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CREB required for the stability of new and reactivated fear memories

Abstract

The cAMP-responsive element binding protein (CREB) family of transcription factors is thought to be critical in memory formation. To define the role of CREB in distinct memory processes, we derived transgenic mice with an inducible and reversible CREB repressor by fusing CREBS133A to a tamoxifen (TAM)–dependent mutant of an estrogen receptor ligand-binding domain (LBD). We found that CREB is crucial for the consolidation of long-term conditioned fear memories, but not for encoding, storage or retrieval of these memories. Our studies also showed that CREB is required for the stability of reactivated or retrieved conditioned fear memories. Although the transcriptional processes necessary for the stability of initial and reactivated memories differ, CREB is required for both. The findings presented here delineate the memory processes that require CREB and demonstrate the power of LBD-inducible transgenic systems in the study of complex cognitive processes.

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Figure 1: Inducible regulation of CRE-mediated transcription and expression of CREBIR in transgenic mice.
Figure 2: Activating the CREB repressor disrupted long (LTM) but not short-term (STM) memory for contextual fear conditioning.
Figure 3: Activating the CREB repressor or pharmacologically disrupting protein synthesis does not affect memory retrieval or expression.
Figure 4: Activating the CREB repressor or inhibiting protein synthesis impaired the stability of a reactivated memory.

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Acknowledgements

This work was supported by an SNRP-NIH, NARSAD and McKnight grant to A.J.S., and an SNRP-NIH grant to S.P.O. S.A.J. was supported by a NARSAD Young Investigator Fellowship. S.K. and S.M. were supported by a Grant-in Aid for High Technology Research from the ministry of Education and by a Grant-in Aid for Scientific Research from the ministry of Education, Science and Culture, Japan. We would like to thank P. Frankland and K. Nader for suggestions and discussions that helped to shape the work described in this manuscript, R. Costa and S. Kushner for comments on a previous version of this manuscript, and Y. Elgersma, Y. I. Robles, H. G. Ortiz-Zuazaga, J. Coblentz and M. Lacuesta for technical advice and assistance.

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Correspondence to Alcino J. Silva.

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Kida, S., Josselyn, S., de Ortiz, S. et al. CREB required for the stability of new and reactivated fear memories. Nat Neurosci 5, 348–355 (2002). https://doi.org/10.1038/nn819

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