Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice.
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.
Silverman
M N
MN
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA , USA.
Macdougall
M G
MG
Hu
F
F
Pace
T W W
TW
Raison
C L
CL
Miller
A H
AH
D000315:Adrenalectomy / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000503:physiopathology* / Q000821:virology; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000821:virology; D005106:Exploratory Behavior / Q000502:physiology; D005938:Glucocorticoids / Q000378:metabolism*; D006566:Herpesviridae Infections / Q000097:blood* / Q000503:physiopathology* / Q000821:virology; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D012260:Ribonucleases / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
D005938:Glucocorticoids; D015850:Interleukin-6; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D012260:Ribonucleases