Regulation of Airway Protective Behaviors

描述（由申请人提供）：本项目的长期目标是确定气管和咽部感觉反馈在咳嗽和吞咽调节中的作用。我们的中心假设是，一个吸入事件会产生一系列的咳嗽和吞咽，这些咳嗽和吞咽会以各种行为互动模式表达出来，并且存在着可解读的规则来调节各种表达模式。咳嗽和吞咽是气道保护行为。吞咽的咽部阶段通过会厌运动、喉部内收以及清理口腔和咽部来防止吸入口腔物质（唾液、食物和液体）。咳嗽是一种吸入反应行为，它清除气道中的物质.这些行为的协调对于保护气道免受进一步的吸气促进事件（例如在咳嗽的吸气阶段发生的吞咽）至关重要。外周输入、操作特征和协调咳嗽和吞咽的主要策略尚不清楚。这种信息的缺乏阻碍了对气道保护缺陷的理解，伴随着伴随帕金森病和阿尔茨海默病等疾病发生的吞咽困难和肌张力障碍的共同发生。该项目的具体目标是：1）确定在吸入事件期间激活气管和咽传入后控制咳嗽和吞咽运动模式协调的操作原则; 2）开发气管感觉通路对咳嗽和吞咽表达的中枢影响的预测性计算分布式网络模型;（3）确定网状结构中神经元在处理气管和咽传入反馈中的作用。我们的初步数据表明，咳嗽和吞咽的生产的感觉反馈的调节作用。通过吸入刺激刺激气管传入增加吞咽的幅度，提供了气道反馈诱导的咽部清除增加的证据。我们已经观察到一个独特的相位限制关系，支配吞咽时发生在咳嗽过程中的咽传入反馈。在第一个目标中，我们将通过同时刺激气管和咽传入的协议来扰乱咳嗽和吞咽运动模式。此外，我们将选择性地操纵传入输入通过双侧电刺激的上级喉神经。在目标2中，我们将使用网络模拟工具测试气管传入刺激对咳嗽和吞咽协调的中枢效应模型，以允许离散的“整合和激发”（IF）群体 和“混合”群体，其结合了用于亚阈值电流的Hodgkin-Huxley式方程。在目标3中，我们将：1）使用多电极阵列从网状结构中的神经元记录，以在以下期间获得多个尖峰序列数据：a）选择性刺激气管或咽以引起咳嗽或吞咽; B）同时刺激气管和咽以引起协调的咳嗽和吞咽;以及c）使用上级喉神经的电刺激选择性操纵咳嗽和吞咽; 2）测试通过将内源性兴奋性氨基酸拮抗剂犬尿烯酸微量注射到内侧网状结构中诱导的味觉障碍和吞咽困难的急性模型。这些实验的结果将大大提高我们对气道和感觉反馈对咳嗽和吞咽协调的影响的理解。

DESCRIPTION (provided by applicant): The long-term goal of this project is to determine the role of tracheal and pharyngeal sensory feedback in the regulation of cough and swallow. Our central hypothesis is that an aspiration event produces a series of coughs and swallows which are expressed in various behavioral interaction patterns, and that there are decipherable rules that regulate the various patterns of expression. Cough and swallow are airway protective behaviors. The pharyngeal phase of swallow prevents aspiration of oral material (saliva, food and liquid), by epiglottal movement, laryngeal adduction, and clearing the mouth and pharynx. Cough is an aspiration- response behavior that clears material from the airway. Coordination of these behaviors is vital to protect the airway from further aspiration-promoting events, such as a swallow occurring during the inspiratory phase of cough. The peripheral inputs, operational characteristics, and primary strategies that coordinate cough and swallow are unknown. This lack of information impedes understanding of the deficits in airway protection, with co-occurrence of dystussia and dysphagia, which occurs with diseases such as Parkinson's disease and Alzheimer's disease. The Specific Aims of the project are: 1) Identify the operational principles that govern the coordination of cough and swallow motor patterns following activation of tracheal and pharyngeal afferents during an aspiration event; 2) Develop a predictive computational distributed network model of the central influence of tracheal sensory pathways on the expression of cough and swallow; and 3) Identify the role of neurons in the reticular formation in processing tracheal and pharyngeal afferent feedback on cough and swallow. Our preliminary data demonstrates a modulatory effect of sensory feedback of the production of cough and swallow. Stimulation of tracheal afferents by an aspiration stimulus increases the magnitude of swallows, providing evidence of airway feedback-induced increased pharyngeal clearance. We have observed a distinct phase restriction relationship that governs when swallow occurs in response to pharyngeal afferent feedback during cough. In the first aim, we will perturb the cough and swallow motor patterns by protocols that simultaneously stimulate tracheal and pharyngeal afferents. Additionally, we will selectively manipulate afferent input through bilateral electrical stimulation of the superior laryngeal nerve. In aim 2, we will test a model of the central effects of tracheal afferent stimulation on the coordination of cough and swallow using network simulation tools to allow both discrete "integrate and fire" (IF) populations and "hybrid" populations that incorporate Hodgkin-Huxley style equations for sub-threshold currents. In aim 3, we will: 1) record from neurons in the reticular formation using a multi-electrode array to obtain multiple-spike train data during: a) the selective stimulation of the trachea or pharynx to elicit cough or swallow; b) simultaneous stimulation of the trachea and pharynx to elicit coordinated cough and swallow; and c) selective manipulation of cough and swallow using electrical stimulation of the superior laryngeal nerve; 2) test an acute model of dystussia and dysphagia induced by microinjection of the endogenous excitatory amino acid antagonist, kynurenic acid, into the medial reticular formation. The results of these experiments will significantly advance our understanding of the influence of airway and sensory feedback on the coordination of cough and swallow.