Chronic stress and lack of reward may reduce the function of the brain's reward circuits, leading to major depressive disorder. The effect of reward treatment on chronic stress-induced depression-like behaviors and its molecular mechanism in the brain remain unclear. In this study, companion communication was used as a reward to study the effect of reward on CUMS-induced depression-like behaviors, and mRNA and miRNA profiles in the medial prefrontal cortex harvested from mice with depression-like and resilient behaviors were established by high-throughput sequencing. The results showed that accompanying with companion ameliorated CUMS-induced depression-like behaviors in mice. Furthermore, 45 differentially expressed genes (DEGs) associated with depression-like behaviors, 8 DEGs associated with resilience and 59 DEGs associated with nature reward (companion) were identified, and 196 differentially expressed miRNAs were found to be associated with companion. Based on the differentially expressed miRNAs and DEGs data, miRNA-mRNA network was established to be associated with companion. Taken together, our data here provided a method to ameliorate depression-like behaviors, and numerous potential drug targets for the prevention or treatment of depression. (C) 2020 Elsevier Inc. All rights reserved.