大鼠慢性不可预测温和应激与小鼠社会挫败抑郁症模型的建立与行为学评价

Establishment and Behavior Evaluation of Rat Chronic Unpredictable Mild Stress and Mouse Social Defeat Models

目的:为了研究重度抑郁症(major depressive disorder,MDD)发病机制,有必要建立稳定的抑郁症啮齿类动物模型。目前文献常用的慢性抑郁症动物模型为慢性不可预测温和应激(chronic unpredictable mild stress,CUMS)和社会挫败(social defeat,SD)两种模型。在该研究中,为了建立更稳定的抑郁症动物模型并比较两种模型的优缺点,对现有两种模型的建立方法和评价指标进行了调整与改进。方法:慢性不可预测应激模型大鼠每天随机接受两种应激因子,进行为期28 d的应激刺激,刺激因素包括通宵照明、夹尾、湿笼、拥挤、冰水游泳、禁水及禁食等。造模过程中将大鼠分为空白对照组,模型组以及氟西汀阳性药对照组(10 mg·kg^(-1))三组。小鼠接受社会挫败应激因素包括攻击鼠对实验鼠5~10 min的身体攻击(physical attack,PA)和24 h的感官接触(sensory interaction,SI),实验时将小鼠分为空白对照和SD应激因素两组。造模后使用糖水偏爱率、强迫游泳不动时间及社会交往率(social interaction ratio,SIR)等指标考察模型是否成功。结果:采用不同组合的慢性不可预测应激条件建立了大鼠CUMS模型,4周造模后,模型组糖水偏爱率(69.3%±3.6%,n=27)和强迫游泳不动时间(131.2±5.8 s,n=27)与非接受刺激的空白对照组大鼠的糖水偏爱率(81.0%±3.2%,n=17)和强迫游泳不动时间(105.1±8.2 s,n=17)比较,糖水偏爱率显著降低,而不动时间显著延长,差异均具有统计学意义(P<0.05);阳性对照氟西汀组大鼠糖水偏爱率(82.1%±3.9%,n=10)和强迫游泳不动时间(108.3±9.7 s,n=10)与空白对照组比较没有显著差异。社会挫败应激经社会交往测试(social interaction test,SIT)后,选取社会交往率小于1(即SIR=有攻击鼠存在时C57BL/6J小鼠在接触区持续时间/无攻击鼠存在时C57BL/6J小鼠在接触区持续时间)的敏感小鼠用于评价糖水偏爱率。糖水偏爱测试结果表明,SD模型组小鼠的糖水偏爱率(69.2%±2.4%,n=16)与对照组(78.6%±3.2%,n=9)相比显著降低(P<0.05)。结论:以糖水偏爱率和强迫游泳不动时间两个核心指标判断大鼠CUMS模型造模成功,小鼠SD模型以社会交往率和糖水偏爱率为指标判断造模成功,且模型相对比较稳定。

Objective：To study the pathogenesis of major depressive disorder（MDD）,it is necessary to establish animal models of depression.There are two common chronic depressive models that are chronic unpredictable mild stress（CUMS）and social defeat（SD）.In this study,we modified these models and compared the advantages and disadvantages of the two models to establish a more stable model of depression.Methods：For CUMS model,rats were treated with randomized two stressors last for 28 days.Stressors include overnight illumination,tail pinch,wet cage,crowding cage,ice water swimming,water and food deprivation.Rats were divided into three groups of blank Control,CUMS and CUMS＋Fluoxetine（10 mg·kg^（-1））as positive control.For SD model,social defeat stress factors include 5 to 10 min physical attack and 24hours sensory interaction.Mice were divided into Control and SD groups.After modeling,we adopt sucrose preference,immobility time of Forced Swimming Test and social interaction ratio to study whether the model is successful.Results：There was a significant decrease of sucrose preference（69.3%±3.6%,n=27）and significant increase of immobility time of Forced Swimming Test（131.2±5.8 s,n=27）in CUMS rats,as compared with control group of rats with sucrose preference（81.0%±3.2%,n=17,P〈0.05）and immobility time（105.1±8.2 s,n=17,P〈0.05）.The sucrose preference（82.1%±3.9%,n=10）and immobility time of Forced Swimming Test（108.3±9.7 s,n=10）were no significant change in CUMS＋Flu group rats,as compared with control group.Mice in social defeat showed that social interaction ratio below 1（determined by SIR1,SIR=Duration in interaction zone of target absent phase/Duration in interaction zone of target present phase）,as compared with social interaction ratio greater than 〈1 in control group.Moreover,SIR of SD mice was significantly lower（69.2%±2.4%,n=16）than that of control group（78.6%±3.2%,n=9,P〈0.05）.Conclusions：Based on the core criteria of sucrose preference,models of CUMS in rats and SD in mice are successfully established,whereas the social defeat model is more reproducible and consistent.