Enhancing Neurogenesis to Improve Brain Recovery After Stroke

该项目的目标是提供一个原理证明，表明内源性NSC可用于促进损伤或疾病后的脑功能恢复。为了实现这一目标，在过去的三年里，我的团队花费了大量的资源来生成和表征小鼠模型，该模型现在提供了一种理想的和前所未有的工具，使我们能够按需以时间控制和组织特异性的方式扩展NSC。在这个小鼠系中，增强的神经发生被发现在SVZ的神经原性生态位中特别强。有趣的是，SVZ是人类大脑中主要的神经原性生态位，它在整个生命过程中贡献了整合在纹状体中的新生神经元。此外，大量证据表明，在动物疾病模型中，SVZ通过增加神经发生和产生迁移到缺血区域的神经元来对损伤如中风作出反应。然而，这两个生理现象之间的联系，增加神经发生和中风后的部分恢复是纯粹相关的和证据表明，一个操作的增强前者可以促进后者是完全失踪。我们的模型的表征使我们能够证明神经元的长期功能整合以及生理条件下认知功能的改善。我们现在计划在疾病背景下扩展这一点，以调查它是否也能改善病理条件下的恢复。如果成功，这将提供一个原则证明，增加NSC和神经发生的内源性库可用于开发神经退行性疾病的新疗法。

The ambition of this project is to provide a proof-of-principle showing that endogenous NSC can be used to promote recovery of brain function after injury or disease. Toward this aim, in the last three years my group spent considerable resources into generating and characterizing a mouse model that now provides an ideal and unprecedented tool allowing us to expand NSC in a temporally controlled and tissue-specific manner on demand. In this mouse line, enhanced neurogenesis was found to be particularly strong in the neurogenic niche of the SVZ. Interestingly, the SVZ is the major neurogenic niche that in the human brain contributes newborn neurons that integrate in the striatum throughout life. Moreover, a large body of evidence has shown that in animal models of disease the SVZ reacts to injury such as stroke by increasing neurogenesis and generating neurons that migrate to the ischemic area. Yet, this link between the two physiologically occurring phenomena of increased neurogenesis and partial recovery after stroke is purely correlative and evidence that a manipulation the enhances the former can promote the latter is entirely missing. The characterization of our model allowed us to demonstrate the long-term functional integration of extranumerary neurons and consequent improvement in cognitive function in physiological conditions. We now plan to extend this in a disease context to investigate if it also improves recovery in pathological conditions. If successful, this will provide a proof-of-principle that increasing the endogenous pool of NSC and neurogenesis can be used toward developing novel therapies of neurodegenerative disease.