Hypoxic Effects on Mammalian Respiratory Neural Network

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是由于自身复苏失败造成的，这是对窒息或严重缺氧的保护性脑干反应。喘息是自我复苏的基本机制，因此对严重缺氧时的生存至关重要。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在很大程度上仍然未知。我们已经能够制造出一种髓质切片，它能产生正常呼吸和喘气的神经元关联。这个切片包含波青格前复合体（pre-Botzinger complex， PBC），这个区域包含产生吸气活动的关键神经元。在过去的资助期内，我们证明了呼吸网络在常氧状态和严重缺氧状态下具有不同的结构：在常氧状态下，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（Nl-3）。这些神经元通过兴奋性连接相互连接，同步神经元活动，促进破裂和抑制性突触连接，建立不同阶段的呼吸和抑制起搏器活动。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，抑制性传播大大减少，呼吸期消失。CI起搏器和非起搏器亚群在缺氧过程中被解除抑制并持续爆发。CI起搏器依赖内源性5 -羟色胺受体2A激活。阻断CI起搏器或5 -羟色胺受体2A激活均可消除喘息，表明这些CI起搏器成为喘息的主要驱动因素。在提出的研究中，我们旨在研究导致呼吸网络重构的调节机制。我们特别研究了从正常呼吸活动到喘气的转变是由来自脑桥A6和A5神经元以及髓质A1/C1神经元的去肾上腺素能输入控制的假设。我们假设这些去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，反之亦然，呼吸起搏器也控制这些去肾上腺素能细胞核的活动。我们的研究将为正常缺氧时神经元对注意力的控制和缺氧引起的喘息时觉醒的控制提供机制上的见解。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喘气减少，无法唤醒。此外，小岛屿发展中国家受害者的去甲肾上腺素能和血清素能代谢受到干扰。

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.