A single-nucleus transcriptomic analysis reveals hippocampal neuronal alterations linked to anxiety- and depression-like behaviors in IBD model mice.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder that often has extraintestinal manifestations. Anxiety and depression are common in patients with IBD. Recent studies have demonstrated that the hippocampus contributes to the pathogenesis of psychiatric comorbidities in IBD. Therefore, this study aimed to elucidate the cellular and molecular changes in the hippocampus before and after the induction of colitis through single-nucleus sequencing technology, thus providing insights into the comorbidity mechanisms. Colitis mouse models were established by adding dextran sulfate sodium (DSS) to the drinking water. Behavioral tests were used to evaluate anxiety- and depression-like behaviors. Single-nucleus RNA sequencing analysis was carried out to identify specific neuronal subpopulations in the hippocampal and their functions. We found that DSS-treated mice exhibited intestinal inflammation and anxiety- and depression-like behaviors. The number of cells in the DG cluster and the Meis2 cluster decreased significantly after DSS treatment. Further analyses revealed that the DG-2 cluster might represent a key hippocampal subpopulation mediating the association between IBD and anxiety/depression. This study provides novel insights into the role of neuronal cells in the pathology of the comorbidity. Neurons of the DG-2 subpopulation may serve as a potential target for future therapeutic interventions.