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。     

Retrieval induces hippocampal-dependent reconsolidation of spatial memory

Nonreinforced retrieval can cause extinction and/or reconsolidation, two processes that affect subsequent retrieval in opposite ways. Using the Morris water maze task we show that, in the rat, repeated nonreinforced expression of spatial memory causes extinction, which is unaffected by inhibition of protein synthesis within the CA1 region of the dorsal hippocampus. However, if the number of nonreinforced retrieval trials is insufficient to induce long-lasting extinction, then a hippocampal protein synthesis-dependent reconsolidation process recovers the original memory. Inhibition of hippocampal protein synthesis after reversal learning sessions impairs retention of the reversed preference and blocks persistence of the original one, suggesting that reversal learning involves reconsolidation rather than extinction of the original memory. Our results suggest the existence of a hippocampal protein synthesis-dependent reconsolidation process that operates to recover or update retrieval-weakened memories from incomplete extinction.     

Retrieval does not induce reconsolidation of inhibitory avoidance memory

It has been suggested that retrieval during a nonreinforced test induces reconsolidation instead of extinction of the mnemonic trace. Reconsolidation would preserve the original memory from the labilization induced by its nonreinforced recall through a hitherto uncharacterized mechanism requiring protein synthesis. Given the importance that such a process would have in terms of maintaining, as part of the animal behavioral repertoire, a learned response that has been devalued by experience, we analyzed its existence for the memory associated with a one-trial, step-down inhibitory avoidance task (IA), a memory whose consolidation and extinction require protein synthesis in the CA1 region of the dorsal hippocampus (CA1) and involve the participation of the basolateral amygdala (BLA) and entorhinal cortex (ENT). Rats were trained in IA, and 24 h later they were submitted either to a pure reactivation session (retrieval without stepping down), which was unable by itself to initiate extinction of the avoidance response, or to a second training session. Fifteen minutes before or 3 h after either the reactivation or the retraining sessions, animals were infused with the protein synthesis inhibitor anisomycin (ANI) into CA1, BLA, or ENT. Contrary to the prediction of the reconsolidation hypothesis, none of these treatments affected subsequent memory retention. Because reconsolidation is regarded to be a direct consequence of retrieval, one would expect that, when given before a retention test or a pure reactivation session, enhancers of memory expression should permanently improve retention and, therefore, facilitate retrieval both in that and in subsequent sessions. Using two well-known retrieval enhancers, noradrenaline and adrenocorticotropin(1-24), we could not find any evidence suggestive of reconsolidation. Hence, our results indicate that there is no retrieval-induced, protein synthesis-dependent process that would cause reconsolidation of IA memory.     

Differential involvement of mGluR1 and mGluR5 in memory reconsolidation and retrieval in a passive avoidance task in 1-day old chicks

Group I metabotropic glutamate receptors (mGluRs) are involved in memory formation. The Ca2+ signal derived from stimulation of IP3 receptors (IP3Rs) via mGluRs, initiates protein synthesis that is required for memory consolidation and reconsolidation. However it has been suggested that different mechanisms are triggered by mGluR1/5 activation in these two processes. It is also not clear whether the transient amnesia observed after blockade of group I mGluRs after a reminder, results from disturbance of memory reconsolidation or temporal impairment of recall. The aim of this study was to examine more closely the role of mGluR1 in memory consolidation and reconsolidation and to detect differences in the participation of mGluR1 and mGluR5 in memory retrieval after initial training and after the remainder of the task. Our results demonstrate, that in chicks performing a one-trial passive avoidance task, antagonists of mGluR1, mGluR5 and IP3R significantly disturb memory consolidation and reconsolidation. Inhibition of mGluR5 and IP3R also impairs memory recall, whereas mGluR1 do not seem to participate in this process. The presented data suggest that activation of mGluR1 and mGluR5 is necessary for the correct course of memory consolidation and reconsolidation, whereas mGluR5 are additionally involved in retrieval processes dependent on Ca2+ release from IP3 activated intracellular stores.     

Reconsolidation of declarative memory in humans

The reconsolidation hypothesis states that a consolidated memory could again become unstable and susceptible to facilitation or impairment for a discrete period of time after a reminder presentation. The phenomenon has been demonstrated in very diverse species and types of memory, including the human procedural memory of a motor skill task but not the human declarative one. Here we provide evidence for both consolidation and reconsolidation in a paired-associate learning (i.e., learning an association between a cue syllable and the respective response syllable). Subjects were given two training sessions with a 24-h interval on distinct verbal material, and afterward, they received at testing two successive retrievals corresponding to the first and second learning, respectively. Two main results are noted. First, the first acquired memory was impaired when a reminder was presented 5 min before the second training (reconsolidation), and also when the second training was given 5 min instead of 24 h after the first one (consolidation). Second, the first retrieval proved to influence negatively on the later one (the retrieval-induced forgetting [RIF] effect), and we used the absence of this RIF effect as a very indicator of the target memory impairment. We consider the demonstration of reconsolidation in human declarative memory as backing the universality of this phenomenon and having potential clinical relevance. On the other hand, we discuss the possibility of using the human declarative memory as a model to address several key topics of the reconsolidation hypothesis.     

Amnesia or retrieval deficit? Implications of a molecular approach to the question of reconsolidation

Post-retrieval interference with a memory has uncovered a phenomenon known to the field as reconsolidation. In this article, we will review the specific molecular mechanisms that have been implicated in reconsolidation. As a result of numerous studies over the past five years, it can now be said with a fair amount of certainty that reconsolidation is not a recapitulation of the mechanisms underlying consolidation, despite what the term "reconsolidation" may suggest. Therefore, in addition to reviewing the known mechanisms of reconsolidation, we will propose that two experimental approaches involving the targeting of specific molecular mechanisms, and the study of these mechanisms during retrieval, may serve useful to the field as it is now able to advance beyond comparisons between consolidation and reconsolidation.     

Cycloheximide produces amnesia for extinction and reconsolidation in an appetitive odor discrimination task in rats

A considerable literature has shown deficits in memory resulting from the administration of protein synthesis inhibitors; however, most of the past literature in this field has focused on acquisition of new memory using aversively-motivated tasks. The effect of protein synthesis inhibition on appetitive learning and memory as well as extinction is less clear. The present study employed an appetitive odor discrimination paradigm to examine the effects of acute cycloheximide administration (1 mg/kg) on reconsolidation and extinction.Male, Long-Evans adult rats were trained to discriminate between two odors (i.e., cocoa and cinnamon) and then received extinction trials following an intraperitoneal injection of cycloheximide or vehicle. Twenty-four hours later, rats were tested via one non-reinforced test trial. Results showed amnesia for extinction as well as original training (i.e., correct odor choice) in cycloheximide-injected rats in this appetitive task, while vehicle-injected controls showed good memory for extinction. These data add to a growing literature showing the importance of protein synthesis inhibition for extinction and reconsolidation in appetitive learning and memory.     

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。     

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.     

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

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

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.     

Infusion of protein synthesis inhibitors in the entorhinal cortex blocks consolidation but not reconsolidation of object recognition memory

Memory consolidation and reconsolidation require the induction of protein synthesis in some areas of the brain. Here, we show that infusion of the protein synthesis inhibitors anisomycin, emetine and cycloheximide in the entorhinal cortex immediately but not 180 min or 360 min after training in an object recognition learning task hinders long-term memory retention without affecting short-term memory or behavioral performance. Inhibition of protein synthesis in the entorhinal cortex after memory reactivation involving either a combination of familiar and novel objects or two familiar objects does not affect retention. Our data suggest that protein synthesis in the entorhinal cortex is necessary early after training for consolidation of object recognition memory. However, inhibition of protein synthesis in this cortical region after memory retrieval does not seem to affect the stability of the recognition trace.     

A role for ERK2 in reconsolidation of fear memories in mice

Recent studies have shown that consolidated fear memories, when reactivated, return to a labile state that requires a new protein synthesis for reconsolidation. Post-retrieval infusion of an inhibitor of protein synthesis blocks memory reconsolidation processes. In a previous research, the role of MAPKs in memory consolidation has been shown in emotional tasks, such as passive and active avoidance. In particular, mice knockout for ERK1 had a better performance in comparison to wild type mice in both passive and active avoidance tasks. In the present study, in order to investigate the involvement of MAPKs in memory reconsolidation processes we administered immediately after retrieval, different doses of SL327 (an inhibitor of MEK, a kinase that activates both ERK1 and ERK2) both in C57BL/6 (C57) mice and ERK1 mutant mice tested in a fear conditioning task. Systemic administration of SL327 dose-dependently reduced the memory reconsolidation of fear memories in C57 mice. Moreover, SL327 administration impaired memory reconsolidation also in ERK1 mutant mice. Altogether, these results clearly indicate a central role for ERK2 protein in memory reconsolidation processes in mice.     

The effects of the dopamine D1 receptor antagonist SCH23390 on memory reconsolidation following reminder-activated retrieval in day-old chicks

This series of experiments examined the involvement of the dopamine D1 receptor antagonist, SCH23390, on memory reconsolidation following reminder-activated retrieval. Day-old male New HampshirexWhite Leghorn chicks were trained on a single trial passive avoidance task. A dose of 0.5 mg/kg of SCH23390 was administered subcutaneously 5 min before reminder trials, which were presented at 30, 60, and 90 min following training. Memory deficits were observed when reminder trials were presented at 30 and 60 min following training, but not when a reminder was presented at 90 min. No effect on memory retention was observed when reminder trials were not presented, suggesting that reconsolidation mechanisms were both contingent on the presentation of the reminder and independent of the consolidation process. Following a reminder presented at 60 min post-training, deficits in memory retention emerged between 45 and 60 min. The deficit was prolonged, lasting for up until 48 h after reminder presentation. The results indicate an important role for the D1 receptor in reconsolidation processes.     

Mapping of olfactory memory circuits: region-specific c-fos activation after odor-reward associative learning or after its retrieval

Although there is growing knowledge about intracellular mechanisms underlying neuronal plasticity and memory consolidation and reconsolidation after retrieval, information concerning the interaction among brain areas during formation and retrieval of memory is relatively sparse and fragmented. Addressing this question requires simultaneous monitoring of activity in multiple brain regions during learning, the post-acquisition consolidation period, and retrieval and subsequent reconsolidation. Immunoreaction to the immediate early gene c-fos is a powerful tool to mark neuronal activation of specific populations of neurons. Using this method, we are able to report, for the first time, post-training activation of a network of closely related brain regions, particularly in the frontal cortex and the basolateral amygdala (BLA), that is specific to the learning of an odor-reward association. On the other hand, retrieval of a well-established associative memory trace does not seem to differentially activate the same regions. The amygdala, in particular, is not engaged after retrieval, whereas the lateral habenula (LHab) shows strong activation that is restricted to animals having previously learned the association. Although intracellular mechanisms may be similar during consolidation and reconsolidation, this study indicates that different brain circuits are involved in the two processes, at least with respect to a rapidly learned olfactory task.     

De novo mRNA synthesis is required for both consolidation and reconsolidation of fear memories in the amygdala

Memory consolidation is the process by which newly learned information is stabilized into long-term memory (LTM). Considerable evidence indicates that retrieval of a consolidated memory returns it to a labile state that requires it to be restabilized. Consolidation of new fear memories has been shown to require de novo RNA and protein synthesis in the lateral nucleus of the amygdala (LA). We have previously shown that de novo protein synthesis in the LA is required for reconsolidation of auditory fear memories. One key question is whether protein synthesis during reconsolidation depends on already existing mRNAs or on synthesis of new mRNAs in the amygdala. In the present study, we examined the effect of mRNA synthesis inhibition during consolidation and reconsolidation of auditory fear memories. We first show that intra-LA infusion of two different mRNA inhibitors dose-dependently impairs long-term memory but leaves short-term memory (STM) intact. Next, we show that intra-LA infusion of the same inhibitors dose-dependently blocks post-reactivation long-term memory (PR-LTM), whereas post-reactivation short-term memory (PR-STM) is left intact. Furthermore, the same treatment in the absence of memory reactivation has no effect. Together, these results show that both consolidation and reconsolidation of auditory fear memories require de novo mRNA synthesis and are equally sensitive to disruption of de novo mRNA synthesis in the LA.     

Differential sensitivity of recent vs. remote memory traces to extinction in a water-maze task in rats

Extinction has mostly been studied in conditioning paradigms, more sparsely in spatial tasks, and never as a function of the age of a spatial memory. Using rats, we compared the time-course of extinction of a recent (5 days) vs. remote (25 days) spatial memory in a water maze, over three probe trials. When the trials were set 24h apart, performance in the remote memory group was significantly worse on the first probe trial and significantly better on the third probe trial, as compared to the recent memory group, thereby showing differences between cognitive operations underlying recent vs. remote memory extinction. In contrast, when trials were given consecutively, both groups showed a similar profile of extinction. Furthermore, in a room with overly-salient cues providing a strong remote memory trace, no difference between groups was observed when the spaced extinction paradigm was used. These results might be related to a balance between reconsolidation and extinction processes occurring after a first retrieval experience, of which the outcome may depend on the extinction protocol, and on the age and strength of a memory.