Nature medicine:前馈抑制的齿状核颗粒细胞募集支配着印迹维持和远程记忆的泛化

生物医学中文摘要2018-12-05 15:37:35

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 细胞骨架因子ABLIM3的动态调节控制了创伤后应激障碍和年龄相关的认知障碍的啮齿动物模型中记忆表征的精确性。



【题目】 前馈抑制的齿状核颗粒细胞募集支配着印迹维持和远程记忆的泛化


【摘要】 随着记忆痕迹在海马皮质网络中的重新组合,记忆变得越来越不精确和一般化。 在患有创伤后应激障碍(PTSD)或年龄相关的认知障碍的个体中,内存精度随时间变化而增加,其特点是对恐惧的过度概括。在海马齿状回(DG)中,记忆被认为是由所谓的“带有牙槽嵴“的齿状颗粒细胞(eDGC)编码的。在此我们使用啮齿类动物展示了,情境恐惧条件反射增加了eDGCs和下游海马CA3区域的抑制性中间神经元(INs)之间的连通性。我们将肌动蛋白结合LIM蛋白3(ABLIM3)鉴定为苔藓纤维末端局限性细胞骨架因子,其水平在学习后降低。DGC中ABLIM3表达的下调足以增加其与CA3地层灵芝(SLINs)的连接性,促进小清蛋白(PV)表达的SLIN激活,增强对CA3的前馈抑制并且随着时间的推移维持DG中的恐惧记忆。此外,DGC中ABLIM3表达的下调赋予海马 - 皮层和扁桃体网络中记忆痕迹的条件性上下文特异性再激活,并减少远程时间点的恐惧记忆泛化。与对年龄相关的CA3过度活动的观察一致,学习未能增加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激活并提高远程存储器的精度。这些研究举例说明了一种基于连接性的策略,其目标是DG-CA3中前馈抑制的分子制动,并可能被利用来减少PTSD个体的时间依赖性记忆泛化,并提高老年人的记忆精确度。




英文原文

【report】Dynamic regulation of the cytoskeletal factor ABLIM3 controls the precision of memory representations in rodent models of post-traumatic stress disorder and age-related cognitive impairment.

 

【title】Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization

 

【authors】Nannan Guo, Marta E Soden, Charlotte Herber, Michael TaeWoo Kim, Antoine Besnard, Paoyan Lin, Xiang Ma, Constance L Cepko, Larry S Zweifel & Amar Sahay

 

【abstract】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.


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