Glial cell regulation of blood flow in capillaries

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.