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。     

提取-消退范式中复合刺激对恐惧消退的影响

情绪障碍治疗的关键在于消退条件性恐惧记忆,研究证明基于记忆再巩固的提取-消退范式能有效消除或改写原有的恐惧记忆。本研究将提取-消退范式应用到更复杂的恐惧记忆中,采用多感官复合刺激(声音+图片)作为条件刺激,以皮电反应作为恐惧反应指标,考察采用单个线索(声音或图片)、复合线索(声音+图片)进行提取-消退对条件性恐惧记忆的消退效果有何差异。结果表明:声音线索提取-消退组出现了自发恢复和重建效应,图片提取-消退组只出现了重建效应,复合刺激提取-消退组未出现自发恢复和重建效应。说明由复合刺激线索引发的条件性恐惧,采用复合刺激中的单个较强线索或原有完整线索进行提取-消退,对恐惧记忆的消退效果最好。     

预期错误在复合恐惧记忆提取消退中的作用

基于记忆再巩固理论的提取消退范式被证明是一种有效和颇有前景的消除不良记忆的方法。本研究将预期错误(Prediction Error, PE)应用于提取消退范式中, 采用多感官复合刺激模型(声音 + 图片)作为条件刺激, 以皮电反应作为恐惧反应指标, 考察在提取阶段不同的预期错误设置(无PE、单个负性PE、单个正性PE和多重PE)对条件性恐惧记忆提取消退效果有何差异。结果表明：无PE组和多重PE组出现了恐惧的自发恢复和重建效应, 而负性PE组和正性PE组均没有出现恐惧的自发恢复和重建效应。说明了在对复合恐惧记忆进行提取消退时, 提取阶段适当的PE才能使记忆进入再巩固过程, 随后传统消退达到抑制恐惧返回效果, 提取阶段没有PE或PE量过多都不能达到恐惧消退效果。     

远期恐惧记忆再巩固更新机制的线索选择性特点

已有动物和人类研究均表明, 通过记忆的再巩固更新机制能有效削弱新形成的条件性恐惧记忆(1天), 并且存在线索选择性特点。然而创伤后应激障碍(PTSD)往往在形成相当一段时间后才能得到治疗, 且现实生活中人们通常一次习得对多个线索的恐惧。因此找到针对多线索创伤记忆的有效治疗方法显得尤为重要。目前未有人研究远期恐惧记忆的再巩固更新机制是否存在线索选择性特点。为探究远期恐惧记忆(>7天)的再巩固更新机制是否同样存在线索选择性特点, 本研究采用被试内实验设计, 以皮肤电作为恐惧反应指标, 多个线索作为条件刺激进行恐惧习得, 习得14天后给被试单独呈现一个线索进行恐惧记忆提取, 10分钟后进行消退训练, 24小时后对不同线索进行自发恢复测试。结果显示：未提取线索的自发恢复程度显著高于提取线索。说明远期记忆(14天)的再巩固更新机制同样存在线索选择性特点, 并确认了提取消退作为一种行为手段对远期恐惧记忆再巩固进行干预的有效性, 对临床干预具有一定指导意义。     

条件性恐惧提取消退的性别差异

基于记忆再巩固理论的提取消退范式能够有效地削弱非适应性恐惧记忆。性别差异是个体差异性研究的关键变量, 但在提取消退范式的研究中仍然比较少见关于性别差异的探索。因此本研究以立体几何图形作为条件刺激, 腕部电击作为非条件刺激, 皮肤电反应为恐惧反应指标, 探究提取消退范式在恐惧消退效果上是否存在性别差异。结果表明, 在恐惧自发恢复测试中, 提取消退范式的所有被试都成功抑制了恐惧复发, 但恐惧重建测试中只有女性被试抑制了恐惧复发。这说明, 提取消退范式在抑制恐惧自发恢复方面效果显著, 在恐惧重建上女性的消退效果显著优于男性。     

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。     

预期错误与急性应激对不同强度恐惧记忆提取消退的影响

在条件性恐惧记忆再巩固模型下, 预期错误被证明是引发记忆不稳定的必要条件, 但其在不同强度恐惧记忆下的作用尚不明确。对于高强度可能导致的提取无效, 缺乏相应的探索以寻找解决办法, 而应激(stress)在其中发挥的作用值得探索。本研究考察人类被试中, 预期错误在不同强度恐惧记忆下的作用, 以及提取之后施加外源性应激对于消退进程的影响。结果发现, 对于较弱的恐惧记忆, 单个预期错误提取后消退可显著抑制恐惧自发恢复; 而对于较强恐惧记忆, 单个预期错误不能提取恐惧记忆进入再巩固, 已消退的记忆还会复发; 且在该种情况下, 如果在提取后施加外源性急性应激, 会进一步增大恐惧恢复。     

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。     

认知重评对负性效价的抑制促进条件性恐惧消退

认知重评能有效降低个体对情感刺激的负性情绪体验, 但指导性认知重评在恐惧记忆治疗中效果存在争议。本文将认知重评范式与辨别式条件恐惧反应范式结合, 以效价和US预期值为指标, 探讨指导性认知重评训练对恐惧情绪习得和消退的影响效果。以低认知重评能力个体为被试, 在实验前24 h进行指导性认知重评训练。条件性恐惧任务为期2天, 第一天完成条件性恐惧的习得和消退任务, 第二天完成条件性恐惧的再消退任务。结果显示, 经过重评训练后个体在条件性恐惧任务中的恐惧情绪效价显著较低, 说明认知重评有效降低低认知重评能力个体在急性应激状态下的负性情绪体验。所有被试均成功完成辨别式条件性恐惧的习得和消退任务, 因此重评训练并不削弱个体对危险或者安全信息的辨别能力。但在条件性恐惧的消退过程中, 认知重评指导训练加快了恐惧消退, 且24 h后测得的条件性恐惧程度显著较低, 说明指导性重评提高了条件性恐惧记忆的消退效率, 并减弱了条件性恐惧的消退返回。     

催产素影响条件化恐惧情绪加工的认知机制及神经基础

恐惧是一种与进化密切相关的情绪,对人类的生存与适应具有重要价值。过度的恐惧可能会导致恐惧症、焦虑症和创伤后应激障碍等病理性恐惧的产生。而催产素对各种病理性恐惧的干预和治疗具有重要的价值。因此,研究拟采用行为和fMRI技术,系统探究催产素影响条件化恐惧情绪加工的认知神经机制。重点关注:(1)催产素影响恐惧习得的认知神经机制;(2)催产素影响恐惧记忆巩固的认知神经机制;(3)催产素影响恐惧记忆再巩固的认知神经机制;(4)催产素影响恐惧消退的认知神经机制。这项研究的开展对于探究催产素影响条件化恐惧情绪加工的认知神经机制具有很高的科学价值,对于各种病理性恐惧的干预与治疗也具有重要的应用价值。     

Disrupting reconsolidation: pharmacological and behavioral manipulations

We previously demonstrated that disrupting reconsolidation by pharmacological manipulations "deleted" the emotional expression of a fear memory in humans. If we are to target reconsolidation in patients with anxiety disorders, the disruption of reconsolidation should produce content-limited modifications. At the same time, the fear-erasing effects should not be restricted to the feared cue itself considering that fear generalization is a main characteristic of anxiety disorders. In Experiment I and Experiment I(b), we addressed these issues using a within-subject differential startle fear conditioning paradigm and a test of fear generalization. In Experiment II, we tested whether a behavioral approach targeting the reconsolidation through extinction learning was also effective in weakening the original fear memory. A behavioral procedure is evidently preferred over drug manipulations provided that similar effects can be obtained. Here, the extinction procedure subsequent to retrieval did not "erase" the emotional expression of the fear memory as the retrieval techniques (i.e., reminder shocks and reacquisition) unveiled a return of the startle fear response to the fear-relevant stimuli. In contrast, β-adrenergic receptor blockade during reconsolidation selectively deleted the fear-arousing aspects of the memory (i.e., startle fear response) along with its category-related information. The pharmacological manipulation rendered the core memory trace too weak to observe fear generalization after successful reacquisition. Hence, relearning following the disruption of reconsolidation seems to be qualitatively different from initial learning. Our findings demonstrate that disrupting reconsolidation by pharmacological manipulations, although selective, undermines the generalization of fear, a key feature of anxiety disorders.     

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。     

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.     

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.     

Epigenetic alterations in the lateral amygdala are required for reconsolidation of a Pavlovian fear memory

Epigenetic mechanisms have been widely implicated in synaptic plasticity and in memory consolidation, yet little is known about the role of epigenetic mechanisms in memory reconsolidation processes. In the present study, we systematically examine the role of histone acetylation and DNA methylation in the reconsolidation of an amygdala-dependent Pavlovian fear memory. We first show that the acetylation of histone 3 (H3), but not histone 4 (H4), is regulated following auditory fear memory retrieval in the lateral nucleus of the amygdala (LA). We next show that histone deacetylase (HDAC) inhibition in the LA enhances both retrieval-induced histone acetylation and reconsolidation of an auditory fear memory. Conversely, inhibition of DNA methytransferase (DNMT) activity in the LA significantly impairs both retrieval-related H3 acetylation and fear memory reconsolidation. The effects of HDAC and DNMT inhibitors on fear memory reconsolidation were observed to be time-limited and were not evident in the absence of memory reactivation. Further, memories lost following DNMT inhibition were not observed to be vulnerable to spontaneous recovery, reinstatement, or to a shift in testing context, suggesting that memory impairment was not the result of facilitated extinction. Finally, pretreatment with the HDAC inhibitor was observed to rescue the reconsolidation deficit induced by the DNMT inhibitor. These findings collectively suggest that histone acetylation and DNA methylation are critical for reconsolidation of fear memories in the LA.     

Systemic and intrahippocampal administrations of the glucocorticoid receptor antagonist RU38486 impairs fear memory reconsolidation in rats

Reconsolidation is the process by which previously consolidated memories are stabilized after retrieval. Several lines of evidence indicate that glucocorticoids modulate distinct phases of learning and memory. These effects are considered to be mediated by mineralocorticoid receptors and glucocorticoid receptors (GRs), which display a high concentration and distinct distribution in the hippocampus. The role of glucocorticoid system in fear memory reconsolidation is the subject of some controversy. Moreover, we found no studies that assessed the role of hippocampal GRs in fear memory reconsolidation. Here, we investigated the effect of GR blockade on fear memory reconsolidation in rats. Rats were trained and tested in an inhibitory avoidance task. Intrahippocampal or systemic administration of the GR antagonist RU38486 immediately following memory reactivation produced a deficit in post-retrieval long-term memory that persisted over test sessions, and memory did not re-emerge following a footshock reminder. These results indicate that hippocampal GRs are required for reconsolidation of fear-based memory.     

Distinctive roles for amygdalar CREB in reconsolidation and extinction of fear memory

Cyclic AMP response element binding protein (CREB) plays a critical role in fear memory formation. Here we determined the role of CREB selectively within the amygdala in reconsolidation and extinction of auditory fear. Viral overexpression of the inducible cAMP early repressor (ICER) or the dominant-negative mCREB, specifically within the lateral amygdala disrupted reconsolidation of auditory fear memories. In contrast, manipulations of CREB in the amygdala did not modify extinction of fear. These findings suggest that the role of CREB in modulation of memory after retrieval is dynamic and that CREB activity in the basolateral amygdala is involved in fear memory reconsolidation.