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Glucocorticoid receptors recruit the CaMKIIα-BDNF-CREB pathways to mediate memory consolidation

Nature Neuroscience volume 15, pages 1707–1714 (2012)Cite this article

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Abstract

Emotionally important events are well remembered. Although memories of emotional experiences are known to be mediated and modulated by stress hormones such as glucocorticoids, little is known about the underlying molecular mechanisms. We found that the hippocampal glucocorticoid receptors that are critically engaged during the formation of long-term inhibitory avoidance memory in rats were coupled to the activation of CaMKIIα, TrkB, ERK, Akt, PLCγ and CREB, as well as a to a substantial induction of Arc and synaptic GluA1. Most of these changes, which are initiated by a nongenomic effect of glucocorticoid receptors, were also downstream of the activation of brain-derived neurotrophic factor (BDNF). Hippocampal administration of BDNF, but not of other neurotrophins, selectively rescued both the amnesia and the molecular impairments produced by glucocorticoid receptor inhibition. Thus, glucocorticoid receptors mediate long-term memory formation by recruiting the CaMKIIα-BDNF-CREB–dependent neural plasticity pathways.

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Figure 1: Hippocampal glucocorticoid receptor activation is required for long-term, but not short-term, inhibitory avoidance memory.
Figure 2: Molecular pathways coupled to hippocampal glucocorticoid receptors following inhibitory avoidance training.
Figure 3: Hippocampal BDNF is required for long-term, but not short-term, inhibitory avoidance memory.
Figure 4: Molecular pathways coupled to BDNF following inhibitory avoidance training.
Figure 5: BDNF selectively rescues the RU486-mediated amnesia.
Figure 6: BDNF rescues the RU486-mediated molecular disruption.

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Acknowledgements

We thank S. Stern, S. Sheng, S. Taubenfeld and S. Katz for technical assistance, A. Suzuki and X. Ye for comments on the manuscript, and R. Testi for valuable discussions. This work was supported by grants from the US National Institutes of Health (RO1-MH065635), National Alliance for Research on Schizophrenia and Depression (NARSAD) and the Philoctetes Foundation to C.M.A. and US National Institutes of Health grant F31-MH816213 to D.Y.C.

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  1. Dillon Y Chen and Dhananjay Bambah-Mukku: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, USA

    Dillon Y Chen & Dhananjay Bambah-Mukku

  2. Center for Neural Science, New York University, New York, New York, USA

    Dhananjay Bambah-Mukku, Gabriella Pollonini & Cristina M Alberini

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Contributions

C.M.A., D.Y.C. and D.B.-M. designed and developed the study. D.Y.C. carried out the behavioral studies. D.Y.C., D.B.-M. and G.P. carried out the biochemical studies and analyses. C.M.A., D.Y.C. and D.B.-M. wrote the manuscript.

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Correspondence to Cristina M Alberini.

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Chen, D., Bambah-Mukku, D., Pollonini, G. et al. Glucocorticoid receptors recruit the CaMKIIα-BDNF-CREB pathways to mediate memory consolidation. Nat Neurosci 15, 1707–1714 (2012). https://doi.org/10.1038/nn.3266

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