Anterior cingulate cortex mediates the comorbidity between colorectal cancer and depression-like behaviors

In this study, we established mice with orthotopic colorectal cancer (CRC mice) and observed depression-like behaviors in the CRC mice. Through whole-brain c-FOS mapping, functional connectivity analysis, gut-brain inverse mapping, and correlation analysis, combined with chemogenetic manipulation, we identified the anterior cingulate cortex (ACC) as a key hub in the depression-related brain network. we performed whole transcriptome sequencing of key neural nuclei to identify molecular changes associated with CRC-depression comorbidity. Furthermore, chemogenetic modulation of neuronal excitability not only alleviated depression-like behavior but also reduced CRC progression in these mice. Importantly, our findings suggest that targeting the ACC, in addition to conventional colorectal cancer therapies, could offer therapeutic and quality-of-life benefits for patients with both CRC and depression.