Investigation of the Modulators of Cerebrovascular Coupling

我们想了解脑卒中引起的皮质功能域的改变是如何导致血液动力学对神经活动增加的反应发生变化的。这将使我们能够完善脑血管系统是为了支持皮层的功能组织而建立的这一概念，并使我们能够通过仔细分析血流动力学反应的时空特征，开发出更好的模型来推断神经元通信的流动。为此，我们将基于血管收缩肽（如内皮素-1 (ET-1)）的空间靶向应用开发局灶性缺血模型，以测试皮层不同子区域的相关性，特别是单个功能区（例如单个面部斑块或单个手指的代表）在指示血流动力学反应的时空特征方面的相关性。我们将使用高分辨率的皮层细胞结构MRI来规划和选择皮层内要缺血的目标亚域，并将缺血后的功能数据与缺血前的数据进行比较。我们还将比较两州的脑血管阻力和血管版图图。由于中风区域变小，这些地图可能不会改变，但由于中风引起的神经元细胞的区域选择性死亡，任务诱导的血流动力学反应将显著不同。这些实验将更好地理解血管树的结构如何影响血流动力学响应的时空特征。

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 will 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. We 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. This study is now submitted for publication and is under review.