Characterize the functional connectivity of hippocampal adult neurogenesis during critical period

 描述（由申请人提供）：越来越多的证据表明，神经发生在成年哺乳动物海马体（包括人类海马体）中持续存在，并且与许多认知行为相关。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。虽然成年出生的齿状颗粒细胞（abDGC）在延长的时间段内继续其形态发育，但当未成熟的年轻abDGC表现出提高的膜兴奋性和提高的突触可塑性时，似乎存在短暂的成熟期。最近通过药物遗传学和成年神经发生的光遗传学下调的研究已经提供了关于abDGC的小群体如何可以施加特定行为影响（从空间模式分离到认知灵活性）以及不同离子电流如何可以有助于在abDGC关键成熟期期间观察到的独特生物物理性质的重要见解。然而，成年神经发生如何影响体内DG神经网络，以及在关键成熟期abDGC的生物物理和突触特性的变化如何与其行为影响相关，在很大程度上还不清楚。最近，我们开发了一个强大的光遗传学平台，能够瞬时沉默一组年龄定义的abDGC，以偏置行为和影响海马神经网络动力学。我们在这里将使用这个光遗传学平台进一步分析年龄定义的abDGC对双侧海马的神经网络影响。此外，我们将使用最近发明的扩展显微镜技术来执行与其功能影响相关的abDGC连接模式的超分辨率解剖学表征。在完成这项研究后，我们希望提供一个详细的，时间分辨的了解通过成熟abDGC的神经网络连接模式的变化，并推进我们的成年神经发生在生理学和病理学的功能意义的理解。

 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.