Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
Institute of Cell Biophysics, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", Pushchino 142290, Russian Federation.
J Neurosci. 2020 Apr 8;40(15):3052-3062. doi: 10.1523/JNEUROSCI.1438-19.2020. Epub 2020 Mar 4.
Maintenance of cardiorespiratory homeostasis depends on autonomic reflexes controlled by neuronal circuits of the brainstem. The neurophysiology and neuroanatomy of these reflex pathways are well understood, however, the mechanisms and functional significance of autonomic circuit modulation by glial cells remain largely unknown. In the experiments conducted in male laboratory rats we show that astrocytes of the nucleus of the solitary tract (NTS), the brain area that receives and integrates sensory information from the heart and blood vessels, respond to incoming afferent inputs with [Ca] elevations. Astroglial [Ca] responses are triggered by transmitters released by vagal afferents, glutamate acting at AMPA receptors and 5-HT acting at 5-HT receptors. In conscious freely behaving animals blockade of Ca-dependent vesicular release mechanisms in NTS astrocytes by virally driven expression of a dominant-negative SNARE protein (dnSNARE) increased baroreflex sensitivity by 70% ( < 0.001). This effect of compromised astroglial function was specific to the NTS as expression of dnSNARE in astrocytes of the ventrolateral brainstem had no effect. ATP is considered the principle gliotransmitter and is released by vesicular mechanisms blocked by dnSNARE expression. Consistent with this hypothesis, in anesthetized rats, pharmacological activation of P2Y purinoceptors in the NTS decreased baroreflex gain by 40% ( = 0.031), whereas blockade of P2Y receptors increased baroreflex gain by 57% ( = 0.018). These results suggest that glutamate and 5-HT, released by NTS afferent terminals, trigger Ca-dependent astroglial release of ATP to modulate baroreflex sensitivity via P2Y receptors. These data add to the growing body of evidence supporting an active role of astrocytes in brain information processing. Cardiorespiratory reflexes maintain autonomic balance and ensure cardiovascular health. Impaired baroreflex may contribute to the development of cardiovascular disease and serves as a robust predictor of cardiovascular and all-cause mortality. The data obtained in this study suggest that astrocytes are integral components of the brainstem mechanisms that process afferent information and modulate baroreflex sensitivity via the release of ATP. Any condition associated with higher levels of "ambient" ATP in the NTS would be expected to decrease baroreflex gain by the mechanism described here. As ATP is the primary signaling molecule of glial cells (astrocytes, microglia), responding to metabolic stress and inflammatory stimuli, our study suggests a plausible mechanism of how the central component of the baroreflex is affected in pathological conditions.
心肺生理稳态的维持依赖于受脑干神经元回路控制的自主反射。这些反射途径的神经生理学和神经解剖学已经得到很好的理解，然而，胶质细胞对自主回路的调节机制及其功能意义在很大程度上仍然未知。在对雄性实验室大鼠进行的实验中，我们发现，孤束核（NTS）中的星形胶质细胞对来自心脏和血管的传入输入产生[Ca]升高的反应，孤束核是接收和整合来自心脏和血管的感觉信息的大脑区域。星形胶质细胞[Ca]反应是由迷走传入纤维释放的递质触发的，谷氨酸作用于 AMPA 受体，5-HT 作用于 5-HT 受体。在清醒自由活动的动物中，通过病毒驱动的显性负 SNARE 蛋白（dnSNARE）表达阻断 NTS 星形胶质细胞中 Ca 依赖性囊泡释放机制，可使压力反射敏感性增加 70%（<0.001）。这种星形胶质细胞功能受损的作用是特异性的，因为在脑桥腹外侧星形胶质细胞中表达 dnSNARE 没有影响。ATP 被认为是主要的神经胶质递质，其释放是通过 dnSNARE 表达阻断的囊泡机制。与这一假说一致，在麻醉大鼠中，NTS 中 P2Y 嘌呤能受体的药理学激活使压力反射增益降低 40%（=0.031），而 P2Y 受体阻断使压力反射增益增加 57%（=0.018）。这些结果表明，NTS 传入末梢释放的谷氨酸和 5-HT 触发 Ca 依赖性星形胶质细胞释放 ATP，通过 P2Y 受体来调节压力反射敏感性。这些数据增加了越来越多的证据支持星形胶质细胞在大脑信息处理中发挥积极作用。心肺反射维持自主平衡，确保心血管健康。压力反射受损可能导致心血管疾病的发展，并作为心血管和全因死亡率的有力预测指标。本研究获得的数据表明，星形胶质细胞是处理传入信息的脑干机制的组成部分，通过释放 ATP 来调节压力反射敏感性。任何与 NTS 中“环境”ATP 水平升高相关的情况都预计会通过这里描述的机制降低压力反射增益。由于 ATP 是神经胶质细胞（星形胶质细胞、小胶质细胞）的主要信号分子，对代谢应激和炎症刺激做出反应，我们的研究表明了一种可能的机制，即中央压力反射成分如何在病理条件下受到影响。
