Article | Published:

CREB required for the stability of new and reactivated fear memories

Nature Neuroscience volume 5, pages 348355 (2002) | Download Citation

Subjects

Abstract

The cAMP-responsive element binding protein (CREB) family of transcription factors is thought to be critical in memory formation. To define the role of CREB in distinct memory processes, we derived transgenic mice with an inducible and reversible CREB repressor by fusing CREBS133A to a tamoxifen (TAM)–dependent mutant of an estrogen receptor ligand-binding domain (LBD). We found that CREB is crucial for the consolidation of long-term conditioned fear memories, but not for encoding, storage or retrieval of these memories. Our studies also showed that CREB is required for the stability of reactivated or retrieved conditioned fear memories. Although the transcriptional processes necessary for the stability of initial and reactivated memories differ, CREB is required for both. The findings presented here delineate the memory processes that require CREB and demonstrate the power of LBD-inducible transgenic systems in the study of complex cognitive processes.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Protein synthesis and memory. Psychol. Bull. 96, 518–559 (1984).

  2. 2.

    In search of cellular mechanisms of memory. Prog. Neurobiol. 32, 277–349 (1989).

  3. 3.

    , & Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature 345, 718–721 (1990).

  4. 4.

    et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79, 49–58 (1994).

  5. 5.

    et al. Induction of a dominant-negative CREB transgene specifically blocks long-term memory in Drosophila melanogaster. Cell 79, 49–58 (1994).

  6. 6.

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

  7. 7.

    et al. Spaced training induces normal long-term memory in CREB mutant mice. Curr. Biol. 7, 1–11 (1997).

  8. 8.

    et al. Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. J. Neurosci. 21, 2404–2412 (2001).

  9. 9.

    , & 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).

  10. 10.

    & 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).

  11. 11.

    & Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59, 675–680 (1989).

  12. 12.

    & The CREB family of transcription activators. Curr. Opin. Genet. Dev. 2, 199–204 (1992).

  13. 13.

    , , , & Identification of residues in the estrogen receptor that confer differential sensitivity to estrogen and hydroxytamoxifen. Mol. Endocrinol. 7, 232–240 (1993).

  14. 14.

    & Ligand-regulated site-specific recombination. Proc. Natl. Acad. Sci. USA 92, 5940–5944 (1995).

  15. 15.

    et al. Ligand-activated site-specific recombination in mice. Proc. Natl. Acad. Sci. USA 93, 10887–10890 (1996).

  16. 16.

    , , & The 3′-untranslated region of CaMKIIα is a cis-acting signal for the localization and translation of mRNA in dendrites. Proc. Natl. Acad. Sci. USA 93, 13250–13255 (1996).

  17. 17.

    et al. Structural organization and chromosomal assignment of the human 14-3-3 eta chain gene (YWHAH). Genomics 36, 63–69 (1996).

  18. 18.

    & Olfactory learning deficits in mutants for leonardo, a Drosophila gene encoding a 14-3-3 protein. Neuron 17, 931–944 (1996).

  19. 19.

    , & Tumour regression in a ligand inducible manner mediated by a chimeric tumour suppressor derived from p53. Oncogene 19, 337–350 (2000).

  20. 20.

    , , , & The dorsal hippocampus is essential for context discrimination but not for contextual conditioning. Behav. Neurosci. 112, 863–874 (1998).

  21. 21.

    Contextual fear, gestalt memories, and the hippocampus. Behav. Brain Res. 110, 73–81 (2000).

  22. 22.

    & Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).

  23. 23.

    , , & Computer-assisted behavioral assessment of Pavlovian fear conditioning in mice. Learn. Mem. 7, 58–72 (2000).

  24. 24.

    , & Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726 (2000).

  25. 25.

    , & Retrograde amnesia produced by electroconvulsive shock after reactivation of a consolidated memory trace. Science 160, 554–555 (1968).

  26. 26.

    & Reconsolidation of memory after its reactivation. Behav. Brain Res. 84, 241–246 (1997).

  27. 27.

    & Characteristics of retrograde amnesia following reactivation of memory in mice. Physiol. Behav. 28, 585–590 (1982).

  28. 28.

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

  29. 29.

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

  30. 30.

    Consolidation: fragility on the road to the engram. Neuron 17, 367–370 (1996).

  31. 31.

    , , , & α-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature 411, 309–313 (2001).

  32. 32.

    , & Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus 10, 47–56 (2000).

  33. 33.

    , , & The consolidation of new but not reactivated memory requires hippocampal C/EBPβ. Nature Neurosci. 4, 813–818 (2001).

  34. 34.

    & Amnesia: a function of the temporal relation of footshock to electroconvulsive shock. Science 159, 219–221 (1968).

  35. 35.

    & Conditions that potentiate the effects of electroconvulsive shock administered 24 hours after avoidance training. Anim. Learn. Behav. 6, 346–351 (1978).

  36. 36.

    , & Retrograde amnesia for old (reactivated) memory: some anomalous characteristics. Science 204, 1319–1320 (1979).

  37. 37.

    , & Nonmonotonic age changes in susceptibility to hypothermia-induced retrograde amnesia in rats. Physiol. Behav. 28, 939–943 (1982).

  38. 38.

    , & Administration of DL-2-amino-5-phosphonovaleric acid (AP5) induces transient inhibition of reminder-activated memory retrieval in day-old chicks. Brain Res. Cogn. Brain. Res. 5, 311–321 (1997).

  39. 39.

    , & Attenuation of emotional and nonemotional memories after their reactivation: role of ß-adrenergic receptors. J. Neurosci. 19, 6623–6628 (1999).

  40. 40.

    & Electroconvulsive shock effects on a reactivated memory trace: further examination. Science 166, 525–527 (1969).

  41. 41.

    & Different requirements for protein synthesis in acquisition and extinction of spatial preferences and context-evoked fear. J. Neurosci. 21, 5773–5780 (2001).

  42. 42.

    & Amnesia: tests of the effect of delayed footshock-electroconvulsive shock pairings. Physiol. Behav. 8, 797–800 (1972).

  43. 43.

    & Amnesia from Ecs: the effect of pairing Ecs and footshock. Psychonomic Sci. 18, 14–15 (1970).

  44. 44.

    , & Reactivation of recent or remote memory before electroconvulsive therapy does not produce retrograde amnesia. Behav. Biol. 18, 335–343 (1976).

  45. 45.

    & Memory extinction, learning anew, and learning the new: dissociations in the molecular machinery of learning in cortex. Science 291, 2417–2419 (2001).

  46. 46.

    Susceptibility of a reactivated memory to the effects of strychnine: a time-dependent phenomenon. Physiol. Behav. 18, 95–99 (1977).

  47. 47.

    , & Effects of glucose and fructose on recently reactivated and recently acquired memories. Prog. Neuropsychopharmacol. Biol. Psychiatry 23, 1285–1317 (1999).

  48. 48.

    Similarities of recently acquired and reactivated memories in interference. Am. J. Psychol. 90, 231–242 (1977).

  49. 49.

    , & Amnesia induced by hyperthermia: an unusually profound, yet reversible, memory loss. Behav. Neural. Biol. 30, 260–277 (1980).

  50. 50.

    , & Fear memory retrieval induces CREB phosphorylation and Fos expression within the amygdala. Eur. J. Neurosci. 13, 1453–1458 (2001).

  51. 51.

    , & Hippocampal expression of the orphan nuclear receptor gene hzf-3/nurr1 during spatial discrimination learning. Neurobiol. Learn. Mem. 74, 161–178 (2000).

Download references

Acknowledgements

This work was supported by an SNRP-NIH, NARSAD and McKnight grant to A.J.S., and an SNRP-NIH grant to S.P.O. S.A.J. was supported by a NARSAD Young Investigator Fellowship. S.K. and S.M. were supported by a Grant-in Aid for High Technology Research from the ministry of Education and by a Grant-in Aid for Scientific Research from the ministry of Education, Science and Culture, Japan. We would like to thank P. Frankland and K. Nader for suggestions and discussions that helped to shape the work described in this manuscript, R. Costa and S. Kushner for comments on a previous version of this manuscript, and Y. Elgersma, Y. I. Robles, H. G. Ortiz-Zuazaga, J. Coblentz and M. Lacuesta for technical advice and assistance.

Author information

Author notes

    • Satoshi Kida
    •  & Sheena A. Josselyn

    The first two authors contributed equally to this work.

Affiliations

  1. Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan

    • Satoshi Kida
    •  & Shoichi Masushige
  2. Departments of Neurobiology, Psychology and Psychiatry and Brain Research Institute, 695 Young Drive South, Gonda Building, UCLA, Los Angeles, California 90095-1761, USA

    • Sheena A. Josselyn
    • , Jeffrey H. Kogan
    •  & Alcino J. Silva
  3. Department of Biology, University of Puerto Rico, Río Piedras Campus, Julio García Díaz Building, Gandara Avenue, San Juan, Puerto Rico 00931, USA

    • Sandra Peña de Ortiz
    •  & Itzamarie Chevere

Authors

  1. Search for Satoshi Kida in:

  2. Search for Sheena A. Josselyn in:

  3. Search for Sandra Peña de Ortiz in:

  4. Search for Jeffrey H. Kogan in:

  5. Search for Itzamarie Chevere in:

  6. Search for Shoichi Masushige in:

  7. Search for Alcino J. Silva in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Alcino J. Silva.

Supplementary information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nn819

Further reading