摘要目的 探讨组蛋白去乙酰化酶抑制剂(histone deacetylases inhibitor)辛二酰苯胺异羟肟酸(suberoylanilide hydroxamic acid,SAHA)对慢性社交挫败应激模型( social defeat,SD)小鼠恐惧记忆消退的影响及作用机制.方法 雄性C57BL/6J小鼠(7~8周龄) 56只,随机分成7组(每组n=8),分为两步:对照组、对照-SAHA组、社交挫败组、社交挫败-SAHA组,验证SAHA对恐惧记忆消退的作用;以及社交挫败组、社交挫败-空载病毒组、社交挫败-BDNF病毒组,验证BDNF对恐惧记忆消退的影响,通过条件性恐惧记忆实验(fear conditioning test,FC)测定小鼠恐惧记忆消退,免疫印迹法( west-ern blot,WB)测定小鼠海马 HDAC2 及 BDNF 的表达水平,免疫荧光法检测小鼠海马病毒过表达BDNF情况.结果 (1)社交挫败组小鼠与对照组相比恐惧记忆消退情况明显受损(P<0. 05),小鼠海马HDAC2表达水平明显升高(0. 50±0. 02),BDNF表达水平明显降低(0. 16±0. 03);(2)应用SAHA后,小鼠恐惧记忆消退明显改善(P<0. 05);与对照组相比腹腔注射SAHA的对照-SAHA组小鼠海马HDAC2水平(0. 26±0. 02)显著降低(P<0. 001),BDNF水平(0. 40±0. 03)明显升高(P<0. 001);与社交挫败组腹腔注射SAHA的社交挫败-SAHA组小鼠HDAC2水平( 0. 39± 0. 03)显著降低(P<0. 001), BDNF水平(0. 28±0. 01)明显升高(P<0. 001);(3)海马过表达BDNF病毒后,小鼠恐惧记忆消退明显改善(P<0. 05). 结论 SAHA可以改善慢性应激社交挫败小鼠恐惧记忆消退,其机制可能与抑制海马HDAC2,从而上调海马BDNF表达有关.

abstractsObjective To investigate the effect and mechanism of suberoylanilide hydroxamic acid (SAHA) on the fear extinction in mice with chronic social defeat stress (SD). Methods Fifty-six male C57BL/6J mice aged 7-8 weeks were randomly divided into control group,social defeat group,control-SAHA group and social defeat-SAHA group to investigate the effect of SAHA and social defeat group,social defeat-AAV BDNF group and social defeat-AAV blank group to investigate the effect of BDNF. Fear extinction in mice was evaluated by fear conditioning test (FC). The levels of BDNF and HDAC2 in mice hippocampus were detected by Western blot (WB). The expression of BDNF-overexpressing virus in hippocampus of mice was detected by immunofluorescence assay. Results (1) Compared with control group,fear extinction in the social defeat group was significantly decreased (P<0. 05). Compared with control group, the level of HDAC2(0. 50±0. 02) in the social defeat group was significantly increased (P<0. 001),while the level of BDNF(0. 16 ± 0. 03) was significantly decreased (P<0. 001) in the social defeat group. ( 2) After using SAHA,fear extinction of mice significantly improved (P<0. 05). Compared with control group,the level of HDAC2 (0. 26±0. 02) in the control-SAHA group was significantly decreased(P<0. 001),and the level of BDNF (0. 40±0. 03) was significantly increased (P<0. 001). Compared with social defeat group,the level of HDAC2 (0. 39±0. 03) in the social defeat-SAHA group was significantly decreased (P<0. 001),and the lev-el of BDNF (0. 28±0. 01) was significantly increased (P<0. 001). (3)After injection BDNF-overexpressing virus,fear extinction was significantly improved(P<0. 05). Conclusion SAHA can enhance fear extinction in mice with chronic social defeat stress and its mechanism may be related to the up-regulation of BDNF ex-pression in hippocampus by inhibiting HDAC2 in hippocampal.