Continuous Neurogenesis in the Mammalian Hippocampus

总结 在过去的二十年里，成人海马神经发生作为一种强大的， 这是一种独特的可塑性，在一个对学习和记忆至关重要的区域。它也被证明是肥沃的土壤， 了解干细胞生物学的基本原理，神经元发育，以及说明 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 以及用于损伤或疾病后的神经修复的移植努力。尽管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，仍然是关键的 由于传统技术的局限性， 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， 成年人大脑中的影响，以及啮齿动物模型对人类神经元发育的保真度。一是 描述胚胎神经前体细胞的起源和特性，这些细胞引起大部分静止的 在啮齿动物模型中维持神经发生的神经干细胞库。基于我们最近 研究发现，胚胎齿状回中表达Hopx的神经祖细胞可以产生组成性 群体在齿状回之前，采用静止状态指示成年神经干细胞，我们将 确定调节这一前体群体及其向静止过渡的分子机制。这些 研究将提供新的见解，内在和外在信号线索，建立一个长期的池， 干细胞在大脑发育和成人。其次，我们建立了一个齿状回的3D类器官模型， 使用人类诱导多能干细胞进行脑回发育，以研究神经细胞的特性。 祖细胞、神经发生和命运特化。这些研究可能会导致潜在的识别 齿状回中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 与啮齿动物模型的差异和相似之处，这将为目前关于 人类齿状回的出生后神经发生。第三，我们将研究成年人的功能特性， 使用光遗传学策略识别和记录电生理学的成年行为小鼠中的神经发生 单个新生颗粒细胞在不同成熟阶段的活性。我们也会调查电路- 在群体水平上沉默这些细胞的水平影响。这些数据将提供新的信息， 评估成人出生的颗粒细胞对信息处理做出独特贡献的假设， 使用高时间分辨率的技术来观察海马体。总之，这些研究联合收割机结合了一系列 方法来回答有关神经干细胞的起源，影响和可塑性的基本问题， 使用啮齿动物和人类模型在齿状回中观察它们的后代。

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.