Regulation of Airway Protective Behaviors

描述(申请人提供)：这个项目的长期目标是确定气管和咽部感觉反馈在调节咳嗽和吞咽中的作用。我们的中心假设是，吸入事件会产生一系列咳嗽和吞咽，这些咳嗽和吞咽以各种行为交互模式表达，并且有可理解的规则来调节各种表达模式。咳嗽和吞咽是呼吸道保护行为。咽部阶段通过会厌运动、喉内收和清理口腔和咽部来阻止口腔物质(唾液、食物和液体)的吸入。咳嗽是一种吸入反应行为，可以清除呼吸道中的物质。这些行为的协调对于保护呼吸道免受进一步的吸入促进事件的影响至关重要，例如在吸气期咳嗽时发生的吞咽。协调咳嗽和吞咽的外周输入、操作特征和主要策略尚不清楚。这种信息的缺乏阻碍了对呼吸道保护缺陷的了解，同时伴有吞咽困难和吞咽困难，这些疾病与帕金森氏症和阿尔茨海默病等疾病一起发生。该项目的具体目标是：1)确定在吸入事件中激活气管和咽部传入后协调咳嗽和吞咽运动模式的操作原则；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分布式计算网络模型；以及3)确定网状结构中神经元在处理关于咳嗽和吞咽的气管和咽部传入反馈中的作用。我们的初步数据表明，感觉反馈对咳嗽和吞咽的产生具有调节作用。吸入刺激对气管传入的刺激增加了吞咽的幅度，为呼吸道反馈引起的咽部清除增加提供了证据。我们观察到了一种独特的时相限制关系，这种关系支配着咳嗽期间咽部传入反馈时吞咽的发生。在第一个目标中，我们将通过同时刺激气管和咽部传入的方案来扰乱咳嗽和吞咽运动模式。此外，我们将通过双侧喉上神经的电刺激来选择性地操纵传入输入。在目标2中，我们将使用网络模拟工具来测试气管传入刺激对咳嗽和吞咽协调的中枢影响的模型，以允许离散的“整合和激发”(IF)种群 和“混合”种群，包含亚阈值电流的霍奇金-赫胥黎方程。在目标3中，我们将：1)使用多电极阵列记录网状结构中的神经元，以获得在以下过程中的多棘波序列数据：a)选择性刺激气管或咽部以引起咳嗽或吞咽；b)同时刺激气管和咽部以引起协调的咳嗽和吞咽；以及c)通过电刺激喉上神经选择性地操纵咳嗽和吞咽；2)测试内源性兴奋性氨基酸拮抗剂脑尿酸微量注射到内源性兴奋性氨基酸拮抗剂脑尿酸诱导的急性营养不良和吞咽困难模型。这些实验结果将极大地促进我们对呼吸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.