In the current study, we used RAGE knockout mice to further confirm that the deletion of RAGE can significantly improve the depressive-like behavior and weight change of mice induced by CUMS, and the FC of the bilateral Cg is significantly increased, which is reflected in the resistance of RAGE knockout mice to the susceptibility of depression, and indicates that the knockout or inhibition of RAGE expression plays a key role in the treatment of MDD. This evidence concerns the gene AGER and depressive symptom measurement.