Project 4

神经干细胞迁移在缺血性脑卒中后脑修复中的作用 我们的长远目标是为直流电场的最终发展提供依据 (EF)作为脑卒中患者的新型脑修复和神经保护疗法。脑缺血诱导 神经干/祖细胞（NSPCs）在脑室下区（SVZ）的增殖。虽然新 生成的NSPCs可以分化成迁移到受损区域的新神经元，只有一小部分 发现新的神经元迁移到损伤区域，这是防止内源性神经元损伤的关键屏障。 神经再生然而，很少有人努力确定促进NSPC的指导线索 移民是为了克服障碍。我们的研究表明，EF可能是一个这样的指导线索。由于EF EF在人CNS中具有潜在的安全性，可开发为脑修复和神经保护剂 疗法我们已经证明，EF刺激引导并加速NSPC向阴极迁移， 这种迁移需要N-甲基-D-天冬氨酸受体（NMDAR）与Rho GT3相互作用 Racl/acfin信号传导。功能性NMDAR被重新分布到EF暴露的NSPC的阴极侧， 证实极化NMDAR在介导EF介导的NSPC迁移中的作用。重要的是我们的 初步研究表明，非侵入性EF刺激可促进SVZ NSPC源性 在体内大鼠中风模型中，新的神经元朝向阴极方向到达缺血边界区。在 在本项目中，我们将继续使用大鼠中风模型来测试EF刺激引导和 加速功能性SVZ NPSC衍生的新神经元向受损脑区域的迁移， 通过NMDAR依赖的Racl/actin信号通路促进功能恢复。我们将首先确定 EF刺激是否引导功能性新神经元迁移到受损脑区， 改善中风动物的神经行为结果。然后我们将确定NMDAR/Racl/acfin的作用， 在缺血脑中介导EF诱导的NSPC迁移的信号转导。这项研究的结果将导致 我们希望了解EF在体内脑卒中模型中是如何指导NSPC迁移的，这对于最终的研究是至关重要的。 EF刺激作为一种新的脑修复和/或神经保护策略的发展。

Role of neuronal stem cell migration in brain repair following ischemic stroke Our long-term goal is to provide evidence for the ultimate development of direct-current electrical field (EF) as a novel brain repair and neuroprotection therapy for stroke patients. Brain ischemia induces proliferation of neural stem/progenitor cells (NSPCs) in the subventricular zone (SVZ). Although the newly generated NSPCs can differenfiate into new neurons that migrate to the damaged regions, only a fraction of the new neurons is found to migrate to the damaged area, which is a critical barrier to prevent endogenous neuroregenerafion. Yet, little effort has been made towards identifying guidance cues that promote NSPC migration to overcome the barrier. Our study suggests that the EF may be one such guidance cue. As EF is potenfially safe in human CNS, EF sfimulafion may be developed as brain repair and neuroprotecfion therapy. We have shown that EF stimulation guides and accelerates NSPC migrafion towards the cathode in vitro, and this migrafion requires interaction of N-methyl-D-aspartate receptors (NMDARs) with Rho GTPase Racl/acfin signaling. Funcfional NMDARs are redistributed to the cathode side of EF-exposed NSPCs, suggesfing a role of polarized NMDARs in mediafing EF-directed NSPC migrafion. Importantly, our preliminary study has shown that a non-invasive EF sfimulafion promotes migration of SVZ NSPC-derived new neurons, towards the cathode direction, to the ischemic boundary zone in an in vivo rat stroke model. In this project, we will continue to use the rat stroke model to test the hypothesis that EF stimulation guides and accelerates the migration of funcfional, SVZ NPSC-derived new neurons to the damaged brain region and promotes functional recovery through NMDAR-dependent Racl/actin signal pathway. We will first determine whether EF sfimulafion directs migrafion of funcfional new neurons to the damaged brain region and improves neurobehavioral outcome of stroke animals. We will then determine the role of NMDAR/Racl/acfin signaling in mediafing EF-induced NSPC migrafion in the ischemic brain. The outcome of this study will lead us to understand how EF directs NSPC migrafion in stroke model in vivo, which is essential for the ultimate development of EF sfimulation as a novel brain repair and/or neuroprotection strategy.