Role of GABAergic inhibitory interneurons in the emergence of environmental representations in the mouse dentate gyrus

海马体网络中空间环境的表征是我们生活叙事的基本组成部分。它们使我们能够迅速灵活地对环境中的变化作出反应。尽管海马主细胞（PC）组合已被证明对独特的体验环境进行编码，并且它们的重新激活被认为可以恢复相关的记忆，但gaba能抑制性中间神经元（INs）在空间表征的形成和稳定中的作用在很大程度上是未知的。在拟议的项目中，(1)我们的目标是通过使用双光子钙成像在高空间和时间分辨率下记录头部固定小鼠在虚拟环境中导航并学习获得目标导向奖励的海马PC和In群体的活动来解决这个基本问题。(2)我们的目标是使用药物和/或光遗传学工具来调节IN活性，以检查它们对PC组件空间表征的影响。(3)我们将在已经建立的计算网络模型的基础上，发展作为海马输入门的齿状回（DG）空间和情境表征的电路机制理论。大量的工作先前已经确定了形态、生理和神经化学上不同的海马IN类型的高度多样性。因此，我们将把拟议项目的重点放在研究表达小白蛋白（PV）的周围抑制性和生长抑素（SOM）阳性的远端树突抑制蛋白（分别为PVIs和SOMIs）在DG中的作用上，这对海马的空间和上下文表征至关重要。因此，我们的主要目标是研究IN类型如何影响代表DG中给定环境的单个PC和PC组件的活动动态。这个项目将有助于我们理解IN类型在环境信息的表示和编码以及环境之间的区分中的作用。

Representations of spatial environments in hippocampal networks are fundamental building blocks to the narrative of our lives. They allow us to rapidly and flexibly respond to changes within our environment. Although hippocampal principal cell (PC) assemblies have been shown to encode unique experienced environments and their re-activation is thought to reinstate the associated memory, the role of GABAergic inhibitory interneurons (INs) in the formation and stabilization of spatial representations is largely unknown. In the proposed project, (1) we aim to address this fundamental question by recording the activity of hippocampal PC and IN populations at high spatial and temporal resolution using 2-photon calcium imaging in head-fixed mice navigating through virtual environments and learn to obtain goal-oriented rewards. (2) We aim to modulate IN activity using pharmaco- and/or optogenetic tools to examine their influence on spatial representation by PC assemblies. (3) We will develop based on our established computational network models, theories on circuit mechanisms underlying the spatial and contextual representation in the dentate gyrus (DG), as the input gate of the hippocampus. A large body of work has previously identified a high diversity of morphologically, physiologically and neurochemically distinct hippocampal IN types. We will therefore focus the proposed project on examining the role of parvalbumin (PV)-expressing perisomatic-inhibitory and somatostatin (SOM)-positive distal dendrite-inhibiting INs (PVIs, SOMIs, respectively) in the DG, which is functionally vital for spatial and contextual representation in the hippocampus. Thus, our major goal is to examine how IN types influence the activity dynamics of individual PCs and PC assemblies representing a given environment in the DG. This project will contribute to our understanding on the role of IN types in the representation and encoding of environmental information and the differentiation between environments.