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 呼吸控制系统的外围和中心元素不是“固定的”，而是经历持续的 （神经塑性）电路重组以优化函数。该系统可以选择性地利用唯一的传入 引起情节性，协调气道保护行为的方式和脑干神经途径（例如 咳嗽，喉添加）。神经塑性受到炎症，短暂传入的诱导和破坏 反馈或中枢神经系统受伤。结果，呼吸反应和气道保护行为以方式改变 这可能是适应性或适应不良的。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由神经可塑性引起的反应变化 控制系统的感官，中央整合和高效的运动元件。这个知识差距 外围和基于中央电路的过程增加了呼吸中不适当抑郁的风险 通过在SPARC计划中研究的神经调节方法保护气道机制。 在这个项目中，我们的目标是了解情感中调制和可塑性的基本原理 控制呼吸和气道防御的途径，大脑网络和高效系统。提议 研究将促进我们对呼吸控制基础电路的理解，为 未来的神经调节策略使弱势临床人群中的肺功能正常化。我们有 组建了一个多学科团队，以利用尖端遗传，神经解剖学，神经生理和 计算建模方法询问呼吸道的感觉，中央和电路通路 控制系统。互补研究将在人类患者人群中进行各种形式的患者 感官或运动功能障碍，包括喉切除术，双肺移植和单侧声音的感官功能障碍 折叠瘫痪。通过这些平行研究，我们将揭示呼吸系统的基本机制 受伤，疾病和/或传入激活引起的神经塑性。来自外围和的新知识 动物模型中的中央电路和具有病理学的人类将用于创建迭代，计算 神经力学模型结合了神经塑性的关键要素。该模型将启用预测 随着我们开发神经调节方法，以告知新的呼吸功能障碍治疗方法。项目 分为四个包含的目标。目标1：识别肺的神经解剖学和功能可塑性 调节气道保护反射的脑干途径的感官机制。目标2：识别简短 气道电动机，脑干和脊柱呼吸运动的时尺度和持续的基于电路的可塑性 感官反馈（气道和隔膜）和/或损伤/疾病引起的途径。目标3：调查密钥 人类呼吸行为中神经可塑性的特征。目标4：开发神经力学计算 神经元系统控制呼吸和气道防御的模型，该防气道结合了由 感觉传入的反馈和伤害/疾病。