A Role for Microglia Activation in Modulating Behavior in a Variable Stress Model for Depression

Major Depressive Disorder is a common mood disorder, affecting more than 300 million people worldwide. Stress, being a potent trigger for various mood disorders, including depression, affects both the peripheral and central immune systems. Microglia are the resident immune cells in the brain and changes in their morphology and state of activation in response to stress have been reported in a number of brain regions, however most studies examined only male subjects. In our studies we investigated morphological changes in microglia in the nucleus accumbens and subregions of the hippocampus in both male and female mice following variable stress. Our findings demonstrate that following 6 days of variable stress female microglia acquire a more activated phenotype compared to microglia in males. These sex specific effects in microglia activation were also observed in the nucleus accumbes, but not the dentate gyrus after 28 days of stress. Utilizing a number of pharmacological agents, we further investigated whether changes in the inflammatory states of microglia modulate behavior in female mice in a variable stress model for depression. We found that rosiglitazone, peroxisome proliferator activated receptor gamma PPAR) agonist, which causes microglial shift to an anti-inflammatory state, conferred social resilience in female mice after 6 days of variable stress. We further demonstrated that blocking pro-inflammatory activation of microglia with minocycline, a tetracyclic antibiotic, did not prevent the stress effects on behavior. Surprisingly, prior pro-inflammatory activation of microglia with lipopolysaccharide (LPS), an endotoxin from gram-negative bacteria, was protective against subsequent variable stress. Finally, I describe the impact of systemic application of these drugs on microglia morphology and activation state, and cytokine levels in the nucleus accumbens of female mice. Taken together this body of work contributes to a growing number of studies demonstrating neuro-immune mechanisms associated with depression.