Abstract
The ability to remember potential dangers in an environment is necessary to the survival of animals and humans. The cyclic AMP–responsive element binding protein (CREB) is a key transcription factor in synaptic plasticity and memory consolidation. We have found that in CaMKIV−/− mice—which are deficient in a component of the calcium–calmodulin-dependent protein kinase (CaMK) pathway, a major pathway of CREB activation—fear memory, but not persistent pain, was significantly reduced. CREB activation by fear conditioning and synaptic potentiation in the amygdala and cortical areas was reduced or blocked. We propose that cognitive memory related to a noxious shock can be disassociated from behavioral responses to tissue injury and inflammation.
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References
Davis, M. The role of the amygdala in fear and anxiety. Annu. Rev. Neurosci. 15, 353–375 (1992).
Davis, M., Walker, D. L. & Lee, Y. Amygdala and bed nucleus of the stria terminalis: differential roles in fear and anxiety measured with the acoustic startle reflex. Phil. Trans. R. Soc. Lond. Ser. B 352, 1675–1687 (1997).
LeDoux, L. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).
Maren, S. Neurobiology of Pavlovian fear conditioning. Annu. Rev. Neurosci. 24, 897–931 (2001).
Frankland, P. W., O'Brien, C., Ohno, M., Kirkwood, A. & Silva, A. J. α-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature 411, 309–313 (2001).
Bliss, T. V. P. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).
McKernan, M. G. & Shinnick-Gallagher, P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390, 607–611 (1997).
Rogan, M. T., Stäubli, U. V. & Ledoux, J. E. Fear conditioning induces associative long-term potentiation in the amygdala. Nature 390, 604–607 (1997).
Maren, S. Long-term potentiation in the amygdala: a mechanism for emotional learning and memory. Trends Neurosci. 22, 561–567 (1999).
Repa, J. C. et al. Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Nat. Neurosci. 4, 724–731 (2001).
Schafe, G. E., Nader, K., Blair, H. T. & LeDoux, J. E. Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosci. 24, 540–546 (2001).
Sheng, M., Thompson, M. A. & Greenberg, M. E. CREB: a Ca2+-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252, 1427–1430 (1991).
Mayr, B. & Montminy, M. R. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rew. Mol. Cell Biol. 2, 599–609 (2001).
Dash, P. K., Hochner, B. & Kandel, E. R. Injection of cAMP-responsive element into the nucleus of aplysia sensory neurons blocks long-term facilitation. Nature 345, 718–721 (1990).
Yin, J. C. P. et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79, 49–58 (1994).
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 CaM-responsive element–binding protein. Cell 79, 59–68 (1994).
Bartsch, D. et al. Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell 83, 979–992 (1995).
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. Proc. Natl. Acad. Sci. USA 94, 2693–2698 (1997).
Falls, W. A., Kogan, J. H., Silva, A. J., Willott, J. F., Carlson, S. & Turner, J. G. Fear-potentiation startle, but not prepulse inhibition of startle, impaired in CREB αδ−/− mutant mice. Behav. Neurosci. 114, 998–1004 (2000).
Yin, J. C. P., 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. Cell 81, 107–115 (1995).
Josselyn, S. A., Shi, C., Carlezon, W. A. Jr., Neve, R. L., Nestler, E. J. & Davis, M. Long-term memory is facilitated by cAMP response element–binding protein overexpression in the amygdala. J. Neurosci. 21, 2404–2412 (2001).
Silva, A. J., Kogan, J. H., Frankland, P. W. & Kida, S. CREB and memory. Annu. Rev. Neurosci. 21, 127–148 (1998).
Gonzalez, G. A. & Montminy, M. R. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59, 675–680 (1989).
Bito, H., Deisseroth, K., & Tsien, R. W. CREB phosphorylation and dephosphorylation: a Ca2+- and stimulus duration–dependent switch for hippocampal gene expression. Cell 87, 1203–1214 (1996).
Deisseroth, K., Bito, H. & Tsien, R. W. Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron 16, 89–101 (1996).
Deisseroth, K., Heist, E. K. & Tsien, R.W. Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 392, 198–202 (1998).
Soderling, T. R. CaM-kinase: modulator of synaptic plasticity. Curr. Opin. Neurobiol. 10, 375–380 (2000).
Hardingham, G. E., Arnold, F. J. L. & Bading, H. Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Nat. Neurosci. 4, 261–267 (2001).
West, A.E. et al. Calcium regulation of neuronal gene expression. Proc. Natl. Acad. Sci. USA 98, 11024–11031 (2001).
Livingston, M. S., Sziber, P. P. & Quinn, W. G. Loss of calcium calmodulin responsiveness in adenylyl cyclase of rutabaga, a Drosophila learning mutant. Cell 37, 205–215 (1984).
Foster, J. L., Guttman, J. J., Hall, L. M. & Rosen, O. M. Drosophila cAMP-dependent protein kinase. J. Biol. Chem. 259, 13049–13055 (1984).
Abel, T., Nguyen, P. V., Barad, M., Deuel, T. A. S., Kandel. E. R. & Bourtchuladze, R. Genetic demonstration of a role for PKA in the late phase of LTP and the hippocampus-based long-term memory. Cell 88, 615–626 (1997).
Wong, S. T. et al. Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP. Neuron 23, 787–798 (1999).
Schafe, G. & LeDoux, J. E. Memory consolidation of auditory pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J. Neurosci. 20 (RC98), 1–5 (2000).
Ho, N. et al. Impaired synaptic plasticity and cAMP response element–binding protein activation in Ca2+/calmodulin-dependent protein kinase type IV/Gr-deficient mice. J. Neurosci. 20, 6459–6472 (2000).
Kang, H., Sun, L.D., Atkins, C.M., Soderling, T.R., Wilson, M.A. & Tonegawa, S. An important role of neural activity–dependent CaMKIV signaling in the consolidation of long-term memory. Cell 106, 771–783 (2001).
Wei, F. et al. Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat. Neurosci. 4, 164–169 (2001).
Kerchner, G. A. et al. Reply to “Do 'smart' mice feel more pain, or are they just better learners?” Nat. Neurosci. 4, 453–454 (2001).
Impey, S., Smith, D. M., Obrietan, K., Donahue, R., Wade, C. & Storm, D.R. Stimulation of cAMP response element (CRE)–mediated transcription during contextual learning. Nat. Neurosci. 1, 595–601 (1998).
Nakamura, Y., Okuno, S., Sato, F. & Fujisawa, H. An immunohistochemical study of Ca2+/calmodulin-dependent protein kinase IV in the rat central nervous system: light and electron microscopic observation. Neurosci. 68, 181–194 (1995).
Schafe, G. E., Atkins, C. M., Swank, M. W., Bauer, E. P., Sweatt, J. D. & LeDoux, J. E. Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning. J. Neurosci 20, 8177–8187 (2000).
Sah, P. & Nicoll, R.A. Mechanisms underlying potentiation of synaptic transmission in rat anterior cingulate cortex in vitro. J. Physiol. (Lond.) 433, 615–630 (1991).
Liao, B., Paschal, B. M. & Luby-Phelps, K. Mechanism of Ca2+-dependent unclear accumulation of calmodulin. Proc. Natl. Acad. Sci. USA 96, 6217–6222 (1999).
Teruel, M. N., Chen, W., Persechini, A. & Meyer, T. Differential codes for free Ca2+-calmodulin signals in nucleus and cytosol. Curr. Biol. 10, 86–94 (2000).
Lisman, J., Malenka, R. C., Nicoll, R. A. & Malinow, R. Learning mechanisms: the case for CaM-KII. Science 276, 2001–2002 (1997).
Silva, A. J., Paylor, R., Wehner, J. M. & Tonegawa, S. Impaired spatial learning in aα-calcium-calmodulin kinase II mutant mice. Science 257, 206–211 (1992).
Bach, M. E., Hawkins, R. D., Osman, M., Kandel, E. R. & Mayford, M. Impairment of spatial but not contextual memory in CaMKII mutant mice with a selective loss of hippocampal LTP in the range of the theta frequency. Cell 81, 905–915 (1995).
Giese, K. P., Fedorov, N. B., Filipkowski, R. K. & Silva, A. J. Autophosphorylation at Thr286 of the α calcium-calmodulin kinase II in LTP and learning. Science 279, 870–873 (1998).
Tang, Y. P. et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 (1999).
Franklin, K. B. J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates (Academic Press, New York, 1997).
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Supported by grants from the National Institute of Neurological Disorders and Stroke 38680, the National Institute on Drug Abuse 10833, the McDonnell Center for Higher Brain Function and Alzheimer Disease Research Center at Washington University.
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Wei, F., Qiu, CS., Liauw, J. et al. Calcium–calmodulin-dependent protein kinase IV is required for fear memory. Nat Neurosci 5, 573–579 (2002). https://doi.org/10.1038/nn0602-855
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DOI: https://doi.org/10.1038/nn0602-855
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