Abstract
Long-term memory formation consists of multiple phases. A new memory is initially labile and sensitive to disruption by a variety of interfering events or agents. To become stable, this new memory undergoes a process known as consolidation, which, in the case of declarative memories, occurs within the medial temporal lobes and requires gene expression. When recalled, memories re-enter a new phase of vulnerability and seem to require a reconsolidation process in order to be maintained. Here we show that consolidation but not reconsolidation of inhibitory avoidance memory requires the expression of the transcription factor CCAAT enhancer binding protein β (C/EBPβ) in the hippocampus. Furthermore, in the same region, de novo protein synthesis is not essential for memory reconsolidation. C/EBPβ is an evolutionarily conserved genetic marker that has a selective role in the consolidation of new but not reactivated memories in the hippocampus.
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References
Squire, L. R. & Alvarez, P. Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr. Opin. Neurobiol. 5, 169–177 (1995).
Dudai, Y. Consolidation, fragility and the road to the engram. Neuron 17, 367–370 (1996).
McGaugh, J. L. Memory—a century of consolidation. Science 287, 248–251 (2000).
Sara, S. J. Retrieval and reconsolidation: toward a neurobiology of remembering. Learn. Mem. 7, 73–84 (2000).
Milner, B., Squire, L. R. & Kandel, E. R. Cognitive neuroscience and the study of memory. Neuron 20, 445–468 (1998).
Squire, L. R. Memory and Brain (Oxford, New York, 1987).
Zola-Morgan, S. & Squire, L. R. Neuroanatomy of memory. Annu. Rev. Neurosci. 16, 547–563 (1993).
Davis, H. P. & Squire, L. R. Protein synthesis and memory: a review. Psychol. Bull. 96, 518–559 (1984).
Alberini, C. M. Genes to remember. J. Exp. Biol. 202, 2887–2891 (1999).
Tischmeyer, W. & Grimm, R. Activation of immediate early genes and memory formation. Cell Mol. Life Sci. 55, 564–574 (1999).
Shafe, G. E. & LeDoux, J. E. Memory consolidation of auditory Pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J. Neurosci. 20, RC 96 (2000).
Taubenfeld, S. M. et al. Fornix-dependent induction of hippocampal CCAAT enhancer-binding protein β and δ co-localizes with phosphorylated cAMP response element binding protein and accompanies long-term memory consolidation. J. Neurosci. 21, 84–91 (2001).
Bailey, C. H., Bartsch, D. & Kandel, E. R. Toward a molecular definition of long-term memory storage. Proc. Natl. Acad. Sci. USA 93, 13445–13452 (1996).
Yin, J. C. P. & Tully, T. CREB and the formation of long-term memory. Curr. Opin. Neurobiol. 6, 264–268 (1996).
Silva, A. J., Kogan, J. H., Frankland, P. W. & Kida, S. CREB and memory. Annu. Rev. Neurosci. 21, 127–148 (1998).
Bernabeu, R. et al. 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. USA 94, 7041–7046 (1997).
Guzowski, J. F. & McGaugh, J. L. Anti-sense oligodeoxynucleotide-mediated disruption of hippocampal CREB protein levels impairs memory of a spatial task. Proc. Natl. Acad. Sci. USA 94, 2693–2698 (1997).
Impey, S. et al. Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat. Neurosci. 1, 595–601 (1998).
Taubenfeld, S. M., Wiig, K. A., Bear, M. F. & Alberini, C. M. A molecular correlate of memory and amnesia in the hippocampus. Nat. Neurosci. 2, 309–310 (1999).
Alberini, C. M., Ghirardi, M., Metz, R. & Kandel, E. R. C/EBP is an immediate–early gene required for the consolidation of long-term facilitation in Aplysia. Cell 76, 1099–1114 (1994).
Davis, M. Neurobiology of fear responses: the role of amygdala. J. Neuropsychiatry Clin. Neurosci. 9, 382–402 (1997).
LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).
Nader, K., Schafe, G. E. & Le Doux, J. E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726 (2000).
Misanin, J. R., Miller, R. R. & Lewis, D. J. Retrograde amnesia produced by electroconvulsive shock after reactivation of consolidated memory trace. Science 160, 554–555 (1968).
Mactutus, C. F., Riccio, D. C. & Ferek, J. M. Retrograde amnesia for old (reactivated) memory: some anomalous characteristics. Science 204, 1319–1320 (1979).
Judge, M. E. & Quartermain, D. Characteristics of retrograde amnesia following reactivation of memory in mice. Physiol. Behav. 28, 585–590 (1982).
Ogawa, S. & Pfaff, D. W. Current status of antisense DNA methods in behavioral studies. Chem. Senses 23, 249–255 (1998).
Gerlai, R. Targeting genes and proteins in the analysis of learning and memory: caveats and future directions. Rev. Neurosci. 11, 15–26 (2000).
Guzowski, J. F. et al. Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J. Neurosci. 20, 3993–4001 (2000).
Quevedo, J. et al. Two time windows of anisomycin-induced amnesia for inhibitory avoidance training in rats: protection from amnesia by pretraining but not pre-exposure to the task apparatus. Learn. Mem. 6, 600–607 (1999).
Wilensky, A. E., Schafe, G. E. & LeDoux, J. E. The amygdala modulates memory consolidation of fear-motivated inhibitory avoidance learning but not classical fear conditioning. J. Neurosci. 20, 7059–7066 (2000).
Lamprecht, R., Hazvi, 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).
Swank, M. W. Phosphorylation of MAP kinase and CREB in mouse cortex and amygdala during taste aversion learning. Neuroreport 11, 1625–1630 (2000).
Bourtchouladze, R. et al. Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learn. Mem. 5, 365–374 (1998).
Rosenblum, K., Meiri, N. & Dudai, Y. Taste memory: the role of protein synthesis in gustatory cortex. Behav. Neural Biol. 59, 49–56 (1993).
Pall, M. et al. The transcription factor C/EBPβ and its role in ovarian function; evidence for direct involvement in the ovulatory process. EMBO J. 16, 5273–5279 (1997).
Hooper, M. L., Chiasson, B. J. & Robertson, H. A. Infusion into the brain of an antisense oligonucleotide to the immediate-early gene c-fos suppresses production of fos and produces a behavioral effect. Neuroscience 63, 917–924 (1994).
Widnell, K. L. et al. Regulation of CREB expression: in vivo evidence for a functional role in morphine action in the nucleous accumbens. J. Pharmacol. Exp. Ther. 276, 306–315 (1996).
Acknowledgements
This work was supported by the Whitehall Foundation (grant # F97-07). The authors thank J. McGaugh and B. Roozendaal for teaching the cannulae implantation technique, J. LeDoux, R. Bourtchouladze, G. Schafe and R. Burwell for reading the manuscript and for discussions, V. Poli for providing the rat C/EBPβ clone, and E. Sklar, A. Beauregard-Young and J. Harper for technical assistance. C.M.A. is on a leave of absence from Dipartimento Materno Infantile e Tecnologie Biomediche, University of Brescia, Italy. B.M. was a recipient of a HFSPO short-term fellowship.
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Taubenfeld, S., Milekic, M., Monti, B. et al. The consolidation of new but not reactivated memory requires hippocampal C/EBPβ. Nat Neurosci 4, 813–818 (2001). https://doi.org/10.1038/90520
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DOI: https://doi.org/10.1038/90520
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