Regulation of Adult Hippocampal Neural Stem Cells by Glutamate Transport

谷氨酸转运对成体海马神经干细胞的调节

• 批准号: 10286497
• 负责人: Elizabeth Diana Kirby
• 金额: $ 42万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286497
• 关键词: Adult; Affect; Amino Acid Transporter; Attention; Automobile Driving; Brain; Brain Diseases; Brain Injuries; Brain region; Cell Maintenance; Cells; Cellular Metabolic Process; Cognitive; Coupled; Data; Disease; Electrophysiology (science); Epilepsy; Excitatory Amino Acid Transporter 1; Excitatory Amino Acids; Family; Gene Expression; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Health; Hippocampus (Brain); Homeostasis; Impairment; Injury; Longevity; Mammals; Mediating; Membrane Potentials; Memory; Modeling; Molecular; Natural regeneration; Nerve Degeneration; Neurons; Neurophysiology - biologic function; Neurotransmitters; Parahippocampal Gyrus; Pathologic; Pathology; Physiological; Population; Process; Production; Property; Receptor Activation; Regulation; Research; Role; Seizures; Signal Transduction; Source; Stroke; Testing; Therapeutic; Trauma; Work; adult neurogenesis; base; dentate gyrus; design; emotion regulation; emotional functioning; experimental study; glutamatergic signaling; granule cell; in vivo; injured; knock-down; mossy fiber; neglect; nerve stem cell; nerve supply; neural stimulation; neurogenesis; novel; receptor; relating to nervous system; repaired; response; stem cell niche; stem cell proliferation; stem cells; tissue regeneration; tissue repair

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.

成人海马体中独特的神经源性生态位承载着神经谱系干细胞（NSC），可产生新的神经干细胞 多种成年哺乳动物的神经元。成人神经发生的这一过程对于最佳状态至关重要 海马认知情绪功能，并提出了成人大脑组织再生的途径。 然而，成体神经发生对局部生态位信号敏感，并且根据局部信号传导，它可能会波动 对海马功能的数量和净贡献显着。更好地理解关键监管 干细胞生态位相互作用的组成部分对于推进支持海马功能的努力至关重要 和修复。已知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。过量的谷氨酸刺激在损伤和疾病中很常见， 对海马体的影响不同，包括创伤、中风、癫痫发作和神经退行性变。我们的目标 该应用的目的是检查兴奋性神经递质谷氨酸刺激的机制 成人神经发生。先前关于成人神经发生的谷氨酸能调节的工作重点是 谷氨酸受体刺激。相比之下，我们的初步数据表明谷氨酸具有意想不到的作用 兴奋性氨基酸转运蛋白 (EAAT) 家族的转运蛋白在谷氨酸诱导的 NSC 刺激中的作用 增殖。众所周知，NSC 表达大量 EAAT，但其功能作用已受到广泛关注。 很少关注。拟议的实验将研究谷氨酸转运通过的中心假设 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 新颖的体内敲低模型来测试 NSC EAAT1 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 膜的化学遗传学操作 电位和电生理学来测试通过 EAAT1 去极化驱动 NSC 的工作假设 激活。拟议研究的这些结果预计将产生积极影响，因为它们将 引入一种新的分子机制，通过该机制，主要的生态位信号——谷氨酸——有助于神经发生 在成人的大脑中。预期的发现将与海马体的基本理解相关 稳态并设计寻求利用 NSC 支持组织修复的治疗方法。