Regulation of Adult Hippocampal Neural Stem Cells by Glutamate Transport

在成人海马区有一个独特的神经源性小生境，它拥有神经谱系干细胞(NSCs)，可以产生新的 大范围的成年哺乳动物的神经元。成人神经发生的这一过程是最佳的 海马体的认知-情绪功能，并暗示了成人大脑中再生组织的途径。 然而，成年神经发生对局部的小生境信号很敏感，并且根据局部信号的不同，它可以波动。 对海马区功能的数量和净贡献显著增加。更好地了解关键的监管 干细胞-巢相互作用的组成部分对于推进支持海马区功能的努力至关重要 并进行修复。一种已知的调节健康和患病或受伤的成人神经发生的主要生态位信号 状态是神经递质谷氨酸。过度的谷氨酸刺激在以下伤害和疾病中很常见 对海马体的不同影响，包括创伤、中风、癫痫和神经变性。我们的目标 在这方面的应用是研究兴奋性神经递质谷氨酸刺激的机制 成人神经发生。先前关于谷氨酸能调节成人神经发生的工作主要集中在 谷氨酸受体刺激。相比之下，我们的初步数据表明，谷氨酸的作用出乎意料 兴奋性氨基酸转运体(EAAT)家族转运蛋白在谷氨酸刺激神经干细胞中的作用 扩散。众所周知，神经干细胞表达大量的EAAT，但它们的功能作用已被 很少有人注意到。拟议中的实验将调查中心假设谷氨酸通过 EAAT1通过细胞去极化促进NSC激活和随后的神经发生。在目标1中，我们将使用 新的体内基因敲除模型验证NSC EAAT1促进NSC增殖的工作假说 从而刺激成人的神经发生。在目标2中，我们将使用NSC膜的化学发生操作 测试通过EAAT1去极化驱动NSC的工作假说的电位和电生理学 激活。这些拟议研究的结果预计将产生积极影响，因为它们将 介绍一种新的分子机制，即一种主要的生态位信号--谷氨酸--促进神经发生 在成人的大脑中。预期中的发现将与对海马体的基本理解有关 动态平衡以及寻求利用神经干细胞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.