Objective  To explore the effect of chronic restraint stress(CRS) on the phenotypic transition of hippocampal astrocytes and depression-like behavior in mice.   Methods  Forty eight male C57BL/6 mice were randomly divided into control groups (control), model groups (CRS) and fluoxetine(FLX) drug intervention groups (CRS+FLX), 16 for each group. The mice of the CRS group were subjected to 3 weeks chronic restraint stress. The mice of CRS+FLX group were treated with fluoxetine by intraperitoneal injection 30 minutes before restraint stress from the day 8 to day 21. The mice in the control group and CRS group were treated with the same amount of normal saline (NS). Depression-like behavior was determined by sucrose preference test and open filed test. The expression of astrocytes marker glial fibrillary acidic protein(GFAP) was detected by immunohistochemistry and Western blotting. The expression of A1 and A2 astrocytes markers were detected by Real-time PCR.   Results  Compared with the control group, mice in the CRS group showed obvious depression-like behavior, including a significantly decrease in the percent of sucrose preference (P＜0.0001), a redcued significantly body weight (P＜0.05), and reduced significantly distance travelling in the central area (P＜0.005) in the open field test, which could be reversed by the FLX intervention (P＜0.05). Compared with the control group, the expression of hippocampal astrocytes marker GFAP in the CRS group increased significantly (P＜0.05), which could be reversed by the FLX intervention (P＜0.05). Compared with the control group, the mRNA expression level of the A1 astrocytes markers ［(H2D1, guanylate binding protein 2(GBP2), Fkbp5, Amigo2)］ in the hippocampus of the CRS group were significanlty up-regulated (P＜0.05), which could be reversed by the FLX intervention (P＜0.05). No difference was found in the A2 astrocytes markers mRNA level among the three groups (P＞0.05), except Sphk1 and PTX3. Compared with the control group  , the protein level of hippocampal A1 markers (C3, Fkbp5, GBP2) in CRS group was significanlty up-regulated (P＜0.05), while no difference in the protein level of hippocampal A2 marker CD14 between the two groups (P=0.8361), FLX intervention could significantly reduce the protein level of A1 markers (P＜0.05), but had no obvious effect on the protein expression of CD14 (P=0.5881).   Conclusion The depression-like behavior of mice in the chronic restraint stress model may be related to the phenotypic changes of astrocytes, and it is mainly due to the high expression of type A1 markers in astrocytes.