记忆再巩固现象及其生物学机制

已经巩固的长时记忆在激活后会经历一段易变而敏感的阶段后重新稳定下来,在此过程中,原有的记忆可以被修饰,加强,改变甚至消除,这个过程称为再巩固。记忆再巩固的研究意义在于它不仅扩展了人们对记忆本质的认识,而且对于临床治疗病理性记忆具有重大的现实意义。本文从行为学层面介绍了记忆的强度、记忆保持时间以及记忆激活方式对不同忆记忆再巩固模型的影响。并从蛋白质合成、基因水平、转录因子等方面简要介绍了再巩固的神经生物学机制的研究脉络。再巩固现象的研究不仅为治疗创伤性病理记忆提供了理论支持,并且为临床治疗药物成瘾相关病理记忆提供了新视角。     

预期错误在恐惧记忆更新中的作用与机制

依据错误驱动的学习理论, 行为预期结果与实际结果之间的不匹配即预期错误(Prediction error, PE)是学习产生的驱动因素。作为显著性信息中的一种, 预期错误和物理显著性、惊讶、新异性等存在信息加工阶段的不同, 与记忆更新的关系也有差异。近年来, 记忆再巩固干预范式(reconsolidation interference)被证明可用于人类条件性恐惧记忆的更新, 其中记忆提取激活阶段所包含的预期错误起到了引发记忆“去稳定”、开启记忆再巩固的关键作用。在促进恐惧记忆更新的行为机制上, PE被认为是记忆去稳定的必要非充分条件。记忆提取必须包含适量的PE, 但其引发的是记忆去稳定、消退还是中间状态, 还需结合记忆本身性质确定。在促进恐惧记忆更新的神经机制上, 杏仁核、导水管周围灰质(PAG)、海马均在PE探测和计算过程中具有重要作用; 前额叶皮层(PFC)及其亚区在PE开启记忆再巩固过程中扮演了重要角色。上述过程又受到神经系统中特定神经递质的重要调节, 尤其是多巴胺能和谷氨酸能。未来研究应进一步探索基于PE计算模型的量化研究, 整合PE与其他边界条件的交互作用, 考察不同类型显著性在记忆再巩固中的作用等; 并亟待使用多学科手段探索PE在恐惧记忆更新中作用的神经与分子机制。同时, 需进一步开展PE作用的个体差异研究, 促进研究结果向临床应用转化。     

如何克服边界条件：来自记忆强度影响记忆去稳定的分子机制的启示

长时记忆在激活后首先会变得不稳定(去稳定过程), 继而会经历一个再巩固过程重新稳定下来以维持记忆的关联性。在再巩固期间给予电击、药理或行为训练以干预记忆再巩固, 可以更改原有记忆的强度或内容。这有望成为临床上治疗病理性记忆的一种方法。然而, 一些边界条件(记忆痕迹强、时间久远等)导致记忆在简单激活后不能去稳定, 不会经历再巩固过程, 使干预再巩固的方法无法发挥作用。动物实验表明, 通过药理学地调控参与记忆去稳定的分子的活动以促进记忆去稳定, 可以成功克服边界条件。可见, 边界条件不是绝对的。未来研究可进一步探索更多、更优的促进记忆去稳定并克服边界条件的方法, 提升干预记忆再巩固疗法的临床应用潜能。     

人类记忆再巩固研究现状及临床应用

巩固的记忆被提取后,进入不稳定状态,再重新稳定下来,这个过程称为记忆再巩固。本文首先阐述人类记忆再巩固主要研究方法和经典范式,梳理记忆再巩固在人类恐惧记忆和情景记忆两个方面的相关研究,并从认知神经科学角度整理记忆再巩固的加工机制。然后总结记忆再巩固应用于创伤性应激障碍和药物成瘾等心理障碍临床治疗的相关文献。最后本文提出未来研究的方向和建议,希冀对人类记忆再巩固的理论研究和临床应用提供新思路。     

陈述性记忆存储和巩固的神经机制

综述了陈述性记忆形成和巩固的神经机制,并对经典模型进行了修正和拓展。主要观点是：陈述性记忆的存储和巩固依赖于新皮层不同脑区之间建立新的联系,内侧颞叶在这一过程中起着重要作用;当陈述性记忆完全巩固后,信息的存储和提取完全依赖于新皮质;一个完整的陈述性记忆的信息被分别存储在解剖上分离的语义记忆与情节记忆存储系统内     

条件性恐惧记忆消退的提取干预范式及其作用的神经机制

基于记忆再巩固理论的恐惧记忆提取干预范式被证明可以有效消退恐惧记忆, 能克服传统消退容易复发的缺点。该范式通过单独呈现条件刺激激活原有恐惧记忆, 使记忆重返不稳定状态, 随后在再巩固时间窗内实施干预则能改写原有记忆。目前该范式起作用的神经机制尚不明确, 本文在现有的人类研究和动物研究基础上, 总结了杏仁核、前额叶和海马三个脑区在提取干预过程中的作用, 以及该领域研究的争议点, 为之后的研究提供思路。     

行为干预情绪记忆再巩固：从实验室到临床转化

重新激活已经储存的记忆会重返暂时不稳定的状态, 需要经历重新稳定, 称为记忆再巩固。在这期间可以通过多种行为手段破坏、强化或更新原始记忆痕迹, 这为开发一种革命性的情绪记忆障碍治疗方法开辟了道路。然而, 即使在简单的实验模型中引发记忆再巩固的条件也是复杂的, 这给临床转化带来了困难与挑战。未来研究可以设置更具生态效应的基础模型, 寻求引发以及干预再巩固的最佳方式, 从神经生理、细胞分子层面进一步深化其内在机理研究。     

对人类不良记忆的修饰：来自记忆再巩固的证据

已经巩固的长时记忆被再次提取后, 进入一个记忆的不稳定期, 在此过程中, 记忆可被更新、强化、削弱甚至抹除, 这个过程称为再巩固。人类不良记忆再巩固研究揭示记忆激活后口服普萘洛尔(propranolol)或进行消退训练可削弱或抹除不良情绪记忆, 此过程中涉及杏仁核、海马、前额叶皮层等脑区的参与及其构成的神经环路的调控。当前临床上利用再巩固原理可通过药物治疗、行为干预或无创脑部刺激的方法改变不良记忆。然而, 由于其形成过程复杂并受多种因素影响, 未来研究应尽可能模拟临床中人类不良记忆形成的复杂环境, 深入探讨再巩固“边界问题”, 推动实验室研究向临床应用的转化。     

条件性恐惧记忆提取消退干预范式

提取消退(retrieval-extinction, Ret+Ext)范式是基于记忆再巩固理论, 利用消退训练(extinction, Ext)能改变条件刺激(conditioned stimulus, CS)的恐惧效价特点, 把消退训练应用到再巩固时间窗内来改写(rewrite)恐惧记忆, 消除恐惧反应。提取消退范式是对传统暴露疗法和药物治疗的创新和拓展, 不仅为创伤性记忆的治疗提供一种非侵入性的技术, 而且也为改写人类记忆、积极心理学探索人类幸福感方面开辟了一种全新的理论视角。     

睡眠影响记忆巩固的同步EEG-fMRI研究

默认网络是静息状态活动较强的大脑结构, 它包含的海马和内侧前额叶两个脑区是记忆巩固的关键部位, 同时静息态也被证明伴随有记忆巩固现象, 我们推测默认网络是睡眠依赖记忆巩固的核心结构。本研究拟借助同步EEG-fMRI在时空分辨率上的优势, 研究默认网络参与睡眠依赖记忆巩固的神经机制。包括：1)发掘默认网络活动的电生理指标, 应用EEG源定位和跨频段耦合分析, 揭示记忆巩固的动态过程; 2)应用滑动时间窗和模块分析, 研究默认网络参与静息态和睡眠过程记忆巩固的异同, 揭示记忆在昼夜更迭中得以强化的神经机制; 3)通过多模态信息融合, 揭示记忆类型和睡眠阶段等因素对睡眠依赖记忆巩固的影响。本研究的开展对阐明睡眠依赖记忆巩固的神经机制具有深刻的理论意义, 并最终可能为治疗学习记忆相关障碍提供全新的思路。     

De novo mRNA synthesis is required for both consolidation and reconsolidation of fear memories in the amygdala

Memory consolidation is the process by which newly learned information is stabilized into long-term memory (LTM). Considerable evidence indicates that retrieval of a consolidated memory returns it to a labile state that requires it to be restabilized. Consolidation of new fear memories has been shown to require de novo RNA and protein synthesis in the lateral nucleus of the amygdala (LA). We have previously shown that de novo protein synthesis in the LA is required for reconsolidation of auditory fear memories. One key question is whether protein synthesis during reconsolidation depends on already existing mRNAs or on synthesis of new mRNAs in the amygdala. In the present study, we examined the effect of mRNA synthesis inhibition during consolidation and reconsolidation of auditory fear memories. We first show that intra-LA infusion of two different mRNA inhibitors dose-dependently impairs long-term memory but leaves short-term memory (STM) intact. Next, we show that intra-LA infusion of the same inhibitors dose-dependently blocks post-reactivation long-term memory (PR-LTM), whereas post-reactivation short-term memory (PR-STM) is left intact. Furthermore, the same treatment in the absence of memory reactivation has no effect. Together, these results show that both consolidation and reconsolidation of auditory fear memories require de novo mRNA synthesis and are equally sensitive to disruption of de novo mRNA synthesis in the LA.     

On the role of hippocampal protein synthesis in the consolidation and reconsolidation of object recognition memory

Upon retrieval, consolidated memories are again rendered vulnerable to the action of metabolic blockers, notably protein synthesis inhibitors. This has led to the hypothesis that memories are reconsolidated at the time of retrieval, and that this depends on protein synthesis. Ample evidence indicates that the hippocampus plays a key role both in the consolidation and reconsolidation of different memories. Despite this fact, at present there are no studies about the consequences of hippocampal protein synthesis inhibition in the storage and post-retrieval persistence of object recognition memory. Here we report that infusion of the protein synthesis inhibitor anisomycin in the dorsal CA1 region immediately or 180 min but not 360 min after training impairs consolidation of long-term object recognition memory without affecting short-term memory, exploratory behavior, anxiety state, or hippocampal functionality. When given into CA1 after memory reactivation in the presence of familiar objects, ANI did not affect further retention. However, when administered into CA1 immediately after exposing animals to a novel and a familiar object, ANI impaired memory of both of them. The amnesic effect of ANI was long-lasting, did not happen after exposure to two novel objects, following exploration of the context alone, or in the absence of specific stimuli, suggesting that it was not reversible but was contingent on the reactivation of the consolidated trace in the presence of a salient, behaviorally relevant novel cue. Our results indicate that hippocampal protein synthesis is required during a limited post-training time window for consolidation of object recognition memory and show that the hippocampus is engaged during reconsolidation of this type of memory, maybe accruing new information into the original trace.     

A role for ERK2 in reconsolidation of fear memories in mice

Recent studies have shown that consolidated fear memories, when reactivated, return to a labile state that requires a new protein synthesis for reconsolidation. Post-retrieval infusion of an inhibitor of protein synthesis blocks memory reconsolidation processes. In a previous research, the role of MAPKs in memory consolidation has been shown in emotional tasks, such as passive and active avoidance. In particular, mice knockout for ERK1 had a better performance in comparison to wild type mice in both passive and active avoidance tasks. In the present study, in order to investigate the involvement of MAPKs in memory reconsolidation processes we administered immediately after retrieval, different doses of SL327 (an inhibitor of MEK, a kinase that activates both ERK1 and ERK2) both in C57BL/6 (C57) mice and ERK1 mutant mice tested in a fear conditioning task. Systemic administration of SL327 dose-dependently reduced the memory reconsolidation of fear memories in C57 mice. Moreover, SL327 administration impaired memory reconsolidation also in ERK1 mutant mice. Altogether, these results clearly indicate a central role for ERK2 protein in memory reconsolidation processes in mice.