86. Orbitofrontal IL-6 enhances reversal learning in the rat

Abstract

Chronic stress is a risk factor for depression. Stress can induce cytokine release and depression is associated with excessive cytokine signaling. Cytokines can damage cells and may be responsible for the depression-like deficits seen after chronic stress. Previously, we demonstrated that chronic intermittent cold (CIC) stress induces behavioral deficits that model depression. Depressed patients show cognitive inflexibility, or an inability to modify behaviors to adapt to environmental change. CIC stress impairs reversal learning, a form of cognitive flexibility that can be measured in the rat using the Attentional Set-shifting Test. To test the hypothesis that elevations in cytokine signaling were responsible for the CIC stress-induced reversal learning deficits, we measured cytokine levels after CIC stress in the orbital frontal cortex (OFC), the dorsomedial striatum, and the amygdala, brain regions involved in reversal learning. Using q-PCR, we found that CIC stress increased IL-6, but not IL-1beta or TNF-alpha, expression. Next, we used a neutralizing IL-6 antibody to determine if the IL-6 increase was responsible for the cognitive deficit. Surprisingly, IL-6 neutralization impaired reversal learning in both CIC and control animals, suggesting that this cytokine actually enhances cognitive flexibility. This effect was region-specific as an acute injection of the IL-6 antibody into the OFC, but not the striatum, impaired reversal learning. Ongoing experiments will determine if OFC IL-6 over-expression can rescue the stress-induced deficit in reversal learning.