Mechanisms underlying dentate gyrus interneuron plasticity and their role in controlling population activity /in vivo/

尽管过去对大脑如何处理信息以使个体有机体适应不断变化的环境的问题进行了深入的研究，但在学习过程中神经网络中如何出现记忆痕迹方面进展甚微。目前的理论表明，经验依赖的突触权重的修改使一组选定的神经元能够在学习过程中形成新的细胞关联，代表新的记忆痕迹(Buzsáki，2010)。然而，细胞关联是如何在空间和时间中出现的，以及GABA能细胞如何对这一过程做出贡献，在很大程度上仍然未知。我们假设，谷氨酸能传递到GABA能抑制细胞的效力的长期可塑性变化是这一过程的关键。我们的目标是在颗粒细胞(GC)输出突触时针对齿状回(DG)中表达小白蛋白(PV)的周身抑制中间神经元(PVI)和生长抑素(SOM)阳性的树突抑制中间神经元(SOMI)来解决这一基本假设。在上一个资助期，我们获得了关于GC-PVI终端长期塑料变化背后的分子机制的详细知识(Hainmüller等人，2014年)。在这里，我们的目标是(1)通过使用海马片制备中的全细胞记录来确定DG-SOMI上谷氨酸能输入的可塑性变化背后的主要分子信号级联(袁，Meyer等人，2017)。(2)结合我们对DG细胞元素及其相互连接的知识，我们将使用双光子(2P)成像技术研究DG中细胞群体在虚拟现实中空间学习期间的空间和时间活动模式。(3)基于我们在第一个资助期所获得的关于PVI可塑性的分子机制的知识，我们将通过应用我们合作伙伴建立的光遗传和分子干扰工具来确定它们在细胞组装形成和行为中的作用。因此，这里提出的第二个资助期的项目将提供关于中间神经元(IN)可塑性在细胞组装形成中的作用以及DG中的信息处理的详细信息。

Despite intensive study in the past on the problem of how information is processed in the brain to enable individual organisms to adapt to their continuously changing environment, little progress has been made on how memory traces emerge in neuronal networks during learning. Current theories suggest that experience-dependent modifications of synaptic weights enable a selected group of neurons to form a new cell association during learning which represents the new memory trace (Buzsáki, 2010). However, how cell associations emerge in space and time and how GABAergic cells may contribute to this process is still largely unknown. We hypothesise that long-lasting plastic changes in the efficacy of glutamatergic transmission onto GABAergic inhibitory cells are essential for this process. We aim to address this fundamental hypothesis at granule cell (GC) output synapses targeting parvalbumin (PV)-expressing perisomatic-inhibitiory interneurons (PVIs) and somatostatin (SOM)-positive dendritic-inhibitory interneurons (SOMIs) in the rodent dentate gyrus (DG). In the last funding period, we gained detailed knowledge on the molecular mechanisms underlying long-lasting plastic changes at GC-PVI terminals (Hainmüller et al., 2014). Here, we aim (1) to determine the main molecular signalling cascades underlying plastic changes at glutamatergic inputs onto DG-SOMIs by using whole-cell recordings in hippocampal slice preparations (Yuan, Meyer et al., 2017). (2) Together with our knowledge on DG’s cellular elements and their inter-connectivity, we will examine the spatial and temporal activity patterns of cell populations in the DG during spatial learning in a virtual-reality using 2-Photon (2P) imaging. (3) Based on our knowledge gained during the 1st funding period on the molecular mechanisms underlying PVI plasticity, we will determine their role in cell assembly formation and behavior by applying optogenetic and molecular interference tools established by our partners. Thus, the here proposed project in the 2nd funding period will provide detailed information on the role of interneuron (IN) plasticity in cell assembly formation and thereby to information processing in the DG.