Balb/c和129/S1小鼠的抑郁与气虚证共易感差异性及越鞠丸干预作用的分子研究

The Differences of Common Susceptibility to Depression-like Phenotypes and Qi Deficiency Syndromes in Balb/c and 129/S1 Mice and the Molecules of the Intervention Effect of Yueju Pills

目的比较Balb/c和129/S1两品系小鼠在不同抑郁症模型造模后的证候差异,以及越鞠丸对慢性不可预知温和刺激造模后两品系小鼠抑郁证候表型和相关信号通路的影响。方法分别在Balb/c、129/S1两个近交品系小鼠上用社交挫败应激与慢性不可预知应激两种方法造模。用糖水偏爱、陌生环境摄食、强迫游泳等测试的指标用于评判小鼠的抑郁/焦虑样状况,并对小鼠前肢抓力、掌纹血色度和负重游泳进行检测,评判其气虚样证候。将慢性不可预知应激抑郁造模后的两品系小鼠分为模型组、越鞠丸组和氟西汀组,给药一周后进行一系列行为学检测,评判越鞠丸对抑郁症及气虚证候的改善作用,采用蛋白免疫印迹法检测小鼠海马与肌肉PKA-CREB信号通路蛋白表达。结果雄性Balb/c和129/S1小鼠在两种模型下均表现出糖水偏好显著降低,强迫游泳时间显著延长或社会交互时间显著缩短等抑郁样行为,而Balb/c小鼠在抓力及掌纹血色表型上都显示气虚样证候,129/S1小鼠则未表现出类似证候。越鞠丸可逆转两品系小鼠在慢性不可预知应激造模后的抑郁表型,但无法逆转造模后Balb/c小鼠的抓力、掌纹血色度和负重游泳时长的气虚样表型;与模型组相比,两品系小鼠越鞠丸组海马和肌肉PKA、CREB磷酸化蛋白表达均明显上调。结论社交挫败应激与慢性不可预知应激造模后,Balb/c与129/S1两品系鼠均表现出抑郁样行为,只有Balb/c小鼠出现气虚样证候。越鞠丸均能逆转两品系小鼠的抑郁样行为,对Balb/c小鼠的气虚样证候没有影响,其抗抑郁作用与激活PKA-CREB信号通路有关。

Objective To compare the differences of the syndrome of the two strains of Balb/c and 129/S1 mice in different depression models, and the effect of Yueju pill on the phenotype of depression and the related molecular pathways of the two-strain mice after suffered chronic unpredictable and mild stress(CUMS). Methods social defeat stress(SD) and CUMS were used to induce depression on Balb/c and 129/S1 inbred mice. Through sucrose preference test,forced swimming test, novelty suppressed feeding test to assess depressive/anxiety-like behavior in mice, and forelimb grasp strength, claw color and exhausted swim of mice were tested to evaluate the qi deficiency syndrome.Model mice of CUMS were divided into model group, Yueju pill group and fluoxetine group. After one week of administration, a series of behavioral tests were conducted to evaluate the improvement effect of Yueju pill on depression and qi deficiency syndrome. Western Blot was used to detect the protein expression of the PKA-CREB signaling pathway in the muscle and hippocampus tissue of mice. Results male Balb/c and 129/S1 mice showed significantly reduced sucrose preference, significantly prolonged forced swimming time or significantly shortened social interaction time and other depressive behaviors under the two models, while Balb/c mice showed qi deficiency syndrome in grasping strength degree of claw color phenotype, while 129/S1 mice showed no similar syndrome. Behavioral results further showed that Yueju pill could reverse the depression phenotype of mice of both strains after CUMS, but could not reverse the qi-deficiency phenotype of Balb/c mice.At the protein level, we observed that compared with the depressed mice,the expression of PKA and CREB phosphorylated protein in hippocampus and muscle in the two strains of Yueju pill group was significantly up-regulated. Conclusion In the SD and CUMS depression modols, both Balb/c and 129/S1 mice showed depression-like behaviors, and only Balb/c mice showed qi deficiency syndrome. Yueju pill can reverse the depression-like behavior of the two strains of mice after CUMS, it cannot effectively reverse the syndrome of qi deficiency in Balb/c mice, and the antidepressant effect of Yueju pill is related to the activation of the PKA-CREB signaling pathway.