Objective To investigate behavior and hippocampal tau alterations following chronic unpredictable mild stress (CUMS),treatment of fluoxetine and re-exposure to CUMS.Methods 32 male SpragueDawley (SD) rats were divided into four groups,with 8 exposed to 21 consecutive days of chronic unprcdicted mild stresses (CUMS) and treated with vehicle,8 exposed to CUMS and treated with fluoxetine,8 exposed to CUMS and treated with fluoxetine and re-exposed to CUMS after washout,and 8 as normal controls treated with vehicle.Behavioral changes in these rats were analyzed.The expression of hippocampal tau and phospho-tau were analyzed using Western Blot.Results (1) Compared with the normal rats,sucrose preference ((52.37 ± 16.76) ％),total traveling distance((2736.59 ± 511.20) cm),velocity((5.69 ± 1.09) cm/s) and frequencies of rearing(2.50 ±2.00) were reduced (P ＜ 0.01) in the depressed rats.These behavioral changes could be reversed after 21d fluoxetine treatment.Compared with the control and CUMS group,sucrose preference ((42.00 ± 8.03)％),total traveling distance ((763.48 ± 457.29) cm),velocity ((2.64 ± 0.97) cm/s) and frequencies of rearing (0.25 ± 0.46)were reduced (P＜0.01 for both) in the re-exposure to CUMS group.(2) Compared with the normal rats,the ptau(Ser356) expression ((152.31 ± 12.34) ％) and p-tau (Thr231) expression ((166.72 ± 17.58) ％) of CUMS group showed a significant increase (P＜ 0.01 for both) in rats submitted to CUMS.These changes could be also reversed after 21d fluoxetine treatment.Compared with the control and CUMS group,the p-tau (Ser356) expression ((221.86 ± 14.34) ％) and p-tau (Thr231) expression ((302.01 ± 20.31) ％) of re-exposure to CUMS group showed a significant increase (P＜ 0.01 for both).The total tau expression of four groups did not change significantly.Conclusion These findings provide evidence that rats exposed to CUMS and re-exposed to CUMS show increased p-tau expression,which suggest that changes in tau phosphorylation may play an important role in the link between depression and AD.

Hypothalamic-pituitary-adrenal (HPA) axis appears to play a key role in the pathogenesis of major depressive disorders (MDD). Treatment of certain selective serotonin reuptake inhibitors (SSRIs) has been shown to reduce the activity of corticotropin-releasing hormone (CRH) neurons and may contribute to their therapeutic action. It has been proposed that the downregulation of CRH activity is final and common step of antidepressant treatment. In this study, we tested whether the polymorphisms of three sites (rs1876828, rs242939 and rs242941) in corticotropin-releasing hormone receptor1 (CRHR1) gene are related to 6 weeks fluoxetine antidepressant effect in 127 Han Chinese patients with MDD. The results show that the rs242941 G/G genotype and homozygous GAG haplotype of the three single-nucleotide polymorphisms (SNPs) are associated with fluoxetine therapeutic response in MDD patients of high-anxiety (HA). The results support the idea that the CRHR1 gene is likely to be involved in the antidepressant response in MDD.