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The activation of cAMP response element-binding protein (CREB) after a learning experience is a common feature in the formation of several associative memories. We recently demonstrated that the increase in the hippocampal phosphorylated CREB (pCREB) levels 1 h after a short exploration of an open field (OF) was associated to detection of spatial novelty and was not related to the memory formation of habituation in this non-associative learning paradigm. Moreover, after a long training of three OF sessions, hippocampal pCREB levels were below to that observed in control rats. The present results show that such decrease does not correlate with memory retrieval or improvement in long-term memory of habituation. Instead, it is associated with the familiarity to the arena. Our experiments revealed that the relevant variable to induce CREB deactivation was the prolonged exploration of the arena (30 min). A 15 min OF exploration was ineffective. Furthermore, the last 5 min period of a prolonged exploration was crucial to change CREB phosphorylation state: when exploration took place in a novel arena the level of pCREB increased; in contrast, when it was performed in the familiar OF, pCREB levels decreased. Taken as a whole, our results suggest that CREB phosphorylation state in the hippocampus switches in response to exposure to a novel or to a familiar spatial environment. © 2005 Elsevier Inc. All rights reserved.


Documento: Artículo
Título:Phosphorylation state of CREB in the rat hippocampus: A molecular switch between spatial novelty and spatial familiarity?
Autor:Moncada, D.; Viola, H.
Filiación:Instituto de Biología Celular y Neurociencias, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave:Familiar environment; Memory of habituation; Novel environment; Open field; pCREB; cyclic AMP responsive element binding protein; animal behavior; animal experiment; animal tissue; article; associative memory; controlled study; environment; enzyme activation; habituation; hippocampus; learning; male; nerve cell plasticity; nonhuman; open field test; protein analysis; protein phosphorylation; rat; signal transduction; spatial discrimination; Animals; Cyclic AMP Response Element-Binding Protein; Exploratory Behavior; Habituation, Psychophysiologic; Hippocampus; Male; Phosphorylation; Rats; Rats, Wistar; Recognition (Psychology); Spatial Behavior; Time Factors
Página de inicio:9
Página de fin:18
Título revista:Neurobiology of Learning and Memory
Título revista abreviado:Neurobiol. Learn. Mem.
CAS:cyclic AMP responsive element binding protein, 130428-87-4, 130939-96-7; Cyclic AMP Response Element-Binding Protein


  • Acquas, E., Wilson, C., Fibiger, H.C., Conditioned and unconditioned stimuli increase frontal cortical and hippocampal acetylcholine release: Effects of novelty, habituation, and fear (1996) The Journal of Neuroscience, 16, pp. 3089-3096
  • Alvarez-Jaimes, L., Centeno-Gonzalez, M., Feliciano-Rivera, M., Maldonado-Vlaar, C.S., Dissociation of the effect of spatial behaviors on the phosphorylation of cAMP-response element binding protein (CREB) within the nucleus accumbens (2005) Neuroscience, 130, pp. 833-842
  • Balschun, D., Wolfer, D.P., Gass, P., Mantamadiotis, T., Welzl, H., Schutz, G., Does cAMP response element-binding protein have a pivotal role in hippocampal synaptic plasticity and hippocampus-dependent memory? (2003) The Journal of Neuroscience, 23, pp. 6304-6314
  • Bernabeu, R., Cammarota, M., Izquierdo, I., Medina, J.H., Involvement of hippocampal AMPA glutamate receptor changes and the cAMP/protein kinase A/CREB-P signalling pathway in memory consolidation of an avoidance task in rats (1997) Brazilian Journal of Medical and Biological Research, 30, pp. 961-965
  • Bogacz, R., Brown, M.W., Comparison of computational models of familiarity discrimination in the perirhinal cortex (2003) Hippocampus, 13, pp. 494-524
  • Bourtchuladze, R., Frenguelli, B., Blendy, J., Cioffi, D., Schutz, G., Silva, A.J., Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein (1994) Cell, 79, pp. 59-68
  • Broadbent, N.J., Squire, L.R., Clark, R.E., Spatial memory, recognition memory, and the hippocampus (2004) Proceedings of the National Academy of Sciences of the United States of America, 101, pp. 14515-14520
  • Brown, M.W., Aggleton, J.P., Recognition memory: What are the roles of the perirhinal cortex and hippocampus? (2001) Nature Reviews Neuroscience, 2, pp. 51-61
  • Cammarota, M., Bevilaqua, L.R., Ardenghi, P., Paratcha, G., Levi de Stein, M., Izquierdo, I., 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 (2000) Molecular Brain Research, 76, pp. 36-46
  • Chrivia, J.C., Kwok, R.P., Lamb, N., Hagiwara, M., Montminy, M.R., Goodman, R.H., Phosphorylated CREB binds specifically to the nuclear protein CBP (1993) Nature, 365, pp. 855-859
  • Colombo, P.J., Learning-induced activation of transcription factors among multiple memory systems (2004) Neurobiology of Learning and Memory, 82, pp. 268-277
  • Colombo, P.J., Brightwell, J.J., Countryman, R.A., Cognitive strategy-specific increases in phosphorylated cAMP response element-binding protein and c-Fos in the hippocampus and dorsal striatum (2003) The Journal of Neuroscience, 23, pp. 3547-3554
  • Eichenbaum, H., A cortical-hippocampal system for declarative memory (2000) Nature Reviews Neuroscience, 1, pp. 41-50
  • Giovannini, M.G., Rakovska, A., Benton, R.S., Pazzagli, M., Bianchi, L., Pepeu, G., Effects of novelty and habituation on acetylcholine, GABA, and glutamate release from the frontal cortex and hippocampus of freely moving rats (2001) Neuroscience, 106, pp. 43-53
  • Grunwald, T., Lehnertz, K., Heinze, H.J., Helmstaedter, C., Elger, C.E., Verbal novelty detection within the human hippocampus proper (1998) Proceedings of the National Academy of Sciences of the United States of America, 95, pp. 3193-3197
  • 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 (1997) Proceedings of the National Academy of Sciences of the United States of America, 94, pp. 2693-2698
  • Hannesson, D.K., Vacca, G., Howland, J.G., Phillips, A.G., Medial prefrontal cortex is involved in spatial temporal order memory but not spatial recognition memory in tests relying on spontaneous exploration in rats (2004) Behavioral Brain Research, 153, pp. 273-285
  • Impey, S., McCorkle, S.R., Cha-Molstad, H., Dwyer, J.M., Yochum, G.S., Boss, J.M., Defining the CREB regulon: A genome-wide analysis of transcription factor regulatory regions (2004) Cell, 119, pp. 1041-1054
  • Izquierdo, L.A., Viola, H., Barros, D.M., Alonso, M., Vianna, M.R., Furman, M., Novelty enhances retrieval: Molecular mechanisms involved in rat hippocampus (2001) European Journal of Neuroscience, 13, pp. 1464-1467
  • Josselyn, S.A., Kida, S., Silva, A.J., Inducible repression of CREB function disrupts amygdala-dependent memory (2004) Neurobiology of Learning and Memory, 82, pp. 159-163
  • Kesner, R.P., Dakis, M., Bolland, B.L., Phencyclidine disrupts long- but not short-term memory within a spatial learning task (1993) Psychopharmacology (Berl), 111, pp. 85-90
  • Kida, S., Josselyn, S.A., de Ortiz, S.P., Kogan, J.H., Chevere, I., Masushige, S., CREB required for the stability of new and reactivated fear memories (2002) Nature Neuroscience, 5, pp. 348-355
  • Kim, J.J., Fanselow, M.S., Modality-specific retrograde amnesia of fear (1992) Science, 256, pp. 675-677
  • Kinney, W., Routtenberg, A., Brief exposure to a novel environment enhances binding of hippocampal transcription factors to their DNA recognition elements (1993) Molecular Brain Research, 20, pp. 147-152
  • Knight, R., Contribution of human hippocampal region to novelty detection (1996) Nature, 383, pp. 256-259
  • Kruse, A.A., Stripling, R., Clayton, D.F., Context-specific habituation of the zenk gene response to song in adult zebra finches (2004) Neurobiology of Learning and Memory, 82, pp. 99-108
  • Lonze, B.E., Ginty, D.D., Function and regulation of CREB family transcription factors in the nervous system (2002) Neuron, 35, pp. 605-623
  • Maren, S., Fanselow, M.S., Electrolytic lesions of the fimbria/fornix, dorsal hippocampus, or entorhinal cortex produce anterograde deficits in contextual fear conditioning in rats (1997) Neurobiology of Learning and Memory, 67, pp. 142-149
  • Mello, C., Nottebohm, F., Clayton, D., Repeated exposure to one song leads to a rapid and persistent decline in an immediate early gene's response to that song in zebra finch telencephalon (1995) The Journal of Neuroscience, 15, pp. 6919-6925
  • Montag-Sallaz, M., Welzl, H., Kuhl, D., Montag, D., Schachner, M., Novelty-induced increased expression of immediate-early genes c-fos and arg 3.1 in the mouse brain (1999) Journal of Neurobiology, 38, pp. 234-246
  • Morris, R.G., Garrud, P., Rawlins, J.N., O'Keefe, J., Place navigation impaired in rats with hippocampal lesions (1982) Nature, 297, pp. 681-683
  • Nadel, L., Moscovitch, M., Memory consolidation, retrograde amnesia and the hippocampal complex (1997) Current Opinion in Neurobiology, 7, pp. 217-227
  • Nakazawa, K., McHugh, T.J., Wilson, M.A., Tonegawa, S., NMDA receptors, place cells and hippocampal spatial memory (2004) Nature Reviews Neuroscience, 5, pp. 361-372
  • O'Keefe, J., Nadel, L., (1978) The hippocampus as a cognitive map, , Oxford University Press, Oxford
  • Perazzona, B., Isabel, G., Preat, T., Davis, R.L., The role of cAMP response element-binding protein in Drosophila long-term memory (2004) The Journal of Neuroscience, 24, pp. 8823-8828
  • Pittenger, C., Huang, Y.Y., Paletzki, R.F., Bourtchouladze, R., Scanlin, H., Vronskaya, S., Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory (2002) Neuron, 34, pp. 447-462
  • Radulovic, J., Kammermeier, J., Spiess, J., Relationship between fos production and classical fear conditioning: Effects of novelty, latent inhibition, and unconditioned stimulus preexposure (1998) The Journal of Neuroscience, 18, pp. 7452-7461
  • Riedel, G., Micheau, J., Lam, A.G., Roloff, E.L., Martin, S.J., Bridge, H., Reversible neural inactivation reveals hippocampal participation in several memory processes (1999) Nature Neuroscience, 2, pp. 898-905
  • Santoro, M.F., Annand, R.R., Robertson, M.M., Peng, Y.W., Brady, M.J., Mankovich, J.A., Regulation of protein phosphatase 2A activity by caspase-3 during apoptosis (1998) The Journal of Biological Chemistry, 273, pp. 13119-13128
  • Shaywitz, A.J., Greenberg, M.E., CREB: A stimulus-induced transcription factor activated by a diverse array of extracellular signals (1999) Annual Review of Biochemistry, 68, pp. 821-861
  • Silva, A.J., Kogan, J.H., Frankland, P.W., Kida, S., CREB and memory (1998) Annual Review of Neuroscience, 21, pp. 127-148
  • Sokolov, E.N., Higher nervous functions; the orienting reflex (1963) Annual Review of Physiology, 25, pp. 545-580
  • Stripling, R., Milewski, L., Kruse, A.A., Clayton, D.F., Rapidly learned song-discrimination without behavioral reinforcement in adult male zebra finches (Taeniopygia guttata) (2003) Neurobiology of Learning and Memory, 79, pp. 41-50
  • Taubenfeld, S.M., Wiig, K.A., Bear, M.F., Alberini, C.M., A molecular correlate of memory and amnesia in the hippocampus (1999) Nature Neuroscience, 2, pp. 309-310
  • Tully, T., Regulation of gene expression and its role in long-term memory and synaptic plasticity (1997) Proceedings of the National Academy of Sciences of the United States of America, 94, pp. 4239-4241
  • Vianna, M.R., Alonso, M., Viola, H., Quevedo, J., de Paris, F., Furman, M., Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat (2000) Learning and Memory, 7, pp. 333-340
  • Viola, H., Furman, M., Izquierdo, L.A., Alonso, M., Barros, D.M., de Souza, M.M., Phosphorylated cAMP response element-binding protein as a molecular marker of memory processing in rat hippocampus: Effect of novelty (2000) The Journal of Neuroscience, 20, pp. RC112
  • Warburton, E.C., Glover, C.P., Massey, P.V., Wan, H., Johnson, B., Bienemann, A., cAMP responsive element-binding protein phosphorylation is necessary for perirhinal long-term potentiation and recognition memory (2005) The Journal of Neuroscience, 25, pp. 6296-6303
  • Winograd, M., Viola, H., Detection of novelty, but not memory of spatial habituation, is associated with an increase in phosphorylated cAMP response element-binding protein levels in the hippocampus (2004) Hippocampus, 14, pp. 117-123
  • Xu, L., Anwyl, R., Rowan, M.J., Spatial exploration induces a persistent reversal of long-term potentiation in rat hippocampus (1998) Nature, 394, pp. 891-894
  • Yamaguchi, S., Hale, L.A., D'Esposito, M., Knight, R.T., Rapid prefrontal-hippocampal habituation to novel events (2004) The Journal of Neuroscience, 24, pp. 5356-5363
  • Yin, J.C., Del Vecchio, M., Zhou, H., Tully, T., CREB as a memory modulator: Induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila (1995) Cell, 81, pp. 107-115
  • Yin, J.C., Tully, T., CREB and the formation of long-term memory (1996) Current Opinion in Neurobiology, 6, pp. 264-268
  • Yin, J.C., Wallach, J.S., Del Vecchio, M., Wilder, E.L., Zhou, H., Quinn, W.G., Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila (1994) Cell, 79, pp. 49-58
  • Zhang, X., Odom, D.T., Koo, S.H., Conkright, M.D., Canettieri, G., Best, J., Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues (2005) Proceedings of the National Academy of Sciences of the United States of America, 102, pp. 4459-4464
  • Zhu, X.O., McCabe, B.J., Aggleton, J.P., Brown, M.W., Differential activation of the rat hippocampus and perirhinal cortex by novel visual stimuli and a novel environment (1997) Neuroscience Letters, 229, pp. 141-143


---------- APA ----------
Moncada, D. & Viola, H. (2006) . Phosphorylation state of CREB in the rat hippocampus: A molecular switch between spatial novelty and spatial familiarity?. Neurobiology of Learning and Memory, 86(1), 9-18.
---------- CHICAGO ----------
Moncada, D., Viola, H. "Phosphorylation state of CREB in the rat hippocampus: A molecular switch between spatial novelty and spatial familiarity?" . Neurobiology of Learning and Memory 86, no. 1 (2006) : 9-18.
---------- MLA ----------
Moncada, D., Viola, H. "Phosphorylation state of CREB in the rat hippocampus: A molecular switch between spatial novelty and spatial familiarity?" . Neurobiology of Learning and Memory, vol. 86, no. 1, 2006, pp. 9-18.
---------- VANCOUVER ----------
Moncada, D., Viola, H. Phosphorylation state of CREB in the rat hippocampus: A molecular switch between spatial novelty and spatial familiarity?. Neurobiol. Learn. Mem. 2006;86(1):9-18.