Neurogenesis of Cough

描述（由申请人提供）：本研究的长期目标是描述产生和调节咳嗽的脑干机制。本研究的中心假设是，核心呼吸网络是由神经元组装体控制的，这些神经元组装体动态地组织成表达气道防御行为所需的调节元件，从而产生咳嗽。这些行为控制组件（BCA）由在电路中协同操作的神经元组成，并且被瞬时配置为处理和存储与给定行为的调节相关的信息。我们建议，咳嗽的BCA是由神经元（中缝神经元和一个新的髓质人口），目前不被认为是中央呼吸模式发生器（CPG）的一部分。BCA发挥呼吸CPG的关键控制功能，允许其a）重新配置以产生与诸如咳嗽的不同呼吸行为相关联的广泛变化的运动模式，以及B）赋予系统新的调节特性，使得每种行为可以由传入系统以功能上适当的方式控制。我们的总体方法将是扩展和测试当前模型，以解释咳嗽反射的已知调节特征。拟议研究的基本原理是，一旦脑干咳嗽模式发生器的组织和调节建立起来，就可以确定病理性咳嗽产生的机制。该项目的具体目标是：1）确定中缝和尾内侧柱神经元在咳嗽的神经发生中的功能相关性，2）开发预测模型，该模型解释了咳嗽的已知调节特征以及中缝和尾内侧柱神经元在该行为的神经发生中的拟议作用，（3）确定中缝核和尾内侧柱神经元在喉炎症诱导的咳嗽高反应性中的作用。在第一个目标中，在咳嗽期间将同时记录多个中缝、尾内侧髓和腹侧呼吸柱（VRC）神经元。先进的尖峰序列分析和同步性指标将用于确定这些神经元之间的合作放电模式，具体到咳嗽。我们的初步数据支持这些神经元群体在控制咳嗽的组装中的重要作用。在目标2中，我们将使用网络模拟工具测试咳嗽网络的修订模型，该工具允许离散的“整合和激发”（IF）群体和“混合”群体，这些群体将Hodgkin-Huxley式方程用于亚阈值电流。我们还将反复纳入特定的脑干神经元群体之间的推断功能的相互作用，确定从分析同时记录多个电极阵列的尖峰列车。在目标3中，同步性和神经元群体动力学的度量将应用于来自急性喉部炎症模型的数据，以识别有助于增强咳嗽的合作放电模式。这些实验的结果将大大推进我们对咳嗽神经机制的理解。咳嗽是负责超过25万访问医生每年在这个国家。患者经常遭受慢性衰弱性咳嗽多年才被成功治疗，主要是因为我们缺乏对健康和疾病中产生这种行为的基本机制的了解。 (End摘要）

DESCRIPTION (provided by applicant): The long range goal of this research is to delineate the brainstem mechanisms by which cough is produced and regulated. The central hypothesis of this research is that the core respiratory network is controlled to produce cough by neuronal assemblies dynamically organized into regulatory elements required for the expression of airway defensive behaviors. These behavioral control assemblies (BCA) are composed of neurons that operate cooperatively in circuits and are transiently configured to process and store information related to the regulation of a given behavior. We propose that BCAs for cough are composed of neurons (raphe neurons and a novel medullary population) that are not currently considered to be part of the central respiratory pattern generator (CPG). BCAs exert a critical controlling function of the respiratory CPG, allowing it to a) reconfigure to generate widely variant motor patterns associated with different respiratory behaviors such as cough, 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. Our overall approach will be to expand and test the current model to account for the known regulatory features of the cough reflex. The rationale for the proposed research is that once the organization and regulation of the brainstem cough pattern generator are established, the mechanisms responsible for the production of pathological cough can be identified. The Specific Aims of the project are: 1) Identify the functional relevance of raphe and caudal medial column neurons in the neurogenesis of cough, 2) Develop a predictive model that accounts for known regulatory features of cough as well as the proposed roles of raphe and caudal medial column neurons in the neurogenesis of this behavior, and 3) Identify the role of raphe and caudal medial column neurons in cough hyperresponsiveness induced by laryngeal inflammation. In the first aim, multiple raphe, caudal medial medullary, and ventral respiratory column (VRC) neurons will be recorded simultaneously during cough. Advanced spike train analysis and metrics of synchrony will be used to determine cooperative discharge patterns among these neurons specific to cough. Our preliminary data support an important role of these populations of neurons in assemblies that control coughing. In aim 2, we will test a revised model of the cough network using network simulation tools that allow both discrete "integrate and fire" (IF) populations and "hybrid" populations that incorporate Hodgkin-Huxley style equations for subthreshold currents. We will also iteratively incorporate inferred functional interactions among specific brainstem neuronal populations identified from analyses of spike trains simultaneously recorded with multiple electrode arrays. In aim 3, metrics of synchrony and neuronal population dynamics will be applied to data from a model of acute laryngeal inflammation to identify cooperative discharge patterns that contribute to enhanced coughing. The results of these experiments will significantly advance our understanding of neural mechanisms for cough. Cough is responsible for over 25 million visits to physicians annually in this country. Patients often suffer from chronic debilitating cough for years before they are successfully treated, largely because of our lack of understanding of the basic mechanisms that produce this behavior in health and disease. (End of Abstract)