The exclusive induction of extinction is gated by BDNF

We have previously reported that the reconsolidation and extinction of hippocampal-dependent contextual fear memory can be initiated by a single context conditioned stimulus (CS) presentation of either short or long duration, and that both processes require protein synthesis in this brain region. Furthermore, reconsolidation depends on Zif268 activity in this region. Here we show that by infusing a recombinant brain-derived neurotrophic factor (rBDNF) directly into the brain of rats, that high levels of mature BDNF in the hippocampus at retrieval constrain the extinction of the fear memory after prolonged memory recall. We also show after a short CS exposure that reconsolidation was impaired using antisense oligonucleotides targeting Zif268, and that, similarly, reductions in conditioned behavior were observed after prolonged CS presentation when extinction is constrained by high levels of BDNF. This is direct evidence that in the mammalian brain extinction proceeds exclusively after prolonged CS exposure. In addition, that BDNF activity in the hippocampus contributes to a molecular switch for the extinction of hippocampal-dependent memory.     

Post-retrieval beta-adrenergic receptor blockade: effects on extinction and reconsolidation of cocaine-cue memories

Contexts and discrete cues associated with drug-taking are often responsible for relapse among addicts. Animal models have shown that interference with the reconsolidation of drug-cue memories can reduce seeking of drugs or drug-paired stimuli. One such model is conditioned place preference (CPP) in which an animal is trained to associate a particular environment with the rewarding effects of a drug. Previous work from this laboratory has shown that intra-nucleus accumbens core infusions of a MEK inhibitor can interfere with reconsolidation of these drug-cue memories. A question that remains is whether post-retrieval drug effects on subsequent memories represent an interference with reconsolidation processes or rather a facilitation of extinction. In this experiment, we explore the effect of post-retrieval injections of propranolol, a beta-adrenergic receptor antagonist, on reconsolidation and extinction of cocaine CPP. After acquisition of cocaine CPP, animals were given post-retrieval propranolol injections once or each day during a protocol of unreinforced preference tests, until the animals showed no preference for the previously cocaine-paired environment. Following a cocaine priming injection, the animals that received daily post-test propranolol injections did not reinstate their preference for the drug-paired side. In contrast, a single post-retrieval propranolol injection followed by multiple days of unreinforced preference tests failed to blunt subsequent cocaine reinstatement of the memory. These data suggest that daily post-retrieval systemic injections of propranolol decrease the conditioned preference by interfering with reconsolidation of the memory for the association between the drug-paired side and the reinforcing effects of the drug, rather than facilitating new extinction learning.     

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。     

Mismatch between what is expected and what actually occurs triggers memory reconsolidation or extinction

In previous experiments on contextual memory, we proposed that the unreinforced re-exposure to the learning context (conditioned stimulus, CS) acts as a switch guiding the memory course toward reconsolidation or extinction, depending on reminder duration. This proposal implies that the system computes the total exposure time to the context, from CS onset to CS offset, and therefore, that the reminder presentation must be terminated for the switching mechanism to become operative. Here we investigated to what extent this requirement is necessary, and we explored the relation between diverse phases in the reconsolidation and extinction processes. We used the contextual memory model of the crab Chasmagnathus which involves an association between the learning context (CS) and a visual danger stimulus (unconditioned stimulus, US). Administration of cycloheximide was used to test the lability state of memory at different time points. The results show that two factors, no-reinforcement during the reminder (i.e., CS re-exposure) and CS offset are the necessary conditions for both processes to occur. Regardless of the reminder duration, memory retrieved by unreinforced CS re-exposure emerges intact and consolidated when tested before CS offset, suggesting that neither reconsolidation nor extinction is concomitant with CS re-exposure. Either process could only be triggered once the definitive mismatch between CS and US is confirmed by CS termination without the expected reinforcement.     

Inhibition of matrix metalloproteinase activity disrupts reconsolidation but not consolidation of a fear memory

The reconsolidation hypothesis posits that memories that have been reactivated can be either enhanced or disrupted by pharmacological manipulation. Synaptic plasticity is presumed to underlie the reconsolidation process. Matrix metalloproteinases are proteins that regulate the extracellular matrix involved in plasticity events, and these proteins have recently been shown to influence learning and memory. However, all studies on the role of matrix metalloproteinases in learning and memory have employed tasks that rely on contextual cues. The goal of this study was to determine the extent to which FN-439 would disrupt the consolidation and/or reconsolidation of a fear memory associated with a conditioned stimulus that signaled tone-shock pairings and that was independent of contextual cues. Male Sprague-Dawley rats were given infusions of FN-439 (35 microg intracerebroventricular) 30 min prior to conditioning (tone-shock paired association) or 30 min prior to a single reactivation session given 24h after conditioning. Administration of FN-439 did not disrupt consolidation of the freezing response when the tone (conditioned stimulus) was presented. In contrast, FN-439 infusion disrupted reconsolidation of the fear memory in a reactivation-dependent manner. The reduced freezing behavior was not due to a decrease in general anxiety levels, since FN-439 had no effect on the percent of open-arm time or open-arm entries in an elevated-plus maze task. Thus, we demonstrated for the first time that matrix metalloproteinase inhibition in the brain is capable of disrupting the reconsolidation of a tone-shock association memory that does not depend on contextual cues. The finding that a fear response to a previously paired conditioned stimulus can be disrupted by treatment with an MMP inhibitor during a single reactivation session suggests that this class of compounds may have therapeutic potential for posttraumatic stress disorder and/or simple phobias.     

Reconsolidation and memory infidelity in Lymnaea

Lymnaea stagnalis were operantly conditioned to not perform aerial respiratory behaviour in a specific context (i.e. context-1). The memory for this learned response was reactivated 3 days later in context-1. During the 1 h reconsolidation period following memory reactivation, randomly picked snails were either maintained in context-1 or exposed to a new context (i.e. context-2). One hour later in the post-reconsolidation period, snails in context-1 were placed for 1 h in context-2 and vice-versa. In neither the hypoxic reconsolidation nor the post reconsolidation periods did snails receive a reinforcing stimulus when they opened their pneumostome. All snails were blindly tested for memory 24 h later period in context-2. Only those snails that had been exposed to context-2 during the reconsolidation period exhibited 'memory' for context-2. That is, memory infidelity was observed. Snails exposed to context-2 in only the post-reconsolidation period did not show memory for context-2. The immediate cooling of snails after their exposure to the new context in the reconsolidation period blocked the formation the implanted memory. Snails trained in context-1 and exposed to context-2 in the consolidation period only, also did not have memory for context-2. However, the memory for context-1 could still be recalled following successful implantation of the 'new' memory. All data presented here are consistent with the notion that during the reconsolidation process memory can be updated.     

Reactivation-dependent amnesia in Pavlovian approach and instrumental transfer

The theory of memory reconsolidation relates to the hypothesized restabilisation process that occurs following the reactivation of a memory through retrieval. Thus the demonstration of reactivation-dependent amnesia for a previously acquired memory is a prerequisite for showing that such a memory undergoes reconsolidation. Here we show that the appetitive Pavlovian representations that underlie Pavlovian approach and Pavlovian-instrumental transfer are destabilized following their retrieval. This reactivation-dependent amnesia demonstrates that the general motivational or incentive properties of appetitive conditioned stimuli, as well as their conditioned reinforcing properties, can be reduced by blocking memory reconsolidation.     

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。     

Appetitive memory reconsolidation depends upon NMDA receptor-mediated neurotransmission

Memory persistence is a dynamic process involving the reconsolidation of memories after their reactivation. Reconsolidation impairments have been demonstrated for many types of memories in rats, and signaling at N-methyl-d-aspartate (NMDA) receptors appears often to be a critical pharmacological mechanism. Here we investigated the reconsolidation of appetitive pavlovian memories reinforced by natural rewards. In male Lister Hooded rats, systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-SH-dibenzo{a,d}cyclohepten-5,10-imine maleate (MK-801, 0.1 mg/kg i.p.) either before or immediately following a brief memory reactivation session abolished the subsequent acquisition of a new instrumental response with sucrose conditioned reinforcement. However, only when injected prior to memory reactivation was MK-801 effective in disrupting the maintenance of a previously-acquired instrumental response with conditioned reinforcement. These results demonstrate that NMDA receptor-mediated signaling is required for appetitive pavlovian memory reconsolidation.     

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

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

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。     

Extinction memory in the crab Chasmagnathus: recovery protocols and effects of multi-trial extinction training

A decline in the frequency or intensity of a conditioned behavior following the withdrawal of the reinforcement is called experimental extinction. However, the experimental manipulation necessary to trigger memory reconsolidation or extinction is to expose the animal to the conditioned stimulus in the absence of reinforcement. Recovery protocols were used to reveal which of these two processes was developed. By using the crab contextual memory model (a visual danger stimulus associated with the training context), we investigated the dynamics of extinction memory in Chasmagnathus. Here, we reveal the presence of three recovery protocols that restore the original memory: the old memory comes back 4 days after the extinction training, or when a weak training is administered later, or once the VDS is presented in a novel context 24 h after the extinction session. Another objective was to evaluate whether the administration of multi-trial extinction training could trigger an extinction memory in Chasmagnathus. The results evince that the extinction memory appears only when the total re-exposure time is around 90 min independently of the number of trials employed to accumulate it. Thus, it is feasible that the mechanisms described for the case of the extinction memory acquired through a single training trial are valid for multi-trial extinction protocols. Finally, these results are in agreement with those reports obtained with models phylogenetically far apart from the crab. Behind this attempt is the idea that in the domain of studies on memory, some principles of behavior organization and basic mechanisms have universal validity.     

The basolateral amygdala and nucleus accumbens core mediate dissociable aspects of drug memory reconsolidation

A distributed limbic-corticostriatal circuitry is implicated in cue-induced drug craving and relapse. Exposure to drug-paired cues not only precipitates relapse, but also triggers the reactivation and reconsolidation of the cue-drug memory. However, the limbic cortical-striatal circuitry underlying drug memory reconsolidation is unclear. The aim of this study was to investigate the involvement of the nucleus accumbens core and the basolateral amygdala in the reconsolidation of a cocaine-conditioned stimulus-evoked memory. Antisense oligodeoxynucleotides (ASO) were infused into each structure to knock down the expression of the immediate-early gene zif268, which is known to be required for memory reconsolidation. Control infusions used missense oligodeoxynucleotides (MSO). The effects of zif268 knockdown were measured in two complementary paradigms widely used to assess the impact of drug-paired CSs upon drug seeking: the acquisition of a new instrumental response with conditioned reinforcement and conditioned place preference. The results show that both intranucleus accumbens core and intrabasolateral amygdala zif268 ASO infusions at memory reactivation impaired the reconsolidation of the memory underlying a cocaine-conditioned place preference. However, knockdown of zif268 in the nucleus accumbens at memory reactivation had no effect on the memory underlying the conditioned reinforcing properties of the cocaine-paired CS measured subsequently, and this is in contrast to the marked impairment observed previously following intrabasolateral amygdala zif268 ASO infusions. These results suggest that both the basolateral amygdala and nucleus accumbens core are key structures within limbic cortical-striatal circuitry where reconsolidation of a cue-drug memory occurs. However reconsolidation of memory representations formed during Pavlovian conditioning are differentially localized in each site.Through Pavlovian association with the effects of addictive drugs, a conditioned stimulus (CS) acquires both general motivational and sensory-specific conditioned reinforcing properties (Everitt et al. 2000). These associations contribute to the high likelihood of relapse in addicted individuals, yet the extinction of drug CSs by nonreinforced exposure has proved to be of limited therapeutic utility (Conklin and Tiffany 2002). In abstinent humans, drug CSs evoke salient and persistent memories of drug-taking experiences, inducing craving and relapse (Childress et al. 1988; O''Brien et al. 1992), while in animals they also precipitate relapse to, or reinstatement of, drug-seeking behavior (de Wit and Stewart 1981; Meil and See 1996; Fuchs et al. 1998; Weiss 2000). Thus, disrupting drug-related memories might significantly diminish relapse propensity on subsequent exposure to drug-paired CSs, and thereby promote abstinence.Exposure to a drug-associated CS also triggers a process of memory reconsolidation, which restabilizes the reactivated and labile memory (Nader 2003). While reconsolidation may adaptively update memories (Dudai 2006; Hupbach et al. 2007; Rossato et al. 2007; Lee 2009), its disruption may reduce the impact of intrusive or aberrant memories on behavior subsequently (Lee et al. 2005, 2006; Brunet et al. 2008; Kindt et al. 2009; Taubenfeld et al. 2009). The reconsolidation of CS–cocaine memories has been shown to depend upon protein synthesis and expression of the plasticity-associated immediate-early gene, zif268, in the basolateral amygdala (BLA), since zif268 knockdown at memory reactivation disrupted the acquired conditioned reinforcing properties of the CS measured in drug-seeking tasks days or weeks later (Lee et al. 2005, 2006).Although the BLA has an established role in CS-drug memory reconsolidation, it remains unclear whether other sites within limbic cortical-ventral striatal circuitry participate in this process. The nucleus accumbens core (AcbC) is a primary candidate, as zif268 is up-regulated in the AcbC as well as in the BLA following exposure to cocaine CSs (Thomas et al. 2003). Furthermore, the AcbC, which is strongly implicated in Pavlovian influences on drug seeking and relapse (Cardinal et al. 2002; Kalivas and McFarland 2003), has been shown to be a site where the reconsolidation of a drug conditioned place preference (CPP) memory can be disrupted (Miller and Marshall 2005).Given the evidence of increased zif268 expression in the AcbC following CS-drug memory reactivation, we investigated its requirement in the reconsolidation of cocaine-associated memories. To address this issue, we employed two different but complementary paradigms widely used to measure the conditioned effects of CSs associated with drugs of abuse: the acquisition of a new instrumental response with conditioned reinforcement (ANR) and CPP. These procedures have been used successfully to investigate the mechanisms underlying the reconsolidation of appetitive Pavlovian memories, but it is likely that they depend upon different associative mechanisms (Everitt et al. 1991; White and McDonald 1993) that in turn depend upon different neural loci within limbic cortical-striatal circuitry (Cardinal et al. 2002). Therefore, to enable a full comparison with the functional involvement of the BLA, we investigated the necessity for BLA zif268 expression in drug memory reconsolidation as assessed in the CPP paradigm.     

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。     

The neurobiology of fear memory reconsolidation and psychoanalytic theory

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

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。     

Differential roles of the basolateral amygdala and nucleus basalis magnocellularis during post-reactivation contextual fear conditioning reconsolidation in rats

The roles of the basolateral amygdala and nucleus basalis magnocellularis in fear conditioning reconsolidation were investigated by means of tetrodotoxin bilateral inactivation performed 96 h after conditioning, immediately after reactivation training. Footshocks of 1.2 mA intensity were employed to induce the generalization phenomenon. Basolateral amygdala inactivation disrupts the contextual fear response and its generalization but not acoustic CS trace retention, when measured 72 and 96 h after tetrodotoxin administration. Nucleus basalis magnocellularis functional inactivation does not affect memory post-reactivation phase of any of the three conditioned fear responses. The present findings show a differential role of the two structures in fear memory reconsolidation and can be a starting point for future investigation of the neural circuits subserving generalization.     

Extinction learning, reconsolidation and the internal reinforcement hypothesis

Retrieving a consolidated memory--by exposing an animal to the learned stimulus but not to the associated reinforcement--leads to two opposing processes: one that weakens the old memory as a result of extinction learning, and another that strengthens the old, already-consolidated memory as a result of some less well-understood form of learning. This latter process of memory strengthening is often referred to as "reconsolidation", since protein synthesis can inhibit this form of memory formation. Although the behavioral phenomena of the two antagonizing forms of learning are well documented, the mechanisms behind the corresponding processes of memory formation are still quite controversial. Referring to results of extinction/reconsolidation experiments in honeybees, we argue that two opposing learning processes--with their respective consolidation phases and memories--are initiated by retrieval trials: extinction learning and reminder learning, the latter leading to the phenomenon of spontaneous recovery from extinction, a process that can be blocked with protein synthesis inhibition.     

记忆再巩固的时间动态性及其生物学机制

记忆巩固需经觉醒状态下的信息编码和睡眠状态下的巩固阶段两个过程。记忆再巩固理论认为记忆巩固是一个需要多次反复巩固的过程,即使已巩固的记忆也会在提取激活后变得不稳定, 需经再巩固才能重返稳定状态, 此过程需要新的蛋白质的合成。记忆再巩固具有较强的时间特征, 发生在记忆巩固之后, 依赖于蛋白质降解的去稳定化阶段和依赖于蛋白质合成的记忆再稳定阶段, 所持续的时间窗为6 h。不同类型的记忆是否引发记忆再巩固或消退行为, 取决于提取试次暴露所持续时间的长短。     

The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear

Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its function as a histone deacetylase inhibitor (HDAC). Here we report that VPA enhances long-term memory for both acquisition and extinction of cued-fear. Interestingly, VPA enhances extinction, but also enhances renewal of the original conditioned fear when tested in a within-subjects design. This effect appears to be related to a reconsolidation-like process since a single CS reminder in the presence of VPA can enhance long-term memory for the original fear in the context in which fear conditioning takes place. We also show that by modifying the intertrial interval during extinction training, VPA can strengthen reconsolidation of the original fear memory or enhance long-term memory for extinction such that it becomes independent of context. These findings have important implications for the use of HDAC inhibitors as adjuncts to behavior therapy in the treatment of phobia and related anxiety disorders.