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。     

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。     

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。     

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。     

阻碍条件性恐惧记忆消退的原因分析

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,对其治疗的关键是消退由创伤应激导致的条件性恐惧记忆,但目前最有效的暴露疗法并不能真正有效地抑制患者恐惧记忆的表达.对条件性恐惧的动物模型研究发现情绪性增强效应、恐惧记忆二级条件化与再巩固、内侧前额叶皮层功能不足等均能够阻碍条件性恐惧记忆的消退.针对这几个方面可以探索治疗创伤后应激障碍的相应方法.     

条件性恐惧记忆消退的提取干预范式及其作用的神经机制

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

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。     

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。     

即刻消退缺损的原因分析及其神经生物学机制

即刻消退缺损(immediate extinction deficit, IED)是指在条件性恐惧习得后, 立即进行的消退训练不能长期抑制恐惧记忆的现象。IED可能与消退起始时的应激水平和事件分割等因素有关。在高应激水平下, 消退记忆的巩固受损导致IED; 而在中等或较低的应激水平条件下, 即刻消退有效但效果可能容易受事件分割的影响。IED的神经生物学机制涉及应激激活蓝斑去甲肾上腺素能系统, 去甲肾上腺素引起杏仁核基底外侧核(basolateral amygdala, BLA)过度兴奋, 然后BLA通过投射突触抑制在恐惧消退中起核心作用的内侧前额叶神经元的活动。未来研究应注意即刻消退缺损引起的长期后果, 并深入探讨如何优化即刻消退在临床上的应用。     

Preextinction Stress Prevents Context-Related Renewal of Fear

Extinction learning, which creates new safety associations, is thought to be the mechanism underlying exposure therapy, commonly used for the treatment of anxiety disorders and posttraumatic stress disorder. The relative strength and availability for retrieval of both the fear and safety memories determine the response in a given situation. While the fear memory is often context-independent and may easily generalize, extinction memory is highly context-specific. “Renewal” of the extinguished fear memory might thus occur following a shift in context. The aim of the current work was to create an enhanced and generalized extinction memory to a discrete stimulus using stress exposure before extinction learning, thereby preventing renewal. In our contextual fear conditioning paradigm, 40 healthy men acquired (Day 1), retrieved and extinguished (Day 2) the fear memories, with no differences between the stress and the control group. A significant difference between the groups emerged in the renewal test (Day 3). A renewal effect was seen in the control group (N = 20), confirming the context-dependency of the extinction memory. In contrast, the stress group (N = 20) showed no renewal effect. Fear reduction was generalized to the acquisition context as well, suggesting that stress rendered the extinction memory more context-independent. These results are in line with previous studies that showed contextualization disruption as a result of pre-learning stress, mediated by the rapid effects of glucocorticoids on the hippocampus. Our findings support research investigating the use of glucocorticoids or stress induction in exposure therapy and suggest the right timing of administration in order to optimize their effects.     

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。     

如何克服边界条件：来自记忆强度影响记忆去稳定的分子机制的启示

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

The effects of post-encoding stress on recognition memory: examining the impact of skydiving in young men and women

Prior studies have indicated that post-encoding stress can protect memories from the effects of forgetting, and this has been taken as evidence that stress facilitates memory consolidation. However, it is not known whether stress acts by directly influencing the strength of the underlying memories or whether it influences the generation process that plays a critical role in tests such as free recall. To address this issue, we examined the effects of stress produced by skydiving on recognition memory for negative and neutral pictures. Relative to a non-stress control condition, post-encoding stress in males was found to increase recognition memory for neutral pictures. However, stress was not found to improve recognition for emotional pictures, nor was it found to influence recognition memory in female participants. Additional analysis of recognition performance suggested that stress increased familiarity-based recognition rather than recollection. This study indicates that stress can improve familiarity-based recognition, thus showing that stress directly increases the strength of the underlying memories.     

Above and beyond emotional valence: the unique contribution of central and traumatic shame memories to psychopathology vulnerability

This paper explores whether shame memories have a distinct impact on emotional difficulties and psychopathology that goes beyond their negative emotional valence. Study 1 (N=292) investigates the contribution of centrality of shame memory, in comparison to the centrality of fear and sadness memories, to explain the memory's traumatic impact, shame, depression, anxiety, stress, paranoid, and dissociative symptoms. Study 2 (N=192) explores the impact of shame traumatic memory on shame and depression, anxiety, and stress symptoms, in comparison to fear and sadness traumatic memories. Both studies used undergraduate student samples. Results show that shame memories' centrality and traumatic features made an independent contribution to current external and internal shame and distinct psychopathological symptoms, after controlling for the effect of fear and sadness, centrality, and traumatic qualities. Moreover, shame memories' centrality and traumatic features were the best global predictors of external and internal shame and depressive symptoms. Centrality of shame memories was also the only significant predictor of paranoid ideation and dissociation. These results offer novel perspectives on the nature of shame and its relation to psychopathology, emphasising the distinct role of shame memories in human functioning and suffering, which goes above and beyond its negative emotional valence.     

Glucocorticoids are required for extinction of predator stress-induced hyperarousal

Background

The role of glucocorticoids in extinction of traumatic memories has not been fully characterized despite its potential as a therapeutic target for acquired posttraumatic stress disorder (PTSD). The predator stress paradigm allows us to determine whether glucocorticoids mediate the extinction of both context-dependent and context-independent fear memories.

Methods

Male C57BL/6J mice were exposed to a predator (cat) then repeatedly exposed to the predator stress context in the absence of the cat. Context-dependent (associative) fear memory was assessed as suppression of activity during re-exposure to the predator stress context without the cat (extinction trials). Context-independent fear (non-associative) was assessed seven days after extinction trials using measures of hyperarousal and anxiety-like behaviours in environments unlike the predator stress context. To assess the role of glucocorticoids, mice were injected with metyrapone (50 mg/kg) 90 min prior to extinction trials in predator stressed mice and context-dependent and context-independent fear memories were assessed. Finally, metyrapone-treated predator stressed mice were injected with corticosterone (5 or 10 mg/kg) immediately following extinction trials and context-dependent and context-independent fear memories were assessed.

Results

Repeated re-exposure to the predator stress context without the cat present extinguished context-dependent fear memory, and also reduced hyperarousal, a generalized, chronic PTSD-like symptom. We show that extinction of context-independent predator stress-induced hyperarousal is dependent on endogenous glucocorticoids during the extinction trials. Furthermore, the inhibition of extinction by metyrapone on startle amplitude was reduced by exogenous administration of corticosterone following extinction trials. Overall, these data implicate glucocorticoids in the extinction of hyperarousal, a core symptom of PTSD.     

Above and beyond emotional valence: The unique contribution of central and traumatic shame memories to psychopathology vulnerability

This paper explores whether shame memories have a distinct impact on emotional difficulties and psychopathology that goes beyond their negative emotional valence. Study 1 (N=292) investigates the contribution of centrality of shame memory, in comparison to the centrality of fear and sadness memories, to explain the memory's traumatic impact, shame, depression, anxiety, stress, paranoid, and dissociative symptoms. Study 2 (N=192) explores the impact of shame traumatic memory on shame and depression, anxiety, and stress symptoms, in comparison to fear and sadness traumatic memories. Both studies used undergraduate student samples. Results show that shame memories' centrality and traumatic features made an independent contribution to current external and internal shame and distinct psychopathological symptoms, after controlling for the effect of fear and sadness, centrality, and traumatic qualities. Moreover, shame memories' centrality and traumatic features were the best global predictors of external and internal shame and depressive symptoms. Centrality of shame memories was also the only significant predictor of paranoid ideation and dissociation. These results offer novel perspectives on the nature of shame and its relation to psychopathology, emphasising the distinct role of shame memories in human functioning and suffering, which goes above and beyond its negative emotional valence.     

恐惧记忆习得与消退的性别差异及其神经机制

大多数人在其一生中都会经历创伤事件,但只有少数人会发展成为创伤后应激障碍（PTSD）。焦虑障碍的易感性和保护因素成为一个重要议题。基于恐惧记忆习得与消退模型的研究发现女性个体表现出“易习得、难消退”的特点。在恐惧相关脑区的脑生理结构、功能/结构连接性、以及大脑可塑性的性别差异可能是该特征的根本原因。性激素作为一种焦虑障碍的保护因素,可以调节这种性别差异,这种调节效应可能是通过影响大脑结构形态（如神经细胞的形态和数量）、调控与记忆相关基因的表达（如HDAC4）而实现的。雌性激素水平的不稳定性可能是女性易感焦虑障碍的重要原因。未来对性别差异的深入研究将有助于推进个性化医疗。