Excessive glucocorticoid exposure during chronic stress causes synapse loss and learning impairment. Under normal physiological conditions, glucocorticoid activity oscillates in synchrony with the circadian rhythm. Whether and how endogenous glucocorticoid oscillations modulate synaptic plasticity and learning is unknown. Here we show that circadian glucocorticoid peaks promote postsynaptic dendritic spine formation in the mouse cortex after motor skill learning, whereas troughs are required for stabilizing newly formed spines that are important for long-term memory retention. Conversely, chronic and excessive exposure to glucocorticoids eliminates learning-associated new spines and disrupts previously acquired memories. Furthermore, we show that glucocorticoids promote rapid spine formation through a non-transcriptional mechanism by means of the LIM kinase–cofilin pathway and increase spine elimination through transcriptional mechanisms involving mineralocorticoid receptor activation. Together, these findings indicate that tightly regulated circadian glucocorticoid oscillations are important for learning-dependent synaptic formation and maintenance. They also delineate a new signaling mechanism underlying these effects.
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We thank B.S. McEwen and Gan laboratory members for critical comments on this manuscript. This work was supported by grants from the US National Institutes of Health (R01 NS047325 and a subcontract of R01MH085324) to W.-B.G. C.L. is supported by grants from the US National Institute of Mental Health (K99 MH097822) and the DeWitt Wallace Reader's Digest Foundation at Weill Cornell Medical College. F.J. and M.V.C. are supported by grants from the US National Institutes of Health (MH086651 and NS21072).
The authors declare no competing financial interests.
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Liston, C., Cichon, J., Jeanneteau, F. et al. Circadian glucocorticoid oscillations promote learning-dependent synapse formation and maintenance. Nat Neurosci 16, 698–705 (2013). https://doi.org/10.1038/nn.3387
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