Investigation of the Modulators of Cerebrovascular Coupling

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This is the final year of this project do to the departure of Afonso Silva from intramural NINDS to UNiversity of Pittsburgh. Dr. Koretsky has been acting section chief since Dr. Silva left. The project will be terminated in the next FY. We want to understand how alterations in cortical functional domains induced by stroke lead to changes in the hemodynamic response to increased neural activity. This will allow us to refine the notion that the cerebrovasculature is built to support the functional organization of the cortex, and enable development of a better model of inferring about the flow of neuronal communication from careful analysis of the spatiotemporal features of the hemodynamic response. For this, we will develop focal ischemic models based on spatially targeted applications of vasoconstricting peptides such as endothelin-1 (ET-1) to test the relevance of different sub-regions of the cortex and, in particular, of individual functional areas (e.g. individual face patches or the representation of individual digits) in dictating the spatiotemporal characteristics of the hemodynamic response. We use high-resolution MRI of the cortical cytoarchitecture to plan and chose the target sub-domains within the cortex to be made ischemic, and compare the post-ischemia functional data with those obtained from the same animals pre-ischemia. We will also compare cerebrovascular resistance and vascular territory maps obtained at both states. Because the stroke area will be made small, it is possible that these maps will not change, but task-induced hemodynamic responses will be significantly different due to the region-selective death of neuronal cells caused by stroke. These experiments will provide a better understanding of how the architecture of the vascular tree influences the spatiotemporal features of the hemodynamic response. OVer the past few years used the spontaneously hypertensive rat (SHR) and its normotensive control WKY to evaluate the effects of an intracortical injection of ET-1. ET-1 produces a larger infarct volume in SHR than in WKY. Both pre- and post-treatment of the animals with JZL184, a powerful and specific inhibitor of the enzyme monoacylglycerol lipase (MAGL) significantly reduces the infarct volume induced by ET-1, thus establishing that MAGL as an important therapeutic target for stroke. In addition, MAGL inhibition significantly improved neurological outcome post-ischemia. MAGL hydrolyzes 2-arachidonoyl glycerol (2-AG), the most abundant endogenous cannabinoid in the brain, into arachidonic acid (AA), an important precursor of pro-inflammatory prostaglandins and leukotrienes. 2-AG exhibits anti-inflammatory and neuroprotective properties not only through modulating the signaling of cannabinoid receptors, but also by controlling AA release. Thus we hypothesized that MAGL inhibition might be a novel anti-inflammatory and neuroprotective strategy for neurological disorders, including ischemic stroke. Inhibition of MAGL leads to suppressed neuroinflammation, as measured by a significant reduction in the number of activated microglia in the ischemic core. Thus, our results suggest that MAGL alone contributes to neuropathology of cerebral ischemia, and thus is a promising therapeutic target for the treatment of ischemic stroke. To validate the work in the primate brain, it will be exciting to reproduce the same above experiments in marmosets, and we intend to do so just as soon as we finish the rodent study.