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

Nature volume 406, pages 722–726 (2000)Cite this article

Abstract

‘New’ memories are initially labile and sensitive to disruption before being consolidated into stable long-term memories1,2,3,4,5. Much evidence indicates that this consolidation involves the synthesis of new proteins in neurons6,7,8,9. The lateral and basal nuclei of the amygdala (LBA) are believed to be a site of memory storage in fear learning10. Infusion of the protein synthesis inhibitor anisomycin into the LBA shortly after training prevents consolidation of fear memories11. Here we show that consolidated fear memories, when reactivated during retrieval, return to a labile state in which infusion of anisomycin shortly after memory reactivation produces amnesia on later tests, regardless of whether reactivation was performed 1 or 14 days after conditioning. The same treatment with anisomycin, in the absence of memory reactivation, left memory intact. Consistent with a time-limited role for protein synthesis production in consolidation, delay of the infusion until six hours after memory reactivation produced no amnesia. Our data show that consolidated fear memories, when reactivated, return to a labile state that requires de novo protein synthesis for reconsolidation. These findings are not predicted by traditional theories of memory consolidation.

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Figure 1: Schematic representation of the amygdala at four different rostral–caudal planes.
Figure 2: A test of whether consolidated fear memories can become labile when reactivated.
Figure 3: Intact memory if anisomycin infusions are delayed by 6 h.
Figure 4: Fourteen days after training, anisomycin infusions after reactivation of the memory still produce amnesia.
Figure 5: Amnesia following anisomycin is not due to nonspecific effects.

References

  1. Müller, G. E. & Pilzecker, A. Experimentelle beitrage zur lehre vom gedachtnis. Z. Psychol. (Suppl. 1) (1900).

  2. Burnham, W. H. Retroactive amnesia: illustrative cases and a tentative explanation. Am. J. Psychol. 14, 382–396 (1903).

    Article  Google Scholar 

  3. Duncan, C. P. The retroactive effect of electroconvulsive shock. J. Comp. Physiol. Psychol. 42, 32–44 ( 1949).

    CAS  Article  Google Scholar 

  4. Hebb, D. O. The Organization of Behavior (Wiley, New York, 1949 ).

    Google Scholar 

  5. Dudai, Y. Consolidation: Fragility on the road to the engram. Neuron 17, 367–370 (1996).

    CAS  Article  Google Scholar 

  6. Goelet, P., Castellucci, V. F., Schacher, S. & Kandel, E. R. The long and short of long-term memory—a molecular framework. Nature 322, 419–422 ( 1986).

    ADS  CAS  Article  Google Scholar 

  7. Flexner, L. B., Flexner, J. B. & Stellar, E. Memory and cerebral protein synthesis in mice as affected by graded amounts of puromycin. Exp. Neurol. 13, 264–272 (1965).

    CAS  Article  Google Scholar 

  8. Davis, H. P. & Squire, L. R. Protein synthesis and memory. A review. Psychol. Bull. 96, 518– 559 (1984).

    CAS  Article  Google Scholar 

  9. Agranoff, B. W. in Basic Neurochemistry (eds Siegel, G. J., Albers, R. W., Agranoff, B. W. & Catzman, R.) 801–820 (Little, Brown, Boston, 1981).

    Google Scholar 

  10. Fanselow, M. S. & LeDoux, J. E. Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala. Neuron 23, 229– 232 (1999).

    CAS  Article  Google Scholar 

  11. Schafe, G. E. & LeDoux, J. E. Memory consolidation of auditory Pavlovian fear conditioning requires protein synthesis and PKA in the amygdala. J. Neurosci. (in the press).

  12. McGaugh, J. L. Memory—a century of consolidation. Science 287 , 248–251 (2000).

    ADS  CAS  Article  Google Scholar 

  13. Misanin, J. R., Miller, R. R. & Lewis, D. J. Retrograde amnesia produced by electroconvulsive shock after reactivation of a consolidated memory trace. Science 160, 203–204 ( 1968).

    Article  Google Scholar 

  14. Judge, M. E. & Quartermain, D. Characteristics of retrograde amnesia following reactivation of memory in mice. Physiol. Behav. 28, 585–590 ( 1982).

    CAS  Article  Google Scholar 

  15. Sara, S. J. Retrieval and reconsolidation: toward a neurobiology of remembering. Learn. Mem. 7, 73–84 ( 2000).

    CAS  Article  Google Scholar 

  16. Mactutus, C. F., Riccio, D. C. & Ferek, J. M. Retrograde amnesia for old (reactivated) memory: Some anomalous characteristics. Science 204, 1319–1320 (1979).

    ADS  CAS  Article  Google Scholar 

  17. Davis, M. Neurobiology of fear responses: the role of the amygdala. J. Neuropsychiat. Clin. Neurosci. 9, 382–402 (1997).

    CAS  Article  Google Scholar 

  18. Fanselow, M. S. Pavlovian conditioning, negative feedback, and blocking: mechanisms that regulate association formation. Neuron 20, 625– 627 (1998).

    CAS  Article  Google Scholar 

  19. LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).

    CAS  Article  Google Scholar 

  20. Blanchard, R. J. & Blanchard, D. C. Crouching as an index of fear. J. Comp. Physiol. Psychol. 67, 370–375 (1969).

    CAS  Article  Google Scholar 

  21. Scholey, A. B., Rose, S. P., Zamani, M. R., Bock, E. & Schachner, M. A role for the neural cell adhesion molecule in a late, consolidating phase of glycoprotein synthesis six hours following passive avoidance training of the young chick. Neuroscience 55, 499–509 ( 1993).

    CAS  Article  Google Scholar 

  22. Brady, J. V. The effects of electroconvulsive shock on a conditioned emotional response: the permanence effect. J. Comp. Physiol. Psychol. 45 , 9–13 (1952).

    CAS  Article  Google Scholar 

  23. Abel, T. et al. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 88, 615–626 (1997).

    CAS  Article  Google Scholar 

  24. Bourtchouladze, R. et al. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79, 59–68 (1994).

    Article  Google Scholar 

  25. Guzowski, J. F. & McGaugh, J. L. Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proc. Natl Acad. Sci. USA 94, 2693–2698 ( 1997).

    ADS  CAS  Article  Google Scholar 

  26. Lamprecht, R., Harzvi, S. & Dudai, Y. cAMP response element-binding protein in the amygdala is required for long- but not short-term conditioned taste aversion memory. J. Neurosci. 17, 8443– 8450 (1997).

    CAS  Article  Google Scholar 

  27. Bartlett, F. C. Remembering (Cambridge Univ. Press, Cambridge, 1932 ).

    Google Scholar 

  28. Martin, K. C. et al. Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91, 927–938 (1997).

    CAS  Article  Google Scholar 

  29. Frey, U. & Morris, R. G. Synaptic tagging and long-term potentiation. Nature 385, 533– 536 (1997).

    ADS  CAS  Article  Google Scholar 

  30. Rosenblum, K., Meiri, N. & Dudai, Y. Taste memory: the role of protein synthesis in gustatory cortex. Behav. Neural Biol. 59, 49– 56 (1993).

    CAS  Article  Google Scholar 

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Acknowledgements

This research was supported in part by NIMH grants to J.E.L. and a HFSF grant to K.N. The work was also supported by a grant from the W. M. Keck Foundation to N.Y.U. The authors thank A. Schoute for technical assistance.

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  1. W. M. Keck Foundation Laboratory of Neurobiology, Center for Neural Science, New York University, New York, 10003, New York, USA

    Karim Nader, Glenn E. Schafe & Joseph E. Le Doux

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  1. Karim Nader
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  2. Glenn E. Schafe
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  3. Joseph E. Le Doux
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Correspondence to Karim Nader.

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Nader, K., Schafe, G. & Le Doux, J. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726 (2000). https://doi.org/10.1038/35021052

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