Behavioral and emotional abnormalities in mice with orthotopic colitis-associated colorectal cancer

Colorectal cancer (CRC) is usually accompanied by emotional and behavioral changes in patients, yet the underlying neurobiological mechanisms remain unclear. There is a lack of robust experimental models to investigate how tumor progression may influence brain function and behavior.

The azoxymethane (AOM) and dextran sulfate sodium (DSS) were used to induce the orthotopic colitis-associated CRC (CAC) mouse models. Then we performed a range of behavioral tests including the sucrose preference test (SPT), elevated plus maze (EPM), tail suspension test (TST), novel object recognition test (NORT), resident-intruder assay, and tube test to evaluate abnormal behaviors of depression, memory impairment, and irritability.

CAC mice exhibited a marked reduction in body weight accompanied by pronounced colon shortening. Histopathological examination using hematoxylin and eosin staining revealed the presence of colonic adenomas and atypical hyperplasia. Behavioral tests using the EPM and TST indicated heightened depressive-like behavior, while the NORT revealed significant memory impairment compared to controls. Meanwhile, the resident-intruder assay and tube tests showed that CAC mice exhibited irritability and aggression. TUNEL staining showed a marked increase in TUNEL-positive cells in the hippocampus of CAC mice, while Western blots revealed downregulated anti-apoptotic Bcl-2 and upregulated pro-apoptotic Bak, Bad, and cleaved PARP. Real-time quantitative polymerase chain reaction further revealed increased expression of IL-6 and IBA-1 in the hippocampus of CAC mice.

The AOM/DSS-induced CAC mouse model recapitulates tumor-associated behavioral and neurobiological alterations, underscoring its application in neuropsychiatric oncology research.