Skip to main content
SpringerLink
Log in

Molecular Mechanisms of Memory Retrieval

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Memory retrieval is a fundamental component or stage of memory processing. In fact, retrieval is the only possible measure of memory. The ability to recall past events is a major determinant of survival strategies in all species and is of paramount importance in determining our uniqueness as individuals. Most biological studies of memory using brain lesion and/or gene manipulation techniques cannot distinguish between effects on the molecular mechanisms of the encoding or consolidation of memories and those responsible for their retrieval from storage. Here we examine recent findings indicating the major molecular steps involved in memory retrieval in selected brain regions of the mammalian brain. Together the findings strongly suggest that memory formation and retrieval may share some molecular mechanisms in the hippocampus and that retrieval initiates extinction requiring activation of several signaling cascades and protein synthesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. James, W. 1890. Principles of Psychology. Holt, New York.

    Google Scholar 

  2. McGaugh, J. L. 1966. Time-dependent processes in memory storage. Science 153:1351-1358.

    Google Scholar 

  3. Moser, M. B. and Moser, E. I. 1998. Distributed encoding and retrieval of spatial memory in the hippocampus. J. Neurosci. 18(18):7535-7542.

    Google Scholar 

  4. Zola, S. M. and Squire, L. R. 1990. The primate hippocampal formation: Evidence for a time limited role in memory storage. Science 250:288-290.

    Google Scholar 

  5. Anagnostaras, S. G., Maren, S., and Fanselow, M. S. 1999. Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination. J. Neurosci. 19(3):1106-1114.

    Google Scholar 

  6. Zola, S. M. and Squire, L. R. 2001. Relationship between magnitude of damage to the hippocampus and impaired recognition memory in monkeys. Hippocampus 11:92-98.

    Google Scholar 

  7. Rempel-Clower, N. L., Zola, S. M., Squire, L. R., and Amaral, D. G. 1996. Three cases of enduring memory impairment after bilateral damage limited to the hippocampal formation. J. Neurosci. 16(16):5233-5255.

    Google Scholar 

  8. Teng, E. and Squire, L. R. 1999. Memory for places learned long ago is intact after hippocampal damage. Nature 400:675-677.

    Google Scholar 

  9. Minichiello, L., Korte, M., Wolfer, D., Kuhn, R., Unsicker, K., Cestari, V., Rossi-Arnaud, C., Lipp, H. P., Bonhoeffer, T., and Klein, R. 1999. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24(2):401-414.

    Google Scholar 

  10. Tsien, J. Z., Huerta, P. T., and Tonegawa, S. 1996. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87(7):1327-1338.

    Google Scholar 

  11. Silva, A. J., Paylor, R., Wehner, J. M., and Tonegawa, S. 1992. Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science 257:206-211.

    Google Scholar 

  12. Bourtchuladze, R., Frenguelli, B., Blendy, J., Cioffi, D., Schutz, G., and Silva, A. J. 1994. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79(1):59-68.

    Google Scholar 

  13. Izquierdo, I. and Medina, J. H. 1997. Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiol. Learn. Mem. 68:285-316.

    Google Scholar 

  14. Setlow, B., Roozendaal, B., and McGaugh, J. L. 2000. Involvement of a basolateral amygdala complex-nucleus accumbens pathway in glucocorticoid-induced modulation of memory consolidation. Eur. J. Neurosci. 1:367-375.

    Google Scholar 

  15. Wilensky, A. E., Schafe, G. E., and LeDoux, J. E. 2000. The amygdala modulates memory consolidation of fear-motivated inhibitory avoidance learning but not classical fear conditioning. J. Neurosci. 20(18):7059-7066.

    Google Scholar 

  16. Goosens, K. A. and Maren, S. 2001. Contextual and auditory fear conditioning are mediated by the lateral, basal, and central amygdaloid nuclei in rats. Learn. Mem. 3:148-155.

    Google Scholar 

  17. Izquierdo, I. and Medina, J. H. 1995. Correlation between the long-term potentiation and the pharmacology of memory and. Neurobiol. Learn. Mem. 68:285-316.

    Google Scholar 

  18. Atkins, C. M., Selcher, J. C., Petraitis, J. J., Trzaskos, J. M., and Sweatt, J. D. 1998. The MAPK cascade is required for mammalian associative learning. Nat. Neurosci. 7:602-609.

    Google Scholar 

  19. McGaugh, J. L. 2000. Memory: a century of consolidation. Science 287:248-251.

    Google Scholar 

  20. Medina, J. H., Schroder, N., and Izquierdo, I. 1999. Two different properties of short-and long-term memory. Behav. Brain. Res. 103:119-121.

    Google Scholar 

  21. Gold, P. E. 1986. The use of avoidance training in studies of modulation of memory storage. Behav. Neural Biol. 46:87-98.

    Google Scholar 

  22. Vianna, M. R. M., Izquierdo, L. A., Barros, D. M., Ardenghi, P., Pereira, P., Rodrigues, C., Moletta, B., Medina, J. H., and Izquierdo, I. 2000. Differential role of hippocampal cAMPdependent protein kinase in short-and long-term memory. Neurochem. Res. 5:621-626.

    Google Scholar 

  23. Vianna, M. R. M., Szapiro, G., McGaugh, J. L., and Izquierdo, I. 2001. Retrieval of memory for fear-motivated training initiates extinction requiring protein synthesis in the rat hippocampus. Proc. Natl. Acad. Sci. U.S.A. (98)21:12251-12254.

    Google Scholar 

  24. Izquierdo, I., Da Cunha, C., Rosat, R., Jerusalinsky, D., Quillfeldt, J. A., Ferreira, M. B. C., and Medina, J. H. 1992. Neurotransmitter receptors involved in memory processing by the amygdala, medial septum and hippocampus of rats. Behav. Neural Biol, 58:16-25.

    Google Scholar 

  25. Holt, W. and Maren, S. 1999. Muscimol inactivation of the dorsal hippocampus impairs contextual retrieval of fear memory. J. Neurosci. 19(20):9054-9062.

    Google Scholar 

  26. Szapiro, G., Izquierdo, L. A., Alonso, M., Barros, D., Paratcha, G., Ardenghi, P., Pereira P., Medina, J. H., and Izquierdo, I. 2000. Participation of hippocampal metabotropic receptors, protein kinase A and mitogen-activated protein kinases in memory retrieval. Neuroscience 99:1-5.

    Google Scholar 

  27. Kandel, E. R. 2001. The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses. Science 294:1030-1038.

    Google Scholar 

  28. Staubli, U., Thibault, O., DiLorenzo, M., and Lynch, G. 1989. Antagonism of NMDA receptors impairs acquisition but not retention of olfactory memory. Behav. Neurosci. 103(1):54-60.

    Google Scholar 

  29. Steele, R. J. and Morris, R. G. 1999. Delay-dependent impairment of a matching-to-place task with chronic and intrahippocampal infusion of the NMDA-antagonist D-AP5. Hippocampus 9(2):118-136.

    Google Scholar 

  30. Riedel, G., Micheau, J., Lam A. G., Roloff, Ev, Martin, S. J., Bridge, H., Hoz, Ld, Poeschel, B., McCulloch, J., and Morris, R. G. 1999. Reversible neural inactivation reveals hippocampal participation in several memory processes. Nat. Neurosci. 10:898-905.

    Google Scholar 

  31. Schulz, B., Fendt, M., Gasparini, F., Lingenhohl, K, Kuhn, R., and Koch, M. 2001. The metabotropic glutamate receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks fear conditioning in rats. Neuropharmacol. 41(1):1-7.

    Google Scholar 

  32. Benowitz, L. I. and Routtemberg, A. 1997. GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci. 20:84-91.

    Google Scholar 

  33. Cammarota, M., Paratcha, G., Levi de Stein, M., Bernabeu, R., Izquierdo, I., and Medina, J. H. 1997. B-50/GAP-43 phosphorylation and PKC activity are increased in rat hippocampal synaptosomal membranes after an inhibitory avoidance training. Neurochem. Res. 4:499-505.

    Google Scholar 

  34. Paratcha, G., Furman, M., Bevilaqua, L., Cammarota, M., Vianna, M., de Stein, M. L., Izquierdo, I., and Medina, J. H. 2000. Involvement of hippocampal PKCbetaI isoform in the early phase of memory formation of an inhibitory avoidance learning. Brain Res. 855(2):199-205.

    Google Scholar 

  35. Weeber, E. J., Atkins, C. M., Selcher, J. C., Varga, A. W., Mirnikjoo, B., Paylor, R., Leitges, M., and Sweatt, J. D. 2000. A role for the beta isoform of protein kinase C in fear conditioning. J. Neurosci. 20(16):5906-5914.

    Google Scholar 

  36. Vianna, M. R., Barros, D. M., Silva, T., Choi, H., Madche, C., Rodrigues, C., Medina, J. H., and Izquierdo, I. 2000. Pharmacological demonstration of the differential involvement of protein kinase C isoforms in short-and long-term memory formation and retrieval of one-trial avoidance in rats. Psychopharmacology 150:77-84.

    Google Scholar 

  37. Yin, J. C. P. and Tully, T. 1996. CREB and the formation of long-term memory. Curre. Opin. Neurobiol. 6:204-208.

    Google Scholar 

  38. Guzowski, J. F. and McGaugh, J. L. 1997. Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proc. Natl. Acad. Sci. 94:2693-2698.

    Google Scholar 

  39. Impey, S., Smith, D. M., Obrietan, K., Donahue, R., Wade, C., and Storm, D. R. 1998. Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat. Neurosci. 1:595-601.

    Google Scholar 

  40. Taubenfeld, S. M., Wiig, K. A., Bear, M. F., and Alberini, C. M. 1999. A molecular correlate of memory and amnesia in the hippocampus. Nat. Neurosci. 2:309-310.

    Google Scholar 

  41. Bernabeu, R., Bevilaqua, L., Ardenghi, P., Bromberg, E., Schmitz, P., Bianchin, M., Izquierdo, I., and Medina, J. H. 1997. Involvement of hippocampal cAMP/cAMP-dependent protein kinase signaling pathways in a late memory consolidation phase of aversively motivated learning in rats. Proc. Natl. Acad. Sci. 94:7041-7046.

    Google Scholar 

  42. Hall, J., Thomas, K. L., and Everitt, B. J. 2001. Fear memory retrieval induces CREB phosphorylation and Fos expression within the amygdala. Eur. J. Neurosci. 7:1453-1458.

    Google Scholar 

  43. Ghosh, A. and Greenberg, M. E. 1995. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science 268:239-247.

    Google Scholar 

  44. Kandel, E. R. and Squire, L. R. 2000. Neuroscience: breaking down scientific barriers to the study of brain and mind. Science 290:1113-1120.

    Google Scholar 

  45. Izquierdo, L. A., Vianna, M., Barros, D. M., Mello e Souza, T., Ardenghi, P., Sant' Anna, M. K., Rodrigues, C., Medina, J. H., and Izquierdo, I. 2000. Short-and long-term memory are differentially affected by metabolic inhibitors given into hippocampus and entorhinal cortex. Neurobiol. Learn. Mem. 73(2):141-149.

    Google Scholar 

  46. Barros, D. M., Izquierdo, L. A, Mello e Souza, T., Ardenghi, P. G., Pereira, P., Medina, J. H., and Izquierdo, I. 2000. Molecular signalling pathways in the cerebral cortex are required for retrieval of one-trial avoidance learning in rats. Behav. Brain Res. 114(1-2):183-192.

    Google Scholar 

  47. McGaugh, J. L. and Izquierdo, I. 2000. The contribution of pharmacology to research on the mechanisms of memory formation. Trends Pharmacol. Sci. 21(6):208-210.

    Google Scholar 

  48. McGaugh, J. L., Castellano, C., and Brioni, J. 1990. Picrotoxin enhances latent extinction of conditioned fear. Behav. Neurosci. 104:264-267.

    Google Scholar 

  49. Barros, D. M., Mello e Souza, T., De David, T., Choi, H., Aguzzoli, A., Madche, C., Ardenghi, P., Medina, J. H., and Izquierdo, I. 2001. Simultaneous modulation of retrieval by dopaminergic D1, β-noradrenergic, serotoninergic1A and cholinergic muscarinic receptors in cortical structures of the rat. Behavi. Brain Res. 124:1-7.

    Google Scholar 

  50. Power, A. E., Roozendaal, B., and McGaugh, J. L. 2000. Glucocorticoid enhancement of memory consolidation in the rat is blocked by muscarinic receptor antagonism in the basolateral amygdala. Eur. J. Neurosci. 10:3481-3487.

    Google Scholar 

  51. Roozendaal, B., de Quervain, D. J., Ferry, B., Setlow, B., McGaugh, J. L. 2001. Basolateral amygdala-nucleus accumbens interactions in mediating glucocorticoid enhancement of memory consolidation. J. Neurosci. 21(7):2518-2525.

    Google Scholar 

  52. de Quervain, D. J., Roozendaal, B., and McGaugh, J. L. 1998. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature 394(6695):787-790.

    Google Scholar 

  53. Izquierdo, I. 1989. Different forms of posttraining memory processing. Behav. Neural Biol. 51:171-202.

    Google Scholar 

  54. Izquierdo, L. A., Schröder, N., Ardenghi, P., Quevedo, J., Bevilaqua, L., Netto, C. A., Izquierdo, I., and Medina, J. H. 1997. Systemic administration of ACTH or vasopressin in rats reverses the amnestic effect of posttraining β-endorphin but not that of intrahippocampal infusion of protein kinase inhibitors. Neurobiol. of Learn. Mem. 68:197-202.

    Google Scholar 

  55. Izquierdo, I. and McGaugh, J. L. 1985. Effect of a novel experience prior to training or testing on retention of an inhibitory avoidance task in mice: involvement of an opioid system. Behav. Neural Biol. 44:228-238.

    Google Scholar 

  56. Izquierdo, L. A., Viola, H., Barros, D. M., Vianna, M. R. M., Furman, M., Levi de Stein, M., Szapiro, G., Rodrigues, C., Choi, H., Madche, C., Medina, J. H., and Izquierdo, I. 2001. Novelty enhances retrieval: Molecular mechanisms involved in rat hippocampus. Eur. J. Neurosc. 13:1464-1467.

    Google Scholar 

  57. Pavlov, I. P. 1927. Conditioned Reflexes: An investigation of the physiological activity of the cerebral cortex. GV Anrep (transl). London: Oxford Univ. Press.

    Google Scholar 

  58. Konorski, J. 1948. Conditioned Reflexes and Neuron Organization. Cambridge: Cambridge Univ. Press.

    Google Scholar 

  59. Falls, W. A., Miserendino, M. J., and Davis, M. 1992. Extinction of fear-potentiated startle: blockade by infusion of NMDA antagonist into the amygdala. J. Neurosci. 12:854-863.

    Google Scholar 

  60. Corcoran, K. A. and Maren, S. 2001. Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction. J. Neurosci. 21(5):1720-1726.

    Google Scholar 

  61. Riccio, D. C. and Richardson, R. 1984. The status of memory after experimentally induced amnesias: gone but not forgotten. Physiol. Psychol. 12:59-72.

    Google Scholar 

  62. Ahlers, S. T., Richardson, R., West, C., and Riccio, D. C. 1989. ACTH produces long-lasting recovery following partial extinction of an active avoidance response. Behav. Neural Biol. 51(1):102-107.

    Google Scholar 

  63. Lu, K. T., Walker, D. L., and Davis, M. 2001. Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle. J. Neurosci. 0: RC162 (1-5).

    Google Scholar 

  64. Szapiro, G., Vianna, M. R. M., McGaugh, J. L., Medina, J. H., and Izquierdo, I. 2002. The role of NMDA glutamate receptors, PKA, MAPK and CAMKII in the hippocampus in extinction of conditioned fear. Hippocampus, in press.

  65. Berman, D. E. and Dudai, Y. 2001. Memory extinction, learning anew and learning the new: Dissociations in the molecular machinery of learning in the cortex. Science 291:2417-2419.

    Google Scholar 

  66. Lattal, K. M. and Abel, T. 2001. Different requirements for protein synthesis in acquisition and extinction of spatial preferences and context-evoked memory. J. Neurosci. 21:5773-5780.

    Google Scholar 

  67. Martin, S. J., Grimwood, P. D., and Morris, R. G. M. 2000. Synaptic plasticity and memory: an evaluation of the hypothesis. Ann. Rev. Neurosci. 23:649-711.

    Google Scholar 

  68. Cammarota, M., Bevilagua, L. R. M., Ardenghi P., Paratcha, G., Levi de Stein, M., Izquierdo, I., and Medina, J. H. 2000. Learning-associated activation of nuclear MAPK, CREB and Elk-1, along with Fos production, in the rat hippocampus after a one trial avoidance learning: abolition by NMDA receptor blockade. Mol. Brain Res. 76:36-46.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Facultad de Medicina, UBA, Instituto de Biologia Celular y Neurociencias, Paraguay 2155, piso 3, 1121, Buenos Aires, Argentina

    German Szapiro, Julieta M. Galante, Miguelina Levi de Stein & Jorge H. Medina

  2. Centro de Memoria, Departamento de Bioquimica, Instituto de Biociencias, UFRGS, 90035-003, Porto Alegre, Brazil

    Daniela M. Barros, Monica R. M. Vianna, Luciana A. Izquierdo & Ivan Izquierdo

  3. Departamento de Fisiología, Facultad de Medicina, UBA, Paragauay 2155 piso 3, 1121, Buenos Aires, Argentina

    Jorge H. Medina

Authors
  1. German Szapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julieta M. Galante
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniela M. Barros
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miguelina Levi de Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Monica R. M. Vianna
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luciana A. Izquierdo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ivan Izquierdo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jorge H. Medina
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Szapiro, G., Galante, J.M., Barros, D.M. et al. Molecular Mechanisms of Memory Retrieval. Neurochem Res 27, 1491–1498 (2002). https://doi.org/10.1023/A:1021648405461

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1021648405461

Search

Navigation