Abstract
One of the molecular events associated with contextual long-term memory (LTM) formation is the induction of cyclic AMP response element (CRE)-mediated transcription1. Here we report that activation of NMDA receptors and of extracellular signal–regulated kinase (ERK) were necessary for stimulation of CRE-mediated transcription during contextual fear conditioning. In addition, we found that inhibition of CRE-regulated transcription during learning blocked LTM, which indicates that this transcriptional activity is critical for memory formation.
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Acknowledgements
Microscopy and image analysis was performed in the W.M. Keck Center for Neural Signaling, University of Washington. This research was supported by National Institutes of Health grants NS 20498 and DC 04158. J.A. was supported in part by PHS NRSA T32 GM07270 from NIGMS and PHS NRSA 1F31MH064311-01 from NIMH. V.P. was supported in part by PHS NRSA 1F31NS042475-01 from NINDS.
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Supplementary information
Supplementary Fig. 1.
Representative confocal images showing CRE-regulated β-galactosidase immunostaining in hippocampal sections taken from transgenic CRE-lacZ reporter mice 8 h after contextual training. (a) The apparent increase in immunostaining within the CA1 region of the hippocampus (vehicle, conditioned) was attenuated by the pre-training infusion of the competitive NMDA receptor antagonist APV (APV, conditioned). Arrows indicate cannulation sites. (b) The apparent increase in immunostaining within the CA1 region of the hippocampus (vehicle, conditioned) is attenuated by the pre-training infusion of PD98059 (PD98059, conditioned). (JPG 55 kb)
Supplementary Fig. 2.
The diffusion and cellular uptake of CRE decoy ODNs are restricted to the CA1 region of the dorsal hippocampus. Confocal micrograph of the dorsal hippocampus of an animal infused 6 hrs prior with 5'-FITC-labeled CRE decoy ODNs. Green fluorescence corresponds to FITC and red fluorescence represents propidium iodide counter-stain. (JPG 25 kb)
Supplementary Fig. 3.
CRE decoy ODNs do not affect training session behavior. The mean velocities of mice infused with the CRE decoy ODNs 6 hr prior to training in contextual fear conditioning was unaffected during the training session, and they exhibited a response to the foot shock that was similar to that of the uninfused control (Conditioned) and scrambled ODN-infused control animals (Naive: n = 5, Conditioned n = 6, +CRE decoy n = 7, +Scrambled ODN n = 6; **** P < 0.01, *P < 0.05). (GIF 4 kb)
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Athos, J., Impey, S., Pineda, V. et al. Hippocampal CRE-mediated gene expression is required for contextual memory formation. Nat Neurosci 5, 1119–1120 (2002). https://doi.org/10.1038/nn951
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DOI: https://doi.org/10.1038/nn951
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