Characterize the functional connectivity of hippocampal adult neurogenesis during critical period

 描述(申请人提供)：越来越多的证据表明，神经发生在成年哺乳动物的海马体中持续存在，包括人类的海马体，并与许多认知行为有关。在成年海马齿状回区域产生的新神经元成熟为齿状颗粒细胞，并整合到现有的神经回路中。成体出生的齿状颗粒细胞(AbDGCs)在较长一段时间内继续其形态发育，幼年abDGCs表现出较高的膜兴奋性和突触可塑性时，似乎有一个短暂的成熟期。最近通过药物遗传学和光遗传下调成年神经发生的研究，为一小群abDGC如何施加从空间模式分离到认知灵活性的特定行为影响，以及不同的离子电流如何对abDGC关键成熟期观察到的独特生物物理性质做出贡献提供了重要的见解。然而，目前还不清楚成体神经发生如何影响体内的DG神经网络，以及abDGCs在关键成熟期的生物物理和突触特性的变化如何与它们的行为影响有关。最近，我们开发了一个强大的光遗传平台，能够瞬时沉默一组年龄定义的abDGC，以偏向行为并影响海马神经网络动力学。在这里，我们将利用这个光遗传平台进一步分析年龄定义的abDGC对双侧海马区的神经网络影响。此外，我们将使用最近发明的扩张显微镜技术对abDGC的连接模式进行超分辨率解剖表征，这些模式与其功能影响相关。随着本研究的完成，我们希望对abDGC在成熟过程中神经网络连接模式的变化提供一个详细的、时间分辨的理解，并促进我们对成人神经发生在生理和病理上的功能意义的理解。

 DESCRIPTION (provided by applicant): Accumulating evidence suggests that neurogenesis continues in the adult mammalian hippocampus including that of humans, and is relevant for many cognitive behaviors. New neurons generated in the dentate gyrus area of the adult hippocampus mature into dentate granule cells and integrate into existing neural circuits. While adult born dentate granule cells (abDGCs) continue their morphological development for an extended period of time, there seems to be a transient maturation period when immature young abDGCs exhibit heightened membrane excitability and elevated synaptic plasticity. Recent studies through pharmacogenetics and optogenetic down regulation of adult neurogenesis have provided important insights on how a small population of abDGCs may exert specific behavioral influence, from spatial pattern separation to cognitive flexibility, and how different ionic currens may contribute to the unique biophysical properties observed during abDGCs critical maturation periods. However, it is largely unclear how adult neurogenesis influences DG neural network in vivo, and how changes in abDGCs' biophysical and synaptic properties during critical maturation period relate to their behavioral impacts. Recently, we developed a robust optogenetic platform capable of transiently silencing a set of age-defined abDGCs to bias behavior and to influence hippocampal neural network dynamics. We here will use this optogenetic platform to further analyze the neural network impacts of age-defined abDGCs on bilateral hippocampus. In addition, we will use the recently invented expansion microscopy technique to perform super-resolution anatomical characterizations of abDGCs' connectivity patterns relevant for their functional impacts. Upon completion of this study, we hope to provide a detailed, time resolved understanding of changes in the neural network connectivity patterns of abDGCs through maturation, and to advance our understanding of the functional significance of adult neurogenesis in physiology and pathology.