Quantification of the State-Dependent Inputs to Hypoglossal Motoneurons

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）影响成年人群中约4%的男性和2%的女性。它是由解剖学上受损气道的个体的部分或完全气道阻塞引起的，这是由于睡眠期间，特别是在其快速眼动（REM）阶段期间上气道肌肉（包括由舌下神经运动神经元支配的颏舌肌）张力降低。由此产生的呼吸不足/呼吸暂停发作导致血红蛋白氧饱和度的反复降低、CO2的积累和频繁的觉醒，这导致慢性睡眠剥夺和碎片化。OSA患者遭受白天过度嗜睡和生活质量下降。OSA还与高血压、糖尿病、冠状动脉疾病、中风和充血性心力衰竭有关。大量的证据表明，两个主要的状态依赖性输入控制舌下神经运动神经元：突触后抑制和胺能障碍。然而，尽管经过几十年的研究，在REM睡眠期间对运动神经元池的抑制机制还没有达成共识。为了了解负责任的机制，我们将在自然睡眠和觉醒期间使用细胞内记录。将进行以下特定目的：（1）确定由抑制性氨基酸介导的突触后抑制对REM睡眠期间舌下神经运动神经元活动抑制的贡献，以及（2）确定胺能障碍对REM睡眠相关的舌下神经运动神经元活动抑制的贡献。我们将获得定量数据的贡献，这两个主要的神经递质系统在抑郁症的活动，舌下运动神经元在REM睡眠。这些知识将促进我们对这些运动神经元兴奋性的状态依赖性控制机制的理解，这些机制可用于开发有效的药物治疗来治疗OSA。阻塞性睡眠呼吸暂停（OSA）是由快速眼动睡眠期间上呼吸道肌肉张力不足的病理引起的。因此，我们将确定控制舌下神经运动神经元的主要状态依赖性输入的相对贡献，以推进我们对舌下神经支配的肌肉张力不足的机制的理解。这些知识是开发有效的OSA药物治疗的先决条件。

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.