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。     

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。     

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。     

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。     

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。     

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。     

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。     

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。     

疼痛恐惧的神经机制及其消退

疼痛恐惧是疼痛基础和临床研究中的一个重要课题。个体对疼痛信息产生过度警觉,诱发不恰当的回避行为,扰乱机体的正常功能,加剧疼痛的现象即为疼痛恐惧。疼痛恐惧可影响个体的疼痛感知以及疼痛相关的注意和回避行为,且在慢性疼痛(如慢性肌骨骼疼痛)的发展、维持个体正常生理功能的丧失中起着重要作用。疼痛恐惧的形成与表达涉及杏仁核、海马、背侧前扣带回皮层、和前额叶皮层等脑区的参与。当前的疼痛恐惧消退的心理-行为干预方法可在疼痛恐惧加工的不同阶段(巩固、再巩固和消退)消退个体的疼痛恐惧。然而,由于恐惧记忆形成过程较为复杂并受多种因素影响,疼痛恐惧记忆消退方法效果较不稳定,其基础研究与临床应用之间仍存在较大的鸿沟。将来研究有必要考虑到疼痛恐惧形成环境的差异以及个体人格特质/心理状态的差异,逐步完善相关消退方法并将其引入临床镇痛,以期帮助患者弱化、擦除甚至改写困扰他们的疼痛恐惧,从而缓解甚至消除病患的疼痛。     

干预条件性恐惧记忆表达的相关影响因素分析

创伤后应激障碍是个体经历严重应激后形成的一种焦虑障碍, 对其治疗的关键是熄灭由创伤应激导致的条件性恐惧记忆。条件性恐惧的动物模型研究发现恐惧记忆一旦获得后就难以熄灭, 容易复发, 而这一点也是PTSD的关键临床症状表现之一。因此, 如何更好更持久地熄灭恐惧记忆, 是一个具有重要理论和临床意义的研究热点。本文围绕促进恐惧记忆的长久消退和破坏恐惧记忆的再巩固两方面的行为或药理干预及机制进行综述。针对本文所述的几种基础实验处理, 临床上可以研究治疗创伤后应激障碍的相应疗法。     

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.     

The neurobiology of fear memory reconsolidation and psychoanalytic theory

Advances in both experimental neuroscience and psychoanalytic theory and technique have made it possible to consider mechanisms by which psychodynamic psychotherapies might have an impact at the cellular and molecular level. Here potential analogies are drawn between (1) the mechanisms and results of blocking the reconsolidation of conditioned fear memories in the laboratory and (2) several key aspects of psychoanalytic process. A review of the biology of conditioned fear memory, including differences between extinction and inhibition of reconsolidation, indicates that this biology may have relevance to various ways in which psychoanalytic therapy is effective. The ideas proposed here might lead to further experimental attempts to understand the molecular biology of psychoanalysis.     

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.     

Administration of corticosterone after memory reactivation disrupts subsequent retrieval of a contextual conditioned fear memory: dependence upon training intensity

Reactivation of stabilized memories returns them to a labile state and causes them to undergo extinction or reconsolidation processes. Although it is well established that administration of glucocorticoids after training enhance consolidation of contextual fear memories, but their effects on post-retrieval processes are not known. In this study, we first asked whether administration of corticosterone after memory reactivation would modulate subsequent expression of memory in rats. Additionally, we examined whether this modulatory action would depend upon the strength of the memory. We also tested the effect of propranolol after memory reactivation. Adult male Wistar rats were trained in a fear conditioning system using moderate (0.4 mA) or high shock (1.5 mA) intensities. For reactivation, rats were returned to the chamber for 90 s 24h later. Immediately after reactivation, rats were injected with corticosterone (1, 3 or 10mg/kg) or vehicle. One, 7 and 14 days after memory reactivation, rats were returned to the context for 5 min, and freezing behavior was scored. The findings indicated that corticosterone when injected after memory reactivation had no significant effect on recall of a moderate memory, but it impaired recall of a strong memory at a dose of 3mg/kg. Propranolol (5mg/kg) given after the reactivation treatment produced a modest impairment that persisted over three test sessions. Further, the results showed that corticosterone, but not propranolol deficit was reversed by a reminder shock. These findings provide evidence that administration of glucocorticoids following memory reactivation reduces subsequent retrieval of strong, but not moderate, contextual conditioned fear memory likely via acceleration of memory extinction. On the other hand, propranolol-induced amnesia may result from blockade of reconsolidation process. Further studies are needed to determine the underlying mechanisms.     

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.     

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。     

Face your fears: attenuating remote fear memories by reconsolidation-updating

Traumatic events generate some of the most enduring memories, yet little is known about how long-lasting fear memories can be attenuated. In this review, we collect the surprisingly sparse evidence on remote fear memory attenuation from both animal and human research. What is becoming apparent is twofold: although remote fear memories are more resistant to change compared with recent ones, they can nevertheless be attenuated when interventions are targeted toward the period of memory malleability instigated by memory recall, the reconsolidation window. We describe the physiological mechanisms underlying remote reconsolidation-updating approaches and highlight how they can be enhanced through interventions promoting synaptic plasticity. By capitalizing on an intrinsically relevant phase of memory, reconsolidation-updating harbors the potential to permanently alter remote fear memories.     

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.