Central Mechanisms of Airway Protection

描述(申请人提供)：多种神经肌肉疾病会导致咳嗽和/或吞咽障碍(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，“核心”呼吸网络是由动态组织成表达呼吸道保护行为所必需的调控元件(BCA-行为控制组件)的神经元组件重新配置的。吞咽的咽相具有重要的呼吸道保护成分，这一机制与咳嗽产生的气流结合在一起，防止吸入并排出穿透呼吸道的物质。调节和协调咳嗽和吞咽以优化呼吸道保护的操作特征、身份和特定的神经机制尚不清楚。目前被接受的咳嗽模型提出，呼吸的中央模式生成网络被迅速重新配置，以产生咳嗽运动模式。目前还没有发表的模型来解释咳嗽和吞咽是如何协调以保护呼吸道免受吸入的。BCAS发挥呼吸CPG的关键控制功能，使其能够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，使得传入系统可以以功能适当的方式控制每一种行为。这项拟议研究的基本原理是，一旦脑干呼吸道保护系统的组织和调节建立起来，就可以确定导致神经系统疾病吸入的机制。该项目的具体目标是：1)确定控制咳嗽和吞咽运动模式协调的操作原则，以保护呼吸道免受吸入。2)确定尾侧内侧柱神经元在咳嗽和吞咽运动模式神经发生中的作用。3)建立了一个具有已知调节机制的咳嗽和吞咽神经发生的预测性计算分布式网络模型。该项目预计将产生以下成果。首先，新发现的尾侧延髓内侧神经元群体在呼吸道保护的神经发生中的作用将变得已知。这些信息将使我们能够测试一个统一的呼吸道保护模型，并阐明该系统的功能组织。其次，将在促进呼吸、咳嗽和吞咽同时表达的挑战中研究这种组织。在这样做的同时，我们还将增进对负责行为选择的中央机制的理解。第三，合成的呼吸道保护网络模型将使我们能够预测该网络中可能受到神经系统疾病影响的元素，从而导致咽喉困难和/或吞咽困难。这些结果将确定负责调节呼吸道保护的中央机制，并提供基本的新信息，促进我们对呼吸、咳嗽和吞咽的中央组织的理解。 公共卫生相关性：各种神经肌肉疾病会导致咳嗽障碍(发音困难)和/或吞咽功能障碍(吞咽困难)。这些呼吸道保护行为的损害会导致吸入引起的肺部感染的增加。与呼吸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的主要死亡原因。

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.