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

项目摘要 呼吸控制系统的外周和中枢元素不是“固定的”，而是经历持续的 (神经整形)电路重组以优化功能。该系统可以选择性地利用唯一的传入 模式和脑干神经通路，以诱导间歇性、协调的呼吸道保护行为(例如， 咳嗽、喉内收)。炎症、一过性传入诱导和破坏神经可塑性 反馈，或中枢神经系统损伤。结果，呼吸反应和呼吸道保护行为在以下方面发生了变化 这可能是适应性的，也可能是适应性差的。脑干网络和感觉控制系统的现有模型 调节呼吸和呼吸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。这一知识鸿沟涉及 以外周和中枢回路为基础的过程增加了呼吸或呼吸中不适当抑郁的风险 SPARC计划中正在研究的神经调节方法的呼吸道保护机制。 在这个项目中，我们的目标是了解传入的调制和可塑性的基本原理 控制呼吸和呼吸道防御的通路、大脑网络和传出系统。建议数 研究将促进我们对呼吸控制基础电路的理解，为 未来神经调节策略以使脆弱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。补充研究将在人类患者群体中进行，这些患者具有不同形式的 感觉或运动功能障碍，包括喉切除、双肺移植和单侧发声 折叠麻痹。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。来自外围设备和设备的新知识 动物模型和有病理的人类的中央回路将被用来创建迭代的、计算的 包含神经可塑性关键要素的神经力学模型。该模型将使预测成为可能 随着我们开发神经调节方法来为呼吸功能障碍的新疗法提供信息。该项目 被分为四个包罗万象的目标。目的1：确定肺的神经解剖和功能可塑性 调节呼吸道保护性反射的脑干通路的感觉机制。目标2：找出短文 呼吸道运动、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(呼吸道和横隔膜)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 控制呼吸和呼吸道防御的神经系统模型，结合了由 感觉传入反馈和损伤/疾病。

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.