Central determinants of airway instability during sleep

从鼻孔延伸到肺泡的气道具有复杂的几何形状和功能。它们的大小、形状以及因此对气流的阻力受到许多因素的影响，包括对上气道扩张和收缩肌肉、气道平滑肌和气道脉管系统的神经元驱动的变化。在睡眠期间，上呼吸道扩张肌的活动减少，并且到呼吸道平滑肌的胆碱能流出增加。这通常会导致睡眠阻塞性呼吸暂停和气道功能恶化。神经解剖预测，神经递质和信号通路介导的睡眠相关的变化还没有很好地理解。这项建议包括集中在睡眠期间参与呼吸和气道通畅性调节的中枢网络的研究。第一部分涉及1）在睡眠期间被激活的CNS细胞群的神经化学组织和轴突投射，2）识别睡眠促进位点的靶神经元及其与舌下神经和气道相关的迷走神经节前神经元的关系，第二部分是3）调节睡眠的神经元的神经化学组织-上呼吸道扩张和收缩肌肉的自动功能和运动活动的相关调节。Fos表达将用于鉴定在睡眠期间激活的神经元，研究这些细胞的基本化学神经解剖学，在睡眠激活的神经元中共定位推定的神经递质，并确定这些结构与舌下神经和气道相关的迷走神经节前神经元之间的通路和连接。这些研究获得的数据将提供与中枢网络、神经化学组织以及睡眠促进细胞和脑干输出神经元之间通讯的化学性质相关的基本信息。这些结果将直接影响我们对睡眠期间中枢介导的呼吸和气道功能的神经化学机制的理解，例如阻塞性睡眠呼吸暂停和哮喘的夜间恶化。

The airways, extending from the nares to the alveoli, have a complex geometry and function. Their size, shape, and consequently resistance to airflow is influenced by numerous factors, including changes in neuronal drive to the upper airway dilating and constricting muscles, airway smooth muscles and airway vasculature. During sleep, activity of the upper airway dilating muscles is reduced and cholinergic outflow to airway smooth muscle is increased. This leads not uncommonly to sleep obstructive apnea and worsening of the airway functions. Neuroanatomical projections, neurotransmitters and signaling pathways mediating sleep-related changes are not well understood. This proposal consists of research focused on the central networks involved in regulation of breathing and airway patency during sleep. The first part deals with 1) the neurochemical organization and axonal projections of the CNS cell groups that are activated during sleep, 2) identification of the target neurons of the sleep promoting sites and their relation to hypoglossal and airway related vagal preganglionic neurons, and the second part with 3) the neurochemical organization of neurons that mediate sleep-related modulations of the automatic functions and motor activities of upper airway dilating and constricting muscles. Fos expression will be used to identify neurons activated during sleep, to investigated the basic chemical neuroanatomy of these cells, to co- localized putative neurotransmitters in sleep activated neurons, and to determine pathways and connections between these structures and the hypoglossal and airway related-vagal preganglionic neurons. The data derived from these studies will provide basic information related to central networks, neurochemical organization, and chemical nature of communications between sleep promoting cells and brainstem output neurons. The results will have a direct bearing on our understanding of neurochemical mechanisms underlying centrally mediated respiratory and airway functions during sleep, such as obstructive sleep apnea and the nocturnal worsening of asthma.