Central determinants of airway instability during sleep

呼吸道从鼻孔延伸到肺泡，具有复杂的几何结构和功能。它们的大小、形状以及对气流的阻力受到许多因素的影响，包括对上呼吸道扩张和收缩肌肉、气道平滑肌肉和气道血管的神经元驱动的变化。睡眠期间，上呼吸道扩张肌肉的活动减少，胆碱能流出到呼吸道平滑肌的数量增加。这并不罕见地导致睡眠阻塞性呼吸暂停和呼吸道功能恶化。神经解剖投射、神经递质和信号通路调节睡眠相关的变化还不是很清楚。这项建议包括对睡眠期间涉及呼吸和呼吸道通畅调节的中央网络的研究。第一部分涉及睡眠时激活的中枢神经系统细胞群的神经化学组织和轴突投射，2)睡眠促进部位的靶神经元的识别及其与舌下和气道相关的迷走神经节前神经元的关系，第二部分涉及参与睡眠相关的神经元的神经化学组织，这些神经元介导与睡眠有关的上呼吸道扩张和收缩肌肉的自主功能和运动活动的调节。Fos的表达将被用来识别睡眠中激活的神经元，研究这些细胞的基本化学神经解剖学，共同定位睡眠激活神经元中可能的神经递质，并确定这些结构与舌下和气道相关的迷走神经节前神经元之间的路径和联系。来自这些研究的数据将提供与中枢网络、神经化学组织以及促进睡眠的细胞和脑干输出神经元之间通信的化学性质有关的基本信息。这些结果将直接影响我们对睡眠中中枢调节的呼吸和呼吸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夜间哮喘的恶化。

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.