Quantification of the State-Dependent Inputs to Hypoglossal Motoneurons

描述(申请人提供)：阻塞性睡眠呼吸暂停(OSA)影响约4%的男性和2%的女性成年人口。这是由于睡眠期间，尤其是在快速眼动(REM)阶段，由于上呼吸道肌肉(包括由舌下运动神经元支配的颧舌肌)张力下降而导致部分或完全呼吸道阻塞。由此导致的低呼吸/呼吸暂停发作会导致反复出现的血红蛋白血氧饱和度下降、二氧化碳积聚和频繁醒来，从而导致慢性睡眠剥夺和支离破碎。阻塞性睡眠呼吸暂停综合症患者白天过度嗜睡，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。大量证据表明，两种主要的状态依赖的输入控制舌下运动神经元：突触后抑制和胺能障碍。然而，尽管进行了几十年的研究，但对于快速眼动睡眠期间这个运动神经元池的抑制机制还没有达成共识。为了了解相关机制，我们将在自然睡眠和清醒状态下使用细胞内记录。具体目的如下：(1)确定抑制性氨基酸介导的突触后抑制对REM睡眠中舌下运动神经元活动抑制的贡献；(2)在舌下运动神经元活动中确定胺能障碍对REM睡眠相关抑制的贡献。我们将获得这两个主要神经递质系统在REM睡眠期间抑制舌下运动神经元活动中所起作用的定量数据。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控制机制的理解，这可能被用来开发有效的药物疗法来治疗OSA。公共卫生相关性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障碍引起的。因此，我们将确定控制舌下运动神经元的主要状态依赖输入的相对贡献，以促进我们对舌下神经支配的肌肉张力的机制的理解。这些知识是开发有效的阻塞性睡眠呼吸暂停综合征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.