Objective To observe the influence of Creb protein over-expression and under-expression in the prefrontal cortex on depressive behavior in rats. Methods Adeno-associated virus (AAV) strains that can knock down Creb expression in the prefrontal cortex of rats were injected by using stereotaxic injection method and screened by using Western blot, qRT-PCR and immunofluorescence methods. 40 Rats were randomly divided into control group（Control）,chronic restraint stress group（CRS）,chronic restraint stress combined with adeno-associated virus interference group（CRS＋AAVI）and chronic restraint stress combined with adeno-associated virus overexpression group（CRS＋AAVO）. During the establishment of animal model, the body weight and food intake of each group of rats were monitored. After the establishment of the animal model, the behavioral changes of rats were monitored by using sucrose preference test, elevated plus maze test, forced swimming test and open field test. The contents of 5-hydroxytryptamine (5-HT), norepinephrine (NE) and corticosterone (CORT) in the prefrontal cortex of rats in each group were measured by using Elisa method. Results The results of Western blot and immunofluorescence detection showed that the expression of Creb protein of rats in shRNA2 group was significantly lower than that of the other groups (P< 0.05). The results of qRT-PCR experiment showed that the expression of Creb mRNA in the shRNA2 group was significantly lower than that of the other three groups. Therefore, the AAV-Creb1-shRNA2 virus strain was selected for modelling of subsequent Creb knock-down experiments in this study. After knock down and high expression Creb AAVs were injected into the brains of rats, compared with other groups, the food intake of rats in the CRS＋AAVI group was significantly reduced compared with other groups (P< 0.05). At the same time, the rats in this group showed slow weight gain, decreased desire and pleasure to explore new environment, significantly increased despair and nervous behavior, significantly decreased 5-HT and NE levels in the prefrontal cortex, and significantly increased CORT levels. While these depressive behaviors and associated neurotransmitter levels were reversed by injection of the overexpressing AAV-Creb1 virus strain. Conclusion Lower expression of Creb in the prefrontal cortex can aggravate the degree of depression in rats, while the high expression of Creb can alleviate the degree of depression of rats to a certain extent. These results further confirm that Creb expression in the prefrontal cortex is one of the important targets involved in the pathogenesis of depression, and can provide ideas and references for the construction of animal gene models and pathogenesis of depression in future.