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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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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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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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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DOI: https://doi.org/10.1038/nn.3266
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