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

M. N. Silverman, M. G. Macdougall, F. Hu, Thaddeus Wesley Warren Pace, Charles L Raison, A. H. Miller

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)408-417
Number of pages10
JournalMolecular Psychiatry
Volume12
Issue number4
DOIs
StatePublished - Apr 30 2007
Externally publishedYes

Fingerprint

Glucocorticoids
Muromegalovirus
Anxiety
Tumor Necrosis Factor-alpha
Cytokines
Interleukin-6
Virus Diseases
Locomotion
Knockout Mice
Brain
Messenger RNA
Adrenalectomy
Infection
Interleukin-1

Keywords

  • Anxiety
  • Glucocorticoids
  • Open-field behavior
  • TNF-alpha
  • TNF-R1-knockout mice
  • Viral infection

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health

Cite this

Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice. / Silverman, M. N.; Macdougall, M. G.; Hu, F.; Pace, Thaddeus Wesley Warren; Raison, Charles L; Miller, A. H.

In: Molecular Psychiatry, Vol. 12, No. 4, 30.04.2007, p. 408-417.

Research output: Contribution to journalArticle

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