Identification Of The Cellular And Molecular Mechanisms Involved In The Generation Of Neural Stem Cells In The Hippocampus

成年哺乳动物的大脑是一个非常复杂的器官，在人类中含有大约1600亿个细胞，包括数百种不同的细胞类型。这些细胞中的大多数是在胚胎发育过程中由神经干细胞产生的，神经干细胞位于大脑的心室壁。值得注意的是，神经元的产生在大脑的特定位置持续一生，海马的齿状回是一个远离脑室系统的V形结构，参与学习和记忆。在齿状回中，成体神经干细胞可以分裂产生神经元，这些神经元在称为成体神经发生的过程中整合到现有的海马网络中。齿状回是神经发育障碍如癫痫和精神分裂症的常见部位，可能是由于齿状回和齿状神经干细胞发育异常所致。然而，人们对齿状回的发育过程以及齿状回中成体神经干细胞的胚胎前体细胞在胚胎发育过程中的行为知之甚少。研究单个神经干细胞的新技术表明，成人和发育中的大脑中的神经干细胞是一个非常异质的细胞群，不同的亚群具有不同的行为。胚胎神经干细胞在成年齿状回中产生神经干细胞，在大脑的一个称为齿状神经上皮的区域中发现。在发育过程中，这些前体细胞从脑室迁移到将要成为齿状回的大脑区域。目前尚不清楚注定成为成体干细胞的神经干细胞与大脑其他部位的干细胞有何不同。我们的试验数据表明，与发育中的大脑其他区域的细胞相比，产生成体神经干细胞的细胞具有不同的特性，例如细胞分裂动力学和迁移能力。“雷帕霉素的机械靶标”（mTOR）途径对于许多细胞功能如细胞生长和迁移是重要的。我们的试验数据表明，发育中的齿状回神经干细胞具有高水平的mTOR信号传导。在这个项目中，我们的目标是探索在发育中的小鼠齿状回中控制神经干细胞生成和迁移的分子和细胞机制。本研究的主要目的是：1）研究发育中的齿状回神经干细胞的细胞周期动力学和迁移，并确定其命运潜力如何随时间变化。2)确定mTOR信号在产生齿状回的神经干细胞中的功能作用。3)识别发育中齿状回神经干细胞的新分子调节因子。在过去的二十年中，齿状回中的成人神经发生作为对认知功能重要的细胞可塑性的一种形式获得了显著的关注。然而，很少有人关注胚胎发育和调节成体神经干细胞产生的分子机制。在这里，我们提出了一个实验计划，以了解成体神经干细胞的起源和产生，并确定新的目标，以加强损伤后的再生或预防发育障碍。

The adult mammalian brain is an exceptionally complex organ which in humans contains around 160 billion cells comprising hundreds of different cell types. The majority of these cells are made during embryonic development by neural stem cells found lining the ventricular walls of the brain. Remarkably, the generation of neurons continues throughout life in a specific location of the brain, the dentate gyrus of the hippocampus, which is a V-shaped structure situated away from the ventricular system, involved in learning and memory. In the dentate gyrus, adult neural stem cells can divide to generate neurons that integrate into the existing hippocampal network in a process called adult neurogenesis. The dentate gyrus is frequently involved in neurodevelopmental disorders such as epilepsy and schizophrenia which may result from abnormal development of the dentate gyrus and the dentate neural stem cells. Yet, little is known about how the dentate gyrus develops and how the embryonic precursors of the adult neural stem cells in the dentate gyrus behave during embryonic development. New techniques where one looks at single neural stem cells have revealed that neural stem cells in both the adult and developing brain are a very heterogenous population of cells and the different sub-populations have distinct behaviours. The embryonic neural stem cells that generate the neural stem cells in the adult dentate gyrus are found in an area of the brain called the dentate neuroepithelium. During development, these precursor cells migrate away from the ventricle to the area of the brain that is going to become the dentate gyrus. It is currently not known how the neural stem cells that are destined to become adult stem cells are different from the stem cells in other parts of the brain. Our pilot data indicate that the cells that give rise to the adult neural stem cells have different properties compared to cells in other areas of the developing brain, such as cell division dynamics and the ability to migrate. The "mechanistic target of rapamycin" (mTOR) pathway is important for many cellular functions such as cell growth and migration. Our pilot data indicate that the neural stem cells in the developing dentate gyrus have high levels of mTOR signalling. In this project, we aim to explore the molecular and cellular mechanisms that control neural stem cell generation and migration in the developing mouse dentate gyrus. The main objective of this proposal is to:1) Examine the cell cycle dynamics and migration of the neural stem cells in the developing dentate gyrus and determine how their fate potential changes with time. 2) Determine the functional role of mTOR signalling in the neural stem cells that generate the dentate gyrus. 3) Identify new molecular regulators of the neural stem cells in the developing dentate gyrus. Adult neurogenesis in the dentate gyrus has garnered significant attention over the past twenty years as a form of cellular plasticity important for cognitive function. Little attention has however been paid to embryonic development and the molecular mechanisms regulating the generation of adult neural stem cells. Here we propose an experimental program to understand the origin and generation of adult neural stem cells and to identify novel targets to enhance regeneration after injury or prevent developmental disorders.