Behavioural and neurobiological consequences of macrophage migration inhibitory factor gene deletion in mice

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  • Cecilie Bay-Richter
  • Shorena Janelidze, Lund Univ, Lund University, Dept Clin Sci, Clin Memory Res Unit
  • ,
  • Analise Sauro, Michigan State Univ, Michigan State University, Dept Psychiat & Behav Med, Denmark
  • Richard Bucala, Yale Univ, Yale University, Sch Med, Dept Med
  • ,
  • Jack Lipton, Michigan State Univ, Michigan State University, Dept Translat Sci & Mol Med, Denmark
  • Tomas Deierborg, Lund Univ, Lund University, Dept Expt Med Sci, BMC, Expt Neuroinflammat Lab
  • ,
  • Lena Brundin, Van Andel Res Inst, Van Andel Institute, Lab Behav Med

Background: Evidence from clinical studies and animal models show that inflammation can lead to the development of depression. Macrophage migration inhibitory factor (MIF) is an important multifunctional cytokine that is synthesized by several cell types in the brain. MIF can increase production of other cytokines, activates cyclooxygenase (COX)-2 and can counter-regulate anti-inflammatory effects of glucocorticoids. Increased plasma levels of MIF are associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and depressive symptoms in patients. In contrast, MIF knockout (KO) mice have been found to exhibit increased depressive-like behaviour. The exact role for MIF in depression is therefore still controversial. To further understand the role of MIF in depression, we studied depressive-like behaviour in congenic male and female MIF KO mice and wild-type (WT) littermates and the associated neurobiological mechanisms underlying the behavioural outcome.

Methods: MIF KO and WT mice were tested for spontaneous locomotor activity in the open-field test, anhedonia-like behaviour in the sucrose preference test (SPT), as well as behavioural despair in the forced swim test (FST) and tail suspension test (TST). Brain and serum levels of cytokines, the enzymes COX-2 and indoleamine-2,3-dioxygenase (IDO) and the glucocorticoid hormone corticosterone were measured by RT-qPCR and/or high-sensitivity electrochemiluminescence-based multiplex immunoassays. Monoamines and metabolites were examined using HPLC.

Results: We found that MIF KO mice of both sexes displayed decreased depressive-like behaviour as measured in the FST. In the TST, a similar, but non-significant, trend was also found. IFN-gamma levels were decreased, and dopamine metabolism increased in MIF KO mice. Decreased brain IFN-gamma levels predicted higher striatal dopamine levels, and high dopamine levels in turn were associated with reduced depressive-like behaviour. In the SPT, there was a sex-specific discrepancy, where male MIF KO mice showed reduced anhedonia-like behaviour whereas female KO mice displayed increased anhedonia-like behaviour. Our results suggest that this relates to the increased corticosterone levels detected in female, but not male, MIF KO mice.

Conclusions: Our findings support that MIF is involved in the generation of depressive-like symptoms, potentially by the effects of IFN-gamma on dopamine metabolism. Our data further suggests a sex-specific regulation of the involved mechanisms.

Original languageEnglish
Article number163
JournalJournal of Neuroinflammation
Volume12
Number of pages11
ISSN1742-2094
DOIs
Publication statusPublished - 4 Sep 2015

    Research areas

  • Macrophage migration inhibitory factor, Depression, Cytokines, Dopamine, Inflammation, NECROSIS-FACTOR-ALPHA, MAJOR DEPRESSION, FACTOR MIF, ANTIDEPRESSANT ACTIVITY, MORNING CORTISOL, INTERFERON-ALPHA, SOCIAL DEFEAT, GROWTH-FACTOR, UP-REGULATION, ANIMAL-MODEL

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