Central Mechanisms of Airway Protection

描述（由申请人提供）：多种神经肌肉疾病导致咳嗽受损（吞咽困难）和/或吞咽受损（吞咽困难）。该项目的长期目标是确定控制和协调咳嗽和吞咽的脑干机制。我们的中心假设是，一个“核心”的呼吸网络是重新配置的神经元组件动态组织成必要的表达气道保护行为的调节元件（BCAs的行为控制组件）。吞咽的咽部阶段具有重要的气道保护成分，并且该机制沿着由咳嗽产生的气流联合收割机以防止吸入并排出穿透气道的物质。调节和协调咳嗽和吞咽以优化气道保护的操作特征、身份和特定神经机制尚不清楚。目前接受的咳嗽模型提出，呼吸的中枢模式生成网络被快速重新配置以产生咳嗽运动模式。没有已发表的模型解释咳嗽如何与吞咽协调以保护气道免受吸入。BCA发挥呼吸CPG的关键控制功能，允许其a）重新配置以产生与咳嗽和吞咽相关的广泛变化的运动模式，以及B）赋予系统新的调节特征，使得每种行为可以由传入系统以功能上适当的方式控制。这项研究的基本原理是，一旦脑干气道保护系统的组织和调节建立起来，就可以确定神经系统疾病中导致误吸的机制。本项目的具体目标是：1）确定控制咳嗽和吞咽运动模式协调的操作原则，以保护气道免受吸入。2)确定尾内侧柱神经元在咳嗽和吞咽运动模式的神经发生中的功能作用。3)开发一个预测性的计算分布式网络模型与已知的调节机制，在咳嗽和吞咽的神经发生。预计该项目将产生以下成果。首先，一个新发现的神经元群体在尾内侧髓质的气道保护的神经发生的作用将成为已知的。这些信息将使我们能够测试气道保护的统一模型，并阐明该系统的功能组织。第二，这个组织将在促进呼吸，咳嗽和吞咽的同时表达的挑战中进行研究。在这样做的过程中，我们也将提高我们对负责行为选择的中央机制的理解。第三，气道保护网络的最终模型将允许我们预测可能受神经系统疾病影响的网络元素，导致吞咽困难和/或吞咽困难。这些结果将定义负责调节气道保护的中枢机制，并提供基本的新信息，促进我们对呼吸、咳嗽和吞咽中枢组织的理解。 公共卫生相关性：多种神经肌肉疾病导致咳嗽受损（吞咽困难）和/或吞咽功能受损（吞咽困难）。这些气道保护行为的损害导致由于吸入引起的肺部感染的增加。与气道防御不足相关的肺部并发症是脊髓损伤和帕金森病患者死亡的主要原因。

DESCRIPTION (provided by applicant): A variety of neuromuscular diseases result in impaired cough (dystussia) and/or impaired swallow (dysphagia). The long-term goal of this project is to determine brainstem mechanisms that control and coordinate cough and swallow. Our central hypothesis is that a "core" respiratory network is reconfigured by neuronal assemblies dynamically organized into regulatory elements (BCAs-behavioral control assemblies) necessary for the expression of airway protective behaviors. The pharyngeal phase of swallow has an important airway protective component, and this mechanism along with airflows generated by cough combine to prevent aspiration and to eject materials that penetrate the airway. The operational features, identity, and specific neural mechanisms which regulate and coordinate cough and swallow to optimize airway protection are unknown. The currently accepted model for cough proposes that the central pattern generating network for breathing is rapidly reconfigured to produce the cough motor pattern. There are no published models that explain how cough is coordinated with swallow to protect the airway from aspiration. BCAs exert a critical controlling function of the respiratory CPG, allowing it to a) reconfigure to generate widely variant motor patterns associated with cough and swallow, and b) impart novel regulatory characteristics to the system such that each behavior can be controlled by afferent systems in a manner that is functionally appropriate. The rationale for the proposed research is that once the organization and regulation of the brainstem airway protection system is established, the mechanisms responsible for aspiration in neurologic disease can be identified. The Specific Aims of this project are: 1) Identify the operational principles that govern the coordination of the cough and swallow motor patterns to protect the airway from aspiration. 2) Determine the functional role of caudal medial column neurons in the neurogenesis of the cough and swallow motor patterns. 3) Develop a predictive computational distributed network model with known regulatory mechanisms in the neurogenesis of cough and swallow. The project is expected to yield the following outcomes. First, the role of a newly identified population of neurons in the caudal medial medulla in the neurogenesis of airway protection will become known. This information will allow us to test a unified model of airway protection and elucidate the functional organization of this system. Second, this organization will be studied during challenges that promote the simultaneous expression of breathing, cough and swallow. In doing so, we also will enhance our understanding of the central mechanisms responsible for behavior selection. Third, the resultant model of the airway protection network will allow us to predict elements of the network that may be affected neurologic disease, resulting in dystussia and/or dysphagia. These outcomes will define the central mechanisms responsible for the regulation of airway protection and provide fundamental new information that will advance our understanding of the central organization of breathing, cough, and swallow. PUBLIC HEALTH RELEVANCE: A variety of neuromuscular diseases result in impaired cough (dystussia) and/or impaired swallow function (dysphagia). Impairment of these airway protective behaviors results in an increase in pulmonary infections due to aspiration. Pulmonary complications related to inadequate airway defense are the leading cause of death in patients with spinal cord injuries and Parkinson's Disease.