Project 4

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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 differentiate 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 neuroregeneration. 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 potentially safe in human CNS, EF stimulation may be developed as brain repair and neuroprotection therapy. We have shown that EF stimulation guides and accelerates NSPC migration towards the cathode in vitro, and this migration requires interaction of N-methyl-D-aspartate receptors (NMDARs) with Rho GTPase Rac1/actin signaling. Functional NMDARs are redistributed to the cathode side of EF-exposed NSPCs, suggesting a role of polarized NMDARs in mediating EF-directed NSPC migration. Importantly, our preliminary study has shown that a non-invasive EF stimulation 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 functional, SVZ NPSC-derived new neurons to the damaged brain region and promotes functional recovery through NMDAR-dependent Rac1/actin signal pathway. We will first determine whether EF stimulation directs migration of functional new neurons to the damaged brain region and improves neurobehavioral outcome of stroke animals. We will then determine the role of NMDAR/Rac1/actin signaling in mediating EF-induced NSPC migration in the ischemic brain. The outcome of this study will lead us to understand how EF directs NSPC migration in stroke model in vivo, which is essential for the ultimate development of EF stimulation as a novel brain repair and/or neuroprotection strategy.