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Early Activation of Extracellular Signal-Regulated Kinase Signaling Pathway in the Hippocampus is Required for Short-Term Memory Formation of a Fear-Motivated Learning

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1. According to its duration there are, at least, two major forms of memory in mammals: short term memory (STM) which develops in a few seconds and lasts several hours and long-term memory (LTM) lasting days, weeks and even a lifetime. In contrast to LTM, very little is known about the neural, cellular and molecular requirements for mammalian STM formation.

2. Here we show that early activation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the hippocampus is required for the establishment of STM for a one-trial inhibitory avoidance task in the rat. Immediate posttraining infusion of U0126 (a selective inhibitor of ERK kinase) into the CA1 region of the dorsal hippocampus blocked STM formation.

3. Reversible inactivation of the entorhinal cortex through muscimol infusion produced deficits in STM and a selective and rapid decrease in hippocampal ERK2 activation.

4. Together with our previous findings showing a rapid decrease in ERK2 activation and impaired STM after blocking BDNF function, the present results strongly suggest that ERK2 signaling in the hippocampus is a critical step in STM processing.

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REFERENCES

  • Abel, T., and Lattal, K. M. (2001). Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr. Opin. Neurobiol. 11:180–187.

    Article  PubMed  CAS  Google Scholar 

  • Adams, J. P., Anderson, A. E., Varga, A. W., Dineley, K. T., Cook, R. G., Pfaffinger, P. J., and Sweatt, J. D. (2000). The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK. J. Neurochem. 75:2277–2287.

    Article  PubMed  CAS  Google Scholar 

  • Ahi, J., Radulovic, J., and Spiess, J. (2004). The role of hippocampal signaling cascades in consolidation of fear memory. Behav. Brain Res. 149:17–31.

    Article  PubMed  CAS  Google Scholar 

  • Alonso, M., Vianna, M. R., Depino, A. M., Mello e Souza, T., Pereira, P., Szapiro, G., Viola, H., Pitossi, F., Izquierdo, I., and Medina, J. H. (2002). BDNF-triggered events in the rat hippocampus are required for both short- and long-term memory formation. Hippocampus 12:551–560.

    Article  PubMed  CAS  Google Scholar 

  • Anderson, A. E., Adams, J. P., Qian, Y., Cook, R. G., Pfaffinger, P. J., and Sweatt, J. D. (2000). Kv4.2 phosphorylation by cyclic AMP-dependent protein kinase. J. Biol. Chem. 275:5337–5346.

    Article  PubMed  CAS  Google Scholar 

  • 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. 1:602–609.

    Article  PubMed  CAS  Google Scholar 

  • Barondes, S. H., and Cohen, H. D. (1968). Arousal and the conversion of “short-term” to “long-term” memory. Proc. Natl. Acad. Sci. U.S.A. 61:923–929.

    Article  PubMed  CAS  Google Scholar 

  • Berman, D. E., Hazvi, S., Rosenblum, K., Seger, R., and Dudai, Y. (1998). Specific and differential activation of mitogen-activated protein kinase cascades by unfamiliar taste in the insular cortex of the behaving rat. J. Neurosci. 18:10037–10044.

    PubMed  CAS  Google Scholar 

  • Berman, D. E., and Dudai, Y. (2001). Memory extinction, learning anew, and learning the new: dissociations in the molecular machinery of learning in cortex. Science 291:2417–2419.

    Article  PubMed  CAS  Google Scholar 

  • 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. U. S. A. 94:7041–7046.

    Article  PubMed  CAS  Google Scholar 

  • Birnbaum, S. G., Varga, A. W., Yuan, L. L., Anderson, A. E., Sweatt, J. D., and Schrader, L. A. (2004). Structure and function of Kv4-family transient potassium channels. Physiol. Rev. 84:803– 833.

    Article  PubMed  CAS  Google Scholar 

  • Blum, S., Moore, A. N., Adams, F., and Dash, P. K. (1999) A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J. Neurosci. 19:3535–3544.

    PubMed  CAS  Google Scholar 

  • Botzer, D., Markovich, S., and Susswein, A. J. (1998) Multiple memory processes following training that a food is inedible in Aplysia. Learn Mem. 5:204–219.

    PubMed  CAS  Google Scholar 

  • 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. 79:59–68.

    Article  PubMed  CAS  Google Scholar 

  • Burrell, B. D., and Sahley, C. L. (2001). Learning in simple systems. Curr Opin Neurobiol. 11:757–764.

    Article  PubMed  CAS  Google Scholar 

  • Cammarota, M., Bevilaqua, L. R., 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. Brain Res. Mol. Brain Res. 76:36–46.

    Article  PubMed  CAS  Google Scholar 

  • Dash, P. K., Hochner, B., and Kandel, E. R. (1990). Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature 345:718–721.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Dudai, Y. (2004). The neurobiology of consolidations, or, how stable is the engram? Annu. Rev. Psychol. 55:51–86.

    Article  PubMed  Google Scholar 

  • Emptage, N. J., and Carew, T. J. (1993). Long-term synaptic facilitation in the absence of short-term facilitation in Aplysia neurons. Science 262:253–256.

    Article  PubMed  CAS  Google Scholar 

  • Frieder, B., and Allweis, C. (1978). Transient hypoxic-amnesia: Evidence for a triphasic memory-consolidating mechanism with parallel processing. Behav Biol. 22:178–189.

    Article  PubMed  CAS  Google Scholar 

  • Giovannini, M. G., Efoudebe, M., Passani, M. B., Baldi, E., Bucherelli, C., Giachi, F., Corradetti, R., and Blandina, P. (2003). Improvement in fear memory by histamine-elicited ERK2 activation in hippocampal CA3 cells. J. Neurosci. 23:9016–9023.

    PubMed  CAS  Google Scholar 

  • 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. U.S.A. 94:2693–2698.

    Article  PubMed  CAS  Google Scholar 

  • Heinemann, U., Schmitz, D., Eder, C., and Gloveli, T. (2000). Properties of entorhinal cortex projection cells to the hippocampal formation. Ann. NY Acad. Sci. 911:112–126.

    Article  PubMed  CAS  Google Scholar 

  • Igaz, L. M., Vianna, M. R., Medina, J. H., and Izquierdo, I. (2002). Two time periods of hippocampal mRNA synthesis are required for memory consolidation of fear-motivated learning. J. Neurosci. 22:6781–6789.

    PubMed  CAS  Google Scholar 

  • Igaz, L. M., Bekinschtein, P., Izquierdo, I., and Medina, J. H. (2004). One-trial aversive learning induces late changes in hippocampal CaMKIIalpha, Homer 1a, Syntaxin 1a and ERK2 protein levels. Brain. Res. Mol. Brain. Res. 132:1–12.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Izquierdo, I., Barros, D. M., Mello e Souza, T., de Souza, M. M., Izquierdo, L. A., and Medina, J. H. (1998). Mechanisms for memory types differ. Nature 393:635–636.

    Article  PubMed  CAS  Google Scholar 

  • Izquierdo, I., Medina, J. H., Vianna, M. R., Izquierdo, L. A., and Barros, D. M. (1999). Separate mechanisms for short- and long-term memory. Behav. Brain Res. 103:1–11.

    Article  PubMed  CAS  Google Scholar 

  • Izquierdo, L. A., Barros, D. M., Ardenghi, P. G., Pereira, P., Rodrigues, C., Choi, H., Medina, J. H., and Izquierdo, I. (2000). Different hippocampal molecular requirements for short- and long-term retrieval of one-trial avoidance learning. Behav. Brain Res. 111:93–98.

    Article  PubMed  CAS  Google Scholar 

  • Izquierdo, L. A., Barros, D. M., Vianna, M. R., Coitinho, A., deDavid e Silva, T., Choi, H., Moletta, B., Medina, J. H., and Izquierdo, I. (2002). Molecular pharmacological dissection of short- and long-term memory. Cell Mol. Neurobiol. 22:269–287.

    Article  PubMed  CAS  Google Scholar 

  • Jerng, H. H., Pfaffinger, P. J., and Covarrubias, M. (2004). Molecular physiology and modulation of somatodendritic A-type potassium channels. Mol. Cell Neurosci. 27:343–369.

    Article  PubMed  CAS  Google Scholar 

  • Jones, R. S. (1993). Entorhinal-hippocampal connections: a speculative view of their function. Trends Neurosci. 16:58–64.

    Article  PubMed  CAS  Google Scholar 

  • Kandel, E. R. (2001). The molecular biology of memory storage: A dialogue between genes and synapses. Science 294:1030–1038.

    Article  PubMed  CAS  Google Scholar 

  • Kelleher, R. J. 3rd, Govindarajan, A., Jung, H. Y., Kang, H., and Tonegawa, S. (2004). Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116:467–479.

    Article  PubMed  CAS  Google Scholar 

  • Kelly, A., Laroche, S., and Davis, S. (2003). Activation of mitogen-activated protein kinase/extracellular signal-regulated kinase in hippocampal circuitry is required for consolidation and reconsolidation of recognition memory. J. Neurosci. 23:5354–5360.

    PubMed  CAS  Google Scholar 

  • Kesner, R. P., and Connor, H. S. (1972). Independence of short- and long-term memory: a neural system analysis. Science 176:432–434.

    Article  PubMed  CAS  Google Scholar 

  • Kida, S., Josselyn, S. A., de Ortiz, S. P., Kogan, J. H., Chevere, I., Masushige, S., and Silva, A. J. (2002). CREB required for the stability of new and reactivated fear memories. Nat. Neurosci. 5:348– 355.

    Article  PubMed  CAS  Google Scholar 

  • Kroll, N. E., Markowitsch, H. J., Knight, R. T., and von Cramon, D. Y. (1997). Retrieval of old memories: the temporofrontal hypothesis. Brain 120(Pt 8):1377–1399.

    Article  PubMed  Google Scholar 

  • Lamprecht, R., Hazvi, S., and Dudai, Y. (1997). 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.

    PubMed  CAS  Google Scholar 

  • Lorenzini, C. A., Baldi, E., Bucherelli, C., Sacchetti, B., and Tassoni, G. (1996). Role of dorsal hippocampus in acquisition, consolidation and retrieval of rat's passive avoidance response: a tetrodotoxin functional inactivation study. Brain Res. 730:32–39.

    Article  PubMed  CAS  Google Scholar 

  • Mansuy, I. M., Winder, D. G., Moallem, T. M., Osman, M., Mayford, M., Hawkins, R. D., and Kandel, E. R. (1998). Inducible and reversible gene expression with the rtTA system for the study of memory. Neuron 21:257–265.

    Article  PubMed  CAS  Google Scholar 

  • McGaugh, J. L. (1966). Time-dependent processes in memory storage. Science 153:1351–1358.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Menzel, R. (1979). Behavioural access to short-term memory in bees. Nature 281:368–369.

    Article  PubMed  CAS  Google Scholar 

  • Morozov, A., Muzzio, I. A., Bourtchouladze, R., Van-Strien, N., Lapidus, K., Yin, D., Winder, D. G., Adams, J. P., Sweatt, J. D., and Kandel, E. R. (2003). Rap1 couples cAMP signaling to a distinct pool of p42/44MAPK regulating excitability, synaptic plasticity, learning, and memory. Neuron. 39:309–325.

    Article  PubMed  CAS  Google Scholar 

  • Muller, U., and Carew, T. J. (1998). Serotonin induces temporally and mechanistically distinct phases of persistent PKA activity in Aplysia sensory neurons. Neuron 21:1423–1434.

    Article  PubMed  CAS  Google Scholar 

  • 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. 855:199–205.

    Article  PubMed  CAS  Google Scholar 

  • Paxinos, G., and Watson, C. (1986). The rat brain in stereotaxic coordinates. Academic Press, San Diego, CA

    Google Scholar 

  • Selcher, J. C., Nekrasova, T., Paylor, R., Landreth, G. E., and Sweatt, J. D. (2001). Mice lacking the ERK1 isoform of MAP kinase are unimpaired in emotional learning. Learn Mem. 8:11–19.

    Article  PubMed  CAS  Google Scholar 

  • Sharma, S. K., Sherff, C. M., Shobe, J., Bagnall, M. W., Sutton, M. A., and Carew, T. J. (2003). Differential role of mitogen-activated protein kinase in three distinct phases of memory for sensitization in Aplysia. J. Neurosci. 23:3899–3907.

    PubMed  CAS  Google Scholar 

  • Squire, L. R., Knowlton, B., and Musen, G. (1993). The structure and organization of memory. Annu Rev Psychol. 44:453–495.

    Article  PubMed  CAS  Google Scholar 

  • Sullivan, E. V., and Sagar, H. J. (1991). Double dissociation of short-term and long-term memory for nonverbal material in Parkinson's disease and global amnesia. A further Analysis Brain 114(Pt 2):893–906.

    Google Scholar 

  • Sutton, M. A., Masters, S. E., Bagnall, M. W., and Carew, T. J. (2001). Molecular mechanisms underlying a unique intermediate phase of memory in aplysia. Neuron 31:143–154.

    Article  PubMed  CAS  Google Scholar 

  • Sweatt, J. D. (2004). Mitogen-activated protein kinases in synaptic plasticity and memory. Curr. Opin. Neurobiol. 14:311–317.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Vianna, M. R., Barros, D. M., Silva, T., Choi, H., Madche, C., Rodrigues, C., Medina, J. H., and Izquierdo, I. (2000a). 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 (Berl) 150:77–84.

    Article  CAS  Google Scholar 

  • Vianna, M. R., Izquierdo, L. A., Barros, D. M., Ardenghi, P., Pereira, P., Rodrigues, C., Moletta, B., Medina, J. H., and Izquierdo, I. (2000b). Differential role of hippocampal cAMP-dependent protein kinase in short- and long-term memory. Neurochem. Res. 25:621–626.

    Article  PubMed  CAS  Google Scholar 

  • Vianna, M. R., Szapiro, G., McGaugh, J. L., Medina, J. H., 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. 98:12251–12254.

    Article  PubMed  CAS  Google Scholar 

  • Viola, H., Furman, M., Izquierdo, L. A., Alonso, M., Barros, D. M., de Souza, M. M., Izquierdo, I., and Medina, J. H. (2000). Phosphorylated cAMP response element-binding protein as a molecular marker of memory processing in rat hippocampus: effect of novelty. J. Neurosci. 20:RC112.

    PubMed  CAS  Google Scholar 

  • Waddell, S., and Quinn, W. G. (2001). Flies, genes, and learning. Annu. Rev. Neurosci. 24:1283–1309.

    Article  PubMed  CAS  Google Scholar 

  • Walz, R., Roesler, R., Barros, D. M., de Souza, M. M., Rodrigues, C., Sant’Anna, M. K., Quevedo, J., Choi, H. K., Neto, W. P., DeDavid e Silva, T. L., Medina, J. H., and Izquierdo, I. (1999). Effects of post-training infusions of a mitogen-activated protein kinase kinase inhibitor into the hippocampus or entorhinal cortex on short- and long-term retention of inhibitory avoidance. Behav. Pharmacol. 10:723–730.

    Article  PubMed  CAS  Google Scholar 

  • 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. 20:5906–5914.

    PubMed  CAS  Google Scholar 

  • Winocur, G., and Bindra, D. (1976). Effects of additional cues on passive avoidance learning and extinction in rats with hippocampal lesions. Physiol. Behav. 17:915–920.

    Article  PubMed  CAS  Google Scholar 

  • Xia, S. Z., Feng, C. H., and Guo, A. K. (1999). Temporary amnesia induced by cold anesthesia and hypoxia in Drosophila. Physiol. Behav. 65:617–623.

    Article  PubMed  CAS  Google Scholar 

  • Yin, J. C., Wallach, J. S., Del Vecchio, M., Wilder, E. L., Zhou, H., Quinn, W. G., and Tully, T. (1994). Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79:49–58.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by research grants from CAPES and the CNPq of Brazil through the National Programme for Nuclei of Excellence (PRONEX), and CONICET and ANPCyT of Argentine.

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Author notes

  1. Milena Winograd

    Present address: Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, Ap. 18, 03550, San Juan de, Alicante, Spain

  2. Mariana Alonso

    Present address: Olfactory Memory and Perception Laboratory, Department of Neuroscience, Pasteur Institute, Paris, France

Authors and Affiliations

  1. Instituto de Biología Celular y Neurociencias, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Piso 3, 1121, Buenos Aires, Argentina

    Lionel Müller Igaz, Milena Winograd, Martín Cammarota, Mariana Alonso & Jorge H. Medina

  2. Centro de Memória, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica de Rio Grande do Sul (PUCRS), 90610-000, Porto Alegre, Brasil

    Martín Cammarota, Luciana A. Izquierdo & Iván Izquierdo

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  1. Lionel Müller Igaz
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Correspondence to Iván Izquierdo.

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Lionel Muller Igaz and Milena Winograd contributed equally to this work

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Igaz, L.M., Winograd, M., Cammarota, M. et al. Early Activation of Extracellular Signal-Regulated Kinase Signaling Pathway in the Hippocampus is Required for Short-Term Memory Formation of a Fear-Motivated Learning. Cell Mol Neurobiol 26, 987–1000 (2006). https://doi.org/10.1007/s10571-006-9116-y

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