Neurogenesis of Cough

咳嗽的神经发生

基本信息

批准号：
7501050
负责人：
DONALD C BOLSER
金额：
$ 58.34万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7501050
关键词：
Abdominal Muscles Accounting Achievement Acute Address Affect Afferent Pathways Animals Antitussive Agents Archives Ballistics Behavior Behavior Control Brain Stem Breathing Cause of Death Characteristics Chronic Classification Clinical Computer Systems Computer software Computing Methodologies Condition Cost-Benefit Data Coughing Country Custom Data Data Analyses Data Set Databases Decision Making Deglutition Development Disclosure Disease Doctor of Philosophy Electrodes Elements Equation Equipment Exhibits Feedback Felis catus Figs - dietary Fire - disasters Florida Force of Gravity Foreign Bodies Frequencies General Population Generations Goals Grant Health Hodgkin Disease Hour Human Resources Hybrids Individual Infection Inflammation Institution Intellectual Property Knowledge Laboratories Larynx Licensing Lung Lung diseases Medial Methodology Methods Metric Modeling Modification Monitor Motor Mucous body substance Muscle Nature Neuromuscular Diseases Neurons Other Resources Outcome Pathologist Pathology Pathway interactions Patients Pattern Persons Pharmaceutical Preparations Phase Physicians Pneumothorax Policies Population Population Dynamics Postdoctoral Fellow Process Production Property Protocols documentation Publications Range Recommendation Reflex action Regulation Regulatory Element Research Research Infrastructure Research Personnel Resolution Resources Respiratory Muscles Respiratory System Respiratory physiology Rib Fractures Role Rosa Rupture Sensory Series Simulate Sleep disturbances Sorting - Cell Movement Source Code Specific qualifier value Spinal Injuries Spinal cord injury Stimulus Structure Students Symptoms Synapses Syncope System Technology Transfer Testing Time TimeLine Tracheobronchial Training Translations Travel United States Universities Variant Videoconferences Videoconferencing Visit Work abstracting airway inflammation base central pattern generator computerized data processing data acquisition design in vivo inhibitor/antagonist innovation knowledge base models and simulation network models neurogenesis neuromechanism neurophysiology novel open source predictive modeling programs raphe nuclei receptor research study respiratory response simulation software development tool

项目摘要

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)

描述（由申请人提供）：这项研究的远距离目标是描述产生和调节咳嗽的脑干机制。这项研究的核心假设是，核心呼吸网络受到控制，以通过动态组织到表达气道防御行为所需的调节元素中产生咳嗽。这些行为控制组件（BCA）由在电路合作运行的神经元组成，并瞬时配置为处理和存储与给定行为调节有关的信息。我们建议用于咳嗽的BCA是由当前尚未被认为是中央呼吸模式发生器（CPG）的一部分的神经元（Raphe神经元和新型髓样种群）组成的。 BCA具有呼吸CPG的关键控制功能，使其具有a）重新配置，以产生与不同呼吸行为（例如咳嗽）相关的广泛变异的运动模式，以及b）对系统赋予每个行为的新型调节特征，以便每种行为可以通过以功能合适的方式传入系统。我们的总体方法是扩展和测试当前模型，以说明咳嗽反射的已知调节特征。拟议的研究的理由是，一旦建立了脑干咳嗽模式发生器的组织和调节，就可以确定导致病理咳嗽产生的机制。该项目的具体目的是：1）确定Raphe和尾部内侧神经元在咳嗽的神经发生中的功能相关性，2）开发一个预测模型，该模型构成了咳嗽的已知调节特征以及Raphe和Raphe和Raphe的作用尾部内侧神经元在这种行为的神经发生中，3）识别raphe和尾骨内侧神经元在喉炎症引起的咳嗽过度反应性中的作用。在第一个目的中，将同时记录多个raphe，尾部髓质和腹侧呼吸柱（VRC）神经元。高级尖峰列车分析和同步的指标将用于确定这些特定于咳嗽的神经元之间的合作放电模式。我们的初步数据支持这些神经元种群在控制咳嗽的组件中的重要作用。在AIM 2中，我们将使用网络仿真工具测试咳嗽网络的修订模型，该工具允许离散的“集成和射击”（if）种群和“混合”种群，并结合了用于亚阈值电流的Hodgkin-Huxley样式方程。我们还将迭代地纳入从同时记录与多个电极阵列的尖峰列车分析中确定的特定脑干神经元种群之间的推断功能相互作用。在AIM 3中，同步和神经元种群动态的指标将应用于急性喉炎症模型的数据，以识别有助于增强咳嗽的合作排放模式。这些实验的结果将显着提高我们对咳嗽神经机制的理解。咳嗽负责该国每年对医师的2500万次访问。在成功治疗之前，患者经常患有长期衰弱的咳嗽多年，这主要是因为我们对在健康和疾病中产生这种行为的基本机制缺乏了解。（抽象的结尾）