Activity-dependent control: neural progenitor cell fate

描述(申请人提供)：神经发生是一种最初被认为仅限于产前的过程，在一生中发生在不同的大脑区域，如脑室下区和齿状回颗粒下区。在过去的十年中，已经积累了大量关于神经前体细胞的鉴定、分离、增殖和多能性的数据。然而，关于祖细胞向特定细胞谱系分化的具体机制，如神经元或神经胶质谱系，人们知之甚少。我们建议研究电活动在神经前体细胞增殖、分化和回路形成中的作用，专门针对齿状回前体细胞群体提出我们的问题。我们的假设是，电活动通过微调谷氨酸受体的表达和激活，推动齿状祖细胞分化为神经元谱系。我们建议使用转基因小鼠在成年器官型海马片培养中研究这些机制，以帮助我们识别特定的细胞群，电生理学来识别未分化和已分化细胞的轮廓，以及双光子显微镜来监测与电刺激相关的形态变化。我们的目标对神经前体细胞在各种神经疾病中的治疗使用有直接影响。在体内识别影响神经前体细胞分化的特定因素的能力将为我们提供重要的洞察力，了解神经前体细胞内源性和外源性激活的潜力，神经发生以及齿状前体细胞作为脑组织重组和修复试剂的用途。

DESCRIPTION (provided by applicant): Neurogenesis, a process first thought to be limited to the prenatal period, occurs throughout life in distinct brain regions, such as the subventricular zone and the dentate gyrus subgranular zone. Over the past decade, a considerable amount of data has been accumulated regarding the identification, isolation, propagation and pluripotency of neural progenitor cells. However, little is known about the specific mechanisms that commit differentiation of progenitor cells toward a specific cell lineage, such as the neuronal or glial lineage. We propose to investigate the role of electrical activity in neural progenitor cell proliferation, differentiation and circuit formation, addressing our questions specifically to the dentate gyrus progenitor cell population. Our hypothesis is that electrical activity drives differentiation of dentate progenitor cells into the neuronal lineage, acting through fine modulation of glutamate receptor expression and activation. We propose to study these mechanisms in the adult organotypic hippocampal slice culture using transgenic mice that help us to identify the specific cell populations, electrophysiology to identify the profiles of undifferentiated and differentiated cells and two-photon microscopy to monitor morphological changes associated with electrical stimulation. Our objectives have a direct impact on the therapeutic use of neural progenitor cells in a variety of neurological disorders. An ability to identify specific factors that influence the differentiation of neural progenitor cells in vivo should provide us with important insights into the potential for endogenous and exogenous activation of progenitor cells, neurogenesis and the utility of dentate progenitor cells as agents for brain tissue reorganization and repair.