Search

Useful memory must balance between stability and malleability. This puts effective memory storage at odds with plasticity processes, such as reconsolidation. What becomes of memory maintenance processes during synaptic plasticity is unknown. Here we examined the fate of the memory maintenance protein PKMζ during memory destabilization and reconsolidation in male rats. We found that NMDAR activation and proteasome activity induced a transient reduction in PKMζ protein following retrieval. During reconsolidation, new PKMζ was synthesized to re-store the memory. Failure to synthesize new PKMζ during reconsolidation impaired memory but uninterrupted PKMζ translation was not necessary for maintenance itself. Finally, NMDAR activation was necessary to render memories vulnerable to the amnesic effect of PKMζ-antisense. These findings outline a transient disruption and renewal of the PKMζ memory maintenance mechanism during plasticity. We argue that dynamic changes in PKMζ protein levels can serve as an exemplary model of the molecular changes underlying memory destabilization and reconsolidation. [ABSTRACT FROM AUTHOR]

Memory reconsolidation is hypothesized to be a mechanism by which memories can be updated with new information. Such updating has previously been shown to weaken memory expression or change the nature of the memory. Here we demonstrate that retrieval-induced memory destabilization also allows that memory to be strengthened by additional learning. We show that for rodent contextual fear memories, this retrieval conditioning effect is observed only when conditioning occurs within a specific temporal window opened by retrieval. Moreover, it necessitates hippocampal protein degradation at the proteasome and engages hippocampal Zif268 protein expression, both of which are established mechanisms of memory destabilization-reconsolidation. We also demonstrate a conceptually analogous pattern of results in human visual paired-associate learning. Retrieval-relearning strengthens memory performance, again only when relearning occurs within the temporal window of memory reconsolidation. These findings link retrieval-mediated learning in humans to the reconsolidation literature, and have potential implications both for the understanding of endogenous memory gains and strategies to boost weakly learned memories. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Conditioned fear memory, a representative model of traumatic memories, is observed across species from lower to higher animals, including humans. Numerous studies have investigated the mechanisms of conditioned fear memory and have led to the identification of the underlying processes involved in fear memory regulation, including cellular and systems consolidation of fear conditioning, destabilization/reconsolidation and extinction after fear memory retrieval, and forgetting of fear memory. These studies suggested that mechanisms for fear memory regulation are shared by humans and other higher animals. Additionally, rodent studies have identified the mechanisms of fear memory at the molecular, cellular, and circuit levels. Findings from these studies in rodents have been applied to facilitate the development and improvement of PTSD intervention. For instance, reconsolidation and extinction of fear memories have been applied for PTSD treatment to improve prolonged exposure (PE) therapy, an effective psychotherapy for PTSD. Combination of medications weakening retrieved traumatic memory (e.g., by facilitating both destabilization and extinction) with PE therapy may contribute to improvement of PTSD. Interestingly, a recent study in mice identified forgetting of fear memory as another potential therapeutic target for PTSD. A better understanding of the mechanisms involved in fear memory processes is likely to facilitate the development of better treatments for PTSD. This review describes fear memory processes and their mechanisms and discusses the pros and cons of applying how this knowledge can be applied in the development of interventions for PTSD. [ABSTRACT FROM AUTHOR]

The presentation of a fearmemory cue can result inmerememory retrieval, destabilization of the reactivatedmemory trace, or the formation of an extinctionmemory. The interaction between the degree of novelty during reactivation and previous learning conditions is thought to determine the outcome of a reactivation session. This study aimed to evaluate whether contextual novelty can prevent cue-induced destabilization and disruption of a fear memory acquired by non-asymptotic learning. To this end, fear memory was reactivated in a novel context or in the original context of learning, and fear memory reactivation was followed by the administration of propranolol, an amnestic drug. Remarkably, fear memory was not impaired by post-reactivation propranolol administration or extinction training under the usual conditions used in our lab, irrespective of the reactivation context. These unexpected findings are discussed in the light of our current experimental parameters and alleged boundary conditions on memory destabilization. [ABSTRACT FROM AUTHOR]

• Standard and novelty-induced object memory destabilization can be studied in mice. • mAChRs are required for destabilizing recent and remote object memories. • nAChRs are required for destabilizing recent, but not remote, object memories. • nAChRs, but not mAChRs, are required for object memory reconsolidation. The content of long-term memory is neither fixed nor permanent. Reminder cues can destabilize consolidated memories, rendering them amenable to change before being reconsolidated. However, not all memories destabilize following reactivation. Characteristics of a memory, such as its age or strength, impose boundaries on destabilization. Previously, we demonstrated that presentation of salient novel information at the time of reactivation can readily destabilize resistant object memories in rats and this form of novelty-induced destabilization is dependent upon acetylcholine (ACh) activity at muscarinic receptors (mAChRs). In the present study, we sought to determine if this same mechanism for initiating destabilization of resistant object memories is present in mice and further expand our understanding of the mechanisms through which ACh modulates object memory destabilization by investigating the role of nicotinic receptors (nAChRs). We provide evidence that in mice mAChRs are necessary for destabilizing object memories that are readily destabilized and those that are resistant to destabilization. Conversely, nAChRs were found to be necessary only when memories are readily destabilized. We then investigated the role of both receptors in the reconsolidation of destabilized object memory traces and determined that nAChRs, but not mAChRs, are necessary for object memory reconsolidation. Together, these results suggest that nAChRs may play a more selective role in the re-storage of object memories following destabilization and that ACh acts through mAChRs to act as an override signal to initiate destabilization of resistant object memories following reactivation with novelty. These findings expand our current understanding of the role of ACh in the dynamic storage of long-term memory. [ABSTRACT FROM AUTHOR]

Reconsolidation and extinction are two processes occurring upon memory retrieval that have received great attention in memory research over the last decade, partly due to their purported potential in the treatment of anxiety disorders. Due to their opposite behavioral effects, the two phenomena have usually been considered as separate entities, with few attempts to build a unified view of how both could be produced by similar mechanisms. Based on computational modeling, we have previously proposed that reconsolidation and extinction are behavioral outcomes of the same set of plasticity systems, albeit working at different synapses. One of these systems seems to be pharmacologically similar to the one involved in initial memory consolidation, and likely involves traditional Hebbian plasticity, while the second seems to be more involved with the labilization of existing memories and/or synaptic changes. In this article, we review the evidence for the existence of a plasticity system specifically involved in memory labilization, as well as its possible molecular requirements, anatomical substrates, synaptic mechanisms and physiological roles. Based on these data, we propose that the field of memory updating might ultimately benefit from a paradigm shift in which reconsolidation and extinction are viewed not as separate processes but as different instantiations of plasticity systems responsible for reinforcement and labilization of synaptic changes. [ABSTRACT FROM AUTHOR]

Systematic investigation of reactivation-induced memory updating began in the 1960s, and a wave of research in this area followed the seminal articulation of "reconsolidation" theory in the early 2000s. Myriad studies indicate that memory reactivation can cause previously consolidated memories to become labile and sensitive to weakening, strengthening, or other forms of modification. However, from its nascent period to the present, the field has been beset by inconsistencies in researchers' abilities to replicate seemingly established effects. Here we review these many studies, synthesizing the human and nonhuman animal literature, and suggest that these failures-to-replicate reflect a highly complex and delicately balanced memory modification system, the substrates of which must be finely tuned to enable adaptive memory updating while limiting maladaptive, inaccurate modifications. A systematic approach to the entire body of evidence, integrating positive and null findings, will yield a comprehensive understanding of the complex and dynamic nature of long-term memory storage and the potential for harnessing modification processes to treat mental disorders driven by pervasive maladaptive memories. • We discuss evidence for reactivation-induced memory updating in humans and animals. • Decades of research indicate that memory reactivation can promote updating. • Replication failures raise valid questions about the nature of this phenomenon. • Conditions for inducing memory destabilization require clarification. • Specificity of destabilization triggers might explain discrepant results. [ABSTRACT FROM AUTHOR]

The extinction of learned associations has traditionally been considered to involve new learning, which competes with the original memory for control over behavior. However, a recent resurgence of interest in reactivation-dependent amnesia has revealed that the retrieval of fear-related memory (with what is essentially a brief extinction session) can result in its destabilization. This review discusses some of the cellular and molecular mechanisms that are involved in the destabilization of a memory following its reactivation and/or extinction, and investigates the evidence that extinction may involve both new learning as well as a partial destabilization-induced erasure of the original memory trace. [ABSTRACT FROM AUTHOR]

According to the reconsolidation theory, memories can be modified through the destabilization-reconsolidation process. The rodent perirhinal cortex (PER; Brodmann areas 35 and 36) critically participates in the process of fear conditioning. Previous studies showed that some of the parahippocampal regions are critical for contextual fear memory reconsolidation. In our research, through a three-day paradigm of CFC, we showed that protein synthesis in PER of rats is required for memory reconsolidation, and activation of CB1 pathway is necessary but not sufficient in inducing memory destabilization. This result underlines parahippocampal regions in destabilization and reconsolidation process of fear memory besides amygdala and hippocampus. [ABSTRACT FROM AUTHOR]

Reminder cues can destabilize consolidated memories, rendering them modifiable before they return to a stable state through the process of reconsolidation. Older and stronger memories resist this process and require the presentation of reminders along with salient novel information in order to destabilize. Previously, we demonstrated in rats that novelty-induced object memory destabilization requires acetylcholine (ACh) activity at M1 muscarinic receptors. Other research predominantly has focused on glutamate, which modulates fear memory destabilization and reconsolidation through GluN2B- and GluN2A-containing NMDARs, respectively. In the current study, we demonstrate the same dissociable roles of GluN2B- and N2A-containing NMDARs in perirhinal cortex (PRh) for object memory destabilization and reconsolidation when boundary conditions are absent. However, neither GluN2 receptor subtype was required for novelty-induced destabilization of remote, resistant memories. Furthermore, GluN2B and GluN2A subunit proteins were upregulated selectively in PRh 24 h after learning, but returned to baseline by 48 h, suggesting that NMDARs, unlike muscarinic receptors, have only a temporary role in object memory destabilization. Indeed, activation of M1 receptors in PRh at the time of reactivation effectively destabilized remote memories despite inhibition of GluN2B-containing NMDARs. These findings suggest that cholinergic activity at M1 receptors overrides boundary conditions to destabilize resistant memories when other established mechanisms are insufficient. [ABSTRACT FROM AUTHOR]

Memory is not a stable record of experience, but instead is an ongoing process that allows existing memories to be modified with new information through a reconsolidation-dependent updating process. For a previously stable memory to be updated, the memory must first become labile through a process called destabilization. Destabilization is a protein degradation-dependent process that occurs when new information is presented. Following destabilization, a memory becomes stable again through a protein synthesis-dependent process called restabilization. Much work remains to fully characterize the mechanisms that underlie both destabilization and subsequent restabilization, however. In this article, we briefly review the discovery of reconsolidation as a potential mechanism for memory updating. We then discuss the behavioral paradigms that have been used to identify the molecular mechanisms of reconsolidation-dependent memory updating. Finally, we outline what is known about the molecular mechanisms that support the memory updating process. Understanding the molecular mechanisms underlying reconsolidation-dependent memory updating is an important step toward leveraging this process in a therapeutic setting to modify maladaptive memories and to improve memory when it fails. [ABSTRACT FROM AUTHOR]

• Reconsolidation and extinction can be impaired in sign-tracking to an audiovisual compound stimulus. • There is an intermediate level of stimulus re-exposure between those sufficient to induce reconsolidation and extinction. • Destabilization can be induced by exposure to the auditory component of the compound stimulus. • Destabilization can be induced both inside and outside the training context. Studies of memory reconsolidation of pavlovian memories have typically employed unimodal conditioned stimuli, despite the use of multimodal compound stimuli in other settings. Here we studied sign-tracking behaviour to a compound audiovisual stimulus. First, we observed not unexpectedly that sign-tracking was poorer to the audiovisual compound than to unimodal visual stimuli. Then, we showed that, depending on the parameters of compound stimulus re-exposure at memory reactivation, systemic MK-801 treatment either impaired extinction to improve sign-tracking at test, or disrupted reconsolidation to impair test behaviour. When memory reactivation consisted of re-exposure to only the auditory component of the compound stimulus, we observed sign-tracking impairments following MK-801 treatment, but only under certain test conditions. This was in contrast to the consistent impairment following reactivation with the full audiovisual compound. Moreover, the parameters of auditory stimulus presentation to enable MK-801-induced impairment at test varied depending on whether the stimulus was presented within or outside the training context. These findings suggest that behaviour under the control of appetitive pavlovian compound stimuli can be modulated by targeting both extinction and reconsolidation, and that it is not necessary to re-expose to the full compound stimulus in order to achieve a degree of modulation of behaviour. [ABSTRACT FROM AUTHOR]

• Memories can be "destabilized" when they are retrieved. • Memory lability depends on experience with the context in which retrieval takes place. • Contextual novelty at retrieval can control alterations in amygdala activity. • Dorsal hippocampal activity controls retrieval-dependent plasticity in the amygdala. The recall of a previously formed fear memory triggers a process through which synapses in the amygdala become "destabilized". This labile state at retrieval may be critical for the plasticity required to modify, update, or disrupt long-term memories. One component of this process involves the rapid internalization of calcium impermeable AMPA receptors (CI-AMPAR). While some recent work has focused on the details of modifying amygdala synapses, much less is known about the environmental factors that control memory updating and the important circuit level processes. Synchrony between the hippocampus and amygdala increases during memory retrieval and stable memories can sometimes be made labile with hippocampal manipulations. Recent work shows that memory lability at retrieval is influenced by the novelty of the retrieval environment, and detection of this novelty likely relies on the dorsal hippocampus (DH). Our goal was to determine how local activity in the DH contributes to memory lability and synaptic destabilization in the amygdala during retrieval when contextual novelty is introduced. We found that contextual novelty during retrieval is necessary for alterations in amygdala activity and CI-AMPAR internalization. In the absence of novelty, suppression of local activity in the DH prior to learning allowed for retrieval-dependent CI-AMPAR internalization in the amygdala. We next tested whether the changes in AMPAR internalization were accompanied by differences in memory lability. We found that a memory was made labile when activity within the DH was disrupted in the absence of contextual novelty. These results suggest that the DH is important for encoding contextual information during learning that regulates retrieval-dependent memory modification in the amygdala. [ABSTRACT FROM AUTHOR]