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.

成人海马中的独特神经源性小众构成神经linege干细胞（NSC），产生了新的 神经元在各种成年哺乳动物中。成人神经发生的过程对于最佳 海马认知情绪功能，并提出了成人大脑中再生组织的途径。 但是，成人神经发生对局部利基信号敏感，并且取决于局部信号，它可能会波动 动态的数量和净贡献对海马功能。更好地了解关键监管 迫切需要干细胞纽约相互作用的组成部分来促进支持海马功能的努力 和维修。已知在健康和患病或受伤的成年神经发生已知的主要小众信号 状态是神经递质谷氨酸。过量的谷氨酸刺激在伤害和疾病中很常见 差异影响海马，包括创伤，中风，癫痫发作和神经变性。我们的目标 在此应用中，是检查运动神经递质谷氨酸刺激的机制 成人神经发生。关于谷氨酸能调节成人神经发生的先前工作，重点是 谷氨酸受体刺激。相反，我们的初步数据表明谷氨酸的意外作用 谷氨酸诱导的NSC模拟中的兴奋性氨基酸转运蛋白（EAAT）家族的转运蛋白 增殖。众所周知，NSC表达了大量的EAAT，但其功能作用已得到 很少关注。提出的实验将研究谷氨酸通过 EAAT1通过细胞去极化促进NSC激活和随后的神经发生。在AIM 1中，我们将使用 新型的体内敲低模型，以测试NSC EAAT1最爱NSC增殖的工作假设 从而刺激成人神经发生。在AIM 2中，我们将使用NSC膜的化学发生操作 潜在和电生理学测试通过EAAT1沉积驱动NSC的工作假设 激活。预计拟议研究的这些结果将产生积极影响，因为它们将 引入了一种新的分子机制 在成人大脑中。预期的发现将具有对海马的基本理解的相关性 体内稳态和设计治疗方法，旨在利用NSC来支持组织维修。