life. OSA is also associated with hypertension, diabetes, coronary artery disease, strokes, and congestive heart failure. A large body of evidence suggests that two major state-dependent inputs control hypoglossal motoneurons: postsynaptic inhibition and aminergic disfacilitation. However, despite decades of research, there is no consensus about the mechanisms of the depression of this motoneuronal pool during REM sleep. In order to understand the responsible mechanisms, we will use intracellular recording during natural sleep and wakefulness. The following Specific Aims will be conducted: (1) to determine the contribution of postsynaptic inhibition mediated by inhibitory amino-acids to the depression of hypoglossal motoneuron activity during REM sleep and (2) to determine the contribution of aminergic disfacilitation to the REM sleep-related depression in the activity of hypoglossal motoneurons. We will obtain quantitative data regarding the contribution of these two major neurotransmitter systems in the depression of activity of hypoglossal motoneurons during REM sleep. This knowledge will advance our understanding of the mechanisms of state-dependent control of excitability of these motoneurons which could be used to develop effective pharmacological therapeutics to treat OSA. PUBLIC HEALTH RELEVANCE Obstructive Sleep Apnea (OSA) is caused by pathologies in the atonia of upper airway muscles during REM sleep. Accordingly, we will determine the relative contributions of the major state-dependent inputs that control hypoglossal motoneurons to advance our understanding of the mechanisms responsible for the atonia of muscles that are innervated by the hypoglossal nerve. This knowledge is a prerequisite for developing effective pharmacological treatments for OSA.