Objective This research investigated the expression of REST in repeated corticosterone injected mice and the effects of REST on depression- and anxiety-like behaviors in model mice. Methods A chronic stress mouse model was established by repeated subcutaneous injections of corticosterone. An AAV virus vector overexpressing REST was injected into the hippocampus of the mouse brain. Then, the depression- and anxiety-like behaviors of mice were assessed by several behavioral tests. Finally, we detected the expression of REST-related genes by real-time RT-PCR. Results Repeated subcutaneous injections of corticosterone for 4 weeks successfully induced depression-like behavior and reduced body weight in mice (P< 0.01). REST overexpression in the hippocampus influenced the performance of model mice in the depression and anxiety behavioral tests. Specifically, it reduced the immobility time of model mice in the tail suspension test and forced swimming test and the number of entries into the central area in the open field test. In addition, REST overexpression increased the exploration frequency and residence time in the enclosed arms of the elevated cross maze. The RNA transcription levels of Bndf, Nt3, Ngf and Fgf2 were also affected in model mice after REST overexpression. Conclusions REST plays a bidirectional role in the corticosterone-induced depression mouse model. Its mechanism may be related to its participation in the regulation of multiple target genes and the comprehensive effect of different signaling pathways.