Objective:To explore the regulation effects of baicalin on the behavior as well as extracellular regulated protein kinase(ERK)and cAMP-response element binding protein(CREB) in chronic unpredictable mild stimulus(CUMS) model mice.Methods:Thirty ICR mice were randomly assigned to control(CON) group, model(CUMS) group, fluoxetine(FLU) group, baicalin high-dose(BA-H) group and baicalin low-dose(BA-L) group with 6 mice in each group.In addition to the CON group, the mice in the other four groups were modeled by CUMS method.The modeling was carried out for 42 days, and intragastric administration was carried out according to groups from the 21st day to the completion of modeling.After administration, the depression like behavior of mice was measured by sugar water preference test and water maze test.Western blot (WB) and reverse transcription polymerase chain reaction (RT-PCR) were used to detect the protein level and mRNA level of ERK and CREB in mouse hippocampus respectively.SPSS 21.0 was used for statistical analysis.After normal test and variance homogeneity test, one-way ANOVA was used for multi group comparison, and Tukey test was used for pairwise comparison.Results:Results from the sugar preference experiment showed that compared with CON group, the sugar preference rate of CUMS group was decreased ((82.88±2.00)%, (64.49±1.24)%, t=19.11, P<0.05). Compared with CUMS group, sugar preference rate in FLU group ((81.90±1.19) %), BA-H group (77.86±2.51)%) and BA-L group ((67.98±2.56)%) increased ( t=24.83, 11.68, 3.00, all P<0.05). The results of water maze test showed that compared with CON group, the number of crossing platform ((6.33±0.82), (1.83±0.75), t=9.93, P<0.05) and the target quadrant residence time ((46.83±4.78)s, (24.25±6.12)s, t=7.13, P<0.05) of mice in CUMS group were decreased, but the the escape latency was prolonged ((14.88±3.00) s, (70.70±4.77) s, t=24.26, P<0.05). Compared with CUMS group, the number of crossing platform ((5.00±0.89)times, (5.17±0.75)times and (3.33±0.82) times, t=6.64, 7.67, 3.31, all P<0.05), and the residence time in the target quadrant ((36.80±2.66) s, (36.82±5.62) s, (33.28±3.56) s, t=4.61, 3.71, 3.13, all P<0.05) in FLU group, BA-H group and BA-L group increased, but the escape latencies were shortened ((23.37±4.86) s, (34.83±4.72) s, (62.15±5.30) s, t=17.02, 13.10, 2.94, all P<0.05). WB results showed that compared with CON group, the expression of ERK protein ((1.00±0.15), (0.36±0.10), t= 6.26, P<0.05) and CREB protein((1.00±0.12), (0.29±0.03), t=10.32, P<0.05) in hippocampus of mice in CUMS group decreased.Compared with CUMS group, ERK protein in hippocampus of mice in FLU, BA-H and BA-L groups increased ((0.87±0.05), (0.77±0.08), (0.67±0.03), t=8.25, 5.7, 5.39, all P<0.05), and CREB protein in FLU, BA-H and BA-L groups were also increased ((0.90±0.12), (0.84±0.14), (0.62±0.04), t=8.94, 6.59, 12.25, all P<0.05). qPCR results showed that compared with CON group, ERK mRNA ((1.00±0.03), (0.41±0.10), t=9.78, P<0.05) and CREB mRNA ((1.00±0.08), (0.61±0.12), t=4.62, P<0.05) were decreased in CUMS group.Compared with CUMS group, ERK mRNA in hippocampus of mice in FLU, BA-H and BA-L groups were increased ((0.71±0.08), (0.69±0.03), (0.59±0.04), t=4.15, 4.65, 2.84, all P<0.05), CREB mRNA in FLU group and BA-H group were increased ((0.87±0.08), (0.86±0.07), t=3.14, 3.19, all P<0.05). Conclusion:BA can improve the depression-like behavior of CUMS model mice.The mechanism of action may be related to the regulation of ERK and CREB proteins.