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Molecular Adaptations to Social Defeat Stress and Induced Depression in Mice

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Abstract

Chronic stress is a risk factor for major depression. Social defeat stress is a well-validated murine model of depression. However, little is known about the gene activity dynamics during the development of a depression-like state. We analyzed the effects of social defeat stress of varying duration (10 and 30 days) on the behavioral patterns and prefrontal-cortex transcriptome of C57BL/6 mice. The 10-day exposure to social defeat stress resulted in a high level of social avoidance with no signs of depression-associated behavior. Most animals exposed to 30 days of social defeat stress demonstrated clear hallmarks of depression, including a higher level of social avoidance, increased immobility in the forced swimming test, and anhedonic behavior. The monitoring of transcriptome changes revealed widespread alterations in gene expression on the 10th day. Surprisingly, the expression of only a few genes were affected by the 30th day of stress, apparently due to a reversal of the majority of the early stress-induced changes to the original basal state. Moreover, we have found that glucocorticoid-sensitive genes are clearly stimulated targets on the 10th day of stress, but these genes stop responding to the elevated corticosterone level by the 30th day of stress. The majority of genes altered by the 30-day stress were downregulated, with the most relevant ones participating in chromatin modifications and neuroplasticity (e.g., guanine nucleotide exchange factors of the Rho-family of GTPases). Very different molecular responses occur during short-term and long-term social stress in mice. The early-stress response is associated with social avoidance and with upregulation and downregulation of many genes, including those related to signal transduction and cell adhesion pathways. Downregulation of a few genes, in particular, genes for histone-modifying methyltransferases, is a signature response to prolonged stress that induces symptoms of depression. Altogether, our data show that the development of depression under social stress conditions is correlated with suppression of the overactive molecular response to induced stress, involving gene regulatory resistance to glucocorticoid molecules, potentially via a chromatin remodeling mechanism.

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Acknowledgments

This work was supported by grants #14-04-01707 from the Russian Foundation for Basic Research (behavioral study), a grant from the Government of the Russian Federation #14.B25.31.0033 (HiSeq Illumina sequencing), a grant from the Russian Science Foundation #14-44-00077 (analysis of ChIP-seq datasets), and a grant from the Russian Science Foundation #16-15-10131 (analysis of RNA-seq data and dataset on dexamethasone-affected genes).

All behavioral experiments were conducted in the Laboratory of Experimental Models of Neurodegenerative Processes at the Institute of Physiology and Basic Medicine, Novosibirsk, Russia. We would like to thank Pavlov K.S. for technical assistance with the behavioral testing.

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Authors and Affiliations

  1. Laboratory of Gene Expression Regulation, Institute of Cytology and Genetics, SB RAS, Lavrentiev ave. 10, 630090, Novosibirsk, Russia

    Natalya Bondar, Leonid Bryzgalov, Nikita Ershov, Vasiliy Reshetnikov & Tatiana Merkulova

  2. Novosibirsk State University, Novosibirsk, Russia

    Natalya Bondar & Tatiana Merkulova

  3. The Center of Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, SB RAS, Novosibirsk, Russia

    Nikita Ershov, Fedor Gusev & Evgeny Rogaev

  4. University of Massachusetts Medical School, Worcester, MA, USA

    Fedor Gusev & Evgeny Rogaev

  5. Laboratory of Molecular Mechanisms of Pathological Processes, Institute of Cytology and Genetics, SB RAS, Novosibirsk, Russia

    Damira Avgustinovich

  6. Laboratory of Experimental Models of Neurodegenerative Processes, Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia

    Mikhail Tenditnik

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  1. Natalya Bondar
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Bondar, N., Bryzgalov, L., Ershov, N. et al. Molecular Adaptations to Social Defeat Stress and Induced Depression in Mice. Mol Neurobiol 55, 3394–3407 (2018). https://doi.org/10.1007/s12035-017-0586-3

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