School of Basic Medicine Sciences, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Pharmacology Research Center, Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200032, China; Research Unit of Addition Memory, Chinese Academy of Medical Sciences (2021RU009), Shanghai 200032, China.
School of Basic Medicine Sciences, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Pharmacology Research Center, Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200032, China; Research Unit of Addition Memory, Chinese Academy of Medical Sciences (2021RU009), Shanghai 200032, China.
Brain Behav Immun. 2024 Jul;119:621-636. doi: 10.1016/j.bbi.2024.04.024. Epub 2024 Apr 24.
Rac1 is a key regulator of the cytoskeleton and neuronal plasticity, and is known to play a critical role in psychological and cognitive brain disorders. To elucidate the engram specific Rac1 signaling in fear memory, a doxycycline (Dox)-dependent robust activity marking (RAM) system was used to label dorsal dentate gyrus (DG) engram cells in mice during contextual fear conditioning. Rac1 mRNA and protein levels in DG engram cells were peaked at 24 h (day 1) after fear conditioning and were more abundant in the fear engram cells than in the non-engram cells. Optogenetic activation of Rac1 in a temporal manner in DG engram cells before memory retrieval decreased the freezing level in the fear context. Optogenetic activation of Rac1 increased autophagy protein 7 (ATG7) expression in the DG engram cells and activated DG microglia. Microglia-specific transcriptomics and fluorescence in situ hybridization revealed that overexpression of ATG7 in the fear engram cells upregulated the mRNA of Toll-like receptor TLR2/4 in DG microglia. Knockdown of microglial TLR2/4 rescued fear memory destabilization induced by ATG7 overexpression or Rac1 activation in DG engram cells. These results indicate that Rac1-driven communications between engram cells and microglia contributes to contextual fear memory destabilization, and is mediated by ATG7 and TLR2/4, and suggest a novel mechanistic framework for the cytoskeletal regulator in fear memory interference.
Rac1 是细胞骨架和神经元可塑性的关键调节剂，已知在心理和认知性脑紊乱中发挥关键作用。为了阐明恐惧记忆中的特定印迹 Rac1 信号，在条件性恐惧训练期间，使用强力四环素（Dox）依赖性活性标记（RAM）系统标记小鼠背侧齿状回（DG）印迹细胞。DG 印迹细胞中的 Rac1 mRNA 和蛋白水平在恐惧条件后 24 小时（第 1 天）达到峰值，并且在恐惧印迹细胞中比在非印迹细胞中更为丰富。在记忆检索之前以时间方式在 DG 印迹细胞中光遗传学激活 Rac1 会降低恐惧环境中的冻结水平。Rac1 的光遗传学激活增加了 DG 印迹细胞中的自噬蛋白 7（ATG7）表达并激活了 DG 小胶质细胞。小胶质细胞特异性转录组学和荧光原位杂交显示，在恐惧印迹细胞中过表达 ATG7 会上调 DG 小胶质细胞中 Toll 样受体 TLR2/4 的 mRNA。小胶质细胞 TLR2/4 的敲低可挽救 ATG7 过表达或 Rac1 在 DG 印迹细胞中的激活引起的恐惧记忆不稳定。这些结果表明，印迹细胞和小胶质细胞之间 Rac1 驱动的通讯有助于上下文恐惧记忆不稳定，并由 ATG7 和 TLR2/4 介导，为恐惧记忆干扰中的细胞骨架调节剂提供了新的机制框架。
