Medullary Mechanisms of Hypoxic Respiratory Excitation

缺氧呼吸兴奋的髓质机制

• 批准号: 7782724
• 负责人: IRENE C SOLOMON
• 金额: $ 30.1万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7782724
• 关键词: Adult; Brain Hypoxia; Breathing; Carotid Body; Complex; Detection; Disinhibition; Enzymes; Felis catus; Generations; Heart; Hypoxia; In Vitro; Ion Channel; Laboratories; Lung; Modality; Modeling; Molecular; Motor; Nerve; Neuraxis; Neuromodulator; Neurons; Neurotransmitters; Nitric Oxide; Nitric Oxide Synthase; Pacemakers; Play; Production; Research Proposals; Role; Sodium Channel; Stimulus; Structure of phrenic nerve; Substance P; Substance P Receptor; Work; improved; in vivo; neuromechanism; research study; respiratory; response; sensor

Severe brain hypoxia results in respiratory excitation, which takes the form of gasping. If gasps sufficiently reoxygenate the lungs and heart, cardiorespiratory function will rapidly improve; thus, survival during severe hypoxic exposures appears to be critically dependent upon gasping, which functionally promotes autoresuscitation. Although gasping is important for survival, the underlying neural mechanisms responsible for the genesis of hypoxia-induced gasping remain unclear. Recent work, including work from our laboratory, has demonstrated that the pre-Botzinger complex (pre-B6tC), which is essential for the generation of normal breathing, is hypoxia chemosensitive, and therefore, may participate in the genesis of hypoxia related gasping. The mechanism(s) by which pre-BotC neurons "sense" hypoxia, leading to respiratory excitation (gasping), however, is not known. Numerous modalities have been suggested to participate in O2 sensing in other "hypoxia chemosensors", including direct effects on ion channel conductance and release of excitatory and inhibitory neurotransmitters and neuromodulators. Recent observations, for example, have suggested that K+ATp channels may be part of the molecular substrate for O2 detection in hypoxia-sensitive central nervous system (CMS) neurons, and that persistent sodium channels may act as Oz sensors. Although both of these types of channels are present in pre-BotC neurons, it remains to be determined whether these channels participate in the hypoxia-sensing function of this region. Recent studies have also proposed that substance P (SP)and nitric oxide (NO),both of which are released during severe brain hypoxia in some CNS regions, may play a role in the hypoxia-sensing function of the carotid body. Although neurokinin-1 (SP) receptors and NO synthase (i.e., enzyme for NO production) are expressed by pre-BotC neurons, it remains to be determined whether these neuroactive agents participate in the hypoxia-sensing function of this region. The major objective of the work proposed in this application is to investigate whether these potential mechanisms participate in the hypoxia-sensing function of the pre-BotC, and the subsequent generation of hypoxia-induced gasping. The experiments proposed in this application will use an in vivo vagotomized, deafferented, decerebrate or anesthetized adult cat model to assess the roles of K+ATp channels, persistent sodium channels, SP, and NO in the hypoxia-sensing function of the pre- BotC. The effects of both focal and systemic hypoxic stimuli will be examined.

严重的大脑缺氧导致呼吸激发，这采取了喘气的形式。如果充分喘气 重新融合肺和心脏，心肺功能将迅速改善。因此，严重的生存 低氧暴露似乎严重取决于喘气，这在功能上促进了 自动震荡。尽管喘着气对于生存很重要，但造成的潜在神经机制 对于缺氧引起的喘气的起源仍不清楚。最近的工作，包括我们的工作 实验室已经证明了前胞津综合体（前B6TC），这对于 正常呼吸的产生是缺氧化学敏感的，因此可能参与 与缺氧相关的喘气。前BOTC神经元“有感觉”缺氧的机制，导致 但是，呼吸激发（喘气）尚不清楚。已建议许多方式 参与其他“低氧化学传感器”中的O2传感，包括对离子通道的直接影响 兴奋性和抑制性神经递质和神经调节剂的电导和释放。最近的 例如，观察结果表明，K+ATP通道可能是O2分子底物的一部分 缺氧敏感的中枢神经系统（CMS）神经元中的检测，并持续的钠通道 可以充当OZ传感器。尽管这两种类型的通道都存在于前BOTC神经元中，但 这些渠道是否参与该区域的低氧感应功能还有待确定。 最近的研究还提出了物质P（SP）和一氧化氮（NO），它们都释放 在某些中枢神经系统地区严重的大脑缺氧期间，可能在低氧敏感功能中起作用 颈动脉身体。尽管神经蛋白1（SP）受体和无合酶（即无生产酶）是 由BOTC前神经元表示，这些神经活性剂是否参与尚待确定 该区域的低氧感应函数。本申请中提出的工作的主要目标是 调查这些潜在机制是否参与前BOTC的低氧感应功能 以及随后的缺氧引起的喘气。本应用程序中提出的实验 将使用体内迷走神经化，脱毛，杂交或麻醉的成年CAT模型来评估 K+ATP通道，持续性钠通道，SP的作用，以及在预性的低氧感应功能中 botc。将检查局灶性和全身性低氧刺激的影响。

项目成果

Analyzing the effects of gap junction blockade on neural synchrony via a motoneuron network computational model.

• DOI: 10.1155/2012/575129
• 发表时间: 2012
• 期刊: Computational intelligence and neuroscience
• 作者: Memelli H;Horn KG;Wittie LD;Solomon IC
• 通讯作者: Solomon IC

Glutamate neurotransmission is not required for, but may modulate, hypoxic sensitivity of pre-Bötzinger complex in vivo.

谷氨酸神经传递不是体内前 Bötzinger 复合体缺氧敏感性所必需的，但可能会调节。

• DOI: 10.1152/jn.00932.2004
• 发表时间: 2005
• 期刊: Journal of neurophysiology
• 影响因子: 2.5
• 作者: Solomon,IreneC

Modulation of gasp frequency by activation of pre-Bötzinger complex in vivo.

通过激活体内前 Bötzinger 复合物来调节喘息频率。

• DOI: 10.1152/jn.00742.2001
• 发表时间: 2002
• 期刊: Journal of neurophysiology
• 影响因子: 2.5
• 作者: Solomon,IreneC

Time-frequency representation of inspiratory motor output in anesthetized C57BL/6 mice in vivo.

体内麻醉 C57BL/6 小鼠吸气运动输出的时频表示。

• DOI: 10.1152/jn.00646.2004
• 发表时间: 2005
• 期刊: Journal of neurophysiology.
• 作者: O'Neal3rd,MarvinH;Spiegel,EvanT;Chon,KiH;Solomon,IreneC
• 通讯作者: Solomon,IreneC

Chemical activation of pre-Bötzinger complex in vivo reduces respiratory network complexity.

体内前 Bötzinger 复合物的化学激活降低了呼吸网络的复杂性。

• DOI: 10.1152/ajpregu.00650.2004
• 发表时间: 2005
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Chen,Xinnian;Chon,KiH;Solomon,IreneC
• 通讯作者: Solomon,IreneC