On the transition from reconsolidation to extinction of contextual fear memories.
ABSTRACT: Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate "null point" period has been observed where neither process seems to be engaged. Here we investigated whether this phenomenon extends to contextual fear memory. Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to the context 2 d later for 3, 5, 10, 20, or 30 min, with immediate injections of MK-801 or saline following reexposure, and tested on the following day. We observed a significant effect of MK-801 with the 3- and 30-min sessions, impairing reconsolidation and extinction, respectively. However, it did not have significant effects with 5-, 10-, or 20-min sessions, even though freezing decreased from reexposure to test. Further analyses indicated that this is not likely to be due to a variable transition point at the population level. In conclusion, the results show that in contextual fear memories there is a genuine "null point" between the parameters that induce reconsolidation and extinction, as defined by the effects of MK-801, although NMDA receptor-independent decreases in freezing can still occur in these conditions.
Project description:Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory reexposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after reexposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.
Project description:The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation.
Project description:BACKGROUND: In auditory fear conditioning, repeated presentation of the tone in the absence of shock leads to extinction of the acquired fear responses. The glutamate N-methyl-D-aspartate receptor (NMDAR) is thought to be involved in the extinction of the conditioned fear responses, but its detailed role in initiating and consolidating or maintaining the fear extinction memory is unclear. Here we investigated this issue by using a NMDAR antagonist, MK-801. METHODS/MAIN FINDINGS: The effects of immediate (beginning at 10 min after the conditioning) and delayed (beginning at 24 h after conditioning) extinctions were first compared with the finding that delayed extinction caused a better and long-lasting (still significant on the 20(th) day after extinction) depression on the conditioned fear responses. In a second experiment, MK-801 was intraperitoneally (i.p.) injected at 40 min before, 4 h or 12 h after the delayed extinction, corresponding to critical time points for initiating, consolidating or maintaining the fear extinction memory. i.p. injection of MK-801 at either 40 min before or 4 h after delayed extinction resulted in an impairment of initiating and consolidating fear extinction memory, which caused a long lasting increased freezing score that was still significant on the 7th day after extinction, compared with extinction group. However, MK-801 administered at 12 h after the delayed extinction, when robust consolidation has been occurred and stabilized, did not affect the established extinction memory. Furthermore, the changed freezing behaviors was not due to an alteration in general anxiety levels, since MK-801 treatment had no effect on the percentage of open-arm time or open-arm entries in an Elevated Plus Maze (EPM) task. CONCLUSIONS/SIGNIFICANCE: Our data suggested that the activation of NMDARs plays important role in initiation and consolidation but not maintenance of fear extinction memory. Together with the fact that NMDA receptor is very important for memory, our data added experimental evidence to the concept that the extinction of conditioned fear responses is a procedure of initiating and consolidating new memory other than simply "erasing" the fear memory.
Project description:Hippocampus-dependent spatial and aversive memory processes entail Ca2+ signals generated by ryanodine receptor (RyR) Ca2+ channels residing in the endoplasmic reticulum membrane. Rodents exposed to different spatial memory tasks exhibit significant hippocampal RyR upregulation. Contextual fear conditioning generates robust hippocampal memories through an associative learning process, but the effects of contextual fear memory acquisition, consolidation, or extinction on hippocampal RyR protein levels remain unreported. Accordingly, here we investigated if exposure of male rats to contextual fear protocols, or subsequent exposure to memory destabilization protocols, modified the hippocampal content of type-2 RyR (RyR2) channels, the predominant hippocampal RyR isoforms that hold key roles in synaptic plasticity and spatial memory processes. We found that contextual memory retention caused a transient increase in hippocampal RyR2 protein levels, determined 5?h after exposure to the conditioning protocol; this increase vanished 29?h after training. Context reexposure 24?h after training, for 3, 15, or 30?min without the aversive stimulus, decreased fear memory and increased RyR2 protein levels, determined 5?h after reexposure. We propose that both fear consolidation and extinction memories induce RyR2 protein upregulation in order to generate the intracellular Ca2+ signals required for these distinct memory processes.
Project description:Memories can be destabilized by the reexposure to the training context, and may reconsolidate into a modified engram. Reconsolidation relies on some particular molecular mechanisms involving LVGCCs and GluN2B-containing NMDARs. In this study we investigate the interference caused by the presence of a distractor - a brief, unanticipated stimulus that impair a fear memory expression - during the reactivation session, and tested the hypothesis that this disruptive effect relies on a reconsolidation process. Rats previously trained in the contextual fear conditioning (CFC) were reactivated in the presence or absence of a distractor stimulus. In the test, groups reactivated in the original context with distractor displayed a reduction of the freezing response lasting up to 20 days. To check for the involvement of destabilization / reconsolidation mechanisms, we studied the effect of systemic nimodipine (a L-VGCC blocker) or intra-CA1 ifenprodil (a selective GluN2B/NMDAR antagonist) infused right before the reactivation session. Both treatments were able to prevent the disruptive effect of distraction. Ifenprodil results also bolstered the case for hippocampus as the putative brain structure hosting this phenomenon. Our results provide some evidence in support of a behavioral, non-invasive procedure that was able to disrupt an aversive memory in a long-lasting way.
Project description:The reactivation of a memory through retrieval can render it subject to disruption or modification through the process of memory reconsolidation. In both humans and rodents, briefly reactivating a fear memory results in effective erasure by subsequent extinction training. Here we show that a similar strategy is equally effective in the disruption of appetitive pavlovian cue-food memories. However, systemic administration of the NMDA receptor partial agonist D-cycloserine, under the same behavioural conditions, did not potentiate appetitive memory extinction, suggesting that reactivation does not enhance subsequent extinction learning. To confirm that reactivation followed by extinction reflects a behavioural analogue of memory reconsolidation, we show that prevention of contextual fear memory reactivation by the L-type voltage-gated calcium channel blocker nimodipine interferes with the amnestic outcome. Therefore, the reconsolidation process can be manipulated behaviourally to disrupt both aversive and appetitive memories.
Project description:In patients suffering from post-traumatic stress disorder (PTSD), fear evoked by trauma-related memories lasts long past the traumatic event and it is often complicated by general anxiety and depressed mood. This poses a treatment challenge, as drugs beneficial for some symptoms might exacerbate others. For example, in preclinical studies, antagonists of the NR2B subunit of N-methyl-d-aspartate receptors and activators of cAMP-dependent protein kinase (PKA) act as potent antidepressants and anxiolytics, but they block fear extinction. Using mice, we attempted to overcome this problem by interfering with individual NR2B and PKA signaling complexes organized by scaffolding proteins. We infused cell-permeable Tat peptides that displaced either NR2B from receptor for activated C kinase 1 (RACK1), or PKA from A-kinase anchor proteins (AKAPs) or microtubule-associated proteins (MAPs). The infusions were targeted to the retrosplenial cortex, an area involved in both fear extinction of remotely acquired memories and in mood regulation. Tat-RACK1 and Tat-AKAP enhanced fear extinction, all peptides reduced anxiety and none affected baseline depression-like behavior. However, disruption of PKA complexes distinctively interfered with the rapid antidepressant actions of the N-methyl-D-aspartate receptors antagonist MK-801 in that Tat-MAP2 blocked, whereas Tat-AKAP completely inverted the effect of MK-801 from antidepressant to depressant. These effects were unrelated to the MK-801-induced changes of brain-derived neurotrophic factor messenger RNA levels. Together, the findings suggest that NR2B-RACK1 complexes specifically contribute to fear extinction, and may provide a target for the treatment of PTSD. AKAP-PKA, on the other hand, appears to modulate fear extinction and antidepressant responses in opposite directions.
Project description:Existing memories, when retrieved under certain circumstances, can undergo modification through the protein synthesis-dependent process of reconsolidation. Disruption of this process can lead to the weakening of a memory trace, an approach which is being examined as a potential treatment for disorders characterized by pathological memories, such as Post-Traumatic Stress Disorder. The success of this approach relies upon the ability to robustly attenuate reconsolidation; however, the available literature brings into question the reliability of the various drugs used to achieve such a blockade. The identification of a drug or intervention that can reliably disrupt reconsolidation without requiring intracranial access for administration would be extremely useful. Electroconvulsive shock (ECS) delivered after memory retrieval has been demonstrated in some studies to disrupt memory reconsolidation; however, there exists a paucity of literature characterizing its effects on Pavlovian fear memory. Considering this, we chose to examine ECS as an inexpensive and facile means to impair reconsolidation in rats. Here we show that electroconvulsive seizure induction, when administered after memory retrieval, (immediately, after 30 min, or after 1 h), does not impair the reconsolidation of cued or contextual Pavlovian fear memories. On the contrary, ECS administration immediately after extinction training may modestly impair the consolidation of fear extinction memory.
Project description:Repetitive replay of fear memories may precipitate the occurrence of post-traumatic stress disorder and other anxiety disorders. Hence, the suppression of fear memory retrieval may help prevent and treat these disorders. The formation of fear memories is often linked to multiple environmental cues and these interconnected cues may act as reminders for the recall of traumatic experiences. However, as a convenience, a simple paradigm of one cue pairing with the aversive stimulus is usually used in studies of fear conditioning in animals. Here, we built a more complex fear conditioning model by presenting several environmental stimuli during fear conditioning and characterize the effectiveness of extinction training and the disruption of reconsolidation process on the expression of learned fear responses. We demonstrate that extinction training with a single-paired cue resulted in cue-specific attenuation of fear responses but responses to other cures were unchanged. The cue-specific nature of the extinction persisted despite training sessions combined with D-cycloserine treatment reveals a significant weakness in extinction-based treatment. In contrast, the inhibition of the dorsal hippocampus (DH) but not the basolateral amygdala (BLA)-dependent memory reconsolidation process using either protein synthesis inhibitors or genetic disruption of cAMP-response-element-binding protein-mediated transcription comprehensively disrupted the learned connections between fear responses and all paired environmental cues. These findings emphasize the distinct role of the DH and the BLA in the reconsolidation process of fear memories and further indicate that the disruption of memory reconsolidation process in the DH may result in generalization of fear inhibition.
Project description:Extinction of a cued-fear memory within the reconsolidation window has been proposed to prevent fear reacquisition by reconsolidation interference. This 'retrieval-extinction' procedure has received interest for its therapeutic potential to reduce the impact of fear memories on behavior. To fully exploit its therapeutic potential, it is critical to understand the mechanisms that underlie the 'retrieval-extinction' effect. If the effect depends upon reconsolidation of the original memory, then it would be predicted that destabilization, induced by prediction error, would be critical for observing the effect. Here, the dependency of the retrieval-extinction effect on memory destabilization or prediction error was investigated in pavlovian cued-fear conditioned adult male rats. The requirement for memory destabilization, and thus reconsolidation, for the retrieval-extinction effect was subsequently investigated using region-specific pharmacological blockade of dopamine D1-receptors. Intra-basolateral amygdala antagonism of dopamine D1-receptors did not prevent the reacquisition of fear associated with the retrieval-extinction procedure. The requirement for prediction error was assessed by using a reinforced or non-reinforced memory retrieval trial before extinction, compared to a no-retrieval, extinction-only control. Both the reinforced (no prediction error) and non-reinforced retrieval sessions led to a decrease in fear reacquisition, suggesting that engagement of prediction error does not influence the occurrence of retrieval-extinction. Together, these data suggest that retrieval-extinction does not require memory destabilization, since behavioral or pharmacological interventions that prevent destabilization did not disrupt any capacity to attenuate fear.