Objective To investigate the effect of venlafaxine on the depression-like behavior， and the expression of CNPase， MBP and Nrg1 Ⅲ -ErbB2 expression in prefrontal cortex （PFC） of cuprizone （CPZ）treated mice. Methods A total of 32 C57BL/6 male mice aged 8-weeks were randomly divided into control group， venlafaxine （Ven） group， model （CPZ） group and CPZ+Ven group. Mice in CPZ and CPZ+Ven groups were fed with diet containing 0.2% CPZ for 5 weeks to establish CPZ model. Ven and CPZ+Ven groups received 20 mg/（kg·d） venlafaxine by gavage for 5 weeks. Control group and CPZ group were gavaged with 200 μl saline every day during the same time period. Open field experiment， sugar-water preference experiment and tail suspension experiment were carried out after 5-week intervention， and then 5 mice in each group were killed immediately. PFC was collected in liquid nitrogen. The protein levels of CNPase and MBP in PFC were detected by Western blot， and the level of Nrg1 Ⅲ-ErbB2 mRNA was detected by RT-PCR. The remaining mice （n=3） were perfused and fixed with 4% PFA，and then the morphological changes of oligodendrocytes were observed by immunofluorescence staining for CNPase. Results The total distance traveled in open field and distance of central movement of CPZ group were shorter than those of the control group ［（12.50±4.73） m vs （25.63±5.64） m， （5.92±1.98） % vs （11.78±4.17） %］. The immobility time of suspended tail test was longer than that of the control group ［（153.75±26.4） s vs （71.62±20.95） s］. Sugar preference index was lower than that of the control group ［（79.16±6.53） % vs （92.67±2.97） %］. The protein expression levels of CNPase and MBP in PFC were lower than those of the control group ［（0.56±0.08） vs （0.85±0.13）， （0.37±0.05） vs （1.01±0.08）］. The mRNA levels of Nrg1 Ⅲ and ErbB2 were lower than those of the control group ［（0.38±0.27） vs （1.06±0.16）， （0.42±0.41） vs （1.01±0.01）］. The differences of all the above were statistically significant （P ＜ 0.05）. The total distance traveled in open field and distance of central movement of CPZ+Ven group were longer than those of the CPZ group ［（22.64±6.59） m vs （12.50±4.73） m， （10.6±2.85） % vs （5.92±1.98） %］. The immobility time of suspended tail test was longer than that of the CPZ group ［（109.25±35.69） s vs （153.75±26.4） s］. Sugar preference index was lower than that of the CPZ group ［（91.63±2.98） % vs （79.16±6.53） %］. The protein expression levels of CNPase and MBP in PFC were lower than those of the CPZ group ［（0.84±0.09） vs （0.56±0.08）， （0.71±0.13） vs （0.37±0.05）］. The mRNA levels of Nrg1 Ⅲ and ErbB2 were lower than those of the CPZ group ［（0.70±0.33） vs （0.38±0.27）， （0.80±0.25） vs （0.42±0.41）］. The differences of all the above were statistically significant （P ＜ 0.05）. CNPase immunofluorescence staining showed that there were fewer CNPase oligodendrocytes in the PFC of mice in the CPZ group than in the control group and the CPZ+Ven group. Conclusions Venlafaxine can up-regulate the levels of CNPase and MBP protein and the mRNA levels of Nrg1 Ⅲ and ErbB2 in the PFC of CPZ mice，increase the number of oligodendrocytes，and alleviate depressionlike behaviors.