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.     

Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory

Mammalian target of rapamycin (mTOR), a central regulator of protein synthesis in neurons, has been implicated in synaptic plasticity and memory. Here we show that mTOR inhibition by rapamycin in the basolateral amygdala (BLA) or dorsal hippocampus (DH) impairs both formation and reconsolidation of memory for inhibitory avoidance (IA) in rats. Male Wistar rats received bilateral infusions of vehicle or rapamycin into the BLA or DH before or after IA training or retrieval. Memory retention was tested at different time points after drug infusion. Rapamycin impaired long-term IA retention when given before or immediately after training or retrieval into the BLA. When infused into the DH, rapamycin produced memory impairment when given before training or immediately after retrieval. The impairing effects of post-retrieval rapamycin required memory retrieval and were not reversed by a reminder shock. The results provide the first evidence that mTOR in the BLA and DH might play a role in IA memory reconsolidation.     

Relationship between short- and long-term memory and short- and long-term extinction

Both the acquisition and the extinction of memories leave short- and long-term mnemonic traces. Here, we show that in male Wistar rats, the short-term memory for a step-down inhibitory avoidance task (IA) is resistant to extinction, and that its expression does not influence retrieval or extinction of long-term memory. It has been known for some time that short- and long-term inhibitory avoidance memory involve separate and parallel processes. Here we show that, instead, short-term extinction of IA long-term memory is the first step towards its long-term extinction, and that this link requires functional NMDA receptors and protein synthesis in the CA1 region of the dorsal hippocampus at the time of the first CS-no US presentation.     

On the role of hippocampal protein synthesis in the consolidation and reconsolidation of object recognition memory

Upon retrieval, consolidated memories are again rendered vulnerable to the action of metabolic blockers, notably protein synthesis inhibitors. This has led to the hypothesis that memories are reconsolidated at the time of retrieval, and that this depends on protein synthesis. Ample evidence indicates that the hippocampus plays a key role both in the consolidation and reconsolidation of different memories. Despite this fact, at present there are no studies about the consequences of hippocampal protein synthesis inhibition in the storage and post-retrieval persistence of object recognition memory. Here we report that infusion of the protein synthesis inhibitor anisomycin in the dorsal CA1 region immediately or 180 min but not 360 min after training impairs consolidation of long-term object recognition memory without affecting short-term memory, exploratory behavior, anxiety state, or hippocampal functionality. When given into CA1 after memory reactivation in the presence of familiar objects, ANI did not affect further retention. However, when administered into CA1 immediately after exposing animals to a novel and a familiar object, ANI impaired memory of both of them. The amnesic effect of ANI was long-lasting, did not happen after exposure to two novel objects, following exploration of the context alone, or in the absence of specific stimuli, suggesting that it was not reversible but was contingent on the reactivation of the consolidated trace in the presence of a salient, behaviorally relevant novel cue. Our results indicate that hippocampal protein synthesis is required during a limited post-training time window for consolidation of object recognition memory and show that the hippocampus is engaged during reconsolidation of this type of memory, maybe accruing new information into the original trace.     

Anisomycin infused into the hippocampus fails to block "reconsolidation" but impairs extinction: the role of re-exposure duration

Recent studies have reported new evidence consistent with the hypothesis that reactivating a memory by re-exposure to a training context destabilizes the memory and induces "reconsolidation." In the present experiments, rats' memory for inhibitory avoidance (IA) training was tested 6 h (Test 1), 2 d (Test 2), and 6 d (Test 3) after training. On Test 1 the rats were either removed from the shock compartment immediately after entry or retained in the shock context for 200 sec, and intrahippocampal infusions of the protein synthesis inhibitor anisomycin (75 microg/side) were administered immediately after the test. Anisomycin infusions administered after Test 1 impaired IA performance on Test 2 in animals given the brief re-exposure, but impaired extinction in animals exposed to the context for 200 sec. Rats with anisomycin-induced retention impairment on Test 2 demonstrated spontaneous recovery of retention performance on Test 3, whereas rats showing extinction on Test 2 showed further extinction on Test 3. The findings indicate that post-retrieval administration of anisomycin impairs subsequent retention performance only in the absence of extinction and that this impairment is temporary.     

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

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

GSK-3β activity in the hippocampus is required for memory retrieval

Several molecules were recently found to be important for the memory retrieval process in the hippocampus; however, the mechanisms underlying the memory retrieval remain poorly understood. GSK-3β has been implicated in the control of synaptic plasticity and memory formation. Here, we investigated the relationship between hippocampal GSK-3β activity and memory retrieval using behavioral and Western blotting methods. We found that GSK-3β was activated in the hippocampus after a retention session in the passive avoidance task. An intrahippocampal injection of the GSK-3β inhibitor, SB 216763, before the retention session blocked memory retrieval (but not reconsolidation) without affecting locomotor activity. These results suggest that GSK-3β activation would be essential for memory retrieval in the hippocampus.     

One retrieval trial induces reconsolidation in an appetitive learning paradigm in honeybees (Apis mellifera)

Combining memory retrieval with the application of a protein synthesis-inhibitor leads to an amnestic effect that is referred to as the reconsolidation phenomenon. Several behavioural studies demonstrate that only a few or weak retrieval trials (that do not result in significant extinction) lead to this phenomenon. In contrast, many trials (that result in significant extinction) combined with a protein synthesis inhibitor result in an inhibition of the extinction memory. Based on these findings it was suggested that extinction is the boundary condition for reconsolidation: when extinction is induced the consolidation of the extinction memory is the dominant process. Recently we were not able to confirm this hypothesis in the honeybee (Apis mellifera): We did not find the reconsolidation phenomenon after one retrieval trial, but demonstrated reconsolidation after five retrieval trials that led to extinction. To exclude that this observation resembles a special case in insects we here wanted to know if one retrieval trial induces reconsolidation as it has been demonstrated before in many other species. To do so we used experimental parameters that had been used before to demonstrate consolidation in the honeybee with the exception that this time the protein synthesis-inhibitor was applied 1 h after one memory retrieval instead after acquisition. We thereby demonstrate the reconsolidation phenomenon after one retrieval trial but only when using the doubled dose of protein synthesis-inhibitor that has been used to inhibit consolidation.     

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.     

The entorhinal cortex plays a role in extinction

In this study, we analyzed the participation of the entorhinal cortex in extinction of a learned aversive response. Rats with infusion cannulae aimed to the entorhinal cortex were trained in a one-trial step-down inhibitory avoidance task (IA) and submitted to four consecutive daily test sessions without the footshock, a procedure that induced extinction of the conditioned response in control animals. When infused into the entorhinal cortex immediately after the first extinction session at doses able to block consolidation of IA memory, the NMDA receptor antagonist, AP5 (25 nmol/side), the inhibitor of protein synthesis anisomycin (300 nmol/side) and the inhibitor of CaMKII, KN-93 (10 nmol/side), but not the MEK1/2 inhibitor PD-98059 (5 nmol/side) hindered extinction of the IA response. The same results were obtained when the interval between the first and second test session was 48 instead of 24h. The data indicate that normal functionality of the NMDA receptors, together with CaMKII activity and protein synthesis are necessary in the entorhinal cortex at the time of the first test session to generate extinction. Our results also suggest that the ERK1/2 pathway does not play a role in this process.     

Interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context-induced cocaine-seeking behavior in rats

Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory reconsolidation; however, it is not known whether these brain regions interact or independently control this phenomenon. To investigate this question, rats were trained to lever press for cocaine reinforcement in a distinct environmental context followed by extinction training in a different context. Rats were then briefly re-exposed to the cocaine-paired context to destabilize cocaine-related memories, or they were exposed to an unpaired context. Immediately thereafter, the rats received unilateral microinfusions of anisomycin (ANI) into the BLA plus baclofen/muscimol (B/M) into the contralateral (BLA/DH disconnection) or ipsilateral DH, or they received contralateral or ipsilateral microinfusions of vehicle. They then remained in their home cages overnight or for 21 d, followed by additional extinction training and a test of cocaine-seeking behavior (nonreinforced active lever responding). BLA/DH disconnection following re-exposure to the cocaine-paired context, but not the unpaired context, impaired subsequent drug context-induced cocaine-seeking behavior relative to vehicle or ipsilateral ANI + B/M treatment. Prolonged home cage stay elicited a time-dependent increase, or incubation, of drug-context-induced cocaine-seeking behavior, and BLA/DH disconnection inhibited this incubation effect despite some recovery of cocaine-seeking behavior. Thus, the BLA and DH interact to regulate the reconsolidation of cocaine-related associative memories, thereby facilitating the ability of drug-paired contexts to trigger cocaine-seeking behavior and contributing to the incubation of cocaine-seeking behavior.     

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。     

Systemic and intrahippocampal administrations of the glucocorticoid receptor antagonist RU38486 impairs fear memory reconsolidation in rats

Reconsolidation is the process by which previously consolidated memories are stabilized after retrieval. Several lines of evidence indicate that glucocorticoids modulate distinct phases of learning and memory. These effects are considered to be mediated by mineralocorticoid receptors and glucocorticoid receptors (GRs), which display a high concentration and distinct distribution in the hippocampus. The role of glucocorticoid system in fear memory reconsolidation is the subject of some controversy. Moreover, we found no studies that assessed the role of hippocampal GRs in fear memory reconsolidation. Here, we investigated the effect of GR blockade on fear memory reconsolidation in rats. Rats were trained and tested in an inhibitory avoidance task. Intrahippocampal or systemic administration of the GR antagonist RU38486 immediately following memory reactivation produced a deficit in post-retrieval long-term memory that persisted over test sessions, and memory did not re-emerge following a footshock reminder. These results indicate that hippocampal GRs are required for reconsolidation of fear-based memory.     

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。     

Disruption of memory reconsolidation impairs storage of other, non-reactivated memory

Two hypotheses were tested in this study. First, blockade of neural activity by lidocaine immediately following the retrieval of a memory may impair the reconsolidation and subsequent expression of that memory. Second, a non-retrieved memory would not be affected by this lidocaine treatment. Since the basolateral nucleus of the amygdala (BLA) is involved in emotion-related memory, an intra-BLA lidocaine infusion was used immediately after the retrieval of two emotion-related memories, the step-through passive avoidance response (PA) and cocaine-induced conditioned place preference (CPP). Intra-BLA lidocaine infusion immediately after cocaine-induced CPP retrieval diminished CPP magnitude in retests. However, intra-BLA lidocaine infusion alone did not affect cocaine-induced CPP performance. Intra-BLA lidocaine infusion immediately after PA retrieval decreased PA performance in retests. Omission of PA retrieval procedure, intra-BLA lidocaine infusion did not affect subsequent PA performance. Surprisingly, intra-BLA lidocaine infusion immediately following the retrieval of PA or cocaine-induced CPP diminished both PA and cocaine-induced CPP performance in the retests. Finally, Fos-staining results revealed that a number of BLA neurons were activated by the retrieval of both cocaine-induced CPP and PA. We conclude that inactivation of neural activity in BLA immediately following retrieval of a fear or cocaine-conditioned memory can impair subsequent expression of both memories. More importantly, retrieval of a memory does not seem to be an absolute condition for rapidly changing the memory.     

Reactivated memory of an inhibitory avoidance response in mice is sensitive to a nitric oxide synthase inhibitor

It is accepted that once consolidation is completed memory becomes permanent. However, it has also been suggested that reactivation (retrieval) of the original memory, again, makes it sensitive to the same treatments that affect memory consolidation when given after training. Previous results demonstrated that the immediate post-training intraperitoneal administration of N^ω-nitro-l-arginine methyl ester (L-NAME), a non-specific inhibitor of nitric oxide synthase (NOS), impairs retention test performance of a one-trial step-through inhibitory avoidance response in adult mice. The effect of L-NAME on retention was attributed to an action on memory consolidation of the original learning. For the first time, we report that the administration of L-NAME after the first retention test (memory reactivation) of the inhibitory avoidance response impairs retention performance over six consecutive days. This impairment effect is dose-and-time dependent and could not be attributed to a retrieval deficit since a mild footshock did not reinstate the original avoidance response and no spontaneous recovery was observed at least 21 days after training. Further support for a storage deficit interpretation as opposed to a retrieval deficit was obtained from the fact that L-NAME’s effects after retrieval were not due to state-dependency. The impairment effect of L-NAME was dependent on the age of the original memory. That is, there was an inverse correlation between the susceptibility of the memory trace when reactivated and the time elapsed between training and the first retrieval session. We suggest an action of L-NAME on memory reactivation-induced processes that are different from memory extinction of the original learning extending the biological significance of nitric oxide on memory.     

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 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.     

Amygdala or hippocampus inactivation after retrieval induces temporary memory deficit

The hypothesis that memory is stored through a single stage of consolidation that results in a stable and lasting long-term memory has been challenged by the proposition that reactivation of a memory induces reconsolidation of the memory. The reconsolidation hypothesis is supported by evidence that, under some conditions, post-retrieval treatments affecting amygdala and hippocampus functioning impair subsequent retention performance. We now report that repeated retention testing attenuates the performance impairment induced by post-retrieval reversible inactivation of the amygdala and hippocampus of rats induced by tetrodotoxin. These findings challenge the reconsolidation hypothesis and suggest that the post-retrieval retention performance impairment is best explained as due to temporary retrieval failure.