Noradrenergic A7 neurons and Upper Airway Motor Control

描述(申请人提供)：阻塞性睡眠呼吸暂停(OSA)是一个日益严重的健康问题，影响着近5%的成年人口。由于呼吸道阻塞和睡眠时反复唤醒，OSA患者白天过度嗜睡，生活质量下降。OSA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。OSA的治疗选择仅限于手术和使用口腔矫治器；目前还没有有效的药物疗法。舌下运动神经元在阻塞性睡眠呼吸暂停综合征的病理过程中起关键作用，因为它们支配舌肌，而舌肌对维持呼吸道通畅很重要。睡眠期间活动减少，特别是快速眼动(REM)睡眠是阻塞性睡眠呼吸暂停综合征(OSA)的主要原因。因此，完全了解睡眠和清醒时控制舌下运动神经元活动的神经网络可能有助于开发治疗OSA的药物策略。在拟议的项目中，我们将使用一个新的动物模型来研究去甲肾上腺素能A7神经元在神经网络中的作用，该网络在自然睡眠-觉醒周期中控制舌下运动神经元的活动。我们将获得有关A7神经元在睡眠和清醒状态下的行为、它们的下游投射以及它们在非REM和REM睡眠中对舌下运动神经元兴奋性抑制机制的贡献的数据。获得的信息将促进我们对控制舌下运动神经元状态依赖活动的神经元网络和神经化学机制的理解，并为开发有效的药物治疗OSA提供基础

DESCRIPTION (provided by applicant): Obstructive Sleep Apnea (OSA) is a growing health problem which affects almost 5% of the adult population. Due to airway obstruction and repetitive waking during sleep, OSA patients have excessive daytime sleepiness and a diminished quality of life. OSA is associated with hypertension, diabetes, coronary artery disease, strokes and congestive heart failure. The treatment options for OSA are limited to surgery and the use of oral appliances; no effective pharmacological therapy is available. Hypoglossal motoneurons play a critical role in pathology of the OSA because they innervate the muscles of the tongue that are important for maintaining airway patency. A decrease in their activity during sleep and especially rapid eye movement (REM) sleep is the main cause of airway obstruction in OSA. Therefore, complete understanding of the neuronal network that controls activity of hypoglossal motoneurons during sleep and wakefulness may help to develop pharmacological strategies to treat OSA. In the proposed project, we will study the role of noradrenergic A7 neurons in the neuronal network that controls activity of hypoglossal motoneurons during the natural sleep-wake cycle using a novel animal model. We will obtain data regarding behavior of A7 neurons during states of sleep and wakefulness, their downstream projections and their contribution to the mechanisms of the depression of hypoglossal motoneurons excitability during non-REM and REM sleep. Obtained information will advance our understanding of the neuronal network and neurochemical mechanisms that control state-dependent activity of hypoglossal motoneurons and provide a foundation for developing effective pharmacological treatments for OSA