Quantification of the State-Dependent Inputs to Hypoglossal Motoneurons

舌下运动神经元状态相关输入的量化

• 批准号: 7741876
• 负责人: Victor Borisovich Fenik
• 金额: $ 28.85万
• 依托单位: WEBSCIENCES INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741876
• 关键词: Adrenergic Agents; Adult; Affect; Amino Acids; Animal Model; Apnea; Behavior Disorders; Carbachol; Carbon Dioxide; Cell Nucleus; Chronic; Complex; Congestive Heart Failure; Consensus; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Disease; Excessive Daytime Sleepiness; Felis catus; Glycine; Hemoglobin; Horns; Hypertension; Hypoglossal nerve structure; Individual; Injection of therapeutic agent; Knowledge; Measures; Mediating; Membrane; Membrane Potentials; Microdialysis; Modeling; Motor Neurons; Movement; Muscle; Muscle Tonus; Nature; Nerve; Neurotransmitters; Norepinephrine; Obstructive Sleep Apnea; Operative Surgical Procedures; Oral; Oxygen; Paralysed; Pathology; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Play; Population; Quality of life; REM Sleep; Rattus; Recurrence; Relative (related person); Research; Resistance; Role; Serotonin; Site; Sleep; Sleep Deprivation; Sleep Wake Cycle; Soft Palate; Spinal; Stroke; Strychnine; System; Testing; Therapeutic; Tongue; Violence; Wakefulness; Woman; adrenergic; airway obstruction; depression; experience; gamma-Aminobutyric Acid; men; neurochemistry; noradrenergic; orofacial; postsynaptic; pressure; prevent; public health relevance; rapid eye movement; receptor; respiratory; tongue root

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.

描述（由申请人提供）：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。它是由解剖学上气道受损的个体在睡眠期间，特别是在快速眼动（REM）阶段，由于上气道肌肉（包括由舌下运动神经元支配的颏舌肌）张力降低而部分或完全气道阻塞引起的。由此导致的低呼吸/呼吸暂停发作导致血红蛋白氧饱和度反复降低、二氧化碳积累和频繁醒来，从而导致慢性睡眠剥夺和碎片化。阻塞性睡眠呼吸暂停患者白天嗜睡过多，生活质量下降。阻塞性睡眠呼吸暂停还与高血压、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，两个主要的状态依赖输入控制舌下运动神经元：突触后抑制和胺能失化。然而，尽管经过了几十年的研究，对于快速眼动睡眠期间这一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时使用细胞内记录。具体目的如下：(1)确定抑制性氨基酸介导的突触后抑制对快速眼动睡眠期间舌下运动神经元活动抑制的贡献；(2)确定胺能失化对快速眼动睡眠相关的舌下运动神经元活动抑制的贡献。我们将获得关于这两种主要神经递质系统在快速眼动睡眠期间舌下运动神经元活动抑制中的作用的定量数据。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性控制机制的理解，并可用于开发有效的药物治疗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失调引起的。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OSA药物治疗的先决条件。