Center for Regenerative Medicine, Massachusetts General Hospital (MGH), Boston, Massachusetts, USA.
Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
Nat Med. 2018 May;24(4):438-449. doi: 10.1038/nm.4491. Epub 2018 Mar 12.
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.
随着记忆痕迹在海马-皮质网络中重新组织，记忆的准确性会随时间推移而降低，并变得更加泛化。创伤后应激障碍（PTSD）或与年龄相关的认知障碍患者的记忆准确性随时间推移而逐渐丧失，其特征是恐惧过度泛化。在海马齿状回（DG）中，记忆被认为是由所谓的“携带记忆的”齿状颗粒细胞（eDGCs）编码的。在这里，我们使用啮齿动物研究表明，情境性恐惧条件反射会增加 DG 与下游海马 CA3 区抑制性中间神经元（IN）之间的连接。我们发现肌动蛋白结合 LIM 蛋白 3（ABLIM3）是一种位于苔藓纤维末端的细胞骨架因子，其水平在学习后下降。DGC 中 ABLIM3 表达的下调足以增加与 CA3 透明层 IN（SLIN）的连接，促进表达 Parvalbumin（PV）的 SLIN 激活，增强对 CA3 的前馈抑制，并随着时间的推移在 DG 中维持恐惧记忆痕迹。此外，DGC 中 ABLIM3 表达的下调赋予了海马皮质和杏仁核网络中记忆痕迹的条件性特定再激活，并减少了远距离（即远端）时间点的恐惧记忆泛化。与 CA3 年龄相关过度活跃的观察结果一致，学习无法增加 17 个月大的小鼠的 DGC-SLIN 连接，而 ABLIM3 表达的下调足以恢复 DGC-SLIN 连接，增加 PV+SLIN 激活并改善远程记忆的准确性。这些研究体现了一种基于连接的策略，该策略针对 DG-CA3 中的前馈抑制分子制动器，可用于减少 PTSD 患者随时间推移的记忆泛化，并改善衰老个体的记忆准确性。
