CHRONIC INFLAMMATION AFFECTS CENTRAL FEAR NETWORK ACTIVITY IN A MOUSE MODEL OF COLITIS

Our recent findings in patients with inflammatory bowel disease (IBD) suggest that chronic inflammation leads to structural and functional changes in the central fear network, facilitating maladaptive fear learning and memory processes. This study aimed to confirm and extend these findings at the cellular and molecular levels using a preclinical mouse model of colitis. The dextran sulfate sodium (DSS) mouse model of colitis was combined with an auditory fear conditioning paradigm. To induce an acute colitis, mice received 4% DSS in their drinking water for seven consecutive days, followed by a two-week recovery period. Chronic colitis was induced by repeated cycles of DSS treatment, with water-treated mice serving as controls. After one or three treatment cycles, the mice underwent auditory fear conditioning while experiencing active disease. Functional and neuroinflammatory changes in key regions of the central fear network were assessed by measuring neuronal activation markers and microglia activation after fear acquisition, extinction training, or recall. Mice with colitis showed significantly altered neuronal activation in the insular cortex as well as in hippocampal and amygdala subregions, during fear acquisition. Importantly, this altered pattern of neuronal activation in the central fear network emerged only after multiple inflammatory hits, but not after a single inflammatory bout. Together, these data confirm our previous findings in IBD patients at the neuronal level, suggesting that disease progression is a critical factor in driving fear learning-related functional brain changes in chronic inflammatory disease. This provides the basis for future studies investigating the underlying immune-to-brain communication pathways.