PDF(Pubmed)
Abstract：
Current models of respiratory CO2 chemosensitivity are centred around the function of a specific population of neurons residing in the medullary retrotrapezoid nucleus (RTN). However, there is significant evidence suggesting that chemosensitive neurons exist in other brainstem areas, including the rhythm-generating region of the medulla oblongata - the preBötzinger complex (preBötC). There is also evidence that astrocytes, non-neuronal brain cells, contribute to central CO2 chemosensitivity. In this study, we reevaluated the relative contributions of the RTN neurons, the preBötC astrocytes, and the carotid body chemoreceptors in mediating the respiratory responses to CO2 in experimental animals (adult laboratory rats). To block astroglial signalling via exocytotic release of transmitters, preBötC astrocytes were targeted to express the tetanus toxin light chain (TeLC). Bilateral expression of TeLC in preBötC astrocytes was associated with ∼20% and ∼30% reduction of the respiratory response to CO2 in conscious and anaesthetized animals, respectively. Carotid body denervation reduced the CO2 respiratory response by ∼25%. Bilateral inhibition of RTN neurons transduced to express Gi-coupled designer receptors exclusively activated by designer drug (DREADDGi ) by application of clozapine-N-oxide reduced the CO2 response by ∼20% and ∼40% in conscious and anaesthetized rats, respectively. Combined blockade of astroglial signalling in the preBötC, inhibition of RTN neurons and carotid body denervation reduced the CO2 -induced respiratory response by ∼70%. These data further support the hypothesis that the CO2 -sensitive drive to breathe requires inputs from the peripheral chemoreceptors and several central chemoreceptor sites. At the preBötC level, astrocytes modulate the activity of the respiratory network in response to CO2 , either by relaying chemosensory information (i.e. they act as CO2 sensors) or by enhancing the preBötC network excitability to chemosensory inputs. KEY POINTS: This study reevaluated the roles played by the carotid bodies, neurons of the retrotrapezoid nucleus (RTN) and astrocytes of the preBötC in mediating the CO2 -sensitive drive to breathe. The data obtained show that disruption of preBötC astroglial signalling, blockade of inputs from the peripheral chemoreceptors or inhibition of RTN neurons similarly reduce the respiratory response to hypercapnia. These data provide further support for the hypothesis that the CO2 -sensitive drive to breathe is mediated by the inputs from the peripheral chemoreceptors and several central chemoreceptor sites.
摘要：
当前的呼吸CO2化学敏感性模型集中在位于延髓后梯形核（RTN）中的特定神经元群的功能上。然而,有大量证据表明，其他脑干区域存在化学敏感神经元，包括延髓的节奏产生区域-preBötzinger复合体（preBötC）。也有证据表明星形胶质细胞，非神经元脑细胞，有助于中央CO2化学敏感性。在这项研究中,我们重新评估了RTN神经元的相对贡献，前BötC星形胶质细胞，和颈动脉体化学感受器在介导实验动物（成年实验室大鼠）对CO2的呼吸反应中。为了通过胞吐释放递质来阻断星形胶质信号，将preBötC星形胶质细胞靶向表达破伤风毒素轻链(TeLC)。TeLC在前BötC星形胶质细胞中的双边表达与清醒和麻醉动物对CO2的呼吸反应的20%和30%减少有关，分别。颈动脉体去神经使CO2呼吸反应降低了约25%。通过应用氯氮平-N-氧化物，双侧抑制被转导以表达由设计药物（DREADDGi）专门激活的Gi偶联设计受体的RTN神经元，使清醒和麻醉大鼠的CO2反应降低了约20％和约40％，分别。前BötC中星形胶质细胞信号的联合阻断，抑制RTN神经元和颈动脉体去神经使CO2诱导的呼吸反应降低约70%。这些数据进一步支持以下假设:CO2敏感的呼吸驱动需要来自外周化学感受器和若干中枢化学感受器位点的输入。在preBötC级别，星形胶质细胞调节响应CO2的呼吸网络的活动，通过中继化学感应信息（即它们充当CO2传感器）或通过增强preBötC网络对化学感应输入的兴奋性。关键点：这项研究重新评估了颈动脉体所扮演的角色，前BötC的后梯形核（RTN）和星形胶质细胞介导CO2敏感的呼吸驱动。获得的数据表明，preBötC星形胶质信号的破坏，阻断来自外周化学感受器的输入或抑制RTN神经元类似地降低了对高碳酸血症的呼吸反应。这些数据为以下假设提供了进一步的支持：CO2敏感的呼吸驱动是由外周化学感受器和几个中央化学感受器位点的输入介导的。
