Neurovascular coupling during intense neuroglial depolarizations

神经元、神经胶质细胞和血管形成一个高度整合的功能单位，统称为 神经血管单位“，耦合血流和新陈代谢，并协调细胞和 健康和疾病过程中的组织元素。我们提供了一种新形式的初步证据 神经血管偶联，其中(1)强烈的神经胶质细胞去极化伴随着突然的 局灶性脑缺血时的血管收缩；(2)缺氧性去极化(AD)和脑梗塞周围 扩散去极化(PID)导致血流量逐步减少，通过这样做，扩大 低灌注区处于危险之中。为了获得初步数据，我们进行了二维脑血流 具有高时间和空间分辨率(实时激光散斑)的(CBF)、体积和氧合测绘 与氧合血红蛋白、脱氧血红蛋白、 和总血红蛋白)。在这里，我们以这些发现为基础，并在此新机制的基础上扩展以探索 缺血期间神经胶质细胞去极化的血管后果。我们的总体假设是AD和 PID导致皮质灌注量突然减少，从而对神经血管单位产生不利影响。 在去极化的缺血组织中，梗死演变的新概念。我们假设通过减弱AD 和PID，这些间歇性血管收缩事件的发生可以被抑制，而扩张 防止了CBF赤字。我们提出了三个具体目标：目标1将检验标点符号为 缺血后早期的去极化事件(即AD和PIDs)会引起急性严重的血管收缩，因此 这样做，进一步损害了CBF。目标2将检验这样一种假设，即已知的治疗方法可以保存膜 离子梯度(例如，抑制K+外流)，例如皮质扩散抑制(CSD)的抑制剂(例如， 托吡酯、缝隙连接阻滞剂、Sigma-1激动剂)，减轻血管收缩，阻止病情恶化 急性卒中时脑血流量作为组织保护的基本机制。目标3将检验这一假设 血管扩张剂机制受损加剧了缺血神经胶质细胞的突然血管收缩 内皮一氧化氮等血管运动调节蛋白分子变化引起的去极化 合成酶。通过这样做，我们希望更好地了解潜在的血管和血液动力学机制 在急性卒中期间扩大梗塞，并开发更合理的方法来保护缺血组织。

Neurons, glia and blood vessels form a highly integrated functional unit collectively termed "the neurovascular unit" that couples blood flow and metabolism and coordinates cross-talk between cell and tissue elements during health and disease. We provide preliminary evidence for a novel form of neurovascular coupling in which (1) intense neuroglial depolarization is accompanied by abrupt vasoconstriction during focal cerebral ischemia, and (2) by which anoxic depolarization (AD) and peri-infarct spreading depolarizations (PIDs) cause step-wise reductions in blood flow, and by so doing, expand the hypoperfused territory at risk. To obtain preliminary data, we performed two-dimensional cerebral blood flow (CBF), volume and oxygenation mapping with high temporal and spatial resolution (real-time laser speckle flowmetry, simultaneously with multiwavelength reflectance imaging of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin). Here we build on these findings and expand on this novel mechanism to explore the vascular consequences of neuroglial depolarization during ischemia. Our overall hypothesis is that AD and PIDs cause abrupt decreases in cortical perfusion, and by so doing, adversely affect the neurovascular unit within depolarized ischemic tissue, a novel concept of infarct evolution. We postulate that by attenuating AD and PIDs, the occurrence of these punctuated vasoconstrictor events can be inhibited, and the expanding CBF deficit prevented. We propose three specific aims: Aim 1 will test the novel hypothesis that punctuated depolarizing events early after ischemia (i.e., AD and PIDs) cause acute severe vasoconstriction, and by so doing, further compromise CBF. Aim 2 will test the hypothesis that treatments known to preserve membrane ionic gradients (e.g., inhibit K+ efflux), such as inhibitors of cortical spreading depression (CSD) (e.g., topiramate, gap junction blockers, sigma-1 agonists), attenuate vasoconstriction, and halt the worsening of CBF during acute stroke as a fundamental mechanism of tissue protection. Aim 3 will test the hypothesis that impaired vasodilator mechanisms exacerbate the abrupt vasoconstriction during ischemic neuroglial depolarization via molecular changes in vasomotor regulatory proteins such as endothelial nitric oxide synthase. By so doing, we hope to better understand vascular and hemodynamic mechanisms underlying infarct expansion during acute stroke and to develop more rational approaches to protect ischemic tissue.