Advertisement

Reconsolidation of Human Memory: Brain Mechanisms and Clinical Relevance

      The processes of memory formation and storage are complex and highly dynamic. Once memories are consolidated, they are not necessarily fixed but can be changed long after storage. In particular, seemingly stable memories may re-enter an unstable state when they are retrieved, from which they must be re-stabilized during a process known as reconsolidation. During reconsolidation, memories are susceptible to modifications again, thus providing an opportunity to update seemingly stable memories. While initial demonstrations of memory reconsolidation came mainly from animal studies, evidence for reconsolidation in humans is now accumulating as well. Here, we review recent advances in our understanding of human memory reconsolidation. After a summary of findings on the reconsolidation of human fear and episodic memory, we focus particularly on recent neuroimaging data that provide first insights into how reconsolidation processes are implemented in the human brain. Finally, we discuss the implications of memory modifications during reconsolidation for the treatment of mental disorders such as posttraumatic stress disorder and drug addiction.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders: DSM-V.
        American Psychiatric Press, Washington, DC2013
        • Coles M.E.
        • Heimberg R.G.
        Memory biases in the anxiety disorders: Current status.
        Clin Psychol Rev. 2002; 22: 587-627
        • Hyman S.E.
        • Malenka R.C.
        • Nestler E.J.
        Neural mechanisms of addiction: The role of reward-related learning and memory.
        Annu Rev Neurosci. 2006; 29: 565-598
        • McGaugh J.
        Memory–a century of consolidation.
        Science. 2000; 287: 248-251
        • Lee J.L.C.
        Reconsolidation: Maintaining memory relevance.
        Trends Neurosci. 2009; 32: 413-420
        • Nader K.
        • Hardt O.
        A single standard for memory: The case for reconsolidation.
        Nat Rev Neurosci. 2009; 10: 224-234
        • Misanin J.R.
        • Miller R.R.
        • Lewis D.J.
        Retrograde amnesia produced by electroconvulsive shock after reactivation of a consolidated memory trace.
        Science. 1968; 160: 554-555
        • Schneider A.M.
        • Sherman W.
        Amnesia: A function of the temporal relation of foot-shock to electroconvulsive shock.
        Science. 1968; 159: 219-221
        • Lewis D.J.
        • Bregman N.J.
        Source of cues for cue-dependent amnesia in rats.
        J Comp Physiol Psychol. 1973; 85: 421-426
        • Lewis D.J.
        • Bregman N.J.
        • Mahan J.
        Cue-dependent amnesia in rats.
        J Comp Physiol Psychol. 1972; 81: 243-247
        • Lewis D.J.
        Psychobiology of active and inactive memory.
        Psychol Bull. 1979; 86: 1054-1083
        • Spear N.
        Retrieval of memory in animals.
        Psychol Rev. 1973; 80: 163-194
        • Przybyslawski J.
        • Sara S.J.
        Reconsolidation of memory after its reactivation.
        Behav Brain Res. 1997; 84: 241-246
        • McGaugh J.L.
        Time-dependent processes in memory storage.
        Science. 1966; 153: 1351-1359
        • Glickman S.
        Preservative neural processes and consolidation of the memory trace.
        Psychol Bull. 1961; 58: 218-233
        • Sara S.J.
        Retrieval and reconsolidation: Toward a neurobiology of remembering.
        Learn Mem. 2000; 7: 73-84
        • Nader K.
        • Schafe G.E.
        • LeDoux J.E.
        Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval.
        Nature. 2000; 406: 722-726
        • Taubenfeld S.M.
        • Milekic M.H.
        • Monti B.
        • Alberini C.M.
        The consolidation of new but not reactivated memory requires hippocampal C/EBPβ.
        Nat Neurosci. 2001; 4: 813-818
        • Debiec J.
        • LeDoux J.E.
        • Nader K.
        Cellular and systems reconsolidation in the hippocampus.
        Neuron. 2002; 36: 527-538
        • Fonseca R.
        • Nagerl U.V.
        • Bonhoeffer T.
        Neuronal activity determines the protein synthesis dependence of long-term potentiation.
        Nat Neurosci. 2006; 9: 478-480
        • Rose J.K.
        • Rankin C.H.
        Blocking memory reconsolidation reverses memory-associated changes in glutamate receptor expression.
        J Neurosci. 2006; 26: 11582-11587
        • Dudai Y.
        The restless engram: Consolidations never end.
        Annu Rev Neurosci. 2012; 35: 227-247
        • Finnie P.S.B.
        • Nader K.
        The role of metaplasticity mechanisms in regulating memory destabilization and reconsolidation.
        Neurosci Biobehav Rev. 2012; 36: 1667-1707
        • Lee J.L.C.
        • Everitt B.J.
        • Thomas K.L.
        Independent cellular processes for hippocampal memory consolidation and reconsolidation.
        Science. 2004; 304: 839-843
        • Walker M.P.
        • Brakefield T.
        • Hobson J.A.
        • Stickgold R.
        Dissociable stages of human memory consolidation and reconsolidation.
        Nature. 2003; 425: 616-620
        • Besnard A.
        • Caboche J.
        • Laroche S.
        Reconsolidation of memory: A decade of debate.
        Prog Neurobiol. 2012; 99: 61-80
        • Kindt M.
        • Soeter M.
        • Vervliet B.
        Beyond extinction: Erasing human fear responses and preventing the return of fear.
        Nat Neurosci. 2009; 12: 256-258
        • McGaugh J.L.
        The amygdala modulates the consolidation of memories of emotionally arousing experiences.
        Annu Rev Neurosci. 2004; 27: 1-28
        • Soeter M.
        • Kindt M.
        Stimulation of the noradrenergic system during memory formation impairs extinction learning but not the disruption of reconsolidation.
        Neuropsychopharmacology. 2012; 37: 1204-1215
        • Soeter M.
        • Kindt M.
        Erasing fear for an imagined threat event.
        Psychoneuroendocrinology. 2012; 37: 1769-1779
        • Sevenster D.
        • Beckers T.
        • Kindt M.
        Prediction error governs pharmacologically induced amnesia for learned fear.
        Science. 2013; 339: 830-833
        • Sevenster D.
        • Beckers T.
        • Kindt M.
        Retrieval per se is not sufficient to trigger reconsolidation of human fear memory.
        Neurobiol Learn Mem. 2012; 97: 338-345
        • Soeter M.
        • Kindt M.
        Dissociating response systems: Erasing fear from memory.
        Neurobiol Learn Mem. 2010; 94: 30-41
        • Schiller D.
        • Phelps E.A.
        Does reconsolidation occur in humans?.
        Front Behav Neurosci. 2011; 5: 24
        • Brunet A.
        • Ashbaugh A.R.
        • Saumier D.
        • Nelson M.
        • Pitman R.K.
        • Tremblay J.
        • et al.
        Does reconsolidation occur in humans: A reply.
        Front Behav Neurosci. 2011; 5: 74
        • Monfils M.H.
        • Cowansage K.K.
        • Klann E.
        • LeDoux J.E.
        Extinction-reconsolidation boundaries: Key to persistent attenuation of fear memories.
        Science. 2009; 324: 951-955
        • Schiller D.
        • Monfils M.H.
        • Raio C.M.
        • Johnson D.C.
        • LeDoux J.E.
        • Phelps E.A.
        Preventing the return of fear in humans using reconsolidation update mechanisms.
        Nature. 2010; 463: 49-53
        • Oyarzun J.P.
        • Lopez-Barroso D.
        • Fuentemilla L.
        • Cucurell D.
        • Pedraza C.
        • Rodriguez-Fornells A.
        • de Diego-Balaguer R.
        Updating fearful memories with extinction training during reconsolidation: A human study using auditory aversive stimuli.
        PLoS One. 2012; 7: e38849
        • Agren T.
        • Engman J.
        • Frick A.
        • Björkstrand J.
        • Larsson E.-M.
        • Furmark T.
        • Fredrikson M.
        Disruption of reconsolidation erases a fear memory trace in the human amygdala.
        Science. 2012; 337: 1550-1552
        • Agren T.
        • Furmark T.
        • Eriksson E.
        • Fredrikson M.
        Human fear reconsolidation and allelic differences in serotonergic and dopaminergic genes.
        Transl Psychiatry. 2012; 2: e76
        • Soeter M.
        • Kindt M.
        Disrupting reconsolidation: Pharmacological and behavioral manipulations.
        Learn Mem. 2011; 18: 357-366
        • Kindt M.
        • Soeter M.
        Reconsolidation in a human fear conditioning study: A test of extinction as updating mechanism.
        Biol Psychol. 2013; 92: 43-50
        • Golkar A.
        • Bellander M.
        • Olsson A.
        • Ohman A.
        Are fear memories erasable?-reconsolidation of learned fear with fear-relevant and fear-irrelevant stimuli.
        Front Behav Neurosci. 2012; 6: 80
        • Warren N.T.
        • Anderson K.M.
        • Kwon C.
        • Bosshardt L.
        • Jovanovic T.
        • Bradley B.
        • Norrholm S.D.
        Human fear extinction and return of fear using reconsolidation update mechanisms: The contribution of on-line expectancy ratings [published online ahead of print October 29].
        Neurobiol Learn Mem. 2013;
        • Loftus E.F.
        Planting misinformation in the human mind: A 30-year investigation of the malleability of memory.
        Learn Mem. 2005; 12: 361-366
        • Fischhoff B.
        Hindsight is not equal to foresight: The effect of outcome knowledge on judgment.
        J Exp Psychol Hum Percept Perform. 1975; 1: 288-299
        • Hupbach A.
        • Gomez R.
        • Hardt O.
        • Nadel L.
        Reconsolidation of episodic memories: A subtle reminder triggers integration of new information.
        Learn Mem. 2007; 14: 47-53
        • Forcato C.
        • Rodriguez M.L.
        • Pedreira M.E.
        • Maldonado H.
        Reconsolidation in humans opens up declarative memory to the entrance of new information.
        Neurobiol Learn Mem. 2010; 93: 77-84
        • Chan J.C.
        • LaPaglia J.A.
        Impairing existing declarative memory in humans.
        Proc Natl Acad Sci U S A. 2013; 110: 9309-9313
        • Hupbach A.
        • Hardt O.
        • Gomez R.
        • Nadel L.
        The dynamics of memory: Context-dependent updating.
        Learn Mem. 2008; 15: 574-579
        • Hupbach A.
        • Gomez R.
        • Nadel L.
        Episodic memory reconsolidation: Updating or source confusion?.
        Memory. 2009; 17: 502-510
        • Strange B.A.
        • Kroes M.C.
        • Fan J.E.
        • Dolan R.J.
        Emotion causes targeted forgetting of established memories.
        Front Behav Neurosci. 2010; 4: 175
        • Forcato C.
        • Burgos V.L.
        • Argibay P.F.
        • Molina V.A.
        • Pedreira M.E.
        • Maldonado H.
        Reconsolidation of declarative memory in humans.
        Learn Mem. 2007; 14: 295-303
        • Schwabe L.
        • Wolf O.T.
        New episodic learning interferes with the reconsolidation of autobiographical memories.
        PLoS One. 2009; 4: e7519
        • Forcato C.
        • Rodriguez M.L.
        • Pedreira M.E.
        Repeated labilization-reconsolidation processes strengthen declarative memory in humans.
        PLoS One. 2011; 6: e23305
        • Coccoz V.
        • Maldonado H.
        • Delorenzi A.
        The enhancement of reconsolidation with a naturalistic mild stressor improves the expression of a declarative memory in humans.
        Neuroscience. 2011; 185: 61-72
        • Coccoz V.
        • Sandoval A.V.
        • Stehberg J.
        • Delorenzi A.
        The temporal dynamics of enhancing a human declarative memory during reconsolidation.
        Neuroscience. 2013; 246: 397-408
        • Schwabe L.
        • Wolf O.T.
        Stress impairs the reconsolidation of autobiographical memories.
        Neurobiol Learn Mem. 2010; 94: 153-157
        • Kroes M.C.W.
        • Tendolkar I.
        • van Wingen G.A.
        • van Waarde J.A.
        • Strange B.A.
        • Fernandez G.
        An electroconvulsive therapy procedure impairs reconsolidation of episodic memories in humans.
        Nat Neurosci. 2014; 17: 204-206
        • Schwabe L.
        • Nader K.
        • Pruessner J.C.
        Beta-adrenergic blockade during reactivation reduces the subjective feeling of remembering associated with emotional episodic memories.
        Biol Psychol. 2013; 92: 227-232
        • Rodriguez M.L.
        • Campos J.
        • Forcato C.
        • Leiquarda R.
        • Maldonado H.
        • Molina V.A.
        • Pedreira M.E.
        Enhancing a declarative memory in humans: The effect of clonazepam on reconsolidation.
        Neuropharmacology. 2013; 64: 432-442
        • Schwabe L.
        • Nader K.
        • Wolf O.T.
        • Beaudry T.
        • Pruessner J.C.
        Neural signature of reconsolidation impairments by propranolol in humans.
        Biol Psychiatry. 2012; 71: 380-386
        • Cahill L.
        • Babinsky R.
        • Markowitsch H.J.
        • McGaugh J.L.
        The amygdala and emotional memory.
        Nature. 1995; 377: 295-296
        • Cahill L.
        • McGaugh J.L.
        Mechanisms of emotional arousal and lasting declarative memory.
        Trends Neurosci. 1998; 21: 294-299
        • Cahill L.
        • Prins B.
        • Weber M.
        • McGaugh J.L.
        Beta-adrenergic activation and memory for emotional events.
        Nature. 1994; 371: 702-704
        • LaBar K.S.
        • Gatenby J.C.
        • Gore J.C.
        • LeDoux J.E.
        • Phelps E.A.
        Human amygdala activation during conditioned fear acquisition and extinction: A mixed-trial fMRI study.
        Neuron. 1998; 20: 937-945
        • Büchel C.
        • Morris J.
        • Dolan R.J.
        • Friston K.J.
        Brain systems mediating aversive conditioning: An event-related fMRI study.
        Neuron. 1998; 20: 947-957
        • Schiller D.
        • Kanen J.W.
        • LeDoux J.E.
        • Monfils M.H.
        • Phelps E.A.
        Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement.
        Proc Natl Acad Sci U S A. 2013; 110: 20040-20045
        • Censor N.
        • Dayan E.
        • Cohen L.G.
        Cortico-subcortical neuronal circuitry associated with reconsolidation of human procedural memories [published online ahead of print June 15].
        Cortex. 2013;
        • Gerloff C.
        • Corwell B.
        • Chen R.
        • Hallett M.
        • Cohen L.G.
        Stimulation over the human supplementary motor area interferes with the organization of future elements in complex motor sequences.
        Brain. 1997; 120: 1587-1602
        • Diekelmann S.
        • Büchel C.
        • Born J.
        • Rasch B.
        Labile or stabile: Opposing consequences for memory when reactivated during waking and sleep.
        Nat Neurosci. 2011; 14: 381-386
        • Sandrini M.
        • Censor N.
        • Mishoe J.
        • Cohen L.G.
        Causal role of prefrontal cortex in strengthening of episodic memories through reconsolidation.
        Curr Biol. 2013; 23: 2181-2184
        • Rubin R.D.
        • Fried R.
        • Franks C.M.
        New applications of ECT.
        in: Rubin R.D. Franks C.M. Advances in Behavior Therapy. Academic Press, New York1968
        • Pitman R.K.
        Post-traumatic stress disorder, hormones, and memory.
        Biol Psychiatry. 1989; 26: 221-223
        • Pitman R.K.
        • Sanders K.M.
        • Zusman R.M.
        • Healy A.R.
        • Cheema F.
        • Lasko N.B.
        • et al.
        Pilot study of secondary prevention of posttraumatic stress disorder with propranolol.
        Biol Psychiatry. 2002; 51: 189-192
        • Vaiva G.
        • Ducrocq F.
        • Jezequel K.
        • Averland B.
        • Lestavel P.
        • Brunet A.
        • Marmar C.R.
        Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma.
        Biol Psychiatry. 2003; 54: 947-949
        • McGhee L.
        • Maani C.V.
        • Garza T.H.
        • DeSocio P.A.
        • Gaylord K.M.
        • Black I.H.
        The effect of propranolol on posttraumatic stress disorder in burned service members.
        J Burn Care Res. 2009; 30: 92-97
        • Brunet A.
        • Orr S.P.
        • Tremblay J.
        • Robertson K.
        • Nader K.
        • Pitman R.K.
        Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder.
        J Psychiatr Res. 2008; 42: 503-506
        • Brunet A.
        • Poundja J.
        • Tremblay J.
        • Bui E.
        • Thomas E.
        • Orr S.P.
        • et al.
        Trauma reactivation under the influence of propranolol decreases posttraumatic stress symptoms and disorder: 3 open-label trials.
        J Clin Psychopharmacol. 2011; 31: 547-550
        • Taylor J.R.
        • Olausson P.
        • Qiunn J.J.
        • Torregrossa M.M.
        Targeting extinction and reconsolidation mechanisms to combat the impact of drug cues on addiction.
        Neuropharmacology. 2009; 56: 186-195
        • Gawin F.H.
        • Kleber H.D.
        Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations.
        Arch Gen Psychiatry. 1986; 43: 107-113
        • de Wit H.
        • Stewart J.
        Reinstatement of cocaine-reinforced responding in the rat.
        Psychopharmacology (Berl). 1981; 75: 134-143
        • Robbins T.W.
        • Cador M.
        • Taylor J.R.
        • Everitt B.J.
        Limbic-striatal interactions in reward-related processes.
        Neurosci Biobehav Rev. 1989; 13: 155-162
        • Conklin C.A.
        • Tiffany S.T.
        Applying extinction research and theory to cue-exposure addiction treatments.
        Addiction. 2002; 97: 155-167
        • Crombag H.S.
        • Shaham Y.
        Renewal of drug seeking by contextual cues after prolonged extinction in rats.
        Behav Neurosci. 2002; 116: 169-173
        • Lee J.L.C.
        • Di Ciano P.
        • Thomas K.L.
        • Everitt B.J.
        Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior.
        Neuron. 2005; 47: 795-801
        • Milton A.L.
        • Lee J.L.C.
        • Everitt B.J.
        Reconsolidation of appetitive memories for both neutral and drug reinforcement is dependent on {beta}-adrenergic receptors.
        Learn Mem. 2008; 15: 88-92
        • Zhao L.Y.
        • Sun L.L.
        • Shi J.
        • Li P.
        • Zhang Y.
        • Lu L.
        Effects of β-adrenergic receptor blockade on drug-related memory reconsolidation in abstinent heroin addicts.
        Drug Alcohol Depend. 2011; 118: 224-229
        • Zhao L.Y.
        • Zhang X.L.
        • Shi J.
        • Epstein D.H.
        • Lu L.
        Psychosocial stress after reactivation of drug-related memory impairs later recall in abstinent heroin addicts.
        Psychopharmacology (Berl). 2009; 203: 599-608
        • Xue Y.X.
        • Luo Y.X.
        • Wu P.
        • Shi H.S.
        • Xue L.F.
        • Chen C.
        • et al.
        A memory retrieval-extinction procedure to prevent drug craving and relapse.
        Science. 2012; 336: 241-245
        • Milekic M.
        • Alberini C.M.
        Temporally graded requirement for protein synthesis following memory reactivation.
        Neuron. 2002; 36: 521-525
        • Suzuki A.
        • Josselyn S.A.
        • Frankland P.W.
        • Masushige S.
        • Silva A.J.
        • Kida S.
        Memory reconsolidation and extinction have distinct temporal and biochemical signatures.
        J Neurosci. 2004; 24: 4787-4795
        • Wang S.H.
        • de Oliveira Alvares L.
        • Nader K.
        Cellular and systems mechanisms of memory strength as a constraint on auditory fear reconsolidation.
        Nat Neurosci. 2009; 12: 905-912
        • Wichert S.
        • Wolf O.T.
        • Schwabe L.
        Reactivation, interference, and reconsolidation: Are recent and remote memories likewise susceptible?.
        Behav Neurosci. 2011; 125: 699-704
        • Forcato C.
        • Argibay P.F.
        • Pedreira M.E.
        • Maldonado H.
        Human reconsolidation does not always occur when a memory is retrieved: The relevance of the reminder structure.
        Neurobiol Learn Mem. 2009; 91: 50-57
        • Wichert S.
        • Wolf O.T.
        • Schwabe L.
        Changing memories after reactivation: A one-time opportunity?.
        Neurobiol Learn Mem. 2013; 99: 38-49
        • Wichert S.
        • Wolf O.T.
        • Schwabe L.
        Updating of episodic memories depends on the strength of new learning after memory reactivation.
        Behav Neurosci. 2013; 127: 331-338
        • Bustos S.G.
        • Giachero M.
        • Maldonado H.
        • Molina V.A.
        Previous stress attenuates the susceptibility to Midazolam׳s disruptive effect on fear memory reconsolidation: Influence of pre-reactivation D-cycloserine administration.
        Neuropsychopharmacology. 2010; 35: 1097-1108
        • Winters B.D.
        • Tucci M.C.
        • DaCosta-Furtado M.
        Older and stronger object memories are selectively destabilized by reactivation in the presence of new information.
        Learn Mem. 2009; 16: 545-553
        • Tronson N.C.
        • Taylor J.R.
        Molecular mechanisms of memory reconsolidation.
        Nat Rev Neurosci. 2007; 8: 262-275