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: 7211085
• 负责人: Jan M. Ramirez
• 金额: $ 26.5万
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211085
• 关键词: Anoxia; Applications Grants; Arousal; Asphyxia; Attention; Biological Neural Networks; Brain; Brain Stem; Breathing; CCL14 gene; Cadmium; Cell Nucleus; Cognition; Complement component C1s; Complex; Data; Excitatory Synapse; Failure; Fire - disasters; Funding; Generations; Goals; Heart; Hypoxia; In Vitro; Infant Mortality; Lead; Membrane; Memory; Metabolism; Nervous system structure; Neuromodulator; Neurons; Norepinephrine; Pacemakers; Pattern; Phase; Pontine structure; Preparation; Property; Publishing; Research; Research Personnel; Resistance; Respiration; Respiratory System; Role; Serotonin Receptor 5-HT2A; Slice; Spinal Cord; Sudden infant death syndrome; Synapses; System; Testing; Work; breath pacemaker; concept; expiration; human HTR2A protein; in vivo; inhibitory neuron; insight; locus ceruleus structure; neuroregulation; noradrenergic; novel; postnatal; research study; respiratory; response; synaptic inhibition; transmission process

DESCRIPTION (provided by applicant): Sudden infant death syndrome (SIDS) remains the leading cause of postnatal infant mortality in the USA. Increasing evidence indicates that SIDS is due to a failure of autoresuscitation, which is a protective brainstem response to asphyxia or severe hypoxia. Gasping is an essential mechanism for autoresuscitation and therefore critically important for survival during severe hypoxia. However, despite considerable relevance, the question how gasping is generated by the nervous system remains largely unknown. We have been able to produce a medullary slice preparation that generates the neuronal correlate for normal breathing and gasping. This slice contains the pre-Botzinger complex (PBC), a region that contains the critical neurons for generating inspiratory activity. During the past funding period we demonstrated that the respiratory network assumes different configurations during normoxia and severe hypoxia: In normoxia the respiratory network is complex and contains cadmium-sensitive (CS) pacemakers, cadmium-insensitive (CI) pacemakers, and three different types of inspiratory nonpacemakers (Nl-3). These neurons are interconnected via excitatory connections that synchronize neuronal activity and facilitate bursting and inhibitory synaptic connections that establish the different phases of respiration and suppress pacemaker activity. In hypoxia, CS pacemakers and the majority of nonpacemakers shut down through the activation of KATP channels. As a consequence inhibitory transmission is greatly diminished, respiratory phases are lost. CI pacemakers and a subpopulation of nonpacemakers are disinhibited and continue to burst throughout hypoxia. CI pacemakers depend on endogenous serotonin receptor 2A activation. Blockade of either CI pacemakers or serotonin receptor 2A activation abolishes gasping indicating that these CI pacemakers become the major drivers of gasping. In the proposed research we aim at examining the modulatory mechanisms that lead to the reconfiguration of the respiratory network. We specifically examine the hypothesis that the transition from normal respiratory activity into gasping is controlled by noradrenergic inputs arriving from pontine A6 and A5 neurons and from medullary A1/C1 neurons. We hypothesize that these noradrenergic neurons not only control pacemaker activity and thereby modulate normal respiration and gasping but also vice versa respiratory pacemakers control activity of these noradrenergic nuclei. Our study will provide mechanistic insight into the neuronal control of attention during normoxia and the control of arousal during hypoxia-induced gasping. Our studies are directly relevant for SIDS as increasing evidence indicates that SIDS victims have diminished gasping and fail to arouse. Moreover SIDS victims have disturbed noradrenergic and serotonergic metabolism.

描述（由申请人提供）：婴儿猝死综合征（SIDS）仍然是美国出生后婴儿死亡的主要原因。越来越多的证据表明，SIDS是由于自动复苏失败，这是一种对窒息或严重缺氧的保护性脑干反应。喘息是自动复苏的基本机制，因此对严重缺氧期间的生存至关重要。然而，尽管有相当大的相关性，神经系统如何产生喘息的问题仍然在很大程度上是未知的。我们已经能够产生一个骨髓切片制备，产生正常呼吸和喘息的神经元相关。这个切片包含前Botzinger复合体（PBC），这是一个包含产生吸气活动的关键神经元的区域。在过去的资助期间，我们证明了呼吸网络在常氧和严重缺氧期间呈现不同的配置：在常氧下，呼吸网络是复杂的，包含镉敏感（CS）起搏器，镉不敏感（CI）起搏器和三种不同类型的吸气非起搏器（NI-3）。这些神经元通过兴奋性连接相互连接，兴奋性连接使神经元活动同步，促进爆发和抑制性突触连接，建立呼吸的不同阶段并抑制起搏器活动。在缺氧时，CS起搏器和大多数非起搏器通过激活KATP通道关闭。因此，抑制性传递大大减弱，呼吸相位丢失。CI起搏器和非起搏器亚群被解除抑制，并在整个缺氧过程中继续爆发。CI起搏器依赖于内源性5-羟色胺受体2A激活。阻断CI起搏器或5-羟色胺受体2A激活可消除喘息，表明这些CI起搏器成为喘息的主要驱动因素。在拟议的研究中，我们的目的是研究导致呼吸网络重构的调节机制。我们具体研究的假设，从正常的呼吸活动到喘息的过渡是由去甲肾上腺素能输入到达脑桥A6和A5神经元和延髓A1/C1神经元控制。我们推测，这些去甲肾上腺素能神经元不仅控制起搏器的活动，从而调节正常的呼吸和喘息，但反之亦然，呼吸起搏器控制这些去甲肾上腺素能核团的活动。我们的研究将提供机制的洞察神经元控制的注意在常氧和控制唤醒在缺氧引起的喘息。我们的研究与小岛屿发展中国家直接相关，因为越来越多的证据表明，小岛屿发展中国家的受害者减少了喘息，无法唤醒。此外，SIDS患者的去甲肾上腺素能和肾上腺素能代谢紊乱。