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MiR-218: a molecular switch and potential biomarker of susceptibility to stress

Abstract

Low miR-218 expression in the medial prefrontal cortex (mPFC) is a consistent trait of depression. Here we assessed whether miR-218 in the mPFC confers resilience or susceptibility to depression-like behaviors in adult mice, using the chronic social defeat stress (CSDS) model of depression. We also investigated whether stress-induced variations of miR-218 expression in the mPFC can be detected in blood. We find that downregulation of miR-218 in the mPFC increases susceptibility to a single session of social defeat, whereas overexpression of miR-218 selectively in mPFC pyramidal neurons promotes resilience to CSDS and prevents stress-induced morphological alterations to those neurons. After CSDS, susceptible mice have low levels of miR-218 in blood, as compared with control or resilient groups. We show further that upregulation and downregulation of miR-218 levels specifically in the mPFC correlate with miR-218 expression in blood. Our results suggest that miR-218 in the adult mPFC might function as a molecular switch that determines susceptibility vs. resilience to chronic stress, and that stress-induced variations in mPFC levels of miR-218 could be detected in blood. We propose that blood expression of miR-218 might serve as potential readout of vulnerability to stress and as a proxy of mPFC function.

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Acknowledgements

This work was funded by the National Institute on Drug Abuse (CF Grant number: R01DA037911), the Canadian Institute for Health Research (CF Grant Number: MOP-74709), the Natural Science and Engineering Research Council of Canada (CF Grant Number: 2982226), and the National Institute of Mental Health (EJN Grant numbers: P50MH096890 and R01MH051399). CF is a research scholar of the Fonds de Recherche du Québec—Santé. ATB received the Integrated Program in Neuroscience fellowship. We thank Dr. Giovanni Hernandez for his help with the revision of the paper, Dr. Elizabeth Ruiz for technical support, and Carlos Torres-Berrío for help in the graphic design. This study used the services of the Molecular and Cellular Microscopy Platform at the Douglas Mental Health University Institute in Montreal, Canada.

Author contributions

ATB and CF designed the project. ATB performed gene expression experiments with mouse brain tissue and blood, stereotaxic surgeries, viral infections, antagomiR infusions, and behavioral experiments. DN and SC performed all the neuroanatomical experiments. EMP performed behavioral experiments. JMR performed gene expression experiments with mouse brain tissue. PL performed stereotaxic surgeries. EJN provided reagents and technical training necessary to perform the research. ATB and CF wrote the paper. CF supervised the project. All authors discussed the results and commented and edited the paper.

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Correspondence to Cecilia Flores.

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Torres-Berrío, A., Nouel, D., Cuesta, S. et al. MiR-218: a molecular switch and potential biomarker of susceptibility to stress. Mol Psychiatry 25, 951–964 (2020). https://doi.org/10.1038/s41380-019-0421-5

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