Pontomedullary Integration of Respiratory Afferents

描述（由申请人提供）：本研究计划的长期目标是阐明在健康和心肺疾病中脑干核控制呼吸的基础上，化学和机械呼吸传入输入的复杂神经处理过程。在过去的项目期间，我们使用了单电极、单单元记录和中央显微注射和损伤技术来探索桥背外侧肺收缩中心和背延髓孤束核（NTS）的神经元结构和功能，它们在迷走神经和化学受体传入输入的整合中起重要作用。在我们研究的下一阶段，我们建议采用最先进的多电极/多神经元记录技术，以便在神经网络水平上表征这些桥脑髓核。我们的实验方法结合了先进的多电极/多神经元记录技术（用于大鼠脑干的小型化）和先进的统计技术（用于集合尖峰序列分析和数据挖掘），以破译记录神经元的连通性。在这个项目中需要解决的一个关键问题是，中枢和外周化学受体的输入是简单地由脑桥呼吸神经元传递给呼吸控制器，还是以特定的方式整合在一起调节通气模式。我们的具体目的是识别和表征四个主要脑桥核中缺氧-高碳酸血症通气相互作用的神经相关性（目的1-4）：脑桥背外侧的外侧和内侧臂旁核和K ' lliker-Fuse核以及脑桥腹外侧的A5区域。我们的假设是，一部分脑桥呼吸神经元可能整合低氧和高碳酸血症输入来调节呼吸驱动和呼吸节律，因此单个神经元和整体膈神经对这些输入组合的反应可能比单独输入（无相互作用）的反应总和更大（积极相互作用）或更小（消极相互作用）。确定低氧-高碳酸血症通气相互作用的神经相关因素以及由此产生的呼吸驱动和呼吸节律调节，将有助于揭示某些高危人群（如充血性心力衰竭患者和高海拔睡眠个体）呼吸不稳定的机制。

DESCRIPTION (provided by applicant): The longterm goal of our research program is to elucidate the complex neural processing of chemical and mechanical respiratory afferent inputs that underlie the control of breathing by brainstem nuclei in health and in cardiopulmonary diseases. In the past project period we have used single-electrode, single-unit recording and central microinjection and lesioning techniques to explore the neuronal structures and functions in the dorsolateral pons pneumotaxic center and the dorsomedullary nucleus tractus solitarius (NTS) which participate importantly in the integration of vagal and chemoreceptor afferent inputs. In the next phase of our research we propose to employ a state-of-the-art multielectrode/multineuronal recording technique in order to characterize these pontomedullary nuclei at the neural networks level. Our experimental approach combines advanced multielectrode/multineuronal recording technology which is miniaturized for application in the rat brainstem, and advanced statistical techniques for ensemble spike train analysis and data mining in order to decipher the connectivity of the recorded neurons. A key question to be addressed in this project is whether central and peripheral chemoreceptor inputs are simply relayed by pontine respiratory neurons to the respiratory controller or are integrated in a specific manner in modulating the ventilatory pattern. Our specific aims are to identify and characterize the neural correlates of hypoxic-hypercapnic ventilatory interaction in four major pontine nuclei (Aims 1-4): Lateral and medial parabrachial nuclei and K"lliker-Fuse nucleus in the dorsolateral pons and the A5 region in the ventrolateral pons. Our hypothesis is that a subset of pontine respiratory neurons may integrate hypoxic and hypercapnic inputs in modulating respiratory drive and respiratory rhythm, such that the individual neuronal response and the overall phrenic nerve response to a combination of these inputs may be greater (positive interaction) or smaller (negative interaction) than the sum of responses to separate inputs (no interaction). Identification of the neural correlates of hypoxic-hypercapnic ventilatory interaction and resultant modulation of respiratory drive and respiratory rhythm will shed light on the mechanisms of respiratory instability in certain at-risk subject populations, such as congestive heart failure patients and individuals sleeping at high altitude. PUBLIC HEALTH RELEVANCE: Breathing is a vital bodily function that is fundamental to life. Understanding how various brainstem centers integrate afferent information in the control of breathing is of fundamental importance in the clinical management of a variety of life-threatening conditions such as respiratory failure, chronic cardiopulmonary or airway diseases, sleep apnea, or exposure to extreme environments such as high altitude.