Memories become less precise and generalized over time as memory traces reorganize in hippocampal-cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal-cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC-SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC-SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG-CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.

中文翻译：

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前馈抑制的齿状颗粒细胞募集控制着图的维持和远程记忆的概括。

随着记忆痕迹在海马皮质网络中重新组织，记忆随着时间的流逝而变得越来越不精确。随时间变化的记忆精度丧失的特征在于，创伤后应激障碍（PTSD）或与年龄相关的认知障碍患者的恐惧过度泛化。在海马齿状回（DG）中，记忆被认为是由所谓的“带有牙gram的”齿状颗粒细胞（eDGC）编码的。在这里，我们显示，使用啮齿动物，情境恐惧条件会增加eDGC与下游海马CA3区抑制性中间神经元（IN）之间的连通性。我们确定肌动蛋白结合LIM蛋白3（ABLIM3）为苔藓纤维末端定位的细胞骨架因子，其水平在学习后降低。DGC中ABLIM3表达的下调足以增加与CA3透明层IN（SLIN）的连接性，促进表达小白蛋白（PV）的SLIN活化，增强对CA3的前馈抑制，并随着时间的推移在DG中保持恐惧记忆图。此外，DGC中ABLIM3表达的下调赋予了海马皮层和杏仁核网络中的记忆痕迹条件性上下文特定的激活，并减少了远程（即远端）时间点的恐惧记忆泛化。与观察到的CA3的年龄相关性亢进一致，学习未能提高17个月大小鼠的DGC-SLIN连接性，而ABLIM3表达的下调足以恢复DGC-SLIN连接性，增加PV + SLIN激活并提高精度的回忆。