Abstract
Established memories undergo a period of vulnerability following retrieval, a process termed ‘reconsolidation.’ Recent work has shown that the hypothetical process of reconsolidation is only triggered when new information is presented during retrieval, suggesting that this process may allow existing memories to be modified. Reconsolidation has received increasing attention as a possible therapeutic target for treating disorders that stem from traumatic memories, yet little is known about how this process changes the original memory. In particular, it is unknown whether reconsolidation can reorganize the neural circuit supporting an existing memory after that memory is modified with new information. Here, we show that trace fear memory undergoes a protein synthesis-dependent reconsolidation process following exposure to a single updating trial of delay conditioning. Further, this reconsolidation-dependent updating process appears to reorganize the neural circuit supporting the trace-trained memory, so that it better reflects the circuit supporting delay fear. Specifically, after a trace-to-delay update session, the amygdala is now required for extinction of the updated memory but the retrosplenial cortex is no longer required for retrieval. These results suggest that updating procedures could be used to force a complex, poorly defined memory circuit to rely on a better-defined neural circuit that may be more amenable to behavioral or pharmacological manipulation. This is the first evidence that exposure to new information can fundamentally reorganize the neural circuit supporting an existing memory.
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References
Alberini CM, Ledoux JE (2013). Memory reconsolidation. Curr Biol 23: R746–R750.
Besnard A (2012). A model of hippocampal competition between new learning and memory updating. J Neurosci 32: 3281–3283.
Campeau S, Miserendino MJ, Davis M (1992). Intra-amygdala infusion of the N-methyl-D-aspartate receptor antagonist AP5 blocks acquisition but not expression of fear-potentiated startle to an auditory conditioned stimulus. Behav Neurosci 106: 569–574.
Clem RL, Huganir RL (2010). Calcium-permeable AMPA receptor dynamics mediate fear memory erasure. Science 330: 1108–1112.
Corcoran KA, Donnan MD, Tronson NC, Guzman YF, Gao C, Jovasevic V et al (2011). NMDA receptors in retrosplenial cortex are necessary for retrieval of recent and remote context fear memory. J Neurosci 31: 11655–11659.
Davis M (2011). NMDA receptors and fear extinction: implications for cognitive behavioral therapy. Dialogues Clin Neurosci 13: 463–474.
Diaz-Mataix L, Ruiz Martinez RC, Schafe GE, LeDoux JE, Doyere V (2013). Detection of a temporal error triggers reconsolidation of amygdala-dependent memories. Curr Biol 23: 467–472.
Duvarci S, Nader K, LeDoux JE (2005). Activation of extracellular signal-regulated kinase- mitogen-activated protein kinase cascade in the amygdala is required for memory reconsolidation of auditory fear conditioning. Eur J Neurosci 21: 283–289.
Falls WA, Miserendino MJD, Davis M (1992). Extinction of fear-potentiated startle–blockade by infusion of an nmda antagonist into the amygdala. J Neurosci 12: 854–863.
Flexner LB, Goodman RH (1975). Studies on memory: inhibitors of protein synthesis also inhibit catecholamine synthesis. Proc Natl Acad Sci USA 72: 4660–4663.
Frankland PW, Ding HK, Takahashi E, Suzuki A, Kida S, Silva AJ (2006). Stability of recent and remote contextual fear memory. Learn Mem 13: 451–457.
Gilmartin MR, Helmstetter FJ (2010). Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex. Learn Mem 17: 289–296.
Gilmartin MR, Kwapis JL, Helmstetter FJ (2012). Trace and contextual fear conditioning are impaired following unilateral microinjection of muscimol in the ventral hippocampus or amygdala, but not the medial prefrontal cortex. Neurobiol Learn Mem 97: 452–464.
Gilmartin MR, Miyawaki H, Helmstetter FJ, Diba K (2013). Prefrontal activity links nonoverlapping events in memory. J Neurosci 33: 10910–10914.
Goltseker K, Levi L, Barak S (2016). Counterconditioning during reconsolidation prevents relapse of cocaine memories. Neuropsychopharmacology 42: 716–726.
Graff J, Joseph NF, Horn ME, Samiei A, Meng J, Seo J et al (2014). Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell 156: 261–276.
Guimarais M, Gregorio A, Cruz A, Guyon N, Moita MA (2011). Time determines the neural circuit underlying associative fear learning. Front Behav Neurosci 5: 89.
Haubrich J, Crestani AP, Cassini LF, Santana F, Sierra RO, Alvares Lde O et al (2015). Reconsolidation allows fear memory to be updated to a less aversive level through the incorporation of appetitive information. Neuropsychopharmacology 40: 315–326.
Iordanov MS, Pribnow D, Magun JL, Dinh TH, Pearson JA, Chen SL et al (1997). Ribotoxic stress response: activation of the stress-activated protein kinase JNK1 by inhibitors of the peptidyl transferase reaction and by sequence-specific RNA damage to the alpha-sarcin/ricin loop in the 28S rRNA. Mol Cell Biol 17: 3373–3381.
Jarome TJ, Ferrara NC, Kwapis JL, Helmstetter FJ (2015). Contextual information drives the reconsolidation-dependent updating of retrieved fear memories. Neuropsychopharmacology 40: 3044–3052.
Jarome TJ, Kwapis JL, Werner CT, Parsons RG, Gafford GM, Helmstetter FJ (2012). The timing of multiple retrieval events can alter GluR1 phosphorylation and the requirement for protein synthesis in fear memory reconsolidation. Learn Mem 19: 300–306.
Jarome TJ, Werner CT, Kwapis JL, Helmstetter FJ (2011). Activity dependent protein degradation is critical for the formation and stability of fear memory in the amygdala. PLoS ONE 6: e24349.
Kim JJ, Fanselow MS (1992). Modality-specific retrograde amnesia of fear. Science 256: 675–677.
Kochli DE, Thompson EC, Fricke EA, Postle AF, Quinn JJ (2015). The amygdala is critical for trace, delay, and contextual fear conditioning. Learn Mem 22: 92–100.
Kwapis JL, Jarome TJ, Helmstetter FJ (2015a). The role of the medial prefrontal cortex in trace fear extinction. Learn Mem 22: 39–46.
Kwapis JL, Jarome TJ, Lee JL, Gilmartin MR, Helmstetter FJ (2014a). Extinguishing trace fear engages the retrosplenial cortex rather than the amygdala. Neurobiol Learn Mem 113: 41–54.
Kwapis JL, Jarome TJ, Lee JL, Helmstetter FJ (2015b). The retrosplenial cortex is involved in the formation of memory for context and trace fear conditioning. Neurobiol Learn Mem 123: 110–116.
Kwapis JL, Jarome TJ, Lonergan ME, Helmstetter FJ (2009). Protein kinase Mzeta maintains fear memory in the amygdala but not in the hippocampus. Behav Neurosci 123: 844–850.
Kwapis JL, Jarome TJ, Schiff JC, Helmstetter FJ (2011). Memory consolidation in both trace and delay fear conditioning is disrupted by intra-amygdala infusion of the protein synthesis inhibitor anisomycin. Learn Mem 18: 728–732.
Kwapis JL, Wood MA (2014b). Epigenetic mechanisms in fear conditioning: implications for treating post-traumatic stress disorder. Trends Neurosci 37: 706–720.
Laurent V, Marchand AR, Westbrook RF (2008). The basolateral amygdala is necessary for learning but not relearning extinction of context conditioned fear. Learn Mem 15: 304–314.
Lee JL (2008). Memory reconsolidation mediates the strengthening of memories by additional learning. Nat Neurosci 11: 1264–1266.
Lee JL (2010). Memory reconsolidation mediates the updating of hippocampal memory content. Front. Behav. Neurosci. 4: 168.
Lee SH, Choi JH, Lee N, Lee HR, Kim JI, Yu NK et al (2008). Synaptic protein degradation underlies destabilization of retrieved fear memory. Science 319: 1253–1256.
Mei B, Li F, Gu Y, Cui Z, Tsien JZ (2011). NMDA receptors are not required for pattern completion during associative memory recall. PLoS ONE 6: e19326.
Milekic MH, Alberini CM (2002). Temporally graded requirement for protein synthesis following memory reactivation. Neuron 36: 521–525.
Misanin JR, Miller RR, Lewis DJ (1968). Retrograde amnesia produced by electroconvulsive shock after reactivation of a consolidated memory trace. Science 160: 554–555.
Monfils MH, Cowansage KK, Klann E, LeDoux JE (2009). Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 324: 951–955.
Morris RG, Inglis J, Ainge JA, Olverman HJ, Tulloch J, Dudai Y et al (2006). Memory reconsolidation: sensitivity of spatial memory to inhibition of protein synthesis in dorsal hippocampus during encoding and retrieval. Neuron 50: 479–489.
Nader K, Hardt O (2009). A single standard for memory: the case for reconsolidation. Nat. Rev. Neurosci. 10: 224–234.
Nader K, Schafe GE, Le Doux JE (2000). Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406: 722–726.
Parsons RG, Gafford GM, Baruch DE, Riedner BA, Helmstetter FJ (2006a). Long-term stability of fear memory depends on the synthesis of protein but not mRNA in the amygdala. Eur J Neurosci 23: 1853–1859.
Parsons RG, Gafford GM, Helmstetter FJ (2006b). Translational control via the mammalian target of rapamycin pathway is critical for the formation and stability of long-term fear memory in amygdala neurons. J Neurosci 26: 12977–12983.
Parsons RG, Ressler KJ (2013). Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci 16: 146–153.
Pavlov IP (1927) Conditioned Reflexes: An Investigation of the Physiological Activity of the Cerebral Cortex. Oxford University Press: London.
Radulovic J, Tronson NC (2008). Protein synthesis inhibitors, gene superinduction and memory: too little or too much protein? Neurobiol Learn Mem 89: 212–218.
Rao-Ruiz P, Rotaru DC, van der Loo RJ, Mansvelder HD, Stiedl O, Smit AB et al (2011). Retrieval-specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fear. Nat Neurosci 14: 1302–1308.
Rossato JI, Bevilaqua LR, Myskiw JC, Medina JH, Izquierdo I, Cammarota M (2007). On the role of hippocampal protein synthesis in the consolidation and reconsolidation of object recognition memory. Learn Mem 14: 36–46.
Rothbaum BO, Davis M (2003). Applying learning principles to the treatment of post-trauma reactions. Ann N Y Acad Sci 1008: 112–121.
Rudy JW (2008). Is there a baby in the bathwater? Maybe: some methodological issues for the de novo protein synthesis hypothesis. Neurobiol Learn Mem 89: 219–224.
Rudy JW, Sutherland RJ (2008). Is it systems or cellular consolidation? Time will tell. An alternative interpretation of the Morris group's recent science paper. Neurobiol Learn Mem 89: 366–369.
Sara SJ (2000). Retrieval and reconsolidation: toward a neurobiology of remembering. Learn Mem 7: 73–84.
Schiller D, Monfils MH, Raio CM, Johnson DC, Ledoux JE, Phelps EA (2010). Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463: 49–53.
Sevenster D, Beckers T, Kindt M (2012). Retrieval per se is not sufficient to trigger reconsolidation of human fear memory. Neurobiol Learn Mem 97: 338–345.
Squire LR (1992). Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99: 195–231.
Suzuki A, Josselyn SA, Frankland PW, Masushige S, Silva AJ, Kida S (2004). Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci 24: 4787–4795.
Tayler KK, Tanaka KZ, Reijmers LG, Wiltgen BJ (2013). Reactivation of neural ensembles during the retrieval of recent and remote memory. Curr Biol 23: 99–106.
Tse D, Takeuchi T, Kakeyama M, Kajii Y, Okuno H, Tohyama C et al (2011). Schema-dependent gene activation and memory encoding in neocortex. Science 333: 891–895.
Winters BD, Tucci MC, Jacklin DL, Reid JM, Newsome J (2011). On the dynamic nature of the engram: evidence for circuit-level reorganization of object memory traces following reactivation. J Neurosci 31: 17719–17728.
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Kwapis, J., Jarome, T., Ferrara, N. et al. Updating Procedures Can Reorganize the Neural Circuit Supporting a Fear Memory. Neuropsychopharmacol 42, 1688–1697 (2017). https://doi.org/10.1038/npp.2017.23
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DOI: https://doi.org/10.1038/npp.2017.23
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