The role of dentate gyrus interneuron plasticity in the representation of location, environment and objects

如何在大脑中处理和表示信息，以使个体生物体能够适应不断变化的环境，这是当前神经科学的基本组成部分。然而，关于记忆痕迹如何在学习过程中出现在神经元网络中的研究进展甚微。目前的理论提出，在学习过程中修改突触权重，使一组选定的主细胞（PC），以形成一个新的细胞协会，这代表了新的信息。然而，这些细胞协会如何随着时间的推移出现，以及GABA能抑制性中间神经元如何有助于这一过程在很大程度上是未知的。我们假设，突触可塑性在兴奋性神经元的输入到中间神经元（INs）支持他们的招聘，从而显着有助于记忆痕迹的形成。在这里，我们的目标是解决这个假设的生长抑素（SOM）表达中间神经元（SOMIs）的齿状回（DG），针对远端树突的本地颗粒细胞（GC），PC的这个大脑区域。我们最近确定了第一组代谢型谷氨酸受体1 α（mGluR 1 α）和mGluR 5作为关键的分子机制，在GC介导的突触到SOMIs的突触可塑性的出现。(1)在这里，我们的目标是在急性海马切片制备进行全细胞记录，以检查主要的分子级联下游的mGluR 1 β潜在的可塑性诱导在GC-SOMI突触，并将它们与我们已经发表的针对小白蛋白（PV）表达的中间神经元的GC突触。(2)我们的目标是应用我们最近测试的小发夹RNA（shRNA）干扰工具mGluR 1 β敲低，研究失去SOMI输入可塑性对神经元网络动力学的影响。我们将使用2-光子成像在DG的头部固定的小鼠导航通过虚拟现实的线性轨道上寻找奖励和1-光子成像的自由移动的小鼠执行DG依赖的对象识别任务。(3)我们将应用基于人口矢量的解码器分析人口活动的线性轨道上获得的，并在自由空间探索研究的影响，在可塑性的编码的当前位置，环境和记忆的对象。因此，该项目的主要目标是研究SOMI可塑性如何影响GC组件编码空间，上下文（在哪里？）和环境中的对象（什么？）。本研究将有助于我们进一步了解IN输入可塑性在记忆中的作用。我们相信这项工作是临床相关的，因为IN功能的缺陷是认知疾病的标志。

How information is processed and represented in the brain to enable individual organisms to adapt behavior to their continuously changing environment is a fundamental building block of current neuroscience. However, little progress has been made on how memory traces emerge in neuronal networks during learning. Current theories propose that during learning modifications of synaptic weights enable a selected group of principal cells (PCs) to form a new cell association, which represents the new information. However, how these cell associations emerge across time and how GABAergic inhibitory interneurons may contribute to this process is largely unknown. We hypothesise that synaptic plasticity at excitatory glutamatergic inputs onto interneurons (INs) supports their recruitment and thereby markedly contribute to memory trace formation. Here, we aim to address this hypothesis on somatostatin (SOM) expressing interneurons (SOMIs) of the dentate gyrus (DG) targeting distal dendrites of local granule cells (GCs), the PCs of this brain area. We recently identified group I metabotropic glutamate receptor 1 (mGluR1) and mGluR5 as key molecular mechanisms underlying the emergence of synaptic plasticity at GC-mediated synapses onto SOMIs. (1) Here, we aim to perform whole-cell recordings in acute hippocampal slice preparations to examine the major molecular cascades downstream of mGluR1 underlying plasticity induction at GC-SOMI synapses and compare them with our already published ones for GC synapses targeting parvalbumin (PV)-expressing interneurons. (2) We aim to apply our recently tested small hairpin RNA (shRNA) interference tools for mGluR1 knockdown, to examine the impact of lost SOMI input plasticity on neuronal network dynamics. We will us 2-photon imaging in the DG of head-fixed mice navigating through a virtual reality on a liner track searching for rewards and 1-photon imaging of freely moving mice performing a DG-dependent object-recognition task. (3) We will apply population-vector based decoder analysis of population activity obtained on the linear track and during free spatial exploration to examine the impact of IN plasticity on the encoding of the current location, the environment and memorized objects. Thus, the major goal of the proposed project is to examine how SOMI plasticity influences activity dynamics of GC assemblies encoding information about space, context (where?) and objects within an environment (what?). This project will contribute to our understanding on the role of IN input plasticity in memory. We believe that this work is clinically relevant, since deficits in IN function are hallmarks of cognitive diseases.