Reconsolidation: the advantage of being refocused

doi:10.1016/j.conb.2006.03.010

Current Opinion in Neurobiology

Volume 16, Issue 2, April 2006, Pages 174-178

https://doi.org/10.1016/j.conb.2006.03.010 Get rights and content

Ample evidence suggests that upon their retrieval, items in long-term memory enter a transient special state, in which they might become prone to change. The process that generates this state is dubbed ‘reconsolidation’. The dominant conceptual framework in this revitalized field of memory research focuses on whether reconsolidation resembles consolidation, which is the process that converts an unstable short-term memory trace into a more stable long-term trace. However, this emphasis on the comparison of reconsolidation to consolidation deserves reassessment. Instead, the phenomenon of reconsolidation, irrespective of its relevance to consolidation, provides a unique opportunity to tap into the molecular, cellular and circuit correlates of memory persistence and retrieval, of which we currently know only little.

Introduction

Even newcomers to the field of memory consolidation quickly observe that the debate on reconsolidation (see glossary) is not at all that new. Yet, they also realize that novelty is not a prerequisite for genuine excitement. The debate on whether items in long-term memory are consolidated just once per item shortly after their encoding or regain upon their reactivation renewed sensitivity to amnestic agents is as emotional as it used to be 40 years ago, and perhaps now even more so. In recent years this revitalized dispute has triggered a surge of publications on reconsolidation. Within less than a decade, the average publication rate of the reconsolidation community has increased over 50 fold, and is now approaching the alarming rate of one paper per week. The only solace offered to the potentially alarmed reader is that the ratio of reviews to original research papers is rather high, meaning that the level of novelty to be digested is acceptable.

Admittedly, the present discussion could tilt the balance even further in favor of the polemics versus the data. As a pre-emptive measure, this treatment of the literature is kept minimal (for a review of the field up until its renaissance in 2000, see Sara [1]; for the influential harbinger of that renaissance, see Nader et al. [2]; for coverage of the literature up to 2004, see Dudai [3] and Alberini [4]). Here, I promote the following viewpoints. First, reconsolidation studies, which seemed to wave proudly an anti-paradigmatic revolutionary flag, now risk becoming another scientific paradigm, which, unless shaken a bit at the outset, will inevitably end up stagnating till a new revolution erupts. Second, in attempting to understand reconsolidation, quite a number of contemporary studies employ similar approaches to those used 40 years ago, and, therefore, they are bound to yield similar answers, or lack of answers. Third, the conceptual focus of research in this field, which is to construe reconsolidation in the framework of consolidation, blurs a potentially more rewarding goal. This goal is to contribute to the understanding of memory persistence and retrieval, of which we know so little, but without which memory will never be understood.

Section snippets

Reconsolidation is generalized to many experimental systems and protocols

Reconsolidation is no longer considered by many as an eccentric phenomenon that can be detected in a few systems only during certain hours of the day. Data accumulated during the past few years have extended significantly the number of memory systems and protocols that display reconsolidation. These now include invertebrates and vertebrates, simple and complex learning, and aversive and reward conditioning (for a selection of recent examples of species and protocols, see [5, 6, 7, 8, 9, 10, 11••

Reconsolidation, however, might not be universal

Whereas consolidation has, to date, been detected in every type and instance of long-term memory formation [3], in the case of reconsolidation the situation seems to be different (e.g. [17]; for a review of earlier reports that failed to find reconsolidation, see Dudai [3]). In certain systems reconsolidation could not be detected, and in others, conditions have been observed in which the phenomenon disappears. This has led to the notion that there are boundary conditions for reconsolidation [18

Reconsolidation is not re-consolidation

Further evidence has been accumulated in recent years concerning the involvement in reconsolidation of identified membrane receptors, downstream signal transduction cascades and transcription factors, subsets of protein synthesis dependent mechanisms and identified neuronal circuits [10, 13, 15, 16••, 19, 20, 21, 22, 23••, 24, 25••, 26]. Of special interest are those studies that further differentiate the molecular and circuit mechanisms of reconsolidation from those of consolidation, and that

Blockade of reconsolidation is not facilitated extinction

Multiple lines of evidence also now exist to refute the possibility that the amnesia following blockade of reconsolidation (post-reconsolidation amnesia) is only an enhanced experimental extinction (see glossary) of the original memory. This evidence is based on behavioral, anatomical and molecular studies. In the case of fear conditioning in the rat, post-reconsolidation amnesia was shown to lack the typical behavioral attributes of extinction, including context-dependent renewal, spontaneous

Reconsolidation entails not only risks to the reactivated memory but also gains

In the majority of experiments on reconsolidation, amnestic agents are used to identify the phenomenon. However, recent reports have augmented the view, expressed earlier [1], that reconsolidation might also provide a window of opportunity for the strengthening of the memory trace [6, 25••]. Of particular interest in this context is the recent report that activation of amygdalar protein kinase A (PKA), a key component of the synaptic plasticity machinery, was sufficient to enhance fear memory

Is reconsolidation an updating mechanism?

A more generalized interpretation of the aforementioned data is that reconsolidation is a manifestation of a memory updating mechanism, that is, adapting the reactivated memory to the new circumstances. This idea has been around in the field for some time now [1, 3, 32]. Recent data on this are, however, conflicting. In the case of long-term taste memory in the insular cortex of the rat, post-retrieval intracortical blockade of protein synthesis disrupted memory only if the experience was

Boundary conditions of reconsolidation

To date, several conditions have been proposed to constrain reconsolidation. The first is trace dominance, that is, the ability of the association to control behavior after retrieval [28]. As noted above, in several systems, if the trace extinguishes, the extinction trace, which hence controls behavior, rather than the original trace which does not, becomes transiently sensitive to the amnestic agents [28, 29, 35]. The second is the age of memory; in some systems, older memories become less

Promising clinical applications

The potential for exploiting reconsolidation for therapeutic purposes is a major incentive in this field, and the attempts to harness this phenomenon for clinical use progress in parallel with the attempts to understand what the phenomenon really means. First and foremost, there are ongoing attempts to use reconsolidation to ameliorate post-traumatic stress disorder (PTSD). One method that has been explored involves administration of a beta adrenergic blocker as a potential post-reconsolidation

Interim summary: what reconsolidation is, and what it is not

Recent developments in the field can be combined with earlier findings to support the following heuristic conclusions:

1.
Reconsolidation is a temporarily altered state of the memory trace following memory reactivation. This altered state is characterized by increased sensitivity to amnestic agents, such as inhibitors of macromolecular synthesis, possibly because of enhanced plasticity of the neuronal circuit that encodes the memory trace or parts of it.
2.
Reconsolidation is widespread but possibly

A shift in focus is needed

The field of reconsolidation is a victim of its own history. This is felt in both the conceptual and the methodological areas. It is consistently evaluated in the context of a conceptual framework of the dual-trace hypothesis (see glossary), which assumes the existence of memory phases (short and fleeting, long and stable), and in the context of consolidation, which converts the ephemeral trace into the seemingly secure world of engrams. This situation might prove to be a far from optimal

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Glossary

Amnestic agents: Chemical or physical agents, such as inhibitors of protein synthesis, electroconvulsive shock, or distracting sensory stimuli, that cause amnesia if applied before consolidation is completed.
Dual-trace hypothesis: The hypothesis that memory items exist in two consecutive states, the first short-term and unstable, the second long-term and relatively stable.
Experimental extinction (alias extinction): The decline in the frequency or intensity of a learned response following the

References (46)

C.M. Alberini
Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes?
Trends Neurosci
(2005)
J.L. Lee et al.
Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior
Neuron
(2005)
A. Bahar et al.
Amygdalar circuits required for either consolidation or extinction of taste aversion memory are not required for reconsolidation
Eur J Neurosci
(2004)
J.L.C. Lee et al.
Independent cellular processes for hippocampal memory consolidation and reconsolidation
Science
(2004)
C.J. Rodriguez-Ortiz et al.
Protein synthesis underlies post-retrieval memory consolidation to a restricted degree only when updated information is obtained
Learn Mem
(2005)
S. Tronel et al.
Linking new information to a reactivated memory requires consolidation and not reconsolidation mechanisms
PLoS Biol
(2005)
R.A. Rescorla et al.
A theory of pavlovian conditioning: variations in the effectiveness of reinforcement and nonreinforcement
S.J. Sara
Retrieval and reconsolidation: toward a neurobiology of remembering
Learn Mem
(2000)
K. Nader et al.
Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval
Nature
(2000)
Y. Dudai
The neurobiology of consolidations, or, how stable is the engram?
Annu Rev Psychol
(2004)

K. Nader et al.

Response to alberini: right answer, wrong question

Trends Neurosci

(2005)

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Contemporary neurocognitive models of memory: A descriptive comparative analysis
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Systemic corticosterone administration impairs the late fear memory reconsolidation via basolateral amygdala glucocorticoid receptors: Dependence on the time window and memory age
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Glucocorticoid receptors (GRs) of the basolateral amygdala (BLA) play an important role in memory reconsolidation. The present study investigated the role of the BLA GRs in the late reconsolidation of fear memory using an inhibitory avoidance (IA) task in male Wistar rats. Stainless steel cannulae were implanted bilaterally into the BLA of the rats. After 7 days of recovery, the animals were trained in a one-trial IA task (1 mA, 3 s). In Experiment One, 48 h after the training session, the animals received 3 systemic doses of corticosterone (CORT; 1, 3, or 10 mg/kg, i.p.) followed by an intra-BLA microinjection of the vehicle (0.3 µl/side) at different time points (immediately, 12, or 24 h) after memory reactivation. Memory reactivation was performed by returning the animals to the light compartment while the sliding door was open. No shock was delivered during memory reactivation. CORT (10 mg/kg) injection 12 h after memory reactivation most effectively impaired the late memory reconsolidation (LMR). In the second part of Experiment One, immediately, 12, or 24 h after memory reactivation, GR antagonist RU38486 (RU; 1 ng/0.3 µl/side) was injected into BLA following a systemic injection of CORT (10 mg/kg) to examine whether it would block the CORT effect. RU inhibited the impairing effects of CORT on LMR. In Experiment Two, the animals received CORT (10 mg/kg) with time windows immediately, 3, 6, 12, and 24 h after memory reactivation. Again, CORT (10 mg/kg) injection 12 h after memory reactivation impaired LMR. Memory reactivation was performed in the third Experiment, 7, 14, 28, or 56 days after the training session. Injection of CORT (10 mg/kg) 12 h later had no significant effect on the LMR. The impairing effect of CORT was seen only in 2-day-old but not 7, 14, 28, and 56-day-old memories. GRs located in BLA seem to play an important role in the LMR of young memory, as with increasing the age of memories, they become less sensitive to manipulation.
Role of Hippocampal Wnt Signaling Pathways on Contextual Fear Memory Reconsolidation
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Memories already consolidated when reactivated return to a labile state and can be modified, this process is known as reconsolidation. It is known the Wnt signaling pathways can modulate hippocampal synaptic plasticity as well as learning and memory. Yet, Wnt signaling pathways interact with NMDA (N-methyl-D-aspartate) receptors. However, whether canonical Wnt/β-catenin and non-canonical Wnt/Ca2 + signaling pathways are required in the CA1 region of hippocampus for contextual fear memory reconsolidation remains unclear. So, here we verified that the inhibition of canonical Wnt/β-catenin pathway with DKK1 (Dickkopf-1) into CA1 impaired the reconsolidation of contextual fear conditioning (CFC) memory when administered immediately and 2 h after reactivation session but not 6 h later, while the inhibition of non-canonical Wnt/Ca²⁺ signaling pathway with SFRP1 (Secreted frizzled-related protein-1) into CA1 immediately after reactivation session had no effect. Moreover, the impairment induced by DKK1 was blocked by the administration of the agonist of the NMDA receptors glycine site, D-Serine, immediately and 2 h after reactivation session. We found that hippocampal canonical Wnt/β-catenin is necessary to the reconsolidation of CFC memory at least two hours after reactivation, while non-canonical Wnt/Ca²⁺ signaling pathway is not involved in this process and, that there is a link between Wnt/β-catenin signaling pathway and NMDA receptors. In view of this, this study provides new evidence regarding the neural mechanisms underlying contextual fear memory reconsolidation and contributes to provide a new possible target for the treatment of fear related disorders.
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Several memory consolidation theories have proposed that following a learning situation the hippocampus gradually stabilizes labile recent memories into long-lasting remote memories. Most work in this field has focused on the dorsal hippocampus (DHip), giving little consideration to a possible contribution by the ventral hippocampus (VHip), particularly when spatial paradigms are used. However, in recent years a growing number of studies have suggested the existence of a functional continuum, related to spatial processing and navigation, along the dorsoventral hippocampal axis. For this reason, in the present study we compare the effect of DHip vs. VHip lesions on long-term spatial memory retention. Using a four-arm plus-shaped maze, rats with lesions in the DHip, VHip or sham-lesioned learned to criterion a place discrimination task based on allothetic cues. During two retraining phases (2 days and 24 days after learning) retention of the spatial information learned during the acquisition phase was evaluated. The main findings revealed no deficit 2 days after learning, but 24 days after learning both lesioned groups showed a profound impairment compared to control animals (expt. 1). In contrast, when rats learned a cue-guided navigation task in the acquisition phase, both lesioned groups performed the two retention tests, 2 days and 24 days after learning, at the same level as the control group (expt. 2). These results suggest not only that the DHip is vital, but also that normal VHip activity is critical during the post-learning period in order for a recent spatial memory to become a stable long-term memory.
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^*: Temporary address: Center for Neural Science, New York University, New York, NY 10003, USA.

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Reconsolidation: the advantage of being refocused

Introduction

Section snippets

Reconsolidation is generalized to many experimental systems and protocols

Reconsolidation, however, might not be universal

Reconsolidation is not re-consolidation

Blockade of reconsolidation is not facilitated extinction

Reconsolidation entails not only risks to the reactivated memory but also gains

Is reconsolidation an updating mechanism?

Boundary conditions of reconsolidation

Promising clinical applications

Interim summary: what reconsolidation is, and what it is not

A shift in focus is needed

References and recommended reading

Glossary

Trends Neurosci

Neuron

Eur J Neurosci

Science

Learn Mem

PLoS Biol

Retrieval and reconsolidation: toward a neurobiology of remembering

Learn Mem

Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval

Nature

The neurobiology of consolidations, or, how stable is the engram?

Annu Rev Psychol

Characterization of fear memory reconsolidation

J Neurosci

Memory strengthening by a real-life episode during reconsolidation: an outcome of water deprivation via brain angiotensin II

Eur J Neurosci

Reconsolidation of a context long-term memory in the terrestrial snail requires protein synthesis

Learn Mem

Memory consolidation and reconsolidation in the rat pup require protein synthesis

J Neurosci

Acquisition, consolidation, reconsolidation, and extinction of eyelid conditioning responses require de novo protein synthesis

J Neurosci

Recalling an aversive experience by day-old chicks is not dependent on somatic protein synthesis

Learn Mem

Inhibition of hippocampal protein synthesis following recall disrupts expression of episodic-like memory in trace conditioning

Hippocampus

Impairing forgetting by preventing new learning and memory

Behav Neurosci

Spontaneous recovery from extinction depends on the reconsolidation of the acquisition memory in an appetitive learning paradigm in the honeybee (apis mellifera)

J Neurosci

Reconsolidation after remembering an odor-reward association requires NMDA receptors

Learn Mem

Consolidation and reconsolidation of incentive learning in the amygdala

J Neurosci

Retrieval does not induce reconsolidation of inhibitory avoidance memory

Learn Mem

Response to alberini: right answer, wrong question

Trends Neurosci