Glial cell regulation of blood flow in capillaries

项目摘要 神经元活动触发中枢神经系统中血流量的增加。血液动力学 反应，称为功能性充血，为活动神经元提供所需的氧气和营养， 对CNS的健康和正常功能至关重要。然而，神经血管耦合机制 调节血液流动机制仍然存在争议。神经血管耦合的一个重要假说 认为活跃的神经元刺激神经胶质细胞，引起细胞内Ca 2+增加，并释放血管舒张 剂.然而，这一假设最近受到了挑战。我们的初步实验 实验室为这一争议提供了解决方案，表明胶质细胞Ca 2+增加介导毛细血管， 而不是小动脉扩张这一假设将在以下目标中得到检验。 目标1.表征终止于毛细血管的Müller神经胶质细胞终足中的Ca 2+信号传导， 小动脉我们将测试这一假设，即视网膜中闪烁诱发的神经元活动引起快速的Ca 2 + 毛细血管而非小动脉终末的米勒细胞终足增加。 目标二。检验Müller细胞Ca 2+信号传导引起毛细血管扩张的假设。我们将测试这个 Müller细胞中毛细血管直径变化与自发性Ca 2+瞬变相关的假设 终足和Müller细胞内Ca 2+波引起的Ca 2+增加。 目标3。检验光诱发毛细血管扩张在Müller缺失时被阻断的假设 细胞Ca ~（2+）信号。我们将检验IP 3R 2敲除小鼠毛细血管扩张受阻的假设， 缺乏神经胶质细胞Ca 2+信号。 目标4。确定负责毛细血管扩张的神经血管偶联信号通路。 我们将检验神经血管与毛细血管的偶联是由神经胶质细胞释放 血管活性花生四烯酸代谢物，包括前列环素、前列腺素E2、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.