HYPOXIC EFFECTS ON MAMMALIAN RESPIRATORY NEURAL NETWORK

缺氧对哺乳动物呼吸神经网络的影响

• 批准号: 6476839
• 负责人: Jan M. Ramirez
• 金额: $ 19.39万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-07 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6476839
• 关键词: bioperiodicity; brain stem; calcium channel; cerebral ischemia /hypoxia; dyspneas; laboratory mouse; neural information processing; neural transmission; potassium channel; pulmonary respiration; respiration regulatory center; synapses; tissue /cell culture; voltage /patch clamp

DESCRIPTION (Adapted from the applicant's abstract): Every year numerous victims suffer brain damage from hypoxic and anoxic insults. To understand the underlying cellular mechanisms this project examines the anoxic effects on the central respiratory network of mice. This network can be isolated in a brainstem slice preparation which generates spontaneously respiratory rhythmic activity. Slices obtained from mice older than one week respond to anoxia in a very similar way as the chemoafferent-denervated but otherwise intact respiratory system. Therefore this preparation will be employed as a model to study the anoxic response of the central respiratory network. The research plan bridges the network, cellular and molecular level using various electrophysiological and pharmacological techniques. Extra and intracellular recording techniques as well as mapping and lesion experiments are performed to identify and characterize different portions of the respiratory system: a network in the so called pre- Boetzinger complex (pBC) which is responsible for generating normal respiration and its anoxia-induced interaction with a neural network which may be responsible for gasping. A model is proposed how the interaction between these neuronal networks leads to the biphasic response to anoxia, which includes an initial augmentation, depression, apnea and then gasping. To understand the neural mechanisms underlying this biphasic response, whole cell, cell attached, outside-out and inside-out patch clamp recording techniques are used. The planned experiments aim at characterizing in great detail the direct anoxic effects on different calcium and potassium channel subtypes. However, this characterization will be supplemented with an analysis of how these direct cellular changes affect indirectly the activation of other cellular properties that are involved in the generation of the respiratory rhythm. Thus, it is only possible to understand the biphasic response in an integrated multi-level approach. A hypothetical model is proposed as to how a suppression of the N-type calcium channel leads indirectly to changes in synaptic transmission and the open probability of calcium-dependent potassium channels. In this model, these alterations result in a decreased activation of the Ih current which will alter the mechanisms of respiratory rhythm generation. To examine this hypothesis, the cascade of these cellular and network events will be analyzed. A better understanding of these neural mechanisms will provide an important foundation for a more rational treatment of various breathing disorders that result in a cessation of breathing such as sleep apnea, recurrent apnea of the newborn and sudden infant death syndrome.

描述（根据申请人的摘要改编）： 每年许多受害者因低氧和缺氧而遭受脑部损害 侮辱。要了解潜在的细胞机制 检查对小鼠中央呼吸网络的缺氧作用。 可以在脑干切片准备中隔离该网络 产生自发的呼吸节奏活性。获得的切片 从一周以上的小鼠以非常相似的方式对缺氧反应 作为化学剂的努力，但呼吸系统完好无损。 因此，该准备工作将被用作研究 中央呼吸网络的缺氧反应。研究计划 使用各种 电生理和药理技术。额外 细胞内记录技术以及映射和病变 进行实验以识别和表征不同的 呼吸系统的一部分：所谓的pre-pre- Boetzinger Complex（PBC），负责产生正常 呼吸及其缺氧引起的与神经网络的相互作用 这可能是造成喘气的原因。提出了一个模型 这些神经元网络之间的相互作用导致双相 对缺氧的反应，包括初始增强，抑郁， 呼吸暂停，然后喘气。了解神经机制 这种双相反应，全细胞，附着的细胞，外部外部和 使用内而外的贴片夹录制技术。计划 实验旨在详细表征直接缺氧 对不同钙和钾通道亚型的影响。然而， 这种表征将通过分析这些表征来补充 直接的细胞变化间接影响其他其他 涉及生成的细胞特性 呼吸节奏。因此，只能理解双相 综合多级方法中的响应。一个假设的模型是 提出了N型钙通道的抑制如何引导 间接与突触传播的变化和开放概率变化 依赖钙的钾通道。在这个模型中，这些 改变导致IH电流激活下降 将改变呼吸节律产生的机制。检查 这个假设，这些细胞和网络事件的级联将 可以分析。更好地了解这些神经机制 为对各种的更合理待遇提供了重要的基础 呼吸障碍，导致呼吸停止 睡眠呼吸暂停，新生儿和猝死的呼吸暂停 综合征。