Patients with inflammatory bowel disease (IBD) have higher rates of psychiatric pathology including depression. The dextran sulfate sodium (DSS)-treated mouse is a well-characterized animal model of colitis that exhibits both IBD- and depressive-like symptoms. Recent our study found that DSS-induced depressive-like behavior may be associated with reduction of myelin-constitute proteins in the prefrontal cortex (PFC), while these changes were prevented through activation of 5-HT_1A receptor by administration of brexpiprazole (Brx). However, it remains unclear about their molecular mechanisms. Therefore, the present study determined changes in proteins associated with 5-HT_1A receptor-mediated signaling in the PFC. Then, we also investigated whether the TrkB inhibitor ANA-12 affected the effects of Brx on DSS-treated mice. Decreased phosphorylation of ERK, CREB and TrkB levels and expression of BDNF level in the PFC of DSS-treated mice were prevented by Brx, and the effects of Brx were inhibited by the selective 5-HT_1A antagonist WAY100635. Furthermore, ANA-12 prevented the effects of Brx on DSS-induced depressive-like behavior and abnormal myelination in the PFC. These findings indicate that myelination regulated by activation of ERK1/2-CREB-BDNF-TrkB pathway in the PFC may be involved in the antidepressant effect of Brx.