Mechanisms Underlying Neural Stem Cell Heterogeneity in the Adult Hippocampus

成体海马神经干细胞异质性的机制

• 批准号: 9070088
• 负责人: MICHAEL Bonaguidi
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070088
• 关键词: Address; Adult; Affect; Area; Astrocytes; Behavior; Bilateral; Biological Models; Brain; Brain Injuries; Cell Lineage; Cell Maintenance; Cell Proliferation; Cell physiology; Cells; Common carotid artery; Decision Making; Development; Environment; Exhibits; Foundations; Gene Delivery; Heterogeneity; Hippocampus (Brain); Homeostasis; Infarction; Injury; Interneurons; Learning; Left; Maintenance; Memory; Mentors; Mitotic; Modeling; Molecular; Neuroglia; Neurons; Operative Surgical Procedures; Outcome; Pathology; Phase; Physiological; Population; Process; Proliferating; Property; Radial; Regulation; Research; Resolution; Signal Transduction; Stem cells; Stimulus; Stroke; Systems Analysis; Time; Tissues; Viral; adult neurogenesis; artery occlusion; base; cell behavior; cell type; cognitive recovery; dentate gyrus; disability; environmental change; gamma-Aminobutyric Acid; in vivo; insight; interdisciplinary approach; nerve stem cell; nestin protein; neuroadaptation; neurogenesis; neuronal circuitry; novel therapeutics; optogenetics; relating to nervous system; repaired; response; response to injury; self-renewal; skills

DESCRIPTION (provided by applicant): Adult neural stem cells (NSCs) contribute to brain plasticity and maintain tissue homeostasis. Understanding how NSCs remodel the adult hippocampus may provide key insight into neural adaptability and repair. NSC function is defined by the ability to maintain a precursor state while generating neuronal and glial progeny. Recently, I developed a new in vivo clonal analysis system to reveal stem cell properties at the single cell level within the adult mammalian hippocampus, an area critical for learning and memory. We previously showed that radial glia-like (RGL) cells can act as stem cells, but exhibit significant heterogeneity in their decisions to proliferate, generate progeny and self-renew. A fundamental remaining question is what mechanisms underlie these differences. I hypothesize that divergent RGL behavior results from differences in their proliferative state and responses to changes in environment including GABA signaling and stroke injury. To address these points, I have established independent model systems that preferentially target quiescent and mitotic RGLs. I will first characterize NSC potential within these intrinsically biased RGL subpopulations by performing in vivo single cell lineage tracing. After establishing this foundation, we will assess how GABA signaling acts as an extrinsic molecular mechanism to regulate stem cell decisions in quiescent and active RGLs under physiological condition. Finally, we will determine how stroke injury dictates RGL cell fate decisions and potential in quiescent and active subpopulations under pathological conditions. Importantly, viral-based gene delivery, optogenetics and stroke surgery skills learned during the mentored phase are essential components toward a multidisciplinary approach for investigating extrinsic niche regulation during the independent phase. Collectively, this research seeks to understand NSC behavior in intrinsically different RGLs and how their decisions interact with specific physiological and pathological mechanisms.

描述(申请人提供)：成人神经干细胞(NSCs)有助于大脑的可塑性和维持组织的动态平衡。了解神经干细胞如何重塑成年海马体可能会为神经适应和修复提供关键的洞察力。神经干细胞的功能被定义为在产生神经元和神经胶质后代的同时维持前体状态的能力。最近，我开发了一种新的体内克隆分析系统，以揭示成年哺乳动物海马区内单个细胞水平的干细胞特性，海马区是学习和记忆的关键区域。我们之前的研究表明，放射状胶质样细胞(RGL)可以作为干细胞，但在决定增殖、产生后代和自我更新方面表现出显著的异质性。一个根本性的遗留问题是，这些差异背后的机制是什么。我假设不同的RGL行为是由于它们的增殖状态和对环境变化的反应的不同，包括GABA信号和中风损伤。为了解决这些问题，我已经建立了独立的模型系统，优先针对静止和有丝分裂的RGL。我将首先通过在活体内进行单细胞谱系追踪来表征这些固有偏向的RGL亚群中的NSC潜力。在建立了这一基础之后，我们将评估GABA信号如何作为一种外部分子机制在生理条件下调节静止和活跃的RGL中的干细胞决定。最后，我们将确定在病理条件下，中风损伤如何在静止和活跃的亚群中决定RGL细胞的命运和潜能。重要的是，在指导阶段学到的基于病毒的基因传递、光遗传学和中风手术技能是在独立阶段研究外部生态位调节的多学科方法的基本组成部分。总而言之，这项研究试图理解本质上不同的RGL中的NSC行为，以及它们的决定如何与特定的生理和病理机制相互作用。