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

肺是少数几个由自主神经（迷走神经）和躯体神经系统的传入和传出成分调节的内脏器官之一。自主神经成分涉及肺和气道中的迷走感觉受体，以及气道平滑肌或粘液分泌腺/细胞的传出神经支配。甚至呼吸或保护气道（咳嗽）所必需的躯体组件包括膈/隔膜和辅助（肋间，腹部）运动系统。这些传入和传出自主/躯体系统由共享的脑干和脊髓网络协调，这些脑干和脊髓网络能够选择性地利用传入和传出成分来产生规律的呼吸或偶发的（触发的）气道保护行为（例如咳嗽、喉内收肌反射）。呼吸系统由一个多尺度的感觉运动控制网络，表现出神经可塑性。在本项目中，我们将通过以下方式研究呼吸系统的选定方面：1）脊髓或脊髓感觉神经的电刺激，2）颅神经传入反馈的短暂扰动，3）间歇性缺氧，4）气道或全身炎症，5）检查影响呼吸和气道防御的临床疾病。几个参与的实验室采用药理学，遗传学和解剖学的方法，旨在了解迷走神经的感觉通路，调节气道功能。CRE小鼠将用于描绘来自不同迷走神经节及其外周投射的气道神经调节剂通路。我们也将通过阐明引起喉内收肌反射的中枢回路来研究负责气道保护的神经机制。膈感觉运动系统的传入和传出通路中的神经可塑性将通过脊神经和/或脊髓的电刺激来诱导。我们在体内的努力将通过感觉反馈和控制呼吸功能的中枢神经系统的计算建模来统一。这些建模工作包括喉内收肌反射和整合气道机械感受器和C纤维反馈的NTS通路的首次模拟。

The lungs are one of the few visceral organs regulated by afferent and efferent components of both the autonomic (vagal) and somatic nervous systems. Autonomic components involve vagal sensory receptors in the lungs and airways, and efferent innervation of airway smooth muscle or mucus secreting glands/cells. Somatic components necessary to even take a breath or defend the airways (cough) include the phrenic/diaphragm and accessory (intercostal, abdominal) motor systems. These afferent and efferent autonomic/somatic systems are coordinated by shared brainstem and spinal cord networks capable of selectively utilizing afferent and efferent components to produce regular breathing, or sporadic (triggered) airway protective behaviors (e.g. cough, laryngeal adductor reflex). The respiratory system consists of a multiscale sensorimotor control network that exhibits neuroplasticity. In this project we will investigate selected aspects of the respiratory system by: 1) electrical stimulation of the spinal cord or spinal sensory nerves, 2) transient perturbations in afferent feedback from cranial nerves, 3) intermittent hypoxia, 4) airway or systemic inflammation and 5) examination of clinical disorders that compromise breathing and airway defense. Several of the participating labs employ pharmacological, genetic and anatomical methods aimed at understanding vagal sensory pathways that regulate airway function. CRE mice will be used to delineate airway neuromodulator pathways from distinct vagal ganglia and their peripheral projections. We also will investigate neural mechanisms responsible for airway protection by elucidation of central circuits that give rise to the laryngeal adductor reflex. Neuroplasticity in afferent and efferent pathways of the phrenic sensorimotor system will be induced by electrical stimulation of spinal nerves and/or spinal cord. Our in vivo efforts will be unified by computational modeling of the sensory feedback and central neural system that controls respiratory function. These modeling efforts include the first simulations of the laryngeal adductor reflex and the NTS pathways that integrate airway mechanoreceptor and C-fiber feedback.