Continuous Neurogenesis in the Mammalian Hippocampus

哺乳动物海马体的连续神经发生

• 批准号: 10650177
• 负责人: HONGJUN SONG
• 金额: $ 94.09万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650177
• 关键词: 3-Dimensional; Address; Adopted; Adult; Animal Model; Brain; Cells; Cues; Cytoplasmic Granules; Data; Development; Disease; Electrophysiology (science); Embryo; Hippocampus; Human; Injury; Learning; Life; Memory; Modeling; Molecular; Mus; Natural regeneration; Nerve Degeneration; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Newborn Infant; Organoids; Population; Property; Rodent Model; Series; Signal Transduction; Specific qualifier value; Techniques; Transplantation; adult neurogenesis; dentate gyrus; developmental disease; granule cell; human model; induced pluripotent stem cell; information processing; insight; interest; nerve injury; nerve stem cell; neural repair; neurogenesis; neuron development; novel; optogenetics; postnatal; preservation; prevent; stem cell biology; stem cells; temporal measurement

SUMMARY Adult hippocampal neurogenesis has garnered significant interest over the past two decades as a robust and unique form of plasticity in a region critical for learning and memory. It has also proven to be fertile ground for understanding fundamental principles of stem cell biology, neuronal development, as well as illustrating the capacity of the mature brain to integrate immature neurons, which has important implications for regeneration and transplantation efforts for neural repair following injury or diseases. Despite considerable progress in understanding the molecular and cellular mechanisms underlying adult neurogenesis, there are still critical outstanding questions in the field that have not been addressed due to the technical limitations of traditional experimental approaches. In the proposed series of studies, we will use several cutting-edge techniques that we have developed or adapted to investigate the developmental origin of adult neurogenesis, its functional impact in the adult brain, and the fidelity of rodent models to human neuronal development. First, we will characterize the origin and properties of embryonic neural precursor cells that give rise to the largely quiescent pool of neural stem cells that maintain neurogenesis throughout life in a rodent model. Building on our recent findings that Hopx-expressing neural progenitors in the embryonic dentate gyrus can generate the constitutive populations in the dentate gyrus before adopting a quiescent state indicative of adult neural stem cells, we will identify the molecular mechanisms regulate this precursor population and its transition into quiescence. These studies will provide novel insight into the intrinsic and extrinsic signaling cues that establish a long-term pool of stem cells in the developing and adult brain. Second, we have developed a 3D organoid model of dentate gyrus development using human induced pluripotent stem cells to investigate the properties of neural progenitors, neurogenesis and fate specification. These studies could lead to the potential identification of human-specific markers of neural stem cells and new granule neurons in the dentate gyrus and mechanistic differences and similarities with rodent models, which would inform the current debate over the extent of postnatal neurogenesis in the human dentate gyrus. Third, we will investigate the functional properties of adult neurogenesis in adult behaving mice using an optogenetic strategy to identify and record electrophysiological activity of single newborn granule cells at different stages of maturation. We will also investigate the circuit- level impact of silencing these cells at the population level. These data would provide novel information to evaluate the hypothesis that adult-born granule cells make a unique contribution to information processing in the hippocampus using techniques with high temporal resolution. Together, these studies combine an array of approaches to answer fundamental questions about the origin, impact, and plasticity of neural stem cells and their progeny in the dentate gyrus using both rodent and human models.

概括 在过去的二十年中，成年海马神经发生引起了人们的浓厚兴趣 在学习和记忆至关重要的区域中可塑性的独特形式。事实证明，它是肥沃的地面 了解干细胞生物学，神经元发展的基本原理，并说明 成熟大脑整合未成熟神经元的能力，这对再生具有重要意义 以及受伤或疾病后神经修复的移植工作。尽管取得了很大进展 了解成人神经发生的基础的分子和细胞机制，仍然存在关键 由于传统的技术局限性，该领域的杰出问题尚未解决 实验方法。在拟议的一系列研究中，我们将使用几种尖端技术 我们已经开发或适应了成人神经发生的发育起源，该起源是其功能 对成人大脑的影响以及啮齿动物模型对人神经元发育的忠诚度。首先，我们会的 表征胚胎神经前体细胞的起源和特性，这些细胞产生了很大的静止 在啮齿动物模型中，在整个生命中保持神经发生的神经干细胞池。建立在我们最近的 调查结果表明，胚胎齿状回中表达Hopx的神经祖细胞可以产生本构 在采用静态状态之前，齿状回的种群表示成年神经干细胞，我们将 确定调节该前体种群的分子机制及其过渡到静止。这些 研究将为建立长期库的内在和外在信号线索提供新的见解 发育中和成人大脑中的干细胞。其次，我们开发了齿状的3D器官模型 使用人类诱导的多能干细胞研究神经的特性 祖细胞，神经发生和命运规范。这些研究可能导致潜在的鉴定 齿状回和机械的神经干细胞和新颗粒神经元的人类特异性标记 与啮齿动物模型的差异和相似性，这将为当前的辩论提供有关范围的辩论 人齿状回的产后神经发生。第三，我们将研究成人的功能特性 使用光遗传学策略来识别和记录电生理学的成年人的神经发生 单个新生颗粒细胞在不同成熟阶段的活性。我们还将调查电路 - 在人群水平上沉默这些细胞的水平影响。这些数据将提供新颖的信息 评估成人出生的颗粒细胞对信息处理的独特贡献的假设 海马使用具有高时间分辨率的技术。这些研究在一起，结合了一系列 回答有关神经干细胞的起源，影响和可塑性的基本问题的方法 它们使用啮齿动物和人类模型中的齿状回的后代。