Pontomedullary Integration of Respiratory Afferents

描述(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，我们使用单电极、单单位记录和中央显微注射和毁损技术，探索了在迷走神经和化学感受器传入传入的整合中起重要作用的桥脑背外侧气中枢和孤束核(NTS)的神经元结构和功能。在我们下一阶段的研究中，我们建议使用最先进的多电极/多神经元记录技术，以便在神经网络水平上表征这些延髓桥核。我们的实验方法结合了先进的多电极/多神经元记录技术和先进的统计技术，用于集合棘波序列分析和数据挖掘，以破译记录的神经元的连接。这个项目要解决的一个关键问题是，中枢和外周化学感受器的输入是简单地由脑桥呼吸神经元传递到呼吸控制器，还是以特定的方式整合在调节呼吸模式中。我们的具体目的是识别和描述桥脑四个主要核团(AIMS 1-4)与低氧-高碳酸血症相互作用的神经关系：桥脑背外侧核、臂旁内侧核和K“lliker-Fuse核，以及脑桥腹外侧区的A5区。我们的假设是，桥脑呼吸神经元的一个子集可能在调节呼吸驱动和呼吸节律时整合了低氧和高碳酸血症的输入，使得单个神经元对这些输入的组合的反应和整个膈神经的反应可能大于(正交互作用)或小于(负交互作用)，而不是对单独输入的反应的总和(无交互作用)。识别低氧-高二氧化碳呼吸相互作用的神经关联以及由此导致的呼吸驱动和呼吸节律的调节将有助于揭示某些高危人群的呼吸不稳定机制，如充血性心力衰竭患者和睡在高海拔地区的人。 与公共健康相关：呼吸是一种至关重要的身体功能，对生命至关重要。了解不同的脑干中心如何将传入信息整合到呼吸控制中，对于临床治疗各种危及生命的疾病，如呼吸衰竭、慢性心肺或呼吸道疾病、睡眠呼吸暂停或暴露在高海拔等极端环境中具有重要意义。

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.