Glial cell regulation of blood flow in capillaries

项目摘要 神经元活动会增加中枢神经系统的血流量。这种血流动力学 反应，称为功能性充血，为活跃的神经元提供所需的氧气和营养，并 对中枢神经系统的健康和正常功能至关重要。然而，神经血管耦合机制 这种调节血流的机制仍然存在争议。神经血管偶联的一个重要假说 认为活跃的神经元刺激神经胶质细胞，引起细胞内钙离子增加，释放血管扩张作用 探员们。然而，这一假设最近受到了挑战。来自我们的初步实验 实验室对这一争议提出了解决方案，认为胶质细胞钙离子增加了中介毛细血管，但 不是小动脉扩张。这一假设将在以下目标中得到检验。 目的1.研究终止于毛细血管和微血管的Müler神经胶质细胞末端的钙信号。 小动脉。我们将验证一种假设，即视网膜中闪光引起的神经元活动会引起快速的钙离子 终止于毛细血管但不在小动脉上的Müler细胞的终足增加。 目的2.验证Müler细胞钙信号引起毛细血管扩张的假说。我们将对此进行测试 Müler细胞内毛细血管直径变化与自发性钙瞬变相关的假说 在Müler细胞内，随着细胞内钙波产生的钙离子浓度的增加，细胞内径增加。 目的3.验证光引起的毛细血管扩张在没有穆勒的情况下被阻断的假设 细胞内钙信号转导。我们将在IP3R2基因缺失的小鼠身上测试毛细血管扩张被阻断的假设 缺乏神经胶质细胞的钙信号。 目的4.确定导致毛细血管扩张的神经血管偶联信号通路。 我们将检验这一假说，即神经血管与毛细血管的耦合是由神经胶质细胞释放的 血管活性花生四烯酸代谢产物，包括前列环素、前列腺素E_2、环氧二十碳三烯酸 酸和20-羟基二十碳四烯酸。

Project Summary Neuronal activity triggers increases in blood flow in the central nervous system. This hemodynamic response, termed functional hyperemia, supplies active neurons with needed oxygen and nutrients and is essential for the health and proper function of the CNS. However, the neurovascular coupling mechanisms that mediate blood flow regulation remain controversial. A prominent hypothesis of neurovascular coupling holds that active neurons stimulate glial cells, evoking cytosolic Ca2+ increases and releasing vasodilating agents. However, this hypothesis has recently been challenged. Preliminary experiments from our laboratory offer a resolution to this controversy, suggesting that glial Ca2+ increases mediate capillary but not arteriole dilation. This hypothesis will be tested in the following aims. Aim 1. Characterize Ca2+ signaling in Müller glial cell endfeet that terminate on capillaries and arterioles. We will test the hypothesis that flicker-evoked neuronal activity in the retina evokes rapid Ca2+ increases in the endfeet of Müller cells terminating on capillaries but not on arterioles. Aim 2. Test the hypothesis that Müller cell Ca2+ signaling evokes capillary dilation. We will test this hypothesis by correlating changes in capillary diameter with spontaneous Ca2+ transients in Müller cell endfeet and with Ca2+ increases produced by intercellular Ca2+ waves in Müller cells. Aim 3. Test the hypothesis that light-evoked capillary dilation is blocked in the absence of Müller cell Ca2+ signaling. We will test the hypothesis that capillary dilation is blocked in IP3R2 null mice, which lack glial cell Ca2+ signaling. Aim 4. Determine the neurovascular coupling signaling pathways responsible for capillary dilation. We will test the hypothesis that neurovascular coupling onto capillaries is mediated by glial release of vasoactive arachidonic acid metabolites, including prostacyclin, prostaglandin E2, epoxyeicosatrienoic acids, and 20-hydroxy-eicosatetraenoic acid.