Continuous Neurogenesis in the Mammalian Hippocampus

摘要 在过去的二十年里，成年海马区的神经发生作为一种健壮的和 在一个对学习和记忆至关重要的区域，具有独特的可塑性。它也被证明是一片肥沃的土地 了解干细胞生物学、神经元发育的基本原理，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 以及损伤或疾病后神经修复的移植努力。尽管在以下方面取得了相当大的进展 了解成人神经发生的分子和细胞机制，仍然是至关重要的 由于传统的技术限制而尚未解决的领域悬而未决的问题 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， 我们已经发展或适应于研究成人神经发生的发育起源，其功能 对成人大脑的影响，以及啮齿动物模型对人类神经元发育的保真度。首先，我们将 描述导致大部分静止的胚胎神经前体细胞的起源和特性 在啮齿动物模型中维持终生神经发生的神经干细胞池。在我们最近的基础上 胚胎齿状回中表达Hopx的神经前体细胞可产生构成 在采用指示成体神经干细胞的静止状态之前，我们将 确定调节这一前体群体及其向静止状态转变的分子机制。这些 研究将提供对内在和外在信号线索的新见解，这些信号线索建立了一个长期的 发育中的和成人大脑中的干细胞。其次，我们开发了一个齿状突起的三维器官模型 用人诱导多能干细胞研究神经特性的脑回发育 祖细胞、神经发生和命运规范。这些研究可能导致潜在的识别 齿状回神经干细胞和新颗粒神经元的人类特异性标记物及其机制 与啮齿动物模型的不同和相似之处，这将为目前关于 人类齿状回的生后神经发生。第三，我们将研究成人的功能特性 用光遗传学策略识别和记录电生理的成年行为小鼠的神经发生 单个新生颗粒细胞在不同成熟阶段的活性。我们还将调查巡回法庭- 在种群水平上沉默这些细胞的水平影响。这些数据将为 评估成人出生的颗粒细胞在信息处理中做出独特贡献的假设 海马体使用高时间分辨率的技术。总而言之，这些研究结合了一系列 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 他们的后代在齿状回中使用啮齿动物和人类模型。

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.