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件不是“固定的”，而是持久的 （神经塑料）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神经。 诱发间歇性、协调性气道保护行为的方式和脑干神经通路（例如， 咳嗽、喉内收）神经可塑性是由炎症、短暂传入神经诱导和破坏的。 结果，呼吸反应和气道保护行为发生了改变。 脑干网络和感觉控制系统的现有模型可能是适应性的，也可能是适应性不良的。 调节呼吸和气道保护并不能解释神经可塑性引起的反应变化 这种知识差距涉及控制系统的感觉、中央集成和传出运动元件。 基于外周和中枢回路的过程会增加呼吸或呼吸不适当抑制的风险 SPARC 计划中正在研究神经调节方法的气道保护机制。 在这个项目中，我们的目标是了解传入调制和可塑性的基本原理 控制呼吸和气道防御的通路、大脑网络和传出系统。 研究将增进我们对呼吸控制回路的理解，为 我们拥有未来的神经调节策略，可以使弱势临床人群的肺功能正常化。 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 计算建模方法来询问呼吸的感觉、中枢和运动通路 控制系统将在人类患者群体中进行各种形式的补充研究。 感觉或运动功能障碍，包括喉切除术、双肺移植和单侧发声功能障碍 通过这些平行研究，我们将揭示呼吸的基本机制。 损伤、疾病和/或传入激活引起的神经可塑性。 动物模型和患有疾病的人类的中央电路将用于创建迭代的计算 包含神经可塑性关键要素的神经力学模型将能够进行预测。 我们正在开发神经调节方法来为呼吸功能障碍的新疗法提供信息。 分为四个目标 目标 1：确定肺的神经解剖学和功能可塑性。 调节脑干通路以实现气道保护性反射的感觉机制 目标 2：识别短波。 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 由感觉反馈（气道和膈肌）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：开发神经力学计算模型。 控制呼吸和气道防御的神经系统模型，其中包含由以下因素引起的可塑性 感觉传入反馈和损伤/疾病。