Pontomedullary Integration of Respiratory Afferents

描述（由申请人提供）：我们研究计划的长期目标是阐明化学和机械呼吸传入输入的复杂神经处理，这些输入是健康和心肺疾病中脑干核团控制呼吸的基础。在过去的项目期间，我们已经使用单电极，单单位记录和中央显微注射和损毁技术，探讨神经元的结构和功能的背外侧脑桥呼吸中枢和背延髓孤束核（NTS），参与了重要的整合迷走神经和化学感受器传入输入。在我们的研究的下一阶段，我们建议采用最先进的多电极/多神经元记录技术，以表征这些脑桥延髓核在神经网络水平。我们的实验方法结合了先进的多电极/multineuronal记录技术，这是小型化的应用在大鼠脑干，和先进的统计技术，合奏尖峰列车分析和数据挖掘，以破译记录的神经元的连接。在这个项目中要解决的一个关键问题是，中枢和外周化学感受器输入是否只是由脑桥呼吸神经元中继到呼吸控制器，或以特定的方式整合在调制呼吸模式。我们的具体目标是识别和表征四个主要脑桥核中缺氧-高碳酸血症相互作用的神经相关物（目标1-4）：脑桥背外侧的臂旁外侧核和臂旁内侧核以及K“lliker-nucleus核和脑桥腹外侧的A5区。我们的假设是，脑桥呼吸神经元的一个子集可能整合缺氧和高碳酸输入调节呼吸驱动和呼吸节律，使个别神经元的反应和整体膈神经反应的组合，这些输入可能是更大的（积极的相互作用）或更小（消极的相互作用）比单独的输入（无相互作用）的反应的总和。缺氧-高碳酸血症的相互作用的神经相关性的鉴定以及由此产生的呼吸驱动和呼吸节律的调节将阐明某些高危受试者群体中呼吸不稳定的机制，例如充血性心力衰竭患者和在高海拔睡眠的个体。 公共卫生相关性：呼吸是一种重要的身体功能，对生命至关重要。了解各种脑干中心如何整合传入信息控制呼吸是至关重要的临床管理的各种危及生命的条件，如呼吸衰竭，慢性心肺或气道疾病，睡眠呼吸暂停，或暴露于极端环境，如高海拔。

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.