BACKGROUND Postretrieval extinction attenuates the pathological memory associated with psychiatric states such as drug addiction in both humans and rodents. The extinction of a learned response requires gene transcription and protein synthesis after memory retrieval in a time-dependent manner, yet the precise physiological basis after retrieval to allow extinction to neutralize a learned behavior is not fully understood. METHODS In a cocaine conditioned place preference paradigm, we used a ribosomal tagging strategy to measure the translational state of hippocampal pyramidal neurons after the retrieval of cocaine-associated context memory. Using approaches of electrophysiology, neuronal tracing, and a doxycycline-dependent robust activity marking system, we investigated the cellular and molecular basis of retrieval-induced plasticity that facilitated the extinction. RESULTS Bioinformatics analysis discovered the specific translational regulation of signaling pathways by retrieval and revealed Nptx2 as the hub gene. Manipulating Nptx2 in dorsal hippocampus bidirectionally regulated the extinction of cocaine-associated context memory as well as the retrieval-driven synaptic remodeling. The pentraxin (PTX) domain of NPTX2 recruited GluA1-AMPA receptors and enhanced the extinction and excitatory synaptic transmission that was prevented by overexpressing carboxyl cytoplasmic tail of GluA1. Furthermore, Nptx2 in retrieval-activated neurons was required for the extinction. CONCLUSIONS The retrieval-driven upregulation of Nptx2 contributes to the synaptic remodeling in dorsal hippocampus and facilitates the extinction of cocaine-associated context memory, indicating a potential target for the treatment of cue-induced cocaine seeking.

中文翻译：

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检索驱动的海马 NPTX2 可塑性促进可卡因相关上下文记忆的消失

背景 检索后灭绝减弱了与人类和啮齿动物的精神状态如毒瘾相关的病理记忆。学习反应的消失需要以时间依赖的方式在记忆检索后进行基因转录和蛋白质合成，但尚未完全了解检索后允许灭绝以中和学习行为的精确生理基础。方法在可卡因条件位置偏好范式中，我们使用核糖体标记策略来测量检索可卡因相关上下文记忆后海马锥体神经元的平移状态。使用电生理学、神经元追踪和依赖强力霉素的稳健活动标记系统的方法，我们研究了促进灭绝的检索诱导可塑性的细胞和分子基础。结果 生物信息学分析通过检索发现了信号通路的特异性翻译调控，并揭示了 Nptx2 作为中枢基因。操纵背侧海马中的 Nptx2 双向调节可卡因相关上下文记忆的消失以及检索驱动的突触重塑。NPTX2 的五联蛋白 (PTX) 结构域招募 GluA1-AMPA 受体并增强了通过过度表达 GluA1 的羧基胞质尾而阻止的灭绝和兴奋性突触传递。此外，灭绝需要检索激活神经元中的 Nptx2。