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Updated: Jul 6, 2026
An Unpredictable Chronic Mild Stress Protocol for Instigating Depressive Symptoms, Behavioral Changes and Negative Health Outcomes in Rodents
Published on: December 2, 2015
Chronic stress primes TLR3-mediated systemic inflammation to produce persistent post-viral fatigue syndrome-like
Battuvshin Lkhagvasuren1, Takafumi Suematsu2, Liu Xiangyu2
1Department of Psychosomatic Medicine, Kyushu University Hospital, Kyushu University, Fukuoka, Japan; Brain Science Institute, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia.
Background:
This study examined the long-term effects of polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA and Toll-like receptor 3 (TLR3) agonist, on behavioral and immune outcomes in chronically stressed mice.
Methods:
Male C57BL/6J mice were exposed to 21 days of wet bedding stress followed by a poly I:C injection. Post viral fatigue syndrome (PVFS)-like symptoms were evaluated over 7 days post-injection using grip strength testing, the forced swim test, von Frey filament testing, the Morris water maze, the open field test, and the social interaction test. Body temperature and locomotor activity were continuously monitored via intraperitoneally implanted dataloggers. Serum concentrations of interleukin-6 (IL-6), IL-10, and C-X-C motif chemokine ligand 10 (CXCL10) were quantified. In separate cohorts, minocycline (a microglial activation inhibitor) or RU486 (a glucocorticoid receptor antagonist) was administered prior to poly I:C injection.
Results:
Following IP injection of poly I:C, body temperatures in both stressed and unstressed mice were significantly elevated, indicating a polyphasic febrile response. At 7 days post-injection, stressed mice treated with poly I:C exhibited persistent fatigue, mechanical allodynia, depressive-like behavior, impaired spatial memory, increased anxiety-like behavior, and reduced social interaction. Serum levels of IL-6 and CXCL10 remained elevated and correlated with behavioral outcomes. Pretreatment with minocycline partially attenuated both the behavioral and immune responses, whereas RU486 pretreatment did not.
Conclusion:
These findings demonstrate that TLR3-mediated systemic inflammation induced by poly I:C produces persistent, multi-domain PVFS-like symptoms in chronically stressed mice. The attenuation by minocycline implicates neuroinflammation as a possible mechanism.
