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Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice

Molecular Psychiatry volume 12, pages 408–417 (2007)Cite this article

Abstract

Endogenous glucocorticoids restrain proinflammatory cytokine responses to immune challenges such as viral infection. In addition, proinflammatory cytokines induce behavioral alterations including changes in locomotor/exploratory activity. Accordingly, we examined proinflammatory cytokines and open-field behavior in virally infected mice rendered glucocorticoid deficient by adrenalectomy (ADX). Mice were infected with murine cytomegalovirus (MCMV), and open-field behavior (36 h post-infection) and plasma concentrations of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 (42 h post-infection) were assessed. Compared to sham-ADX-MCMV-infected animals, ADX-MCMV-infected mice exhibited significant reductions in total distance moved, number of center entries, and time spent in center. These behavioral alterations were accompanied by significantly higher plasma concentrations of TNF-alpha and IL-6, both of which were correlated with degree of behavioral change. To examine the role of TNF-alpha in these behavioral alterations, open-field behavior was compared in wild-type (WT) and TNF-R1-knockout (KO), ADX-MCMV-infected mice. TNF-R1-KO mice exhibited significantly attenuated decreases in number of rearings, number of center entries and time spent in center, but not distance moved, which correlated with plasma IL-6. Given the potential role of brain cytokines in these findings, mRNA expression of TNF-alpha, IL-1 and IL-6 was assessed in various brain regions. Although MCMV induced increases in proinflammatory cytokine mRNA throughout the brain (especially in ADX animals), no remarkable differences were found between WT and TNF-R1-KO mice. These results demonstrate that endogenous glucocorticoids restrain proinflammatory cytokine responses to viral infection and their impact on locomotor/exploratory activity. Moreover, TNF-alpha appears to mediate cytokine-induced changes in open-field behaviors, especially those believed to reflect anxiety.

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Acknowledgements

We thank Drs Brad Pearce and Gerald Vogt (Emory University, Atlanta, GA) for their help in harvesting low stress samples. In addition, we thank Dr Christine Biron (Brown University, Providence, RI) for supplying stocks of MCMV, and Minida Dowdy (Emory University, Atlanta, GA) for managing the TNF-R1-KO breeding colony. This work was supported in part by National Institute of Health Grants, MH47674 (AHM), MH00680 (AHM) and F31-MH63598 (MNS).

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  1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    M N Silverman, F Hu, T W W Pace, C L Raison & A H Miller

  2. Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    M G Macdougall

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Silverman, M., Macdougall, M., Hu, F. et al. Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice. Mol Psychiatry 12, 408–417 (2007). https://doi.org/10.1038/sj.mp.4001921

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