Journal
BIOLOGICAL PSYCHIATRY
Volume 73, Issue 7, Pages 622-630Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2012.09.021
Keywords
Antidepressant; depression; learned helplessness; neural-immune interactions; ROR gamma T; Th17 cells
Categories
Funding
- National Institute of Mental Health [MH038752, MH090236, MH095380]
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Background: Recognition of substantial immune-neural interactions is revising dogmas about their insular actions and revealing that immune-neural interactions can substantially impact central nervous system functions. The inflammatory cytokine interleukin-6 promotes susceptibility to depression and drives production of inflammatory T helper 17 (Th17) T cells, raising the hypothesis that in mouse models, Th17 cells promote susceptibility to depression-like behaviors. Methods: Behavioral characteristics were measured in male mice administered Th17 cells, CD4(+) cells, or vehicle and in retinoid-related orphan receptor-gamma T (ROR gamma T)(+/GFP) mice or male mice treated with ROR gamma T inhibitor or anti-interleukin-17A antibodies. Results: Mouse brain Th17 cells were elevated by learned helplessness and chronic restraint stress, two common depression-like models. Th17 cell administration promoted learned helplessness in 89% of mice in a paradigm where no vehicle-treated mice developed learned helplessness, and impaired novelty suppressed feeding and social interaction behaviors. Mice deficient in the ROR gamma T transcription factor necessary for Th17 cell production exhibited resistance to learned helplessness, identifying modulation of ROR gamma T as a potential intervention. Treatment with the ROR gamma T inhibitor SR1001, or anti-interleukin-17A antibodies to abrogate Th17 cell function, reduced Th17-dependent learned helplessness. Conclusions: These findings indicate that Th17 cells are increased in the brain during depression-like states, promote depression-like behaviors in mice, and specifically inhibiting the production or function of Th17 cells reduces vulnerability to depression-like behavior, suggesting antidepressant effects may be attained by targeting Th17 cells.
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