Brainstem respiratory neuron interactions

描述（由申请人提供）：中枢化学感受器监测脑二氧化碳- ph值，并提供驱动呼吸的重要组成部分，与外周化学感受器一起操作，快速感知动脉O2和二氧化碳- ph值。哮喘是一种常见的经常危及生命的疾病，与PaO2、PaCO2和呼吸驱动的变化有关，但人们对化学反应性脑区与呼吸网络之间的回路知之甚少，这些回路在急性哮喘发作期间的运动模式产生或这些通路的作用。该项目的目标是确定三个脑干化学反应区和脑桥髓神经网络之间的功能连通性，并在已建立的哮喘致敏动物模型中测试基于模型的网络机制，以调节低碳酸血症和急性挑战诱发急性发作期间的呼吸驱动。Aim 1提出了一个假设，即位于后梯形核/面旁呼吸组、延髓吻侧和孤立束核的中枢化学反应神经元通过多种途径调节呼吸运动模式发生器，包括压力感受器和外周化学感受器反射共享的回路。目的2：探讨低碳酸血症时中枢化感受器调节外周化感受器影响呼吸的机制。低碳酸血症和低氧血症常伴随急性哮喘发作。对缺氧的化疗敏感性降低可能是导致患者发生接近死亡事件的一个因素。因此，Aim 3追求的假设是，化学受体反射回路机制在抗原刺激诱发的恶化过程中被挪用和重新配置。实验方法结合了先进的多电极阵列技术、网络分析和预测建模的计算方法、通过选择性激活中枢和外周化学感受器的电路询问以及其他挑战。预期结果包括呼吸网络结构的新概念框架，低碳酸血症缺氧时控制呼吸的适应性化学受体反射回路机制的证据，以及哮喘动物模型系统中急性抗原攻击诱发发作期间确定的中枢和外周反射回路功能的首次网络规模评估。

DESCRIPTION (provided by applicant): Central chemoreceptors monitor brain CO2-pH and provide an essential component of the drive to breathe, operating with peripheral chemoreceptors that rapidly sense arterial O2 and CO2-pH. Asthma is a common often life-threatening disorder associated with changes in PaO2, PaCO2, and the drive to breathe, yet little is known about circuits that link chemoresponsive brain regions to the respiratory network for motor pattern generation or the roles of these pathways during acute asthma attacks. The goal of this project is to identify functional connectivity among three brainstem chemoresponsive regions and the pontomedullary network for breathing, and to test model-based predictions on network mechanisms for regulating the drive to breathe during hypocapnia and acute challenge-evoked exacerbations in an established sensitized animal model of asthma. Aim 1 addresses the hypothesis that central chemoresponsive neurons in the retrotrapezoid nucleus/parafacial respiratory group, the rostral medullary raphi, and nucleus of the solitary tract regulate the respiratory motor pattern generator through multiple pathways, including circuits shared by baroreceptor and peripheral chemoreceptor reflexes. Aim 2 targets mechanisms of central chemoreceptor modulation of peripheral chemoreceptor influences on breathing during hypocapnia. Hypocapnia and hypoxemia frequently accompany acute asthma attacks. Reduced chemosensitivity to hypoxia is a likely contributing factor in patients with near-fatal episodes. Thus, Aim 3 pursues the hypothesis that chemoreceptor reflex circuit mechanisms are appropriated and reconfigured during antigen challenge-evoked exacerbations. The experimental approach combines advanced multi-electrode array technologies, computational methods for network analysis and predictive modeling, circuit interrogation by selective activation of central and peripheral chemoreceptors and other challenges. Expected outcomes include a new conceptual framework on respiratory network architecture, evidence for adaptive chemoreceptor reflex circuit mechanisms that control breathing during hypocapnic hypoxia, and the first network-scale assessment of identified central and peripheral reflex circuit functions during acute antigen-challenge evoked episodes in an animal model system of asthma.