联合型记忆提取-再巩固的信号转导和神经环路机制

Memory reconsolidation, a rebuilding process triggered by recall of an established memory, depends on de novo protein synthesis and β-adrenergic signaling, but the underlying mechanisms have not been identified. Our previous study demonstrates that β-arrestin-biased β-adrenergic signaling regulates reconsolidation of object recognition memory and reveals the potential for β-arrestin-biased ligands in the treatment of memory-related disorders. Our preliminary study also indicates that a small population of neurons correspond to associative memory storage, suggesting a cellular correlate of a memory engram. However, many questions, including what proteins are synthesized during memory reconsolidation process, whether the de novo protein synthesis occurs in the engram cell, and whether β-arrestin-biased signaling in these cells mediates memory reconsolidation and synaptic remodeling through regulation of protein synthesis, are to be addressed. In this project, we plane to use conditioned fear memory and conditioned place preference memory as models of associative memory and focus our study on basic scientific questions about the molecular and circuitry mechanisms of associative memory reconsolidation, and reveal the key role of β-arrestin-biased β-adrenergic translational signaling pathway in regulation of gene expression in reconsolidation-related engram cells and the reconsolidation of associative memory.

记忆提取及再巩固是记忆动态存储的重要阶段。记忆提取后，已经巩固的记忆被再次激活，原先稳定的记忆变得脆弱易变，在再巩固后重新形成稳定的记忆。在此时间窗内进行干预，记忆能被擦除、强化、修改或更新。因此理解记忆提取-再巩固的机制具有重要的科学意义，对于治疗相关疾病也具有重要的价值。我们在前期工作中发现，记忆的再巩固并不依赖于G蛋白信号通路，而是由β-arrestin偏向性蛋白合成信号通路所介导；联合型记忆的提取和再巩固可能依赖于特定脑区的少量神经元（痕迹细胞）。本项目将在此基础上，采用条件性恐惧和位置偏爱记忆模型，运用即早基因启动子驱动的转基因鼠以及Cre/loxp病毒表达体系，结合转录组和翻译组分析，探讨联合型记忆提取-再巩固依赖的信号转导网络，揭示记忆提取-再巩固的痕迹细胞的作用和分子标记物，解析记忆痕迹细胞的神经环路组成和功能重塑，阐述记忆再巩固的分子和环路机制。

记忆提取和再巩固是记忆动态存储的重要阶段。记忆提取导致已经巩固的记忆被再次激活，原先稳定的记忆变得脆弱易变，在再巩固后重新形成稳定的记忆。在此时间窗内进行干预，记忆能被擦除、强化、修改或更新。因此理解记忆提取-再巩固的机制具有重要的科学意义，对于治疗相关疾病也具有重要的价值。我们主要采用位置偏爱和条件性恐惧记忆模型，运用即早基因启动子驱动的转基因鼠以及Cre/loxp病毒表达体系，采用光遗传学操控，结合转录组和翻译组分析，探讨联合型记忆提取-再巩固依赖的神经环路基础和信号转导网络。我们的研究揭示了腹侧海马CA1至伏隔核记忆痕迹神经元环路其突触可塑性的增强介导了可卡因奖赏记忆的提取和储存（Zhou et al., Nat Neurosci 2019）；前额叶皮层SST阳性以及PV阳性的中间能神经元通过不同类型阿片受体，协同调控前额叶皮层的抑制性微环路，减弱兴奋性神经元的抑制性输入，促进吗啡奖赏记忆提取（Jiang et al., Mol Psychiatry 2019）；前额叶皮质GRK5-mTOR信号通路调控了药物奖赏的记忆的提取（Niu et al., Cereb Cortex 2018）；前额叶皮层β-arrestin偏向性β-肾上腺素受体信号通路的激活促进可卡因成瘾记忆的消退，进而抑制环境线索诱导的可卡因成瘾记忆的提取（Huang et al., Sci Signal 2018）；背侧海马CA1兴奋性神经元内的Tet3和NPTX2的表达参与调控可卡因奖赏记忆的提取和再巩固（Liu et al., Int J Neuropsychopharmacol 2018；Wang et al., Biol Psychiatry 2019）。我们的研究结果揭示了奖赏关联型记忆编码的细胞机制及其信号转导和转录调控机制。项目执行期间在Nat Neurosci、Mol Psychiatry等SCI杂志上发表论文12篇，研究结果为联合型记忆提取-再巩固的神经生物学机制提供理论依据，为干预记忆相关疾病提供药物靶点。