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

尽管过去对大脑中如何处理信息以使个体生物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元网络中如何出现记忆痕迹的问题上几乎没有取得进展。目前的理论表明，突触权重的经验依赖性修改使一组选定的神经元能够在学习过程中形成一个新的细胞关联，这代表了新的记忆痕迹（Buzsáki，2010）。然而，细胞联合如何在空间和时间中出现，以及GABA能细胞如何参与这一过程，在很大程度上仍然未知。我们假设，持久的可塑性的变化，在GABA能抑制性细胞的多巴胺能传输的功效是必不可少的这一过程。我们的目的是解决这个基本假设在颗粒细胞（GC）输出突触靶向小白蛋白（PV）表达perisomatic-inhibitiory interneurons（PVIs）和生长抑素（SOM）阳性树突抑制性interneurons（SOMIs）在啮齿动物齿状回（DG）。在上一个资助期，我们获得了关于GC-PVI末端长期塑性变化的分子机制的详细知识（Hainmüller等人，2014）。在此，我们的目标是（1）通过使用海马切片制备物中的全细胞记录来确定在海马能输入到DG-SOMI上的可塑性变化的基础上的主要分子信号传导级联（Yuan，Meyer et al.，2017年）。(2)结合我们对DG细胞元素及其相互连接的了解，我们将使用2-光子（2 P）成像在虚拟现实中研究DG中空间学习期间细胞群的空间和时间活动模式。(3)基于我们在第一个资助期内获得的关于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学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，在第二个资助期内，这里提出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的详细信息，从而在DG中进行信息处理。

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.