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生物适应不断变化的环境进行了深入的研究，但在学习过程中记忆痕迹如何在神经元网络中出现的问题上却进展甚微。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在学习过程中形成新的细胞关联，这代表了新的记忆痕迹（Buzsáki, 2010）。然而，细胞关联是如何在空间和时间上出现的，以及gaba能细胞如何参与这一过程，在很大程度上仍然是未知的。我们假设谷氨酸能传递到gaba能抑制细胞的长效可塑性变化对这一过程至关重要。我们的目标是在啮齿动物齿状回（DG）中针对表达小白蛋白（PV）的周围抑制中间神经元（PVIs）和生长抑素（SOM）阳性的树突抑制中间神经元（SOMIs）的颗粒细胞（GC）输出突触中解决这一基本假设。在上一个资助期内，我们获得了GC-PVI终端持久塑性变化的分子机制的详细知识（hainmller等，2014）。在这里，我们的目标是(1)通过使用海马切片制备中的全细胞记录来确定谷氨酸能输入到DG-SOMIs的可塑性变化的主要分子信号级联（Yuan， Meyer等，2017）。(2)结合我们对DG细胞元素及其相互连接的了解，我们将利用2光子（2P）成像技术在虚拟现实中研究DG细胞群在空间学习过程中的时空活动模式。(3)基于我们在第一个资助期获得的关于PVI可塑性的分子机制的知识，我们将利用我们的合作伙伴建立的光遗传学和分子干涉工具来确定它们在细胞组装形成和行为中的作用。因此，本文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.