Temporally graded requirement for protein synthesis following memory reactivation

Learning of new information is transformed into long-lasting memory through a process known as consolidation, which requires protein synthesis. Classical theory held that once consolidated, memory was insensitive to disruption. However, old memories that are insensitive to protein synthesis inhibitors can become vulnerable if they are recalled (reactivated). These findings led to a new hypothesis that when an old memory is reactivated, it again becomes labile and, similar to a newly formed memory, requires a process of reconsolidation in order to be maintained. Here, we show that the requirement for protein synthesis of a reactivated memory is evident only when the memory is recent. In fact, memory vulnerability decreases as the time between the original training and the recall increases.     

Repeated labilization-reconsolidation processes strengthen declarative memory in humans

The idea that memories are immutable after consolidation has been challenged. Several reports have shown that after the presentation of a specific reminder, reactivated old memories become labile and again susceptible to amnesic agents. Such vulnerability diminishes with the progress of time and implies a re-stabilization phase, usually referred to as reconsolidation. To date, the main findings describe the mechanisms associated with the labilization-reconsolidation process, but little is known about its functionality from a biological standpoint. Indeed, two functions have been proposed. One suggests that destabilization of the original memory after the reminder allows the integration of new information into the background of the original memory (memory updating), and the other suggests that the labilization-reconsolidation process strengthens the original memory (memory strengthening). We have previously reported the reconsolidation of human declarative memories, demonstrating memory updating in the framework of reconsolidation. Here we deal with the strengthening function attributed to the reconsolidation process. We triggered labilization-reconsolidation processes successively by repeated presentations of the proper reminder. Participants learned an association between five cue-syllables and their respective response-syllables. Twenty-four hours later, the paired-associate verbal memory was labilized by exposing the subjects to one, two or four reminders. The List-memory was evaluated on Day 3 showing that the memory was improved when at least a second reminder was presented in the time window of the first labilization-reconsolidation process prompted by the earlier reminder. However, the improvement effect was revealed on Day 3, only when at least two reminders were presented on Day 2 and not as a consequence of only retrieval. Therefore, we propose central concepts for the reconsolidation process, emphasizing its biological role and the parametrical constrains for this function to be operative.     

New Episodic Learning Interferes with the Reconsolidation of Autobiographical Memories

It is commonly assumed that, with time, an initially labile memory is transformed into a permanent one via a process of consolidation. Yet, recent evidence indicates that memories can return to a fragile state again when reactivated, requiring a period of reconsolidation. In the study described here, we found that participants who memorized a story immediately after they had recalled neutral and emotional experiences from their past were impaired in their memory for the neutral (but not for the emotional) experiences one week later. The effect of learning the story depended critically on the preceding reactivation of the autobiographical memories since learning without reactivation had no effect. These results suggest that new learning impedes the reconsolidation of neutral autobiographical memories.     

The Role and Dynamic of Strengthening in the Reconsolidation Process in a Human Declarative Memory: What Decides the Fate of Recent and Older Memories?

Several reports have shown that after specific reminders are presented, consolidated memories pass from a stable state to one in which the memory is reactivated. This reactivation implies that memories are labile and susceptible to amnesic agents. This susceptibility decreases over time and leads to a re-stabilization phase usually known as reconsolidation. With respect to the biological role of reconsolidation, two functions have been proposed. First, the reconsolidation process allows new information to be integrated into the background of the original memory; second, it strengthens the original memory. We have previously demonstrated that both of these functions occur in the reconsolidation of human declarative memories. Our paradigm consisted of learning verbal material (lists of five pairs of nonsense syllables) acquired by a training process (L1-training) on Day 1 of our experiment. After this declarative memory is consolidated, it can be made labile by presenting a specific reminder. After this, the memory passes through a subsequent stabilization process. Strengthening creates a new scenario for the reconsolidation process; this function represents a new factor that may transform the dynamic of memories. First, we analyzed whether the repeated labilization-reconsolidation processes maintained the memory for longer periods of time. We showed that at least one labilization-reconsolidation process strengthens a memory via evaluation 5 days after its re-stabilization. We also demonstrated that this effect is not triggered by retrieval only. We then analyzed the way strengthening modified the effect of an amnesic agent that was presented immediately after repeated labilizations. The repeated labilization-reconsolidation processes made the memory more resistant to interference during re-stabilization. Finally, we evaluated whether the effect of strengthening may depend on the age of the memory. We found that the effect of strengthening did depend on the age of the memory. Forgetting may represent a process that weakens the effect of strengthening.     

Differential Involvement of Brain-Derived Neurotrophic Factor in Reconsolidation and Consolidation of Conditioned Taste Aversion Memory

Consolidated memory can re-enter states of transient instability following reactivation, which is referred to as reconsolidation, and the exact molecular mechanisms underlying this process remain unexplored. Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity and memory processes. We have recently observed that BDNF signaling in the central nuclei of the amygdala (CeA) and insular cortex (IC) was involved in the consolidation of conditioned taste aversion (CTA) memory. However, whether BDNF in the CeA or IC is required for memory reconsolidation is still unclear. In the present study, using a CTA memory paradigm, we observed increased BDNF expression in the IC but not in the CeA during CTA reconsolidation. We further determined that BDNF synthesis and signaling in the IC but not in the CeA was required for memory reconsolidation. The differential, spatial-specific roles of BDNF in memory consolidation and reconsolidation suggest that dissociative molecular mechanisms underlie reconsolidation and consolidation, which might provide novel targets for manipulating newly encoded and reactivated memories without causing universal amnesia.     

Cellular and systems reconsolidation in the hippocampus

Cellular theories of memory consolidation posit that new memories require new protein synthesis in order to be stored. Systems consolidation theories posit that the hippocampus has a time-limited role in memory storage, after which the memory is independent of the hippocampus. Here, we show that intra-hippocampal infusions of the protein synthesis inhibitor anisomycin caused amnesia for a consolidated hippocampal-dependent contextual fear memory, but only if the memory was reactivated prior to infusion. The effect occurred even if reactivation was delayed for 45 days after training, a time when contextual memory is independent of the hippocampus. Indeed, reactivation of a hippocampus-independent memory caused the trace to again become hippocampus dependent, but only for 2 days rather than for weeks. Thus, hippocampal memories can undergo reconsolidation at both the cellular and systems levels.     

Consolidation and reconsolidation: two lives of memories?

Most studies on memory consolidation consider the new information as if it were imposed on a tabula rasa, but considerable evidence indicates that new memories must be interleaved within a large network of relevant pre-existing knowledge. Early studies on reconsolidation highlighted that a newly consolidated memory could be erased after reactivation, but new evidence has shown that an effective reactivation experience must also involve memory reorganization to incorporate new learning. The combination of these observations on consolidation and reconsolidation highlights the fundamental similarities of both phenomena as the integration of new information and old, and it suggests reconsolidation = consolidation as a neverending process of schema modification.     

The labile nature of consolidation theory

'Consolidation' has been used to describe distinct but related processes. In considering the implications of our recent findings on the lability of reactivated fear memories, we view consolidation and reconsolidation in terms of molecular events taking place within neurons as opposed to interactions between brain regions. Our findings open up a new dimension in the study of memory consolidation. We argue that consolidation is not a one-time event, but instead is reiterated with subsequent activation of the memories.     

Molecular mechanisms of memory reconsolidation

Memory reconsolidation has been argued to be a distinct process that serves to maintain, strengthen or modify memories. Specifically, the retrieval of a previously consolidated memory has been hypothesized to induce an additional activity-dependent labile period during which the memory can be modified. Understanding the molecular mechanisms of reconsolidation could provide crucial insights into the dynamic aspects of normal mnemonic function and psychiatric disorders that are characterized by exceptionally strong and salient emotional memories.     

Proteolysis of proBDNF is a key regulator in the formation of memory

It is essential to understand the molecular processes underlying long-term memory to provide therapeutic targets of aberrant memory that produce pathological behaviour in humans. Under conditions of recall, fully-consolidated memories can undergo reconsolidation or extinction. These retrieval-mediated memory processes may rely on distinct molecular processes. The cellular mechanisms initiating the signature molecular events are not known. Using infusions of protein synthesis inhibitors, antisense oligonucleotide targeting brain-derived neurotrophic factor (BDNF) mRNA or tPA-STOP (an inhibitor of the proteolysis of BDNF protein) into the hippocampus of the awake rat, we show that acquisition and extinction of contextual fear memory depended on the increased and decreased proteolysis of proBDNF (precursor BDNF) in the hippocampus, respectively. Conditions of retrieval that are known to initiate the reconsolidation of contextual fear memory, a BDNF-independent memory process, were not correlated with altered proBDNF cleavage. Thus, the processing of BDNF was associated with the acquisition of new information and the updating of information about a salient stimulus. Furthermore, the differential requirement for the processing of proBDNF by tPA in distinct memory processes suggest that the molecular events actively engaged to support the storage and/or the successful retrieval of memory depends on the integration of ongoing experience with past learning.     

Rites of passage of the engram: reconsolidation and the lingering consolidation hypothesis

Memory consolidation refers to the progressive stabilization of items in long-term memory as well as to the memory phase(s) during which this stabilization takes place. The textbook account is that, for each item in memory, consolidation starts and ends just once. In recent years, however, the notion that memories reconsolidate upon their reactivation and hence regain sensitivity to amnestic agents has been revitalized. This issue is of marked theoretical and clinical interest. Here we review the recent literature on reconsolidation and infer, on the basis of the majority of the data, that blockade of reconsolidation does not induce permanent amnesia. Further, in several systems, reconsolidation occurs only in relatively fresh memories. We propose a framework model, which interprets reconsolidation as a manifestation of lingering consolidation, rather than recapitulation of a process that had already come to a closure. This model reflects on the nature of consolidation in general and makes predictions that could guide further research.     

Removing pathogenic memories

Experimental research examining the neural bases of nondeclarative memory has offered intriguing insight into how functional and dysfunctional implicit learning affects the brain. Long-term modifications of synaptic transmission, in particular, are currently considered the most plausible mechanism underlying memory trace encoding and compulsions, addiction, anxiety, and phobias. Therefore, an effective psychotherapy must be directed to erase maladaptive implicit memories and aberrant synaptic plasticity. This article describes the neurobiological bases of pathogenic memory disruption to provide some insight into how psychotherapy works. At least two mechanisms of unwanted memory erasing appear to be implicated in the effects of psychotherapy: inhibition of memory consolidation/reconsolidation and extinction. Behavioral evidence demonstrated that these two ways to forget are profoundly distinct in nature, and it is increasingly clear that their cellular, synaptic, and molecular underpinnings are different. Accordingly, the blockade of consolidation/reconsolidation erases memories by reversing the plasticity associated with memory maintenance, whereas extinction is a totally new form of plasticity that, similar to the plasticity underlying the old memory, requires protein synthesis-dependent synaptic remodeling.     

Total recall. Reconsolidation theory unifies cognitive psychology and neuroscience and creates new therapeutic options for memory-related disorders

New research reveals that long-term memory is not entirely stable and can be modified or potentially erased. These insights open new therapeutic possibilities for a range of memory-related diseases and disorders.There are many popular ideas about human memory serving as the repository of experiences etched into the substance of our brains until they are wiped out through death or disease. As the British writer Oscar Wilde put it, “Memory [...] is the diary that we all carry about with us.” And even if we sometimes cannot remember a particular event or person, we rarely doubt our memories. Friedrich Nietzsche, the German philosopher, placed great faith in memory, noting that, “The existence of forgetting has never been proved: we only know that some things don''t come to mind when we want them.”Despite these popular notions of infallible human memories, our understanding of how long-term memory works has changed dramatically during the past decade: it seems that our memories are not as permanent as we once thought. This has profound implications for both neuroscience and for treating a range of cognitive disorders including PTSD (post-traumatic stress disorder), drug addiction, chronic pain and even possibly Alzheimer disease....it seems that our memories are not as permanent as we once thoughtFor a long time, neurologists and psychiatrists had assumed that after an initial period of consolidation, during which memories are liable to change or be erased, memories eventually become enshrined and immune to alteration. But since 2000, this memory consolidation theory has gradually been replaced by a new one called reconsolidation, which posits that long-term memories can, at least in some circumstances, be changed. On activation or recall, the memory of an object or event enters an update process during which it can be strengthened, weakened or modified, just as short-term memories can be during the initial consolidation phase. The new reconsolidation theory has created great excitement among cognitive disorder researchers and practitioners. As many disorders are associated with some form of long-term memory malfunction or impairment, a reliable method that can reactivate and amend these memories would have great potential as a treatment; indeed a number of clinical trials to treat PTSD are currently testing this new understanding of memories.As many disorders are associated with some form of long-term memory malfunction or impairment, a reliable method that can reactivate and amend these memories would have great potential as a treatment...As happens so often in science, reconsolidation is actually an old idea that has been reincarnated. The theory first emerged in the 1960s when neurologists found that fear memories in rats could be greatly weakened if they were reactivated on recall (Misanin et al, 1968). Before then, it had been assumed that retrograde amnesia—the inability to access memories formed during or just before a traumatic event or illness—worked backwards in time to affect recently acquired memories. Retrograde amnesia also occurs in humans as a result of head injuries or, sometimes, extreme trauma. The experiments in rats, however, showed that even older memories might be vulnerable if they were in an active state of recall at the time of the trauma, but interest in the research waned because of the lack of any neurological or molecular basis for the theory. This all changed with the publication of a seminal paper in 2000 by Karim Nader at McGill University in Montreal, Canada, who demonstrated the reconsolidation of a fear memory in the lateral amygdala (Nader et al, 2000). This walnut-sized region in the medial temporal lobe of the brain has a key role in emotional memory in that it orchestrates the production of hormones or neurotransmitters such as dopamine, noradrenaline and adrenaline.Various forms of extinction training have long been applied to some disorders, notably PTSD...The work by Nader and Joseph LeDoux at New York University, USA, heralded the beginning of a unification between the previously largely distinct fields of neuroscience and cognitive psychology. Neuroscience had been driven chiefly by animal research to identify the underlying molecular, genetic and neurochemical basis of behaviour, emotion and memory. Cognitive psychology had been based almost entirely on behavioural experiments in humans. This unification process is still in its infancy, but advances in imaging techniques, particularly functional magnetic resonance imaging, promises to combine behavioural experiments in humans with observing changes in brain activity. According to Valérie Doyère, from the Centre of Neurosciences at Paris-Sud University in France, it will help resolve questions about how different regions of the brain interact during memory recall and reconsolidation. “I think the next step is to do neural imaging, as this would help detect at which step in the network the system has been modified or blocked,” Doyère, a pioneer of reconsolidation theory and collaborator of LeDoux and Nader, explained. “That is difficult to know unless you do have some way of analysing the neural network activity to try and see what you update and where.”Even without this insight, a lot of progress has been made in linking molecular events at the neuron level with the reconsolidation process—at least in animals. The starting point was the discovery by Nader and colleagues that reconsolidation in rats involved protein synthesis. They noted from other work that the initial consolidation of fear memories in rats could be inhibited by infusion of the protein synthesis inhibitor anisomycin into the amygdala, shortly after fear training. Such training typically involves traditional methods first used by the Russian physiologist Ivan Pavlov (1849–1936) in which an animal is given a so-called conditional stimulus (CS), such as a particular sound, followed shortly by an unconditional stimulus (US), such as an electric shock. The animal learns to associate the two so that exposure to the sound triggers fear: it begins with the activation of the amygdala, which is followed by a signalling cascade that leads to elevated heart and respiratory rates, with an associated increase in glucose production in preparation for the ''fight or flight'' response. The administration of anisomycin shortly after this training process blocks consolidation and prevents the animal from associating the CS signal with the US response.Similarly, Nader found that if the rats were exposed to the CS some days after the initial conditioning, to recall the association between the sound and the electric shock, anisomycin blocked reconsolidation and generated amnesia: the rats ''forgot'' the association between CS and US and had a greatly reduced fear response on exposure to the CS. Nader argued that this must mean the reconsolidation of the memory had been interrupted, because if the rats were given anisomycin after the initial training, but without exposure to the CS sound, they retained their fear conditioning. This link between memory reconsolidation and protein synthesis has also been demonstrated in other animals, including primitive invertebrates such as worms, suggesting that this is an evolutionarily conserved adaptation (Rose & Rankin, 2006).Attempts to observe this link between reconsolidation and protein synthesis in humans, however, have remained elusive. “We can''t test whether the mechanisms in humans are mediated by protein synthesis because those drugs would not be approved for human use,” Nader said. “Usually, rodent preps are used to understand the molecular mechanisms, and these seem to generalize to humans.”Indeed, Nader argues that evidence for reconsolidation in humans is now very strong in the light of recent work by LeDoux, demonstrating that the principles of fear extinction training in rats could be applied to humans to weaken the association between a CS trigger and memory of the US (Schiller et al, 2010). Human participants were shown an object and then given a mild electric shock in classical Pavlovian conditioning—the authors tested for the presence of the fear memory by measuring the change in skin electrical conductance in response to seeing the object. Once this fear memory was established, the authors reminded the participants of the object a day later to initiate the reconsolidation process, but then provided information that the same object was now ''safe''—this being called ''extinction training''. A day later, the participants were tested again to see whether the object elicited a fear response.The key point is that extinction training had to be conducted within the reconsolidation window, when the memory was temporarily unstable, to eliminate the fear response. The researchers also showed that rewriting the fear memory was specific to the CS object that was reactivated. If participants had been conditioned to associate several different objects with fear, then extinction training would only work on the specific object used during the training. Participants would continue to associate the other objects with fear, indicating that extinction training is selective.Various forms of extinction training have long been applied to some disorders, notably PTSD—an anxiety disorder that occurs in the aftermath of exposure to a traumatic experience involving death or the threat of death. The victim ingests a trauma memory that is emotionally overwhelming and cannot be resolved in the normal way, often intruding spontaneously into consciousness with a continued state of hypervigilance. The idea of extinction training is to force sufferers to actively recall memories frequently, but success has so far been mixed.The ability to stimulate memory could inspire new treatments for sufferers from memory loss...Although anisomycin cannot be given to PTSD sufferers to edit long-term memories, propranolol is an alternative. It has already been approved to treat hypertension as a so-called beta blocker that blocks the beta andrenergic receptor and diminishes the effect of stress hormones. Having been largely replaced by other drugs for treating high blood pressure, interest in propranolol was revived by its potential for treating PTSD in association with psychotherapy (Brunet et al, 2007). It also triggered research into the role of beta adrenergic receptors in PTSD, notably by Jacek Debiec and colleagues at New York University, who found that adrenergic signalling in the amygdala is involved in the memory consolidation process (Debiec et al, 2011).Drugs such as propranolol seem to suppress memory reconsolidation and thereby weaken the emotions associated with trauma memories. This is the theory, and early evidence of success has attracted significant interest in the USA, where PTSD is a particular problem given the country''s longstanding involvement in armed conflicts and the resulting large number of former soldiers suffering from the syndrome.The US Department of Defense''s standard treatment for PTSD has been cognitive behavioural therapy, in which individuals learn to identify thoughts that make them feel afraid or upset and then try to replace them with less distressing thoughts. But the potential of propanolol to replace or enhance cognitive behavioural therapy has prompted the US National Institutes of Health to conduct a phase II clinical trial, for which it is currently recruiting volunteers.The urgency of finding a more complete cure for PTSD has been increased by recent indications that the disorder not only diminishes quality of life for sufferers and their families, but also has serious long-term effects on physical as well as mental health, including premature ageing and a heightened risk of dementia. This link was confirmed by a recent retrospective study of 181,093 US war veterans aged 55 years or older, 53,155 of whom had PTSD (Yaffe et al, 2010). Kristine Yaffe (University of California, San Francisco and the San Francisco Veterans Affairs Medical Center) and her colleagues found that veterans with PTSD had a 10.6% risk of developing dementia compared with 6.6% among the general elderly population without PTSD. Although this result was statistically significant given that the study was adjusted for other factors such as demographic variation and psychiatric illnesses, it did not entirely preclude other risk factors. The causes of the higher risk of dementia were related to either the physiological stress on the brain with associated inflammation, or the systemic effect of long-term disruption to memory functioning, or probably a combination of both.The emphasis in treating PTSD and addictive disorders is on weakening aspects of long-term memory, but the emerging reconsolidation theory can equally provide clinical benefits by strengthening connections, as LeDoux pointed out. “Memory reconsolidation is not a process of weakening memory from the evolutionary point of view. It is an update mechanism. It allows memories to be changed when new information is available,” he said. “An extreme example from our work is that fear memory can be increased or decreased, depending on how you activate beta-adrenergic receptors. Block these during retrieval and you get a weakening of memory; stimulate these and you get an enhancement.” As happens so often in science, reconsolidation is actually an old idea that has been reincarnatedThe ability to stimulate memory could inspire new treatments for sufferers from memory loss, according to Doyère. “In the case of a disease like Alzheimer''s, it may be possible to reincorporate some elements and recover memory that has been lost. At least it may be possible to delay some of the symptoms,” she explained. Yet, more work is needed to expand on the emerging theory of reconsolidation, particularly in humans, because human memory recall goes beyond what happens in most animals. “Humans have the knowledge of a memory association and that may reactivate the emotional value,” Doyère commented. In other words, humans can better exploit their associated knowledge of events that they recall either wittingly or possibly in dreams, and this can affect the reconsolidation process. Moreover, there is also the role of sleep and dreaming in long-term memory recall and reconsolidation. In any case, it seems that reconsolidation as a unifying theory has both great therapeutic and scientific potential to explore human memory.     

Memory reconsolidation: sensitivity of spatial memory to inhibition of protein synthesis in dorsal hippocampus during encoding and retrieval

Reconsolidation is a putative neuronal process in which the retrieval of a previously consolidated memory returns it to a labile state that is once again subject to stabilization. This study explored the idea that reconsolidation occurs in spatial memory when animals retrieve memory under circumstances in which new memory encoding is likely to occur. Control studies confirmed that intrahippocampal infusions of anisomycin inhibited protein synthesis locally and that the spatial training protocols we used are subject to overnight protein synthesis-dependent consolidation. We then compared the impact of anisomycin in two conditions: when memory retrieval occurred in a reference memory task after performance had reached asymptote over several days; and after a comparable extent of training of a delayed matching-to-place task in which new memory encoding was required each day. Sensitivity to intrahippocampal anisomycin was observed only in the protocol involving new memory encoding at the time of retrieval.     

Reconsolidation and the Dynamic Nature of Memory

Memory reconsolidation is the process in which reactivated long-term memory (LTM) becomes transiently sensitive to amnesic agents that are effective at consolidation. The phenomenon was first described more than 50 years ago but did not fit the dominant paradigm that posited that consolidation takes place only once per LTM item. Research on reconsolidation was revitalized only more than a decade ago with the demonstration of reconsolidation in a well-defined behavioral protocol (auditory fear conditioning in the rat) subserved by an identified brain circuit (basolateral amygdala). Since then, reconsolidation has been shown in many studies over a range of species, tasks, and amnesic agents, and cellular and molecular correlates of reconsolidation have also been identified. In this review, I will first define the evidence on which reconsolidation is based, and proceed to discuss some of the conceptual issues facing the field in determining when reconsolidation does and does not occur. Last, I will refer to the potential clinical implications of reconsolidation.Learning and memory are commonly depicted as going through a set of phases. There is the learning or encoding phase, in which information is acquired, by stabilization phase, in which specific mechanisms are engaged to stabilize initially unstable new information (referred to as synaptic consolidation) (Glickman 1961; McGaugh 1966), the “storage” or maintenance phase, during which other mechanisms are involved to maintain the memory, and the retrieval phase, in which specific mechanisms permit a memory to be retrieved (Miller and Springer 1973; Spear 1973). For a long time, from a neurobiological perspective, only acquisition and memory stabilization (Martin et al. 2000; Kandel 2001; Dudai 2004) were considered to be active phases, in the sense that neurons had to perform certain computations or synthesize new RNA and proteins for these phases of memory processing to be performed successfully. After acquisition and stabilization, all other phases were implicitly thought by many to be passive readout of changes in the circuits mediating the long-term memory (LTM). However, the picture has now changed and the maintenance of memory is portrayed as an active process. One of the reasons for this change is the demonstration that a consolidated LTM can become susceptible to disruption and restoration, a process termed “reconsolidation” (Spear 1973; Nader et al. 2000; Sara 2000). There are now detailed molecular and cellular models of this time-dependent active memory phase.This review will first describe the logic of the findings that brought the existence of the consolidation process to light. I will then describe how we concluded that a consolidated memory undergoes reconsolidation in a well-defined behavioral protocol (auditory fear conditioning in the rat). I will then refer to the range of species, tasks, and treatments in which reconsolidation have been reported. One aspect of reconsolidation that has attracted experimental attention involves the finding that there seem to be conditions that facilitate, inhibit, or even prevent reconsolidation from occurring. I present an approach that could help to identify such conditions. Last, I will discuss potential clinical implications of reconsolidation.     

The role of group I metabotropic glutamate receptors in memory consolidation and reconsolidation in the passive avoidance task in 1-day-old chicks

Although reconsolidation of memory after reminder does not seem to be the simple reiteration of the sequential stages occurring during memory consolidation, both phenomena probably employ similar mechanisms including activation of glutamate receptors and protein synthesis. It is known that group I metabotropic glutamate receptors (mGluRs) are involved in memory consolidation and modulation of protein synthesis. The aim of present study was to investigate the role of mGluR5 in memory consolidation and reconsolidation and to determine whether inhibition of these receptors may affect protein synthesis in these processes. The one-trial passive avoidance task on chicks was used as the experimental model of learning. Injection of the mGluR5 antagonist MPEP into a specific chick brain region IMM resulted in amnesia, provided the injection was made either shortly before or after training, or approximately 4 h after training. This amnesia was permanent, resembling the effects of protein synthesis inhibitors. MPEP injection immediately after reminder resulted in only a transient amnesia revealed 1h later. Increased expression of Zif/268 and c-Fos proteins 2 h after initial training was abolished bilaterally in chicks injected with MPEP. Injection of MPEP immediately after reminder did not inhibit c-Fos and Zif/268 expression, on the contrary, their expression was increased, specifically in left IMM and was similar to that observed after initial training. These results show that at least in the chick model mGluR5 play an important role in both consolidation and reconsolidation of memory but the mechanisms triggered by their activation in these processes differ. It is suggested that Ca(2+) signal derived from mGluR5 stimulation is necessary for complete memory consolidation, whereas during reconsolidation other mGluR5 triggered mechanisms of protein synthesis activation and regulation may be involved.     

New insights in human memory interference and consolidation

Learning new facts and skills in succession can be frustrating because no sooner has new knowledge been acquired than its retention is being jeopardized by learning another set of skills or facts. Interference between memories has recently provided important new insights into the neural and psychological systems responsible for memory processing. For example, interference not only occurs between the same types of memories, but can also occur between different types of memories, which has important implications for our understanding of memory organization. Converging evidence has begun to reveal that the brain produces interference independently from other aspects of memory processing, which suggests that interference may have an important but previously overlooked function. A memory's initial susceptibility to interference and subsequent resistance to interference after its acquisition has revealed that memories continue to be processed 'off-line' during consolidation. Recent work has demonstrated that off-line processing is not limited to just the stabilization of a memory, which was once the defining characteristic of consolidation; instead, off-line processing can have a rich diversity of effects, from enhancing performance to making hidden rules explicit. Off-line processing also occurs after memory retrieval when memories are destabilized and then subsequently restabalized during reconsolidation. Studies are beginning to reveal the function of reconsolidation, its mechanistic relationship to consolidation and its potential as a therapeutic target for the modification of memories.     

Protein synthesis subserves reconsolidation or extinction depending on reminder duration

When learned associations are recalled from long-term memory stores by presentation of an unreinforced conditioned stimulus (CS), two processes are initiated. One, termed reconsolidation, re-activates the association between the conditioned and unconditioned stimuli and transfers it from a stable protein synthesis-independent form of storage to a more labile protein-dependent state. The other is an extinction process in which presentation of the CS alone degrades the association between CS and US. To address the mechanistic relationship between reconsolidation and extinction, we have used an invertebrate model of contextual memory, which involves an association between the learning context and a visual danger stimulus. Here, we show that re-exposure duration to the learning context acts as a switch guiding the memory course toward reconsolidation or extinction, each depending on protein synthesis. Manipulation of this variable allows findings of impaired extinction to be discriminated from those of disrupted reconsolidation.