Regulation of Adult Hippocampal Neural Stem Cells by Glutamate Transport

在成年海马中的一个独特的神经源性小生境中，神经系干细胞（NSC）可以产生新的神经干细胞。 神经元中的一种。成年神经发生的这一过程对于最佳的 海马的认知情感功能，并提出了一个途径，再生组织在成年人的大脑。 然而，成人神经发生对局部小生境信号很敏感，依赖于局部信号，它可以波动 在数量和对海马功能的净贡献上都有显著的变化。更好地了解关键监管 干细胞-生态位相互作用的组成部分是迫切需要的，以推进支持海马功能的努力 和修复。已知调节健康和患病或受伤的成年神经发生的主要小生境信号 是神经递质谷氨酸。过量的谷氨酸盐刺激在伤害和疾病中很常见， 不同程度地影响海马体，包括创伤、中风、癫痫发作和神经变性。我们的目标 本申请的目的是研究兴奋性神经递质谷氨酸刺激 成人神经发生以前关于成体神经发生的多巴胺能调节的工作集中在 谷氨酸受体刺激相比之下，我们的初步数据表明谷氨酸盐具有意想不到的作用， 兴奋性氨基酸转运蛋白（EAAT）家族转运蛋白在谷氨酸诱导的NSC刺激中的作用 增殖众所周知，神经干细胞表达大量EAAT，但其功能作用已被广泛接受。 很少注意。拟议的实验将调查中心假设，谷氨酸转运通过 EAAT 1通过细胞去极化促进NSC活化和随后的神经发生。在目标1中，我们将使用 一种新的体内敲低模型，用于检验NSC EAAT 1促进NSC增殖的工作假设 从而刺激成人神经发生。在目标2中，我们将使用NSC膜的化学遗传操作， 电位和电生理学来测试通过EAAT 1去极化驱动NSC的工作假设 activation.这些拟议研究的结果预计将产生积极影响，因为它们将 介绍了一种新的分子机制，通过这种机制，一种主要的小生境信号-谷氨酸-促进了神经发生 在成人的大脑中。预期的研究结果将与海马神经元的基本理解相关， 本发明还涉及寻求利用NSC来支持组织修复的治疗方法的设计。

A unique neurogenic niche in the adult hippocampus hosts neural-lineage stem cells (NSCs) that generate new neurons in a wide range of adult mammals. This process of adult neurogenesis is essential for optimal hippocampal cognitive-emotional function and suggests an avenue for regenerating tissue in the adult brain. However, adult neurogenesis is sensitive to local niche signals, and depending on local signaling, it can fluctuate dramatically in quantity and net contribution to hippocampal function. Better understanding of the key regulatory components of stem cell-niche interactions is critically needed to advance efforts to support hippocampal function and repair. A major niche signal known to modulate adult neurogenesis in both healthy and diseased or injured states is the neurotransmitter glutamate. Excess glutamate stimulation is common in injuries and illnesses that differentially impact the hippocampus, including trauma, stroke, seizure, and neurodegeneration. Our objective in this application is to examine the mechanisms by which the excitatory neurotransmitter glutamate stimulates adult neurogenesis. Previous work on glutamatergic regulation of adult neurogenesis focuses on the role of glutamate receptor stimulation. Our preliminary data, in contrast, suggest an unexpected role for glutamate transporters from the excitatory amino acid transporter (EAAT) family in glutamate-induced stimulation of NSC proliferation. NSCs are widely known to express large quantities of EAATs yet their functional role has received little attention. The proposed experiments will investigate the central hypothesis that glutamate transport through EAAT1 promotes NSC activation and subsequent neurogenesis via cell depolarization. In Aim 1, we will use novel in vivo knockdown models to test the working hypothesis that NSC EAAT1 facilitates NSC proliferation and thereby stimulates adult neurogenesis. In Aim 2, we will use chemogenetic manipulation of NSC membrane potential and electrophysiology to test the working hypothesis that depolarization via EAAT1 drives NSC activation. These results of the proposed studies are expected to have a positive impact because they will introduce a novel molecular mechanism by which a major niche signal—glutamate—contributes to neurogenesis in the adult brain. The expected findings will have relevance both to fundamental understanding of hippocampal homeostasis and to design of therapeutic approaches that seek to capitalize on NSCs to support tissue repair.