Brainstem respiratory neuron interactions

描述(申请人提供)：中枢化学感受器监测大脑的二氧化碳酸碱度，并提供呼吸动力的基本组件，与快速感知动脉O2和二氧化碳酸碱度的外周化学感受器一起工作。哮喘是一种常见的、往往危及生命的疾病，与PaO2、PaCO2和呼吸动力的变化有关，但人们对连接化学反应大脑区域和呼吸网络以产生运动模式的电路或这些通路在急性哮喘发作中的作用知之甚少。该项目的目标是确定三个脑干化学反应区域和桥髓呼吸网络之间的功能连接，并在已建立的致敏哮喘动物模型中测试基于模型的预测，以调节在低碳酸血症和急性挑战诱发哮喘加重期间的呼吸动力。目的1提出一种假说，即斜方后核/面旁呼吸群、延髓端部和孤束核的中枢性化学反应神经元通过多条通路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所共有的回路。目的2针对中枢化学感受器调节外周化学感受器在低碳酸血症时影响呼吸的机制。低碳酸血症和低氧血症经常伴随急性哮喘发作。对低氧的化疗敏感性降低可能是导致患者出现近乎致命的发作的一个可能因素。因此，Aim 3提出的假设是，在抗原激发的恶化过程中，化学感受器反射回路机制被适当地和重新配置。该实验方法结合了先进的多电极阵列技术、用于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进行电路询问以及其他挑战。预期成果包括呼吸网络结构的新概念框架、在低二氧化碳低氧期间控制呼吸的适应性化学感受器反射回路机制的证据，以及首次在哮喘动物模型系统中对急性抗原挑战诱发发作期间识别的中枢和外周反射回路功能进行网络规模评估。

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.