Functional mapping of peripheral and central circuits for airway protection and breathing

气道保护和呼吸的外周和中央回路的功能图

• 批准号: 9301247
• 负责人: DONALD C BOLSER
• 金额: $ 265.43万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-25 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301247
• 关键词: Afferent Neurons; Afferent Pathways; Animal Model; Behavior; Beryllium; Biological; Brain; Brain Stem; Breathing; Cause of Death; Characteristics; Clinical; Collaborations; Communication; Complex; Computer Simulation; Computers; Coughing; Data Files; Disease; Elements; Feedback; Florida; Foundations; Functional disorder; Future; Gases; Genetic; Goals; Human; Impairment; Infection; Inflammation; Injury; Institution; Knowledge; Laboratory Research; Laryngectomy; Larynx; Lung; Lung Transplantation; Maps; Mental Depression; Modality; Modeling; Motor; Motor Neurons; Motor Pathways; Neural Pathways; Neuromechanics; Neuromuscular Diseases; Neuronal Plasticity; Neurons; Paralysed; Pathology; Pathway interactions; Patients; Penetration; Peripheral; Population; Process; Recording of previous events; Reflex action; Regulation; Research; Research Personnel; Respiration; Respiratory Diaphragm; Respiratory physiology; Risk; Sensory; Sensory Receptors; Spinal; System; Time; Universities; base; central nervous system injury; experience; flexibility; functional plasticity; in vivo; motor disorder; multidisciplinary; nervous system disorder; network models; neurophysiology; neuroregulation; novel; patient population; protective behavior; relating to nervous system; respiratory; response; sensory feedback; sensory input; sensory mechanism; spinal pathway; success; vocal cord

PROJECT ABSTRACT The peripheral and central elements of the respiratory control system are not “fixed,” but undergo sustained (neuroplastic) circuit reorganization to optimize function. This system can selectively utilize unique afferent modalities and brainstem neural pathways to elicit episodic, coordinated airway protective behaviors (e.g. cough, laryngeal adduction). Neuroplasticity is induced and undermined by inflammation, transient afferent feedback, or CNS injury. As a result, breathing responses and airway protective behaviors are altered in ways that can be adaptive or maladaptive. Existing models of the brainstem network and sensory control system regulating breathing and airway protection do not explain changes in responses caused by neuroplasticity in sensory, central integrating and efferent motor elements of the control system. This knowledge gap concerning peripheral and central circuit-based processes increases the risk of inappropriate depression in breathing or airway protective mechanisms by the neuromodulatory approaches being investigated in the SPARC initiative. In this project, our goal is to understand fundamental principles of modulation and plasticity in afferent pathways, brain networks and efferent systems controlling breathing and airway defense. The proposed research will advance our understanding of circuits underlying respiratory control, laying the foundation for future neuromodulatory strategies to normalize lung function in vulnerable clinical populations. We have assembled a multidisciplinary team to utilize cutting edge genetic, neuroanatomical, neurophysiological and computational modeling approaches to interrogate sensory, central and motor pathways of the respiratory control system. Complementary studies will be performed in human patient populations with various forms of sensory or motor dysfunction, including those with laryngectomy, double lung transplants and unilateral vocal fold paralysis. Through these parallel studies, we will reveal fundamental mechanisms of respiratory neuroplasticity resulting from injury, disease and/or afferent activation. New knowledge from peripheral and central circuits in animal models and humans with pathologies will be used to create an iterative, computational neuromechanical model that incorporates key elements of neuroplasticity. This model will enable predictions as we develop neuromodulatory approaches to inform novel treatments for respiratory dysfunction. The project is separated into four encompassing aims. Aim 1: Identify neuroanatomical and functional plasticity of lung sensory mechanisms that regulate brainstem pathways for airway protective reflexes. Aim 2: Identify short time-scale and sustained, circuit-based plasticity in airway motor, brainstem and spinal respiratory motor pathways induced by sensory feedback (airway and diaphragm) and/or injury/disease. Aim 3: Investigate key features of neuroplasticity in human respiratory behaviors. Aim 4: Develop a neuromechanical computational model of the neural system controlling breathing and airway defense that incorporates plasticity induced by sensory afferent feedback and injury/disease.

项目摘要 呼吸控制系统的外周和中枢元件不是“固定的”，而是经历持续的 （神经可塑性）电路重组以优化功能。该系统可以选择性地利用独特的传入 模式和脑干神经通路，以引起偶发的，协调的气道保护行为（例如， 咳嗽、喉内收）。神经可塑性是由炎症、瞬时传入 反馈或CNS损伤。因此，呼吸反应和气道保护行为在一定程度上被改变， 可以是适应性的，也可以是不适应性的。脑干网络和感觉控制系统的现有模型 调节呼吸和气道保护不能解释神经可塑性引起的反应变化， 控制系统的感觉、中枢整合和传出运动元件。这一知识空白涉及到 基于外周和中央回路的过程增加了呼吸中不适当抑制的风险， 呼吸道保护机制的神经调节方法正在研究中，在呼吸道的倡议。 在这个项目中，我们的目标是了解传入神经元的调制和可塑性的基本原理， 神经通路、大脑网络和控制呼吸和气道防御的传出系统。拟议 研究将促进我们对呼吸控制回路的理解，为 未来的神经调节策略，以使脆弱的临床人群的肺功能正常化。我们有 组建了一个多学科团队，利用尖端的遗传学，神经解剖学，神经生理学和 询问呼吸系统感觉、中枢和运动通路的计算建模方法 控制系统补充研究将在患有各种形式的糖尿病的人类患者群体中进行。 感觉或运动功能障碍，包括喉切除术，双肺移植和单侧声带 褶皱麻痹通过这些平行研究，我们将揭示呼吸的基本机制， 由损伤、疾病和/或传入激活引起的神经可塑性。从外围设备和 在动物模型和人类的中央电路与病理将被用来创建一个迭代的，计算 神经力学模型，包括神经可塑性的关键要素。这个模型可以预测 因为我们开发了神经调节方法，为呼吸功能障碍的新治疗提供信息。项目 分为四个目标。目的1：确定肺的神经解剖和功能可塑性 调节脑干通路的呼吸道保护反射的感觉机制。目标2：识别短期 气道运动、脑干和脊髓呼吸运动的时间尺度和持续的、基于回路的可塑性 感觉反馈（气道和横膈膜）和/或损伤/疾病引起的通路。目标3：调查关键 人类呼吸行为的神经可塑性特征。目标4：开发一种神经机械计算 一种控制呼吸和气道防御的神经系统模型，包括由 感觉传入反馈和损伤/疾病。