焦虑预处理加重MPTP诱导的急性PD小鼠运动行为损害

Anxiety preconditioning exacerbates motor behavior impairment in mice withMPTP-induced acute Parkinson′s disease

目的探讨焦虑预处理对1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropridine,MPTP)诱导的急性帕金森病(Parkinson disease,PD)模型小鼠运动、情绪和认知的影响。方法将68只13周龄雄性C57BL/6J小鼠随机分为对照组、焦虑预处理组、急性PD模型组、焦虑预处理的急性PD模型组,每组17只,通过旷场实验,高架十字迷宫实验,爬杆试验和水迷宫实验以及黑质-纹状体酪氨酸羟化酶阳性(tyrosine hydroxylase positive,TH+)神经元的变化,探究焦虑预处理对PD小鼠运动、情绪、认知及多巴胺神经元的影响。结果焦虑预处理后第2天高架十字迷宫实验显示,焦虑预处理组开臂进入次数占总进臂次数百分比(percentage entries of open arm entries,OE%)和开臂滞留时间占总进臂时间百分比(percentage time spent on open arms,OT%)少于对照组,急性PD模型组OE%和OT%少于焦虑预处理的急性PD模型组(P<0.05)。焦虑预处理后第6天高架十字迷宫实验显示,4组的OE%和OT%比较差异均无统计学意义(P>0.05)。焦虑预处理后第5天行旷场实验,4组在中心路程百分比、时间百分比、穿格次数百分比比较差异均无统计学意义(P>0.05)。焦虑预处理后第7天爬杆实验显示,与对照组、焦虑预处理组和急性PD模型组比较,焦虑预处理的急性PD模型组爬杆时间增加(P<0.05)。焦虑预处理后第8~13天水迷宫实验显示,与对照组和焦虑预处理组比较,焦虑预处理的急性PD模型组的小鼠的寻台潜伏期较长,目标平台象限的滞留时间短,运动路程较长,穿越平台次数较长(P<0.05)。急性PD模型组和焦虑预处理的急性PD模型组黑质TH+神经元数少于对照组和焦虑预处理组,差异有统计学意义(P<0.05)。焦虑预处理的急性PD模型组黑质TH+神经元数与急性PD模型组比较差异无统计学意义(P>0.05)。急性PD模型组的纹状体TH+神经元的平均光密度值(mean optical density,MOD)值低于对照组,焦虑预处理的急性PD模型组低于焦虑预处理组(P<0.05)。结论焦虑预处理可能在一定程度上损害MPTP诱导的急性PD模型的纹状体多巴胺能神经元,并可加重小鼠运动功能损害。

Objective To investigate the impact of anxiety preconditioning on movement,emotion and cognition in an1-methyl-4-phenyl-1,2,3,6-tetrahydropridine(MPTP)-induced Parkinson′s disease(PD)mice model.Methods Sixty-eight healthy male C57BL/6J mice(aged 13 weeks)were randomly divided into 4 groups:control group(n=17),anxiety preconditioning group(n=17),acute PD model group(n=17),and acute PD model with anxiety preconditioning group(n=17).Based on open field test,elevated plus maze test,pole climbing test,water maze test and changes of tyrosine hydroxylase positive(TH+)neurons in the nigra-striatum,the effects of anxiety preconditioning on motor,emotion and cognition and dopaminergic neurons of PD mice were investigated.Results On the 2nd day after anxiety preconditioning,the elevated plus maze test showed that the percentage of open arm entries(OE%)and open arm retention time(OT%)in the anxiety preconditioning group were lower than those in the control group.The OE%and OT%in the acute PD model group were lower than those in the acute PD model with anxiety preconditioning group(P<0.05).On the 6th day after anxiety preconditioning,the elevated plus maze test showed no statistically significant difference in OE%and OT%among the four groups(P>0.05).On the 5th day after anxiety preconditioning,an open field test was conducted,and there was no significant difference in the percentage of center distance,time,and number of grid crossings among the four groups(P>0.05).On the 7th day after anxiety preconditioning,the pole climbing test showed that compared with the control group,anxiety preconditioning group,and acute PD model group,the pole climbing time of the acute PD model with anxiety preconditioning group increased(P<0.05).On the 8th to 13th day after anxiety preconditioning,the water maze test showed that compared with the control group and anxiety preconditioning group,the mice in the acute PD model with anxiety preconditioning group had a longer latency for seeking the platform,a shorter retention time in the target platform quadrant,a longer exercise distance,and a larger number of platform crossings(P<0.05).The number of TH+neurons in the substantia nigra of the acute PD model group and the acute PD model with anxiety preconditioning group was lower than that of the control group and the anxiety preconditioning group,and the difference was statistically significant(P<0.05).There was no statistically significant difference in the number of TH+neurons in the substantia nigra between the acute PD model with anxiety preconditioning group and the acute PD model group(P>0.05).The mean optical density(MOD)of TH+neurons in the striatum of the acute PD model group was lower than that of the control group,and lower in the acute PD model with anxiety preconditioning group than in the anxiety preconditioning group(P<0.05).Conclusion Anxiety preconditioning could probably to some extent damage striatum dopaminergic neurons and aggravate the damage of the motor function in MPTP-induced acute PD mice.