Brainstem respiratory neuron interactions

描述（申请人提供）：中枢化学感受器监测大脑CO2-pH值，并提供呼吸驱动力的重要组成部分，与快速感知动脉O2和CO2-pH值的外周化学感受器一起工作。哮喘是一种常见的、通常危及生命的疾病，与PaO 2、PaCO 2和呼吸驱动力的变化相关，然而，对于将化学反应性脑区与呼吸网络连接起来以产生运动模式的回路或这些通路在急性哮喘发作期间的作用知之甚少。该项目的目标是确定三个脑干化学反应区域和呼吸桥脑延髓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，以调节低碳酸血症和急性激发诱发加重期间呼吸动力的网络机制。目的1提出了一个假说，即在后斜方核/面旁呼吸组，延髓头端，孤束核的中央化学反应神经元调节呼吸运动模式发生器通过多种途径，包括电路共享的压力感受器和外周化学感受器反射。目的2探讨低碳酸血症时外周化学感受器对呼吸影响的中枢化学感受器调节机制。低碳酸血症和低氧血症经常伴随急性哮喘发作。对缺氧的化学敏感性降低可能是导致患者出现近乎致命发作的因素。因此，目的3追求的假设，即化学感受器反射电路机制的适当性和抗原激发诱发的恶化过程中重新配置。该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。预期结果包括一个新的概念框架的呼吸网络架构，适应性化学感受器反射电路机制，控制呼吸在低碳酸血症缺氧的证据，并确定在急性抗原激发诱发发作的哮喘动物模型系统的中枢和外周反射电路功能的第一个网络规模的评估。

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.