心理科学进展, 2019, 27(2): 268-277 doi: 10.3724/SP.J.1042.2019.00268

研究前沿

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

曹杨婧文, 李俊娇, 陈伟, 杨勇, 胡琰健, 郑希付,

华南师范大学心理学院; 华南师范大学心理应用研究中心;广东省心理健康与认知科学重点实验室, 广州 510631

The effect of retrieval intervention paradigm to conditioned fear extinction and its neural mechanism

CAOYANG Jingwen, LI Junjiao, CHEN Wei, YANG Yong, HU Yanjian, ZHENG Xifu,

Guangdong Key Laboratory of Mental Health and Cognitive Science, Guangzhou 510631, China

通讯作者: 郑希付, E-mail: zhengxifu@m.scnu.edu.cn

第一联系人:

曹杨婧文和李俊娇为共同第一作者。

收稿日期: 2018-04-10   网络出版日期: 2019-02-15

基金资助: * 国家自然科学基金项目.  31371057
国家社会科学基金重大项目.  14ZDB259
广东省自然科学基金项目.  2014A030310303
幸福广州心理服务与辅导基地资助.  2014A030310303

Received: 2018-04-10   Online: 2019-02-15

摘要

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。

关键词: 条件性恐惧 ; 记忆再巩固 ; 提取干预

Abstract

The memory reconsolidation theory holds that consolidated memories can be reactivated into an unstable state again, which is called the reconsolidation process. During this period, the activated memories are susceptive to new information and therefore, the interruption of it can update or eliminate original memories. Behavioral or pharmacological interventions after memory reactivation are proved to be an effective way to extinguish fear memories and prevent relapse. The behavioral intervention, which is the so-called retrieval-extinction paradigm can eliminate conditioned fear through applying extinction training during the reconsolidation time window. The neural mechanisms of this effect, however, are still largely unknown. Based on reviewing present studies in animals and humans, we concluded the critical brain areas which were proved to be playing an important part in retrieval extinction process and their effect mechanisms, including hippocampus, prefrontal cortex and amygdala. Furthermore, we summarized the controversial points in theories and manipulations in order to provide insights for future explorations.

Keywords: conditioned fear ; reconsolidation ; retrieval intervention

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本文引用格式

曹杨婧文, 李俊娇, 陈伟, 杨勇, 胡琰健, 郑希付. (2019). 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 . 心理科学进展, 27(2), 268-277

CAOYANG Jingwen, LI Junjiao, CHEN Wei, YANG Yong, HU Yanjian, ZHENG Xifu. (2019). The effect of retrieval intervention paradigm to conditioned fear extinction and its neural mechanism. Advances in Psychological Science, 27(2), 268-277

传统的记忆巩固理论认为新形成的记忆在初期不稳定, 但一旦巩固下来, 就不易受到破坏或改变。然而经研究发现, 记忆还存在再巩固的过程, 即记忆的形成不是一次性的, 已巩固的记忆被激活后会重新回到不稳定状态, 而只有新的蛋白质合成才能使得记忆再次稳定下来, 即所谓的记忆再巩固过程, 整个过程大概持续6个小时(Dudai, 2004; Nader, 2003; Nader, Schafe, & Doux, 2000; Sara, 2000; Schiller et al., 2010)。这为破坏、改写或者擦除创伤性记忆, 进而治疗相关负性情绪障碍带来了曙光。基于记忆再巩固的理论, 近年来出现了条件性恐惧记忆的提取干预范式, 其原理在于:激活已经巩固的恐惧记忆后, 在记忆再巩固时间窗(reconsolidation window)内, 通过药物、行为等手段干预破坏记忆再巩固过程, 以达到改变原有恐惧联接或记忆更新的目的, 从而有效阻止恐惧复发(Schiller, Kanen, Ledoux, Monfils, &Phelps, 2013)。大量实验证明了提取干预范式在消除恐惧记忆以及阻止恐惧返回方面的有效性(Agren et al., 2012; Li et al., 2017; Liu et al., 2014; Monfils, Cowansage, Klann, & Ledoux, 2009; Schiller et al., 2013; Schiller et al., 2010; Soeter & Kindt, 2015; Zeng et al., 2014), 但也有一些研究对该范式的效果提出了质疑(Costanzi, Cannas, Saraulli, Rossi- Arnaud, & Cestari, 2011; Goode, Holloway-Erickson, & Maren, 2017; Chan, Leung, Westbrook, & Mcnally, 2010)。基于提取干预范式在消退恐惧记忆上的优势, 以及在创伤后应激障碍(Post-Traumatic Stress Disorder, PTSD)、焦虑障碍(Anxiety Disorder)等临床疾病治疗上的前景, 近年来该领域的研究不断涌现, 但其背后的神经机制尚不明晰。本文将从人类研究和动物研究两方面, 回顾和总结提取干预范式作用于恐惧记忆消退的神经机制。

1 条件性恐惧的传统消退范式

条件性恐惧记忆模型能够阐明PTSD动物对恐惧性刺激的情绪记忆编码过程, 因此常被用来研究恐惧记忆的获得、保持与消退过程(Kim & Jung, 2006; 安献丽, 郑希耕, 2008)。该范式以巴甫洛夫的条件反射为基础, 首先对动物进行厌恶性刺激(非条件刺激, unconditioned stimulus, US,如电击、噪音)与中性刺激(条件性刺激, conditioned stimulus, CS, 如声音、灯光或环境)进行匹配训练(CS-US), 之后当动物再接触这个CS时, 便会表现出条件性恐惧反应。而当条件性线索反复单独呈现, 却不匹配US时, 动物先前习得的对CS的条件性恐惧反应会逐渐消失(CS-no US), 这便是条件性恐惧的传统消退范式——消退训练的原理。临床上针对创伤后应激障碍、恐惧症等患者的暴露疗法, 即以消退训练为其基本原理(Hofmann, 2008)。

尽管动物对CS的恐惧反应能够通过消退训练得到抑制, 但这种已被抑制的条件性恐惧反应在多种情况下可能被重新诱发, 如续新(renewal)、快速重新获得(reacquisition)、自发恢复(spontaneous recovery)、重建(reinstatement)等(Myers & Davis, 2002)。传统的消退并没有改变之前已有的条件性恐惧记忆(CS-US), 而是形成了一种新的消退记忆, 即抑制性记忆(CS-noUS), 两者相互竞争(Bouton, García-gutiérrez, Zilski, & Moody, 2006), 个体的行为表达是两种记忆痕迹竞争的结果。因此消退后的记忆容易复发, 这也是使用暴露疗法进行临床治疗的主要问题。如何更好更持久地消退恐惧记忆, 一直是研究者们关注的热点(曾祥星, 向燕辉, 杜娟, 郑希付, 2014)。

2 条件性恐惧的提取干预范式

近年来, 记忆再巩固理论再次回到研究者们的视野, 为解决恐惧消退存在的问题提供了新的思路。记忆再巩固理论认为, 当记忆线索出现时, 记忆有可能被重新激活(即提取)进入不稳定状态, 而对新信息再次表现出敏感。记忆的再巩固并不是记忆巩固的重复, 记忆巩固仅发生在首次学习之后, 而记忆再巩固则发生在已巩固的记忆被激活之后, 即两者之间存在时间上的分离。除此之外, 参与两个阶段的核团和分子存在特异性, 即两者在神经机制上也有所区别(吴艳, 李勇辉, 隋南, 2009; 曾祥星, 杜娟, 王凯欣, 郑希付, 2015)。

提取已巩固的恐惧记忆会引发两种近乎对立的过程:再巩固和消退。如果提取线索达到某些条件, 原先的恐惧记忆会充分激活并去稳定(destabilization)。研究证明记忆被重新提取后, 通过在再巩固的时间窗里对不稳定的记忆进行药理学的干预, 能抑制再巩固过程所需蛋白质的合成, 而该记忆在随后的测试中则不能被提取, 这表明记忆可能已被擦除或被持久抑制(Duvarci & Nader, 2004; Nader et al., 2000; Sara, 2000)。因此, 通过给予药理制剂去调控参与记忆再巩固的神经分子, 可以改变记忆痕迹的分子组成, 阻断记忆的再巩固, 消退对CS的恐惧反应。Kindt, Soeter和Vervliet (2009)首先对人类被试在记忆再巩固阶段使用β受体抑制剂心得安(Propranolol)进行干预, 成功消退了恐惧记忆。

因为大部分阻断再巩固的药物对人体有潜在的伤害, 所以不能轻易应用于临床病人。心得安等药物对人类虽然不具有毒性, 但是如果能用非药物的方式达到类似的效果, 则更具有优势。故研究者们开始探索使用非药物的行为干预手段破坏原始记忆的可能性。Monfils等(2009)首先在动物身上使用行为干预即消退训练, 其在再巩固时间窗内应用行为消退成功破坏了恐惧记忆, 阻止了恐惧记忆的自发恢复和重建; 而在再巩固时间窗之外则无破坏记忆的效果。

Schiller等(2010)随后将提取后实施行为消退的范式——提取消退范式, 应用于人类, 结果显示原始恐惧成功消退而且没有出现复发, 其效果持续一年以上。该研究呈现了一个标准的三天的研究范式:第一天为条件性恐惧习得阶段; 第二天为记忆提取-消退阶段, 先通过呈现一个独立的提取试次——不跟随电击的CS+, 激活原有的恐惧记忆使之进入再巩固, 10分钟后, 即在再巩固时间窗之内进行消退训练, 即呈现一系列CS而不跟随电击; 第三天为恐惧复发测试阶段。

该发现表明, 在再巩固的时间窗里使用行为方式改写情绪性记忆是可行的, 且能更为安全地阻止人的条件性恐惧反应的复发, 具有很好的临床应用前景。有研究者将该范式用于声音引起的负性记忆消退, 也得到了一致性结果(Oyarzún et al., 2012)。也有人比较了行为干预和药物干预两种方式, 发现两者在消退恐惧记忆上的效果是类似的(Ferrer Monti et al., 2017)。我们实验室是国内最早引入提取消退这一再巩固行为干预范式的实验室之一, 并对提取消退范式的边界条件进行探索。我们的研究表明, 提取消退范式可以成功消退恐惧记忆并阻止复发(Li et al., 2017; Zeng et al., 2014; 陈伟 等, 2018; 庄楚群 等, 2017)。虽然陆续有一些实验室验证了提取消退范式的作用(Agren et al., 2012; Monfils et al., 2009; Schiller et al., 2010), 但是目前对于行为干预的提取消退范式的有效性仍存在一些争议(Costanzi et al., 2011; Kindt & Soeter, 2013; Chan et al., 2010)。

提取的记忆是否能进入再巩固有赖于原始记忆和记忆提取的条件, 即所谓的记忆再巩固的“边界条件” (Elsey & Kindt, 2017a; Sevenster et al., 2013)。现有研究表明, 这些边界条件包括原始记忆的强度、提取线索呈现时间、提取线索的类型, 以及预期错误等(Beckers & Kindt, 2017; Besnard, Caboche, & Laroche, 2012; Sevenster et al., 2013)。特别是在记忆提取阶段, 操作程序上的细微差别都会影响到是否能成功激活记忆进入不稳定状态, 从而决定了最终能否成功消退记忆并阻止复发。因而探讨记忆再巩固的边界条件研究目前成为提取干预范式研究的重点与热点问题。而对提取干预范式的神经机制的研究, 能促进对记忆再巩固过程的认识, 从而推进对再巩固边界条件的研究。

3 恐惧记忆提取干预范式的神经机制:人类研究

3.1 杏仁核

杏仁核是形成消退记忆的必不可少的脑区, 恐惧记忆的形成和消退都依赖于杏仁核的参与, 但是这并不意味着消退就一定擦除了恐惧记忆在杏仁核上的痕迹。Agren等(2012)将22名被试分为两组, 实验组在再巩固时间窗内进行消退, 对照组在再巩固时间窗外进行消退(相当于传统消退范式), 结果发现对照组的被试在第三天杏仁核被激活并出现了恐惧的重建。相对于对照组, 实验组的被试则有效地减少了由CS引起的杏仁核的激活并且抑制了之后恐惧的表达。他们团队在18个月后对之前的被试进行追踪, 让被试再次完成快速重新获得测试。结果发现, 和对照组相比, 实验组的被试更少地出现恐惧返回的现象。与此同时, 对照组第三天的杏仁核激活情况能够预测18个月后对照组恐惧记忆的返回情况(Björkstrand et al., 2015)。

Schiller等(2013)的一项fMRI研究结果也证明了相对于控制组, 进行提取干预的实验组在消退阶段能更好地减少杏仁核的激活。另一项研究表明, 提取消退范式还可以消退临床患者的对蜘蛛的恐惧记忆, Johannes及其同事利用提取消退范式使得蜘蛛恐怖症患者减少了对蜘蛛的恐惧, 效果至少可以维持6个月; 提取消退组相对于对照组更能够持续地抑制杏仁核的活动(Björkstrand et al., 2016, 2017)。这暗示了提取干预范式或许是以杏仁核为基础的, 可以消退那些依赖于杏仁核的记忆。这和Nader等(2000)对大鼠的研究揭示的抑制基底杏仁核的蛋白质合成能成功阻止恐惧记忆的再巩固的结论, 以及Monfils等(2009)等人提出的提取干预范式与杏仁核的可塑性有关的看法相吻合。

3.2 腹内侧前额叶

腹内侧前额叶皮层(ventromedial prefrontal cortex, vmPFC)被认为是情绪反应抑制的关键脑区, 同时也参与到决策、自我控制、道德判断等任务中。vmPFC在个体根据特定的社会情境控制和调节自己的情绪性反应过程中起着重要作用; 在发育早期存在腹内侧前额叶缺陷的个体, 在成年后会表现出反社会行为和道德判断功能损害(Boes et al., 2011)。

在Schiller及其团队的fMRI实验中, 让被试于第一天习得以下规律:两个不同CS+均匹配电击, 一个CS-不匹配电击。在第二天, 其中一个CS+会被提取, 而另一个不被提取, 这意味着只有提取的CS+才可能经历再巩固过程, 而未被提取的CS+没有进入再巩固, 只是进行了传统消退。对脑功能成像的数据进行分析发现, 在恐惧消退过程的前半段, 提取组相对于未提取组显著减少了vmPFC的参与。而且只有未被提取的CS+在消退时涉及了vmPFC的参与, 有提取的CS+以及CS-的vmPFC的参与较少。这似乎说明与传统消退范式不同, 在提取消退范式中, vmPFC参与的减少反而能更有利于消退, 更能阻止恐惧记忆的自发恢复。除此之外, 对杏仁核和腹内侧前额叶的功能连接分析发现, 控制组两个脑区之间的功能连接强于提取消退组(Schiller et al., 2013)。Agren等人(2012)的研究也表明, 提取消退过程中vmPFC与杏仁核的匹配或联接是缺失的。这些研究结果说明提取消退和传统消退在消退过程中虽然都有杏仁核的参与, 但是杏仁核可能参与不同的神经环路。有研究者指出部分前额叶的参与和持续性地减少条件性防御行为相关(Koenigs et al., 2008; Phelps, Delgado, Nearing, & Ledoux, 2004), 这暗示了减少vmPFC的参与或许能够改变消退或者是暴露的本质, 从而更好地阻止之后的防御性反应。

如前文所提起的vmPFC的作用, 在提取消退过程中vmPFC参与的减少, 可能是削弱了vmPFC对杏仁核的监控和调节能力, 从本质上改变消退的性质, 更新了记忆。但是, 这一研究并不能说明vmPFC是区分提取消退和传统消退的特异性脑区。而且大脑中涉及监控调节能力的脑区不止一个, 例如负责认知监控、工作记忆和元认知的背侧前额叶皮质(dorsal prefrontal cortex, dPFC)等, 其作用同样值得探索。

Kroes等人(2016)的研究可以视为对该问题的补充, 其实验表明, 在实施消退训练之前, 让被试口服心得安, 可以有效减弱恐惧反应并阻止恐惧复发。Kroes等人发现, 在消退过程中, 背内侧前额叶皮质(dorsal medial prefrontal cortex, dmPFC)的激活程度不断降低, 其进一步推测该模式的作用机制是一方面通过降低dmPFC的激活而减弱了恐惧记忆的提取。

3.3 海马

海马和vmPFC以及杏仁核均有关联, 担任着调节恐惧表达的任务, 而且情境对恐惧消退而言是十分重要的, 而海马则与涉及环境线索的条件性恐惧相关(Orsini & Maren, 2012; Tovote, Fadok, & Lüthi, 2015)。

Milad等(2009)在对创伤记忆保留的被试和那些成功消退创伤的被试进行记忆提取时发现, 相对于成功消退的被试, 那些未成功消退的被试在记忆被激活时海马区域的激活程度更低。在Kroes等(2016)的实验中, 利用在消退训练之前使用心得安来破坏记忆的再巩固, 实验结果发现, 随着被试对CS+的恐惧逐渐减少, 海马区域被激活强度变得越高, 这说明海马或许能够提供一种“环境安全”的信号, 从而能够减少恐惧。但是在提取干预范式下, 对海马这一脑区探索的人类研究较少, 需要进一步探究海马在提取干预范式中扮演的角色。

3.4 其他脑区

根据Foa的情绪加工理论(Emotion Processing Theory, EPT)理论, 恐惧情绪得以缓解的两大必要条件, 一是恐惧的记忆要先被唤醒, 二是在记忆被唤醒之后要有新信息的出现(Foa & Kozak, 1986)。如前文所述, 提取干预范式存在一些边界条件, 而预期错误(prediction error)就是一个与新信息相关的至关重要的边界条件。在Rescorla- Wagner预期错误模型中, 由于原本预期会出现的US实际上没有出现, 这种对行为结果的期望与实际产生的结果之间的不匹配影响了CS的连接度(associability, 即进入新连接的能力) (Rescorla & Wagner, 1972)。近年来大量研究表明, 记忆提取阶段的预期错误是记忆能成功提取进入再巩固的关键(Asem, Schiffino, & Holland, 2015; Sevenster et al., 2013)。只有出现了预期错误(例如原来CS+匹配电击, 现在不再匹配), 记忆才具有更新的动力, 如果没有预期错误, 则记忆为“仅提取”, 预期错误是记忆去稳定(destabilization)的必要条件(Beckers & Kindt, 2017; Elsey & Kindt, 2017b)。一般认为, 不同类型记忆的预期错误的神经信号存在差异, 例如奖赏学习记忆(reward-learning memory)、条件性恐惧记忆(fear conditioning memory)等。在正强化条件性学习(appetitive conditioning)模型中, 多巴胺信号和预期错误息息相关。尽管许多研究者认为在消退时使得负强化消失也是一种正强化条件性学习模型, 但是实际上, 在厌恶性条件学习中很难观察到多巴胺和预期错误的关系(Li & Mcnally, 2014)。对条件性恐惧而言, 腹侧纹状体(ventral striatum, vStr)的信号被认为能够反映预期错误的出现(Schiller, Levy, Niv, Ledoux, & Phelps, 2008)。为了验证预期错误在恐惧记忆提取干预中的作用, Kroes等(2016)通过分析腹侧纹状体的激活强度和恐惧反应的皮肤电信号之间的关系, 发现消退过程中的vStr激活强度与第三天的恐惧自发恢复或重建没有显著相关。但是由于Kroes等人并没有直接设置预期错误, 只是分析了腹侧纹状体的激活程度, 而且因为实验中没有操纵预期错误, 该脑区的激活不能说明一定是由预期错误导致的。因此, 尽管行为研究已经证明预期错误在提取干预范式中的关键性作用, 但是预期错误开启记忆再巩固的神经机制仍是未知的。例如, 条件性恐惧记忆的预期错误信号体现在哪个脑区, 与恐惧消退或复发的关系怎样等等, 都还需要更多脑成像研究的探索。

4 恐惧记忆提取干预范式的神经机制:动物研究

4.1 杏仁核

一般认为, 在传统的恐惧消退实验中, 中央杏仁核在条件性恐惧的习得和表达上至关重要。而光遗传学的研究表明, 在外侧杏仁核中存在着恐惧学习神经元和消退学习神经元的分离(Herry et al., 2008)。前文在以人类为被试的研究中也有发现杏仁核不同的部分或许在再提取干预过程中扮演了不同的角色, 这在人类实验中是难以验证的, 动物实验正好弥补了这一缺点。

Díaz-Mataix的团队(2014)发现在提取之后在大鼠杏仁核中部注射蛋白质合成抑制剂茴香霉素(anisomycin), 能够阻止恐惧记忆进入再巩固。该实验通过改变提取阶段CS-US之间的时间间隔, 证明了时间性的预期错误(Temporal Difference, TD)也可以开启记忆再巩固。并在提取后把大鼠分为四组, 其中两组分别在外侧杏仁核和中央杏仁核部位注入茴香霉素, 另两组为安慰剂组, 分别在外侧杏仁核和中央杏仁核注入安慰剂。结果发现在外侧杏仁核被注入蛋白质合成抑制剂的小鼠在提取24小时之后的僵直反应显著低于其他三组。介于外侧杏仁核中的消退学习神经元只对消退了的刺激有反应, 而且还与内侧前额叶(medial prefrontal cortex, mPFC)相连接(Orsini & Maren, 2012)。这似乎也说明了在提取干预范式中, 无论是动物被试实验还是人类被试实验, 杏仁核- vmPFC神经环路所起的作用是一致的

此外, 该实验发现这种由时间性预期错误开启的再巩固是依赖于外侧杏仁核而非中央杏仁核内蛋白质的合成。为了证明他们的结论, 他们对提取导致的锌指蛋白225 (zinc finger protein 225, zif268)的活性变化进行测量。Zif-268能够很好地反映出由于恐惧记忆再巩固而引起的突触可塑性的变化。结果发现, 相对于在大鼠的记忆未被提取以及仅用原始CS-US进行提取的两组而言, 利用缩短CS-US之间时间间隔进行提取的小组, 外侧杏仁核的Zif-268显著活跃于另外两组。研究者认为对厌恶刺激的预期错误的探测是触发杏仁核中厌恶刺激再巩固的基本机制。杏仁核或许参与了对预期错误的探测。这暗示了杏仁核会对不规律的时间变化或是预料之外的事情做出反应, 并相应地显示出一些神经生理上的活动变化。

4.2 腹内侧前额叶

研究者使用动物模型, 研究vmPFC在记忆提取过程中的作用。Quirk等人的研究发现, vmPFC这一脑区的损伤总体上对消退训练的学习没有影响, 但是却影响了消退训练记忆的保持(Quirk, Russo, Barron, & Lebron, 2000)。Milad和Quirk (2002)进一步研究发现, 对于那些没有接受过消退训练的大鼠而言, 在呈现CS的同时, 刺激其vmPFC区域, 它的恐惧表达也减弱了, 种种迹象表明, vmPFC或许只是抑制了恐惧的表达。

边缘前皮层(prelimbic cortex, PL)作为vmPFC的一个亚皮层, 是恐惧表达和复发的重要脑区, 并不参与消退记忆的形成和巩固(Laurent & Westbrook, 2009)。Do-monte, Quiñones-laracuente和Quirk (2015)利用光遗传技术对大鼠的c-Fos细胞(早期立即基因的一种, 用以标记该脑区是否被激活)进行研究发现, 对恐惧记忆提取的神经环路会随着时间的变化而发生变化:在习得后早期(6 h)对大鼠的恐惧记忆进行提取, 发现主要依赖于边缘前皮层-基底外侧杏仁核(PL-BLA, basolateral amygdala)环路, 而随着时间的变化(24 h, 7 d)则会逐渐转向边缘前皮层-丘脑室旁核(PL-PVT, paraventricular nucleus of the thalamus)环路。这表明当恐惧记忆产生之后, 检索恐惧记忆的大脑回路会随着时间推移发生改变。Penzo等人(2015)进一步对这一机制进行了研究, 发现PVT的神经元能对中央杏仁核区域储存恐惧记忆的神经元起作用, 调控恐惧记忆的加工, 这种活性来自于大脑的神经营养因子(brain-derived neurotrophic factor, BDNF)。

在解剖上, 边缘前皮层除了接受来自外侧杏仁核的投射, 还接受来自海马与听觉皮层的投射, 杏仁核与海马的共同投射使边缘前皮层区的神经元兴奋(Ishikawa & Nakamura, 2003), 提示边缘前皮层可能是通过整合来自不同区域的信号产生一段持续的反应。他们的研究也阐述了前额叶皮层在提取恐惧范式中的重要性。除此以外, 该实验证明背侧丘脑中线(dMT)会影响习得较久(至少24 h)后的提取, 并促进恐惧记忆的保留。

4.3 海马

一般认为, 短时记忆储存于海马, 记忆经过巩固过程进入长期记忆之后即转移到大脑皮层。以往研究发现, 对长时恐惧记忆直接进行消退无法达到令人满意的效果, 而提取干预范式则有更好的效果(Schiller et al., 2010), 这可能是因为提取干预范式能够将长时恐惧记忆提取到短时记忆中进行干预, 而传统消退范式并不能。

Debiec, Ledoux和Nader (2002)的一项研究表明, 依赖于海马的情境恐惧记忆在被提取后也可以通过被注射入海马的蛋白质合成抑制剂所破坏从而引起遗忘。该研究进一步发现, 即使是在习得后45天以后再进行提取, 遗忘效应依旧存在。这提示了对依赖于海马的记忆的重新激活引起了对海马的再次依赖。但是Ishii等(2012)的一项研究结果则表明提取后进行消退训练无法更新依赖于海马的情境条件性恐惧记忆。目前而言, 对于提取干预范式能否更新依赖于海马的记忆尚存争议。

Gräff等人(2014)在对消退大鼠遥远恐惧记忆研究时发现, 提取干预这种治疗方法对减少遥远记忆束手无策。他们发现这是因为成功的提取干预范式会引起由组蛋白去乙酰化酶2 (Histone Deacetylase 2, HDAC2)调节的海马部分神经元可塑性的变化, 但是这个过程在遥远记忆中是缺失的。在随后的实验中, 他们发现在再巩固时间窗内对海马区域注射HDAC2定向抑制剂能够消退遥远恐惧记忆。这至少说明HDAC2定向抑制剂能够在提取消退训练不足以更新记忆时起作用。

在上述动物实验中, 对于提取干预范式能不能更新依赖于海马的恐惧记忆存在矛盾的结果, 这可能是因为缺乏对提取干预范式的边界条件的探索, 导致有部分实验无法对原来的条件性恐惧记忆进行有效提取, 没有经历再巩固过程导致。同时也有可能是因为海马在消退学习中有着双重作用, 它既能抑制也能促进恐惧的表达。但是Gräff等人的实验提示我们, 在提取干预范式中, 海马这一脑区可能与遥远恐惧记忆有关。

5 总结与展望

无论是动物实验还是人类实验都显示, 条件性恐惧记忆的提取干预范式和传统消退范式之间的不同主要体现在前额叶皮层上, 目前发现的有腹内侧和背外侧前额叶皮层。毋庸置疑腹内侧前额叶在提取干预过程中起着重要的作用, 但是它是否是在条件性恐惧记忆中提取干预范式区别于传统消退范式的特异性脑区, 还有没有其他更重要的特异性脑区, 以及它和其他脑区是如何联系的等, 这些都还需要大量同类研究的验证和探索。再者, vmPFC在提取过程中的作用也是值得探讨的。在今后的研究中, 我们还可以关注以下几个方面。

5.1 条件性恐惧记忆提取干预范式作用的神经环路研究

已有研究证明, 杏仁核-前额叶皮层环路在条件性恐惧的提取干预范式中起到了重要的作用(Schiller et al., 2013)。但目前关于神经环路的研究还局限在杏仁核-腹内侧前额叶环路, 而消退的过程还与诸多的脑区相关, 例如前扣带回(ACC)、腹侧纹状体(vStr)、尾状核(Caudate)、脑岛(Insular)、背外侧前额叶(dlPFC)等。Agren等(2012)发现没有进入再巩固的对照组的杏仁核与脑岛、海马以及中线前扣带回功能连接强于成功进行了提取消退的实验组。很多fMRI研究都发现背侧前扣带回(dorsal Anterior Cingulate Cortex, dACC)的激活与条件性刺激有关(Cheng, Knight, Smith, Stein, & Helmstetter, 2003; Knight, Smith, Cheng, Stein, & Helmstetter, 2004; Milad et al., 2007; Morris et al., 1998; Sehlmeyer et al., 2011)。Fullana和Sehlmeyer都发现无论在恐惧习得还是消退时, dACC都会被激活(Fullana et al., 2016; Fullana et al., 2018; Sehlmeyer et al., 2009)。dACC有可能是从前脑岛接受了被试的认知、情感以及身体状态的信号, 从而促进了自主行为反应的稳定(Critchley, 2009)。Fullana等人的一项元分析研究发现脑岛也参与了消退学习(Fullana et al., 2018)。而且脑岛和前扣带回之间的强连接和负性反应状态(例如, 恐惧预期)的激活密切相关(Etkin, Egner, & Kalisch, 2011; Medford & Critchley, 2010)。

因而我们需要更多的完善脑区间功能连接和神经环路的研究, 澄清脑区间协同作用的机制, 为区分提取干预范式和传统消退范式提供更多的角度, 从而探讨提取干预范式的有效性的问题。另外, 目前研究主要探究的是提取之后的消退过程的神经机制, 缺少对提取过程的神经机制的探索。对提取过程的神经机制的探索有利于澄清提取干预范式的边界条件的作用机制。

5.2 条件性恐惧记忆再巩固边界条件的神经机制研究

如前文所述, 恐惧记忆提取后能否进入再巩固存在边界条件。我们认为, 可以大致将恐惧记忆再巩固的边界条件分为记忆本身条件和提取边界条件, 前者包括记忆本身的特性如记忆的强度、年龄等, 后者则强调在提取阶段的操作和实验设置等条件, 另外还包含记忆条件和提取条件的交互作用。Bsnard等人发现提取试次所暴露时间的长短是决定引发记忆再巩固还是记忆消退效果的因素之一, 而不同记忆条件对提取试次暴露的时间有不同的要求(Besnard et al., 2012)。此外, 人类的久远记忆(remote memory)和强记忆(strong memory)难于进入再巩固, 需要提取试次暴露更长的时间; 而新近记忆易于进入再巩固, 只需要较短的提取时间。研究发现对于短时记忆而言, 较短时间的提取(1 s和4 s)使得记忆更容易被干扰, 而没有提取或是过长的提取(30 s或3 min)反而会阻碍恐惧记忆的消退(Hu et al., 2018)。对于提取边界条件, Schiller团队和Kindt团队都发现, 提取的线索必须具备特异性, 不能为CS+和CS-的共同特征线索。而且, 不同的类型的记忆本身可能存在不同的提取边界条件, 有实验发现复合线索刺激引发的条件性恐惧, 采用复合线索中单个较强线索或者完整线索进行提取后消退时, 效果最好(庄楚群 等, 2017)。我们对复合线索的提取消退进行进一步的研究发现, 只有当提取时呈现的线索与原始恐惧线索有2/3的重合时, 效果最好, 这有可能是2/3的部分提取是能够产生预期错误, 而又不引起过分恐惧的一个临界点(Li et al., 2017)。目前虽然诸多行为实验表明, 预期错误是开启再巩固的必要条件, 是提取消退的重要边界条件, 但是我们课题组发现在对复合恐惧记忆进行提取消退时, 提取阶段适当的预期错误才能使记忆进入再巩固过程, 提取阶段没有预期错误或预期错误量过多都不能达到恐惧消退效果(陈伟 等, 2018)。目前关于预期错误在开启再巩固中作用的神经机制研究是比较匮乏的。对提取边界条件的一系列研究还多处于行为层面, 要想知道这些边界条件是如何影响提取消退的, 还亟需影像学机制和分子机制的研究, 从多个层面上共同探索干扰再巩固模式阻止恐惧复发的作用本质。

5.3 条件性恐惧记忆提取干预范式的个体差异性研究

由于目前对提取干预的行为和神经机制的研究尚处在对基本问题的澄清上(例如到底有没有效果, 在什么情况下有效果等), 因此探索个体间差异对其影响的研究较少。例如, 特质焦虑水平不同的个体或具有不同性别、年龄、人格特征的个体, 在使用提取干预范式的效果上有无差异, 造成这种差异背后的原因是什么, 影响传统消退效果的个性差异是否同样影响提取消退的效果等等, 还缺少相应的研究。

5.4 不同类型记忆的提取干预范式作用的神经机制的研究

最后, 条件性恐惧记忆包含不同的成分和类型, 例如依赖于海马的恐惧记忆和依赖于杏仁核的恐惧记忆等。不同类型的恐惧记忆的消退可能存在不同的机制, 在以后的研究可以对其进行区分比较, 进一步深入对恐惧记忆消退本质的理解。提取干预范式被证明也能消退成瘾记忆(Germeroth et al., 2017; Reichelt & Lee, 2013; Xue et al., 2017; Xue & Lu, 2012; 李平, 王晓琴, 孙振武, 王功伍, 2018)。我们在之后的研究中, 除了可以探讨不同类型条件性恐惧记忆的的区分比较之外, 或许还可以增加对不同记忆类型的探讨, 如奖赏记忆等和条件性恐惧记忆在再巩固的提取干预范式中神经机制的差异, 以增加对记忆遗忘机制的探索。

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创伤后应激障碍的动物模型及其神经生物学机制

心理科学进展, 16( 3), 371-377.

URL     [本文引用: 1]

创伤后应激障碍是指个体由于经历对生命具有威胁的事件或严重的创伤,导致症状长期持续的精神障碍.研究创伤后应激障碍的主要动物模型为条件性恐惧和应激敏感化模型.研究表明,创伤后应激障碍中长时程留存的恐惧性记忆,高唤醒等症状与大脑杏仁核,内侧前额叶皮层和海马三个脑区及下丘脑-垂体-肾上腺轴负反馈功能增强密切相关.其中杏仁核活动增强是条件性恐惧记忆获得、保持和表达的关键神经基础.内侧前额叶皮层对杏仁核的去抑制及海马向杏仁核传递的威胁性环境信息,促进创伤后应激障碍症状的出现.在经历创伤应激后糖皮质激素受体的上调及多巴胺活动的增强是创伤后应激障碍产生的主要神经基础.对创伤后应激障碍的药物治疗研究证明多巴胺D2受体在改善患者症状中的作用比较重要,但仍需作更深入的探索.

陈伟, 李俊娇, 曹杨婧文, 杨勇, 胡琰健, 郑希付 . ( 2018).

预期错误在复合恐惧记忆提取消退中的作用

心理学报, 50(7), 739-749.

URL     [本文引用: 2]

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。

吴艳, 李勇辉, 隋南 . ( 2009).

记忆再巩固现象及其生物学机制

心理科学进展, 17( 4), 699-705.

URL     [本文引用: 1]

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。

李平, 王晓琴, 孙振武, 王功伍 . ( 2018).

药物成瘾记忆及其神经环路研究进展

生物学杂志, 35( 1), 93-96+100.

URL     [本文引用: 1]

药物成瘾严重危害人类健康和社会安全,对成瘾机理和防治方法的研究一直是国内外研究的热点。近年来随着对人和动物详细神经网络的逐步阐明,特别是光遗传学技术的迅速发展和应用,人们已在成瘾相关的脑区及其神经环路研究方面取得了重要进展,确认药物成瘾特别是心理成瘾是一种脑疾病,是一种顽固的病态性记忆(成瘾记忆),因此可采用干扰记忆过程的策略治疗心理成瘾。成瘾记忆涉及多个脑区,这些脑区及其神经环路同样在正常学习和记忆中发挥重要作用。主要对近年来有关药物成瘾记忆及其相关神经环路机制的研究进展作一简要介绍。

曾祥星, 杜娟, 王凯欣, 郑希付 . ( 2015).

记忆再巩固的时间动态性及其生物学机制

心理科学进展, 23( 4), 582- 590.

URL     [本文引用: 1]

Memories are consolidated through the information encoding process during waking and the re- processing consolidation during sleeping. Memory reconsolidation theory claims that memory consolidation process needs to be repeated for many times. More specifically, it states that consolidated memories transiently return to a labile state upon each retrieval process and must be restabilized to persist further through a reconsolidation process involving new protein synthesis. At this labile state, memories are easily amenable to enhancement or disruption. Memory reconsolidation is also a time-dependent process, it occurs after memory consolidation and persists for about 6 hours, including the protein degradation destabilization phase and the protein synthesis stabilization phase. Re-exposure of the retrieval trial can trigger either memory reconsolidation or extinction, which depends on the duration of retrieval stimulus presentation.

曾祥星, 向燕辉, 杜娟, 郑希付 . ( 2014).

条件性恐惧记忆提取消退干预范式

.心理科学进展, 22( 3), 431-438.

URL     [本文引用: 1]

Based on the reconsolidation theory of memory, the retrieval-extinction paradigm employ the extinction training within the reconsolidation window to rewrite fear memory of subjects and reduce their fear response by decreasing the valence of fear stimulus. The Ret+Ext paradigm is an innovation and development of traditional exposure therapies and drug treatment. It provides a new non-invasive model for trauma treatments and a new theoretical perspective for the rewriting human memory and the exploring human well-beings on the Positive Psychology.

庄楚群, 王文清, 胡静初, 张蔚欣, 王鹏贵, 郑希付 . ( 2017).

提取-消退范式中复合刺激对恐惧消退的影响

.心理学报, 49( 3), 329-335.

URL     [本文引用: 2]

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.

Agren T., Engman J., Frick A., Björkstrand J., Larsson E-M., Furmark T., & Fredrikson M . ( 2012).

Disruption of reconsolidation erases a fear memory trace in the human amygdala

.Science, 337( 6101), 1550-1552.

URL     PMID:22997340      [本文引用: 5]

Abstract Memories become labile when recalled. In humans and rodents alike, reactivated fear memories can be attenuated by disrupting reconsolidation with extinction training. Using functional brain imaging, we found that, after a conditioned fear memory was formed, reactivation and reconsolidation left a memory trace in the basolateral amygdala that predicted subsequent fear expression and was tightly coupled to activity in the fear circuit of the brain. In contrast, reactivation followed by disrupted reconsolidation suppressed fear, abolished the memory trace, and attenuated fear-circuit connectivity. Thus, as previously demonstrated in rodents, fear memory suppression resulting from behavioral disruption of reconsolidation is amygdala-dependent also in humans, which supports an evolutionarily conserved memory-update mechanism.

Asem J. S. A., Schiffino F. L., & Holland P. C . ( 2015).

Dorsolateral striatum is critical for the expression of surprise-induced enhancements in cue associability

.European Journal of Neuroscience, 42( 5), 2203-2213.

URL     PMID:26108257      [本文引用: 1]

Abstract The dorsolateral striatum (DLS) is frequently implicated in sensory-motor integration, including the performance of sensory orienting responses (ORs) and learned stimulus esponse habits. Our laboratory previously identified a role for the DLS in rats' performance of conditioned ORs to Pavlovian cues for food delivery. Here, we considered whether DLS is also critical to another aspect of attention in associative learning, the surprise-induced enhancement of cue associability. A large behavioral literature shows that a cue present when an expected event is omitted enters into new associations more rapidly when that cue is subsequently paired with food. Research from our laboratory has shown that both cue associability enhancements and conditioned ORs depend on the function of a circuit that includes the amygdala central nucleus and the substantia nigra pars compacta. In three experiments, we explored the involvement of DLS in surprise-induced associability enhancements, using a three-stage serial prediction task that permitted separation of DLS function in registering surprise (prediction error) and enhancing cue associability, and in using that increased associability to learn more rapidly about that cue later. The results showed that DLS is critical to the expression, but not the establishment, of the enhanced cue associability normally produced by surprise in this task. They extend the role of DLS and the amygdalo-nigro-striatal circuit underlying learned orienting to more subtle aspects of attention in associative learning, but are consistent with the general notion that DLS is more important in the expression of previously acquired tendencies than in their acquisition.

Beckers T. & Kindt, M. ( 2017).

Memory reconsolidation interference as an emerging treatment for emotional disorders: Strengths, limitations, challenges, and opportunities

.Annual Review of Clinical Psychology, 13( 1), 99-121.

URL     PMID:5424072      [本文引用: 2]

Experimental research on emotional memory reconsolidation interference, or the induction of amnesia for previously established emotional memory, has a long tradition, but the potential of that research for the development of novel interventions to treat psychological disorders has been recognized only recently. Here we provide an overview of basic research and clinical studies on emotional memory reconsolidation interference. We point out specific advantages of interventions based on memory reconsolidation interference over traditional treatment for emotional disorders. We also explain how findings from basic research suggest limitations and challenges to clinical translation that may help to understand why clinical trials have met with mixed success so far and how their success can be increased. In closing, we preview new intervention approaches beyond the induction of amnesia that the phenomenon of memory reconsolidation may afford for alleviating the burden imposed by emotional memories and comment on theoretical controversies regarding the nature of memory reconsolidation.

Besnard A., Caboche J., & Laroche S . ( 2012).

Reconsolidation of memory: A decade of debate

.Progress in Neurobiology, 99( 1), 61-80.

URL     PMID:22877586      [本文引用: 2]

Memory consolidation refers to a slow process that stabilises a memory trace after initial acquisition of novel events. The consolidation theory posits that once a memory is stored in the brain, it remains fixed for the lifetime of the memory. However, compelling evidence has suggested that upon recall, memories can re-enter a state of transient instability, requiring further stabilisation to be available once again for recall. Since its rehabilitation in the past ten years, this process of reconsolidation of memory after recall stimulated intense debates in the field of cognitive neuroscience. In this review we compile this plentiful literature with a particular emphasis on some of the key questions that have emerged from the reconsolidation theory. We focus on tracing the characterisation of the boundary conditions that constrain the occurrence of memory reconsolidation. We also discuss accumulating evidence supporting the idea that reconsolidation, as implied by its definition, is not a mere repetition of consolidation. We review seminal studies that uncovered specific mechanisms recruited during reconsolidation that are not always crucially involved in consolidation. We next address the physiological significance of reconsolidation since several lines of evidence support the idea that reconsolidation, as opposed to consolidation, may offer a unique opportunity to update memories. We finally discuss recent evidence for or against the potential that the process of memory reconsolidation offers for ongoing efforts to develop novel strategies to combat pathogenic memories.

Björkstrand J., Agren T., Åhs F., Frick A., Larsson E-M., Hjorth O., .. Fredrikson M . ( 2016).

Disrupting reconsolidation attenuates long-term fear memory in the human amygdala and facilitates approach behavior

.Current Biology, 26( 19), 2690-2695.

URL     PMID:27568591      [本文引用: 1]

Using functional neuroimaging, Bj02rkstrand et02al. show that disruption of reconsolidation with exposure to fear-relevant cues after memory activation attenuates neural and behavioral fear expression in subjects with a lifelong fear of spiders. This demonstrates that behavioral reconsolidation disruption is possible even for decades-old fear memories.

Björkstrand J., Agren T., Åhs F., Frick A., Larsson E-M., Hjorth O., .. Fredrikson M . ( 2017).

Think twice, it's all right: Long lasting effects of disrupted reconsolidation on brain and behavior in human long-term fear

.Behavioural Brain Research, 324, 125-129.

URL     PMID:28214541      [本文引用: 1]

Memories can be modified when recalled. Experimental fear conditioning studies support that amygdala-localized fear memories are attenuated when reconsolidation is disrupted through extinction training immediately following memory activation. Recently, using functional brain imaging in individuals with lifelong spider fears, we demonstrated that fear memory activation followed by repeated exposure to feared cues after 10min, thereby disrupting reconsolidation, attenuated activity in the amygdala during later re-exposure, and also facilitated approach behavior to feared cues. In contrast, repeated exposure 6h after fear memory activation, allowing for reconsolidation, did not attenuate amygdala activity and resulted in less approach behavior as compared to the group that received disrupted reconsolidation. We here evaluated if these effects are stable after 6 months and found that amygdala activity was further reduced in both groups, with a tendency towards greater reductions in the 10min than the 6h group. Hence, disrupted reconsolidation results in long lasting attenuation of amygdala activity. The behavioral effect, with more approach towards previously feared cues, in the 10min than the 6h group also persisted. Thus, the brain effect of disrupted reconsolidation is stable over 6 months and the behavioral effect also remained. We therefore conclude that disrupted reconsolidation result in a long-lasting diminished fear memory representation in the amygdala which may have clinical importance.

Björkstrand J., Agren T., Frick A., Engman J., Larsson E-M., Furmark T., & Fredrikson M . ( 2015).

Disruption of memory reconsolidation erases a fear memory trace in the human amygdala: An 18-month follow-up

.Plos One, 10( 7), e0129393.

URL     PMID:4488556      [本文引用: 1]

Fear memories can be attenuated by reactivation followed by disrupted reconsolidation. Using functional magnetic resonance imaging we recently showed that reactivation and reconsolidation of a conditioned fear memory trace in the basolateral amygdala predicts subsequent fear expression over two days, while reactivation followed by disrupted reconsolidation abolishes the memory trace and suppresses fear. In this follow-up study we demonstrate that the behavioral effect persists over 18 months reflected in superior reacquisition after undisrupted, as compared to disrupted reconsolidation, and that neural activity in the basolateral amygdala representing the initial fear memory predicts return of fear. We conclude that disrupting reconsolidation have long lasting behavioral effects and may permanently erase the fear component of an amygdala-dependent memory.

Boes A. D., Grafft A. H., Joshi C., Chuang N. A., Nopoulos P., & Anderson S. W . ( 2011).

Behavioral effects of congenital ventromedial prefrontal cortex malformation

.BMC Neurology, 11, 151.

URL     PMID:22136635      [本文引用: 1]

pAbstract/p pBackground/p pA detailed behavioral profile associated with focal congenital malformation of the ventromedial prefrontal cortex (vmPFC) has not been reported previously. Here we describe a 14 year-old boy, B.W., with neurological and psychiatric sequelae stemming from focal cortical malformation of the left vmPFC./p pCase Presentation/p pB.W.s behavior has been characterized through extensive review Patience of clinical and personal records along with behavioral and neuropsychological testing. A central feature of the behavioral profile is severe antisocial behavior. He is aggressive, manipulative, and callous; features consistent with psychopathy. Other problems include: egocentricity, impulsivity, hyperactivity, lack of empathy, lack of respect for authority, impaired moral judgment, an inability to plan ahead, and poor frustration tolerance./p pConclusions/p pThe vmPFC has a profound contribution to the development of human prosocial behavior. B.W. demonstrates how a congenital lesion to this cortical region severely disrupts this process./p

Bouton M. E., García-gutiérrez A., Zilski J., & Moody E. W . ( 2006).

Extinction in multiple contexts does not necessarily make extinction less vulnerable to relapse

.Behaviour Research and Therapy, 44( 7), 983-994.

URL     PMID:16198302      [本文引用: 1]

Three fear-conditioning experiments with rat subjects examined the effects of extinction in multiple contexts on a final relapse (renewal) effect that occurred when the extinguished fear cue was tested in a new context (Experiments 1 and 3) or in the context in which fear conditioning had first occurred (Experiment 2). Rats that received extinction in three contexts demonstrated more fear during extinction than rats that received the same number and temporal distribution of extinction trials in one context; extinction was partially lost with each context switch. Although extinction in multiple contexts thus had an impact on extinction behavior, it did not reduce the size of the final renewal effect. Fear during extinction was occasionally positively correlated with fear during final testing, but the two were never negatively correlated. The results suggest that extinction in multiple contexts does not necessarily weaken fear renewal, and that extinction procedures that generate high levels of responding in extinction do not necessarily make extinction learning less context-specific.

Chan W. Y. M., Leung H. T., Westbrook R. F., & Mcnally G. P . ( 2010).

Effects of recent exposure to a conditioned stimulus on extinction of Pavlovian fear conditioning

.Learning and Memory, 17( 10), 512-521.

URL     [本文引用: 2]

Cheng D. T., Knight D. C., Smith C. N., Stein E. A., & Helmstetter F. J . ( 2003).

Functional MRI of human amygdala activity during Pavlovian fear conditioning: stimulus processing versus response expression

.Behavioral Neuroscience, 117( 1), 3-10.

URL     PMID:12619902      [本文引用: 1]

Although laboratory animal studies have shown that the amygdala plays multiple roles in conditional fear, less is known about the human amygdala. Human subjects were trained in a Pavlovian fear conditioning paradigm during functional magnetic resonance imaging (fMRI). Brain activity maps correlated with reference waveforms representing the temporal pattern of visual conditional stimuli (CSs) and subject-derived autonomic responses were compared. Subjects receiving paired CS-shock presentations showed greater amygdala activity than subjects receiving unpaired CS-shock presentations when their brain activity was correlated with a waveform generated from their behavioral responses. Stimulus-based waveforms revealed learning differences in the visual cortex, but not in the amygdala. These data support the view that the amygdala is important for the expression of learned behavioral responses during Pavlovian fear conditioning.

Costanzi M., Cannas S., Saraulli D., Rossi-Arnaud C., & Cestari V . ( 2011).

Extinction after retrieval: Effects on the associative and nonassociative components of remote contextual fear memory

.Learning and Memory, 18( 8), 508-518.

URL     PMID:21764847      [本文引用: 2]

Long-lasting memories of adverse experiences are essential for individuals' survival but are also involved, in the form of recurrent recollections of the traumatic experience, in the aetiology of anxiety diseases (e.g., post-traumatic stress disorder [PTSD]). Extinction-based erasure of fear memories has long been pursued as a behavioral way to treat anxiety disorders; yet, such a procedure turns out to be transient, context-dependent, and ineffective unless it is applied immediately after trauma. Recent evidence indicates that, in both rats and humans, extinction training can prevent the return of fear if administered within the reconsolidation window, when memories become temporarily labile and susceptible of being updated. Here, we show that the reconsolidation-extinction procedure fails to prevent the spontaneous recovery of a remote contextual fear memory in a mouse model of PTSD, as well as the long-lasting behavioral abnormalities induced by traumatic experience on anxiety and in both social and cognitive domains (i.e., social withdrawal and spatial learning deficits). Such a failure appears to be related to the ineffectiveness of the reconsolidation-extinction procedure in targeting the pathogenic process of fear sensitization, a nonassociative component of traumatic memory that causes animals to react aberrantly to harmless stimuli. This indicates fear sensitization as a major target for treatments aimed at mitigating anxiety and the behavioral outcomes of traumatic experiences.

Critchley H.D . ( 2009).

Psychophysiology of neural, cognitive and affective integration: FMRI and autonomic indicants. I

nternational Journal of Psychophysiology, 73( 2), 88-94.

URL     PMID:2722714      [本文引用: 1]

Behaviour is shaped by environmental challenge in the context of homoeostatic need. Emotional and cognitive processes evoke patterned changes in bodily state that may signal emotional state to others. This dynamic modulation of visceral state is neurally mediated by sympathetic and parasympathetic divisions of the autonomic nervous system. Moreover neural afferents convey representations of the internal state of the body back to the brain to further influence emotion and cognition. Neuroimaging and lesion studies implicate specific regions of limbic forebrain in the behavioural generation of autonomic arousal states. Activity within these regions may predict emotion-specific autonomic response patterns within and between bodily organs, with implications for psychosomatic medicine. Feedback from the viscera is mapped hierarchically in the brain to influence efferent signals, and ultimately at the cortical level to engender and reinforce affective responses and subjective feeling states. Again neuroimaging and patient studies suggest discrete neural substrates for these representations, notably regions of insula and orbitofrontal cortex. Individual differences in conscious access to these interoceptive representations predict differences in emotional experience, but equally the misperception of heightened arousal level may evoke changes in emotional behaviour through engagement of the same neural centres. Perturbation of feedback may impair emotional reactivity and, in the context of inflammatory states give rise to cognitive, affective and psychomotor expressions of illness. Changes in visceral state during emotion may be mirrored in the responses of others, permitting a corresponding representation in the observer. The degree to which individuals are susceptible to this ontagion predicts individual differences in questionnaire ratings of empathy. Together these neuroimaging and clinical studies highlight the dynamic relationship between mind and body and help identify neural substrates that may translate thoughts into autonomic arousal and bodily states into feelings that can be shared.

Debiec J., Ledoux J. E., & Nader K . ( 2002).

Cellular and systems reconsolidation in the hippocampus

.Neuron, 36( 3), 527-538.

URL     PMID:12408854      [本文引用: 1]

Cellular theories of memory consolidation posit that new memories require new protein synthesis in order to be stored. Systems consolidation theories posit that the hippocampus has a time-limited role in memory storage, after which the memory is independent of the hippocampus. Here, we show that intra-hippocampal infusions of the protein synthesis inhibitor anisomycin caused amnesia for a consolidated hippocampal-dependent contextual fear memory, but only if the memory was reactivated prior to infusion. The effect occurred even if reactivation was delayed for 45 days after training, a time when contextual memory is independent of the hippocampus. Indeed, reactivation of a hippocampus-independent memory caused the trace to again become hippocampus dependent, but only for 2 days rather than for weeks. Thus, hippocampal memories can undergo reconsolidation at both the cellular and systems levels.

Díaz-Mataix L., Tallot L., & Doyère V . ( 2014).

The amygdala: A potential player in timing CS-US intervals

.Behavioural Processes, 101, 112-122.

URL     PMID:23973708      [本文引用: 1]

Pavlovian conditioning is the reference paradigm for the study of associative learning based on the programmed relation of two stimuli, the conditioned stimulus (CS) and the unconditioned stimulus (US). Some authors believe that learning the CS–US interval is a co-requisite of or a pre-requisite to learning the CS–US association. There is a substantial literature showing that the amygdala is a critical player in Pavlovian conditioning, with both aversive and appetitive USs. We review a sparse but growing body of literature suggesting that the amygdala may also participate in processing the timing of the CS–US interval. We discuss whether the amygdala, in particular its central, basal and lateral nuclei, in concert with the network it belongs to, may play a role in learning the CS–US interval. We also suggest new and dedicated strategies that would result in better knowledge of the neural mechanisms underlying the learning of the CS–US time interval in isolation from the CS–US association.

Do-monte F. H., Quiñones-laracuente K., & Quirk G. J . ( 2015).

A temporal shift in the circuits mediating retrieval of fear memory

.Nature, 519( 7544), 460-463.

URL     PMID:4376623      [本文引用: 1]

Fear memories allow organisms to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning1,2, but little is known about how retrieval circuits change with time3,4. Here we show that the dorsal midline thalamus of rats is required for retrieval of auditory conditioned fear at late timepoints (24 h, 7 d, 28 d), but not early timepoints (0.5 h, 6 h) after learning. Consistent with this, the paraventricular subregion of the dorsal midline thalamus (PVT) showed increased cFos expression only at late timepoints, indicating that PVT is gradually recruited for fear retrieval. Accordingly, the conditioned tone responses of PVT neurons increased with time following training. The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval5 7, sends dense projections to PVT8. Retrieval at late timepoints activated PL neurons projecting to PVT, and optogenetic silencing of these projections impaired retrieval at late, but not early times. In contrast, silencing of PL inputs to the basolateral amygdala (BLA) impaired retrieval at early, but not late times, indicating a time-dependent shift in retrieval circuits. Retrieval at late timepoints also activated PVT neurons projecting to the central nucleus of the amygdala (CeA), and silencing these projections at late, but not early, times induced a persistent attenuation of fear. Thus, PVT may serve as a critical thalamic node recruited into cortico-amygalar networks for retrieval and maintenance of long-term fear memories.

Dudai, Y. ( 2004).

The neurobiology of consolidations, or, how stable is the engram?

Annual Review of Psychology, 55( 1), 51-86.

URL     PMID:14744210      [本文引用: 1]

Abstract Consolidation is the progressive postacquisition stabilization of long-term memory. The term is commonly used to refer to two types of processes: synaptic consolidation, which is accomplished within the first minutes to hours after learning and occurs in all memory systems studied so far; and system consolidation, which takes much longer, and in which memories that are initially dependent upon the hippocampus undergo reorganization and may become hippocampal-independent. The textbook account of consolidation is that for any item in memory, consolidation starts and ends just once. Recently, a heated debate has been revitalized on whether this is indeed the case, or, alternatively, whether memories become labile and must undergo some form of renewed consolidation every time they are activated. This debate focuses attention on fundamental issues concerning the nature of the memory trace, its maturation, persistence, retrievability, and modifiability.

Duvarci S. & Nader, K. ( 2004).

Characterization of fear memory reconsolidation

.Journal of Neuroscience the Official Journal of the Society for Neuroscience, 24( 42), 9269-9275.

URL     PMID:15496662      [本文引用: 1]

Reactivation of consolidated memories returns them to a protein synthesis-dependent state. One interpretation of these findings is that the memory reconsolidates after use. Two alternative interpretations are that protein synthesis inhibition facilitates extinction and that postreactivation protein synthesis inhibition leads to an inability to retrieve the consolidated memory. First, using two different approaches, we report that reconsolidation cannot be reduced down to facilitated extinction. We show that the reconsolidation deficit does not show renewal after a contextual shift, whereas an extinguished auditory fear memory does under the same conditions and the deficit occurs regardless of whether the memory is reactivated with an extinction [conditioned stimulus (CS) alone] or a reinforced trial (CS-unconditioned stimulus). To address the issue of whether postreactivation anisomycin leads to an inability to retrieve the consolidated memory, we used two traditional assays for retrieval deficits. First, we demonstrate that the amnesia induced by blockade of reconsolidation does not show any spontaneous recovery. Second, we show that application of reminder shock does not result in the reinstatement of the memory. These findings support the idea that reactivation of consolidated memories initiates a second time-dependent memory formation process.

Elsey J. W.B., & Kindt, M. ( 2017 a).

Breaking boundaries: optimizing reconsolidation-based interventions for strong and old memories

.Learning and Memory, 24( 9), 472-479.

URL     PMID:28814473      [本文引用: 1]

Abstract Recent research has demonstrated that consolidated memories can enter a temporary labile state after reactivation, requiring restabilization in order to persist. This process, known as reconsolidation, potentially allows for the modification and disruption of memory. Much interest in reconsolidation stems from the possibility that maladaptive memory traces-a core feature of several psychiatric conditions-could be tackled by disrupting their reconsolidation. However, research has indicated a range of supposed boundary conditions on the induction of reconsolidation. Stronger memories, often resulting from exposure to stressful conditions, or older memories, appear to be relatively resistant to undergoing reconsolidation. This may be taken as a potential stumbling block for reconsolidation-based interventions: in clinical practice, old and strong maladaptive memories are the norm rather than the exception. Yet, boundary conditions have been derived from limited experimental evidence, are not unique to reconsolidation-based interventions, and do not seem to be absolute. In this paper, we review a range of experimental studies that have aimed to disrupt old memories, or memories that were strengthened by stress manipulations, through reconsolidation. Such research highlights several techniques that could be used to optimize reconsolidation-based approaches and overcome putative boundary conditions. We supplement this review of experimental literature with a case study of a reconsolidation-based treatment of a strong and decades-old phobia for mice, further suggesting that age and strength of memory may not be insurmountable barriers. Translating findings from basic science, to human experiments, to clinical applications and back again, can potentially unlock powerful new treatments for the many people who suffer daily from anxiety disorders. 2017 Elsey and Kindt; Published by Cold Spring Harbor Laboratory Press.

Elsey J. W.B., & Kindt, M. ( 2017 b).

Tackling maladaptive memories through reconsolidation: From neural to clinical science

.Neurobiology of Learning and Memory, 142, 108-117.

URL     [本文引用: 1]

Behavioral neuroscience has greatly informed how we understand the formation, persistence, and plasticity of memory. Research has demonstrated that memory reactivation can induce a labile period, during which previously consolidated memories are sensitive to change, and in need of restabilization. This process is known as reconsolidation. Such findings have advanced not only our basic understanding of memory processes, but also hint at the prospect of harnessing these insights for the development of a new generation of treatments for disorders of emotional memory. However, even in simple experimental models, the conditions for inducing memory reconsolidation are complex: memory labilization appears to result from the interplay of learning history, reactivation, and also individual differences, posing difficulties for the translation of basic experimental research into effective clinical interventions. In this paper, we review a selection of influential animal and human research on memory reconsolidation to illustrate key insights these studies afford. We then consider how these findings can inform the development of new treatment approaches, with a particular focus on the transition of memory from reactivation, to reconsolidation, to new memory formation, as well as highlighting possible limitations of experimental models. If the challenges of translational research can be overcome, and if reconsolidation-based procedures become a viable treatment option, then they would be one of the first mental health treatments to be directly derived from basic neuroscience research. This would surely be a triumph for the scientific study of mind and brain.

Etkin A., Egner T., & Kalisch R . ( 2011).

Emotional processing in anterior cingulate and medial prefrontal cortex

.Trends in Cognitiveences, 15( 2), 85-93.

URL     PMID:21167765      [本文引用: 1]

Negative emotional stimuli activate a broad network of brain regions, including the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. An early influential view dichotomized these regions into dorsal–caudal cognitive and ventral–rostral affective subdivisions. In this review, we examine a wealth of recent research on negative emotions in animals and humans, using the example of fear or anxiety, and conclude that, contrary to the traditional dichotomy, both subdivisions make key contributions to emotional processing. Specifically, dorsal–caudal regions of the ACC and mPFC are involved in appraisal and expression of negative emotion, whereas ventral–rostral portions of the ACC and mPFC have a regulatory role with respect to limbic regions involved in generating emotional responses. Moreover, this new framework is broadly consistent with emerging data on other negative and positive emotions.

Ferrer Monti R. I., Alfei J. M., Mugnaini M., Bueno A. M., Beckers T., Urcelay G. P., & Molina V. A . ( 2017).

A comparison of behavioral and pharmacological interventions to attenuate reactivated fear memories

.Learning and Memory, 24( 8), 369-374.

URL     PMID:28716956      [本文引用: 1]

Two experiments using rats in a contextual fear memory preparation compared two approaches to reduce conditioned fear: (1) pharmacological reconsolidation blockade and (2) reactivation-plus-extinction training. In Experiment 1, we explored different combinations of reactivation-plus-extinction parameters to reduce conditioned fear and attenuate reacquisition. In Experiment 2, memory reactivation was followed by extinction training or administration of midazolam (MDZ) (vs. vehicle) to reduce conditioned fear and attenuate spontaneous recovery. We found both treatments to be equally effective in both experiments. This study suggests that parameters leading to memory destabilization during reactivation are critical to observe long-lasting effects of MDZ or reactivation plus extinction.

Foa E.B., & Kozak, M.J . ( 1986).

Emotional processing of fear: Exposure to corrective information

.Psychological Bulletin, 99( 1), 20-35.

URL     [本文引用: 1]

Fullana M. A., Albajes-eizagirre A., Soriano-mas C., Vervliet B., Cardoner N., Benet O., .. Harrison B. J . ( 2018).

Fear extinction in the human brain: A meta-analysis of fMRI studies in healthy participants

.Neuroscience & Biobehavioral Reviews, 88, 16-25.

URL     PMID:29530516      [本文引用: 2]

The study of fear extinction represents an important example of translational neuroscience in psychiatry and promises to improve the understanding and treatment of anxiety and fear-related disorders. We present the results of a set of meta-analyses of human fear extinction studies in healthy participants, conducted with functional magnetic resonance imaging (fMRI) and reporting whole-brain results. Meta-analyses of fear extinction learning primarily implicate consistent activation of brain regions linked to threat appraisal and experience, including the dorsal anterior cingulate and anterior insular cortices. An overlapping anatomical result was obtained from the meta-analysis of extinction recall studies, except when studies directly compared an extinguished threat stimulus to an unextinguished threat stimulus (instead of a safety stimulus). In this latter instance, more consistent activation was observed in dorsolateral and ventromedial prefrontal cortex regions, together with other areas including the hippocampus. While our results partially support the notion of a shared neuroanatomy between human and rodent models of extinction processes, they also encourage an expanded account of the neural basis of human fear extinction.

Fullana M. A., Harrison B. J., Soriano-mas C., Vervliet B., Cardoner N., Àvila-parcet A., & Radua J . ( 2016).

Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies

.Mol Psychiatry, 21( 4), 500-508.

URL     PMID:26122585      [本文引用: 1]

Abstract Classical Pavlovian fear conditioning remains the most widely employed experimental model of fear and anxiety, and continues to inform contemporary pathophysiological accounts of clinical anxiety disorders. Despite its widespread application in human and animal studies, the neurobiological basis of fear conditioning remains only partially understood. Here we provide a comprehensive meta-analysis of human fear-conditioning studies carried out with functional magnetic resonance imaging (fMRI), yielding a pooled sample of 677 participants from 27 independent studies. As a distinguishing feature of this meta-analysis, original statistical brain maps were obtained from the authors of 13 of these studies. Our primary analyses demonstrate that human fear conditioning is associated with a consistent and robust pattern of neural activation across a hypothesized genuine network of brain regions resembling existing anatomical descriptions of the 'central autonomic-interoceptive network'. This finding is discussed with a particular emphasis on the neural substrates of conscious fear processing. Our associated meta-analysis of functional deactivations-a scarcely addressed dynamic in fMRI fear-conditioning studies-also suggests the existence of a coordinated brain response potentially underlying the 'safety signal' (that is, non-threat) processing. We attempt to provide an integrated summary on these findings with the view that they may inform ongoing studies of fear-conditioning processes both in healthy and clinical populations, as investigated with neuroimaging and other experimental approaches.

Germeroth L. J., Carpenter M. J., Baker N. L., Froeliger B., Larowe S. D., & Saladin M. E . ( 2017).

Effect of a brief memory updating intervention on smoking behavior: A randomized clinical trial

.Jama Psychiatry, 74( 3), 214-223.

URL     PMID:28146243      [本文引用: 1]

Recent research on addiction-related memory processes suggests that protracted extinction training following brief cue-elicited memory retrieval (ie, retrieval-extinction [R-E] training) can attenuate/eradicate the ability of cues to elicit learned behaviors. One study reported that cue-elicited craving among detoxified heroin addicts was substantially attenuated following R-E training and through 6-month follow-up. To build on these impressive findings by examining whether R-E training could attenuate smoking-related craving and behavior. This prospective, mixed-design, human laboratory randomized clinical trial took place between December 2013 and September 2015. Participants were recruited in Charleston, South Carolina. Study sessions took place at the Medical University of South Carolina. The participants were 168 screened volunteer smokers, of whom 88 were randomized; 72 of these 88 participants (81.8%) attended all the follow-up sessions through 1 month. The primary eligibility criteria were current nicotine dependence (DSM criteria), smoking 10 or more cigarettes per day, and a willingness to attempt smoking cessation. Participants were randomly assigned to receive either smoking-related memory retrieval followed by extinction training (the R-E group) or nonsmoking-related retrieval followed by extinction training (the NR-E group). Primary outcomes were cue-elicited craving and physiological responding to familiar and novel cues in the R-E group vs the NR-E group over a 1-month follow-up period. Secondary outcomes were smoking-related behaviors. A total of 44 participants were randomly assigned to the R-E group (mean age, 48.3 years; 72.7% male); a total of 44 participants were randomly assigned to the NR-E group, with 43 attending at least 1 training session (mean age, 46.7 years; 55.8% male). The mean craving response to both familiar and novel smoking cues was significantly lower for participants in the R-E group than for participants in the NR-E group at 1-month follow-up (for both cue types: t122565=652.1, P65=65.04, d65=650.44, and Δ65=650.47 [95% CI, 0.04-0.90]). The mean numbers of cigarettes smoked per day at 2 weeks and 1-month were significantly lower for the R-E group than for the NR-E group (treatment main effect: F1,6865=655.4, P65=65.02, d65=650.50, and Δ65=652.4 [95% CI, 0.4-4.5]). Significant differences in physiological responses, urine cotinine level, number of days abstinent, lapse, and relapse were not observed between groups (all between P65=65.06 and .75). Retrieval-extinction training substantially attenuated craving to both familiar and novel smoking cues and reduced the number of cigarettes smoked per day by participants 1 month after treatment relative to extinction training alone. Between-group differences were not observed for physiological responses, cotinine level, number of days abstinent, relapse, or lapse. In summary, R-E training is a brief behavioral treatment that targets smoking-related memories and has the potential to enhance relapse prevention. clinicaltrials.gov Identifier: NCT02154685.

Goode T. D., Holloway-Erickson C. M., & Maren S . ( 2017).

Extinction after fear memory reactivation fails to eliminate renewal in rats

.Neurobiology of Learning and Memory, 142( Pt A), 41-47.

URL     PMID:28274824      [本文引用: 1]

Retrieving fear memories just prior to extinction has been reported to effectively erase fear memories and prevent fear relapse. The current study examined whether the type of retrieval procedure influences the ability of extinction to impair fear renewal, a form of relapse in which responding to a conditional stimulus (CS) returns outside of the extinction context. Rats first underwent Pavlovian fear conditioning with an auditory CS and footshock unconditional stimulus (US); freezing behavior served as the index of conditioned fear. Twenty-four hours later, the rats underwent a retrieval-extinction procedure. Specifically, 1h prior to extinction (45 CS-alone trials; 44 for rats receiving a CS reminder), fear memory was retrieved by either a single exposure to the CS alone, the US alone, a CS paired with the US, or exposure to the conditioning context itself. Over the next few days, conditional freezing to the extinguished CS was tested in the extinction and conditioning context in that order (i.e., an ABBA design). In the extinction context, rats that received a CS+US trial before extinction exhibited higher levels of conditional freezing than animals in all other groups, which did not differ from one another. In the renewal context, all groups showed renewal, and none of the reactivation procedures reduced renewal relative to a control group that did not receive a reactivation procedure prior to extinction. These data suggest retrieval-extinction procedures may have limited efficacy in preventing fear renewal.

Gräff J., Joseph N. F., Horn M. E., Samiei A., Jia M., Seo J., .. Tsai L-H . ( 2014).

Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories

.Cell, 156( 1-2), 261-276.

URL     PMID:24439381      [本文引用: 1]

An HDAC2 inhibitor reinstates synaptic and structural plasticity to stably attenuate remote fear-associated memories.

Herry C., Ciocchi S., Senn V., Demmou L., Müller C., & Lüthi A . ( 2008).

Switching on and off fear by distinct neuronal circuits

.Nature, 454( 7204), 600-606.

URL     PMID:18615015      [本文引用: 1]

Switching between exploratory and defensive is fundamental to survival of many , but how this transition is achieved by specific neuronal circuits is not known. Here, using the converse behavioural states of fear extinction and its context-dependent renewal as a model in , we show that bi-directional transitions between states of high and low fear are triggered by a rapid switch in the balance of activity between two distinct populations of basal amygdala neurons. These two populations are integrated into discrete neuronal circuits differentially connected with the hippocampus and the medial prefrontal cortex. Targeted and reversible neuronal inactivation of the basal amygdala prevents behavioural changes without affecting or expression of . Our findings indicate that switching between distinct behavioural states can be triggered by selective activation of specific neuronal circuits integrating sensory and contextual information. These observations provide a new framework for understanding context-dependent changes of fear .

Hofmann S.G . ( 2008).

Cognitive processes during fear acquisition and extinction in animals and humans: Implications for exposure therapy of anxiety disorders

.Clinical Psychology Review, 28( 2), 199-210.

URL     PMID:17532105      [本文引用: 1]

Anxiety disorders are highly prevalent. Fear conditioning and extinction learning in animals often serve as simple models of fear acquisition and exposure therapy of anxiety disorders in humans. This article reviews the empirical and theoretical literature on cognitive processes in fear acquisition, extinction, and exposure therapy. It is concluded that exposure therapy is a form of cognitive intervention that specifically changes the expectancy of harm. Implications for therapy research are discussed.

Hu J., Wang W., Homan P., Wang P., Zheng X., & Schiller D . ( 2018).

Reminder duration determines threat memory modification in humans

.Sci Rep, 8( 1), 8848.

URL     PMID:29891856      [本文引用: 1]

Abstract Memory reminders can return a memory into an unstable state such that it will decay unless actively restabilized into long-term memory through reconsolidation. Exposure to a memory reminder, however, does not always lead to destabilization. The 'trace dominance' principle posits that the extent of exposure to memory reminders governs memory susceptibility to disruption. Here, we provide a first systematic investigation of reminder duration effects on02threat memory modification in humans. Reminder duration was parametrically varied across02155 participants in a three-day protocol. We found that short reminders (165s and 465s) made the memory prone to interference from post-retrieval extinction, suggesting that the memory had been updated. In contrast, no reminder or long reminders (3065s and 365min) made the memory resistant to such interference, and robustly return. Reminder duration therefore influences memory stability and may be a critical determinant of therapeutic efficacy.

Ishii D., Matsuzawa D., Matsuda S., Tomizawa H., Sutoh C., & Shimizu E . ( 2012).

No erasure effect of retrieval- extinction trial on fear memory in the hippocampus- independent and dependent paradigms

.Neuroscience Letters, 523( 1), 76-81.

URL     PMID:22750210      [本文引用: 1]

Recently, Monfils et al. [9] and Clem and Huganir [3] have shown that an isolated retrieval trial before the extinction sessions (retrieval–extinction) in mice and rats prevented the renewal and spontaneous recovery of the original fear memory by inhibiting reconsolidation in a hippocampus-independent manner. In contrast, Chan et al. [2], using the same paradigm, reported that retrieval extinction in rats augmented the renewal and reinstatement of extinguished fear. However, it remains unclear whether or not retrieval extinction in a hippocampus-independent paradigm erases the original fear memory by inhibiting reconsolidation. We therefore conducted three experiments to investigate whether or not retrieval extinction erases the original fear memory by inhibiting reconsolidation in mice. Our major findings were as follows. (1) Retrieval–extinction in mice did not suppress spontaneous recovery and fear renewal in a hippocampus-independent paradigm. (2) Fear renewal was observed when retrieval–strong extinction in a hippocampus-independent paradigm was performed. (3) Retrieval extinction in a hippocampus-dependent paradigm did not erase the original fear memory. These results suggested that fear extinction after retrieval in mice does not inhibit reconsolidation of previously consolidated fear memory in either a hippocampus-independent or -dependent paradigm.

Ishikawa A. & Nakamura, S. ( 2003).

Convergence and interaction of hippocampal and amygdalar projections within the prefrontal cortex in the rat

.Journal of Neuroscience, 23( 31), 9987-9995.

URL     PMID:14602812      [本文引用: 1]

The orbital and medial prefrontal cortex (OMPFC) receives inputs from the CA1/subicular (CA1/S) region of the ventral hippocampus and the basolateral nucleus of the amygdala (BLA). Despite many studies about these projections, little is known as to how CA1/S and BLA inputs converge and interact within the OMPFC. Extracellular recordings of single-unit activity in the OMPFC were performed in sodium pentobarbitone-anesthetized rats. OMPFC neurons driven by CA1/S or BLA stimulation were more frequently encountered in the ventral portion of the prelimbic (v-PrL) and infralimbic cortex (IL). OMPFC neurons showing excitatory convergence of both inputs from the CA1/S and BLA were also located predominantly in the v-PrL and IL. The excitatory latencies of these neurons from both the CA1/S and BLA revealed almost identical values. Excitatory responses of OMPFC neurons to CA1/S (or BLA) stimulation were markedly augmented by simultaneous BLA (or CA1/S) stimulation, whereas the inhibitory influence of the BLA (or CA1/S) on CA1/S-induced (or BLA-induced) excitation was apparent when BLA (or CA1/S) stimulation was given 20-40 msec before CA1/S (or BLA) stimulation. Similar results were also observed when reciprocal connections between the CA1/S and BLA were severed to exclude the influences of these connections on one another. From these studies, we concluded that excitatory and inhibitory inputs from the hippocampus and amygdala converge and interact in the v-PrL and IL. Furthermore, the results indicate that simultaneous activation of hippocampal and amygdalar neurons may be important for amplification of OMPFC neuronal activity.

Kim J.J., & Jung, M.W . ( 2006).

Neural circuits and mechanisms involved in Pavlovian fear conditioning: A critical review

.Neuroscience & Biobehavioral Reviews, 30( 2), 188-202.

URL     PMID:16120461      [本文引用: 1]

Pavlovian or classical fear conditioning is recognized as a model system to investigate the neurobiological mechanisms of learning and memory in the mammalian brain and to understand the root of fear-related disorders in humans. In recent decades, important progress has been made in delineating the essential neural circuitry and cellular–molecular mechanisms of fear conditioning. Converging lines of evidence indicate that the amygdala is necessarily involved in the acquisition, storage and expression of conditioned fear memory, and long-term potentiation (LTP) in the lateral nucleus of the amygdala is often proposed as the underlying synaptic mechanism of associative fear memory. Recent studies further implicate the prefrontal cortex–amygdala interaction in the extinction (or inhibition) of conditioned fear. Despite these advances, there are unresolved issues and findings that challenge the validity and sufficiency of the current amygdalar LTP hypothesis of fear conditioning. The purpose of this review is to critically evaluate the strengths and weaknesses of evidence indicating that fear conditioning depend crucially upon the amygdalar circuit and plasticity.

Kindt M. & Soeter, M. ( 2013).

Reconsolidation in a human fear conditioning study: A test of extinction as updating mechanism

.Biological Psychology, 92( 1), 43-50.

URL     PMID:21986472      [本文引用: 1]

Disrupting reconsolidation seems to be a promising approach to dampen the expression of fear memory. Recently, we demonstrated that disrupting reconsolidation by a pharmacological manipulation specifically targeted the emotional expression of memory (i.e., startle response). Here we test in a human differential fear-conditioning paradigm with fear-relevant stimuli whether the spacing of a single unreinforced retrieval trial relative to extinction learning allows for "rewriting" the original fear association, thereby preventing the return of fear. In contrast to previous findings reported by Schiller et al. (2010), who used a single-method for indexing fear (skin conductance response) and fear-irrelevant stimuli, we found that extinction learning within the reconsolidation window did not prevent the recovery of fear on multiple indices of conditioned responding (startle response, skin conductance response and US-expectancy). These conflicting results ask for further critical testing given the potential impact on the field of emotional memory and its application to clinical practice. (C) 2011 Elsevier B.V. All rights reserved.

Kindt M., Soeter M., & Vervliet B . ( 2009).

Beyond extinction: Erasing human fear responses and preventing the return of fear

.Nature Neuroscience, 12( 3), 256-258.

URL     PMID:19219038      [本文引用: 1]

F1000Prime Recommended Article: Beyond extinction: erasing human fear responses and preventing the return of fear.

Knight D. C., Smith C. N., Cheng D. T., Stein E. A., & Helmstetter F. J . ( 2004).

Amygdala and hippocampal activity during acquisition and extinction of human fear conditioning

.Cognitive Affective & Behavioral Neuroscience, 4( 3), 317-325.

[本文引用: 1]

Koenigs M., Huey E. D., Raymont V., Cheon B., Solomon J., Wassermann E. M., & Grafman J . ( 2008).

Focal brain damage protects against post-traumatic stress disorder in combat veterans

.Nature Neuroscience, 11( 2), 232-237.

URL     PMID:18157125      [本文引用: 1]

Post-traumatic stress disorder (PTSD) is an often debilitating mental illness that is characterized by recurrent distressing memories of traumatic events. PTSD is associated with hypoactivity in the ventromedial prefrontal cortex (vmPFC), hyperactivity in the amygdala and reduced volume in the hippocampus, but it is unknown whether these neuroimaging findings reflect the underlying cause or a secondary effect of the disorder. To investigate the causal contribution of specific brain areas to PTSD symptoms, we studied a unique sample of Vietnam War veterans who suffered brain injury and emotionally traumatic events. We found a substantially reduced occurrence of PTSD among those individuals with damage to one of two regions of the brain: the vmPFC and an anterior temporal area that included the amygdala. These results suggest that the vmPFC and amygdala are critically involved in the pathogenesis of PTSD.

Kroes M. C., Tona K-D., den Ouden H. E. M., Vogel S., van Wingen G. A., & Fernández G . ( 2016).

How administration of the beta-blocker propranolol before extinction can prevent the return of fear

.Neuropsychopharmacology Official Publication of the American College of Neuropsychopharmacology, 41( 6), 1569-1578.

URL     PMID:26462618      [本文引用: 3]

Combining beta-blockers with exposure-therapy has been advocated to reduce fear, yet experimental studies combining beta-blockers with memory reactivation have had contradictory results. We explored how beta-blockade might affect the course of safety learning and the subsequent return of fear in a double-blind placebo-controlled functional magnetic resonance imaging study in humans (N=46). A single dose of propranolol prior to extinction learning caused a loss of conditioned fear responses, and prevented the subsequent return of fear and decreased explicit memory for the fearful events in the absence of drug. Fear-related neural responses were persistently attenuated in the dorsal medial prefrontal cortex (dmPFC), increased in the hippocampus 24h later, and correlated with individual behavioral indices of fear. Prediction error-related responses in the ventral striatum persisted during beta-blockade. We suggest that this pattern of results is most consistent with a model where beta-blockade can prevent the return of fear by i) reducing retrieval of fear memory, via the dmPFC and ii) increasing contextual safety learning, via the hippocampus. Our findings suggest that retrieval of fear memory and contextual safety learning form potential mnemonic target mechanisms to optimize exposure-based therapy with beta-blockers.

Laurent V. & Westbrook, R.F . ( 2009).

Inactivation of the infralimbic but not the prelimbic cortex impairs consolidation and retrieval of fear extinction

.Learning and Memory, 16( 9), 520-529.

URL     PMID:19706835      [本文引用: 1]

Rats were subjected to one or two cycles of context fear conditioning and extinction to study the roles of the prelimbic cortex (PL) and infralimbic cortex (IL) in learning and relearning to inhibit fear responses. Inactivation of the PL depressed fear responses across the first or second extinction but did not impair learning or relearning fear inhibition (experiment 1). Inactivation of the IL did not affect inhibition across the first extinction but disrupted its long-term retention. Inactivation of the IL impaired inhibition across the second extinction, and inactivation before or after this extinction impaired long-term retention (experiments 2 and 3). Inactivation of the IL before the retention test restored extinguished fear responses (experiment 4). These results show for the first time that neuronal activity in the PL is involved in the expression of fear responses but not in the learning that underlies long-term fear inhibition. They also confirm that the IL is involved in this inhibitory learning: Specifically, they show that the IL is critical for consolidation and retrieval of this inhibitory learning. The role of the IL is discussed in terms of a contemporary neural model of fear extinction.

Li J., Chen W., Caoyang J., Wu W., Jie J., Xu L., & Zheng X . ( 2017).

Moderate partially reduplicated conditioned stimuli as retrieval cue can increase effect on preventing relapse of fear to compound stimuli

.Frontiers in Human Neuroscience, 11, 575.

URL     PMID:29249946      [本文引用: 3]

The theory of memory reconsolidation argues that consolidated memory is not unchangeable. Once a memory is reactivated it may go back into an unstable state and need new protein synthesis to be consolidated again, which is called “memory reconsolidation”. Boundary studies have shown that interfering with reconsolidation through pharmacologic or behavioral intervention can lead to the updating of the initial memory, for example, erasing undesired memories. Behavioral procedures based on memory reconsolidation interference have been shown to be an effective way to inhibit fear memory relapse after extinction. However, the effectiveness of retrieval–extinction differs by subtle differences in the protocol of the reactivation session. This represents a challenge with regard to finding an optimal operational model to facilitate its clinical use for patients suffering from pathogenic memories such as those associated with post-traumatic stress disorder. Most of the laboratory models for fear learning have used a single conditioned stimulus (CS) paired with an unconditioned stimulus (US). This has simplified the real situation of traumatic events to an excessive degree, and thus, limits the clinical application of the findings based on these models. Here, we used a basic visual compound CS model as the CS to ascertain whether partial repetition of the compound CSs in conditioning can reactivate memory into reconsolidation. The results showed that the no retrieval group or the 1/3 ratio retrieval group failed to open the memory reconsolidation time window. The 2/3 repetition retrieval group and the whole repetition retrieval group were able to prevent fear reinstatement, whereas only a 2/3 ratio repetition of the initial compound CS as a reminder could inhibit spontaneous recovery. We inferred that a retrieval–extinction paradigm was also effective in a more complex model of fear if a sufficient prediction error (PE) could be generated in the reactivation period. In addition, in order to achieve an optimal effect, a CS of moderate discrepancy should be used as a reminder.

Li S. S.Y., & Mcnally, G.P . ( 2014).

The conditions that promote fear learning: Prediction error and Pavlovian fear conditioning

.Neurobiology of Learning and Memory, 108( 1), 14-21.

URL     PMID:23684989      [本文引用: 1]

A key insight of associative learning theory is that learning depends on the actions of prediction error: a discrepancy between the actual and expected outcomes of a conditioning trial. When positive, such error causes increments in associative strength and, when negative, such error causes decrements in associative strength. Prediction error can act directly on fear learning by determining the effectiveness of the aversive unconditioned stimulus or indirectly by determining the effectiveness, or associability, of the conditioned stimulus. Evidence from a variety of experimental preparations in human and non-human animals suggest that discrete neural circuits code for these actions of prediction error during fear learning. Here we review the circuits and brain regions contributing to the neural coding of prediction error during fear learning and highlight areas of research (safety learning, extinction, and reconsolidation) that may profit from this approach to understanding learning.

Liu J., Zhao L., Xue Y., Shi J., Suo L., Luo Y., .. Lu L . ( 2014).

An unconditioned stimulus retrieval extinction procedure to prevent the return of fear memory

.Biological Psychiatry, 76( 11), 895-901.

URL     PMID:24813334      [本文引用: 1]

Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. We introduced a technique to target all diverse cues associated with an aversive event that causes fear. In human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as that used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Presentation of a lower intensity US before extinction disrupted the associations between the different CS and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear.

Medford N. & Critchley, H.D . ( 2010).

Conjoint activity of anterior insular and anterior cingulate cortex: awareness and response

.Brain Structure & Function, 214( 5-6), 535-549.

URL     PMID:20512367      [本文引用: 1]

There is now a wealth of evidence that anterior insular and anterior cingulate cortices have a close functional relationship, such that they may be considered together as input and output regions of a functional system. This system is typically engaged across cognitive, affective, and behavioural contexts, suggesting that it is of fundamental importance for mental life. Here, we review the literature and reinforce the case that these brain regions are crucial, firstly, for the production of subjective feelings and, secondly, for co-ordinating appropriate responses to internal and external events. This model seeks to integrate higher-order cortical functions with sensory representation and autonomic control: it is argued that feeling states emerge from the raw data of sensory (including interoceptive) inputs and are integrated through representations in conscious awareness. Correspondingly, autonomic nervous system reactivity is particularly important amongst the responses that accompany conscious experiences. Potential clinical implications are also discussed.

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