Chronic gut inflammation differentially modulates mitochondrial and antioxidant transcriptional programs in limbic...

Chronic inflammatory diseases are frequently comorbid with depression and anxiety, often persisting during periods of inflammatory remission. This suggests functional changes to neural circuits involved in the contextual regulation of motivation and threat processing. Here, we test how chronic gut inflammation evoked by dextran sodium sulfate (DSS) affects gene expression in several limbic brain structures associated with these functions. We assessed post-mortem expression of mRNA transcripts in the anterior cingulate cortex (ACC), CA1 hippocampus, nucleus accumbens (NAc), and primary motor cortex (M1) as a non-limbic control. The levels of mRNA associated with mitochondrial function, inflammation, and synaptic connectivity were altered in DSS-treated animals, but the specific pattern of changes was heterogeneous among brain structures. Chronic gut inflammation affected transcript expression in the CA1 and NAc more so than in the ACC and M1. These differences involved genes related to antioxidant systems and mitochondrial function. For example, expression of the cytochrome oxidase 1 gene mt-co1, which is necessary for oxidative phosphorylation, was reduced in ACC and NAc of DSS animals, suggesting reduced capacity for ATP production in these regions. Markers of gut inflammation correlated with expression of several transcripts in the ACC, including markers of synapses and GABA synthesis. The NAc showed strong correlations of mitochondrial function and measures of mitochondrial fission, inflammation, synaptic connectivity, and GABA synthesis. In sum, the effects of chronic relapsing gut inflammation on mitochondrial and antioxidant transcriptional programs were heterogeneous across key limbic brain structures.