Neurogenesis of Cough

描述(申请人提供)：这项研究的长期目标是描绘咳嗽产生和调节的脑干机制。这项研究的中心假设是，核心呼吸网络通过动态组织成表达呼吸道防御行为所需的调节元件的神经元集合来控制咳嗽的发生。这些行为控制组件(BCA)由在电路中协同工作的神经元组成，并被瞬时配置为处理和存储与给定行为的调节相关的信息。我们认为咳嗽的BCA是由神经元(中缝神经元和一个新的髓质群体)组成的，而这些神经元目前并不被认为是中枢呼吸模式发生器(CPG)的一部分。BCAS发挥呼吸CPG的关键控制功能，使其能够a)重新配置，以产生与不同呼吸行为(如咳嗽)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。我们的总体方法将是扩展和测试当前的模型，以解释已知的咳嗽反射的调节特征。提出这项研究的基本原理是，一旦脑干咳嗽模式生成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)确定中缝和尾侧内侧柱神经元在咳嗽神经发生中的功能相关性；2)建立一个预测模型，解释已知的咳嗽调节特征以及中缝和尾侧内侧柱神经元在这一行为的神经发生中所扮演的角色；以及3)确定中缝和尾侧内侧柱神经元在喉部炎症诱导的咳嗽高反应性中的作用。第一个目的是在咳嗽时同时记录多个中缝、延髓尾侧内侧和腹侧呼吸柱(VRC)神经元。先进的棘波序列分析和同步性度量将被用来确定这些特定于咳嗽的神经元之间的协同放电模式。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扮演的重要角色。在目标2中，我们将使用网络模拟工具测试修改后的咳嗽网络模型，该网络模拟工具允许离散的“积分与激发”(IF)种群和包含亚阈值电流的Hodgkin-Huxley方程的“混合”种群。我们还将反复合并从多个电极阵列同时记录的棘波序列分析中识别的特定脑干神经元群体之间的推断功能相互作用。在目标3中，同步性和神经元种群动力学的指标将应用于急性喉炎模型的数据，以确定有助于增强咳嗽的协同放电模式。这些实验结果将极大地促进我们对咳嗽神经机制的理解。在这个国家，每年有超过2500万人因咳嗽而去看医生。患者经常在成功治疗之前遭受多年的慢性咳嗽，这主要是因为我们缺乏对在健康和疾病中产生这种行为的基本机制的了解。(摘要结束)

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)