Antigen‐Induced Arthritis in Mice induces Depression‐Like Behavior and Microglial Activation in Hippocampus after the Resolution of Peripheral Inflammation
Authors: Lopes Fernando , Vicentini Fernando , Cluny Nina L. , Mathews Alex J. , Lee Benjamin H. , Almishri Wagdi , Griffin Lattece , Munsie Nicole , McKay Derek M. , Swain Mark G. , Sharkey Keith A. 
Published: June 2021

Rheumatic Arthritis (RA) affects 1 in 100 adults globally and is of unknown etiology. RA is characterized by inflammation that affects most commonly the joints and relapsing symptoms, such as swollen, painful and tender joints, and joint stiffness. RA is also accompanied by neurological and psychological manifestations including chronic pain, fatigue, depression, social withdrawal and weight loss that together significantly reduce quality‐of‐life in those affected by RA. While efforts to understand the mechanisms of joint inflammation have led to important treatments, such as anti‐TNFα therapy, the mechanisms that lead to the chronic pain and depression observed in patients with RA, even in remission, have yet to be uncovered. The aim of this work was to develop a model that reproduces in rodents the depression‐like phenotype observed in patients with RA and assess the mechanisms underlying these changes.

Antigen‐induced arthritis (AIA) was induced in 8–10 weeks old C57BL/6J mice by sensitization with methylated bovine serum albumin (mBSA) followed by intra‐articular challenge 14 days later. Depression‐like behavior was assessed using the tail suspension test (TST). Immunohistochemistry was used to investigate microglial activation (based on Iba1 immunoreactivity), and multiplex assay to measure cytokine levels in different regions of the brain.

As reported previously, the peak of inflammatory response in the knee of mice with AIA was observed 24 h after challenge and inflammation was no longer observed at 13 days as gauged by the number of infiltrated neutrophils to the knee cavity. However, 13 days after the challenge, AIA mice displayed depression‐like behaviors; spending a longer immobility time in the TST compared with controls; this behavioral effect was reversed by the antidepressant imipramine. Depression‐like behaviors were not observed at the peak of joint inflammation. Iba1 expression was increased in the hippocampus of mice with AIA at 13 days, suggesting microglial activation in this region after the resolution of peripheral inflammation. Iba1 immunoreactivity in the circumventricular organs of mice 13d after AIA challenge was not different to tissue from control mice. Multiplex assay revealed an increase in KC, MCP‐1 and TNFa in the hippocampus in mice with AIA at the peak of the inflammation that was not maintained 13 days after challenge, suggesting that the maintenance of microglial activation is not dependent on local cytokine production.

In conclusion, this is the first report of an animal model of arthritis that reproduces depression‐like behavior after the resolution of peripheral inflammation. This is associated with microglial activation in the hippocampus.

Support or Funding Information

Canadian Institutes of Health Research

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.