研究目的:本研究以运动时间为切入点，比较不同介入时间和持续时间的运动干预对帕金森病（Parkinson’s disease, PD）模型大鼠运动行为功能影响的差异，寻找跑台运动干预防治 PD 的最适运动时间，为 PD 病人的临床康复制定个性化运动干预方案提供实验依据；并从 DA角度阐释运动对PD 运动功能障碍改善的可能机制，为运动疗法在 PD 临床治疗中得到进一步应用提供参考依据。 研究方法：选用清洁级雄性 SD 大鼠并随机将其分为 6 组：假手术安静组（Control）、PD 安静组（PD）、PD预运动组（PD+Pre)，4周PD运动组（PD+4Ex）、6周PD运动组（PD+6Ex）、8周PD运动组（PD+8Ex）。在大鼠的右侧前脑内侧束特定位点（AP:-4.3,R:1.5,H:7.6-7.8），注射药品 6-羟基多巴胺（6-OHDA）建立 PD 大鼠模型，Control 组大鼠在同样的位点注射等量生理盐水。造模后第 7天在大鼠颈部的皮下注射阿扑吗啡（apomorphine ,APO）进行旋转行为测试，30min 内大鼠向健侧旋转圈数的绝对值（向健侧旋转圈数减去向损伤侧旋转圈数）大于 100 转则PD 大鼠造模成功。PD+Pre组在手术前进行跑台运动干预，PD+4Ex组、PD+6Ex组和PD+8Ex组在手术后 24h 进行跑台运动干预；各运动组每次运动干预方案为11m/min，30min/d，5d/Week。PD+Pre组和PD+4Ex组运动干预持续周期为4周，PD+6Ex组和PD+8Ex组分别为6周和8周。运动干预过程中采用遥测心率系统进行运动强度监测，运动干预结束后，利用圆筒试验与网格试验对各组大鼠感觉运动行为功能进行检测，并采用免疫组化和免疫印迹技术对其纹状体TH的表达水平进行检测。 研究结果： 1.APO 诱导旋转试验结果显示，在造模后第 7 天 Control 组大鼠不存在明显旋转现象 ，而PD 模型大鼠的净旋转次数均大于 100 转；PD 大鼠的成模率约为 60%。心率遥测实验结果显示：大鼠在以11m/min的速度进行跑台运动时，平均心率为40117.3 bts/min，属于中等运动强度。 2.圆筒试验结果显示，与 Control 组相比，PD 与各PD运动组大鼠的左侧前肢触壁次数占总次数的比例显著减少（P＜0.01)，PD 组相比，各 PD 运动组大鼠左前肢触壁次数显著增加（P＜0.05，P＜0.05，P＜0.01，P＜0.01），且PD+6Ex和PD+8Ex组大鼠前肢使用不对称情况改善效果最为显著。网格测试结果显示,与 Control 组相比，PD与各 PD运动组大鼠在网格上移动的潜伏期时间显著增长（P＜0.01）；与 PD 组比较，PD+6Ex和PD+8Ex运动组大鼠在网格上移动的潜伏期时间显著减少（P＜0.01，P＜0.01）。 3.免疫组化结果显示，与 Control组相比， PD 与各 PD 运动组大鼠纹状体 TH 表达水平出现非常显著降低（P＜0.01）；与 PD组相比，PD+Pre、PD+4Ex、PD+6Ex 和PD+8Ex组大鼠纹状体 TH 的表达水平显著增加（P＜0.05,P＜0.05, P＜0.01, P＜0.01）。各组大鼠纹状体 TH 免疫印迹检测结果的变化趋势与免疫组化结果一致。 4.相关性分析显示，PD+6Ex 和PD+8Ex组大鼠纹状体 TH 表达水平变化与前肢不对称性之间存在高度相关性（r=0.787，r=0.807）；PD+Pre和PD+4Ex 组大鼠纹状体 TH 表达水平变化与前肢使用不对称性程度存在较低相关性（r=0.752,r=0.741）。PD+6Ex 和PD+8Ex组大鼠纹状体 TH 表达水平变化与移动潜伏期之间均存在高度相关性（r= 0.769，r=0.779 ），PD+Pre和PD+4Ex 组大鼠纹状体 TH 表达水平变化与潜伏期之间存在较低的相关性( r=0.692，r=0.682)。 研究结论： 1.与PD安静组相比，4预运动和术后4周、6周和8周的中等强度跑台运动均可改善 PD 模型大鼠感觉运动功能障碍且随着运动时间的延长干预效果更好。 2.中等强度跑台运动可显著上调纹状体 TH 表达水平且随着运动时间的延长有上升趋势。运动干预改善 PD 大鼠行为能力的神经保护作用和时间效应的机制可能与增强TH表达，保护DA 能神经元有关。 关键词：帕金森模型大鼠，纹状体，多巴胺，运动干预时间，感觉运动功能

THE TIME EFFECT OF EXERCISE INTERVENTION ON DA NEUROPROTECTION IN PARKINSON RATS ABSTRACT Objectives: In this paper, exercise time was taken as the starting point to compare the effects of exercise interventions at different times on the motor function of Parkinson's disease (PD)model rats and to find out the optimal exercise time for PD training. To provide an experimental basis for the development of personalized exercise intervention programs for the clinical rehabilitation of PD patients; and to illustrate the possible mechanisms of exercise improvement for PD motor dysfunction from the perspective of DA, and to provide reference for the further use of exercise therapy in PD clinical treatment. Methods: Clean grade male SD rats were selected then divided randomly into 6 groups: Control group (Con), PD group (PD), PD pre-exercise group (PD+Pre), 4-week exercise PD group (PD+4Ex), 6 weeks exercise PD group (PD+6Ex), 8-week exercise PD group (PD+8Ex). The rat model of PD was established by injecting 6-hydroxydopamine (6-OHDA) into the medial forebrain of the right side of the forebrain injection site（AP:-4.3,R:1.5,H:7.6-7.8）, and rats of the Control group were given the same amount of saline at the same injection site. On the 7th day after modeling, apomorphine was injected into the neck subcutaneously to test the rotation behavior. The number of absolute rotations in the inward direction (minus the number of rotations toward the injury side) was greater than 100 turns after the injection of APO on the 7th day after the rats were modeled. Transferred to determine the success criteria of 6-OHDA toxin induced PD rat model. In the PD pre-exercise group, 4 weeks of treadmill exercise intervention was performed before surgery, PD+4Ex group, PD+6Ex group, and PD+8Ex group were treadmill exercise interventions 24 hours after surgery. The exercise group had a running speed of 11m/min. The frequency is 5day/Week and the exercise time is 30min/day. The exercise intensity monitoring was performed using the telemetry heart rate system during the exercise intervention. After the exercise intervention, the motor behaviors of the rats in each group were detected by the cylinder test and the grid test, and the expression level of TH was examined by immunohistochemistry and Western blot techniques. Result: 1. APO induced rotation test results showed that there was no obvious rotation phenomenon in Control group rats on the 7th day after model establishment, but the net rotation number of PD model rats was greater than 100 rpm; the rate of PD rats was about 60 %.The results of heart rate telemetry experiment showed that the speed of 11m/min was moderate exercise intensity for rats. 2. The results of the cylinder test showed that compared with the Control group, the radio of the number of touches on the left forelimb (damaged forelimb) in the PD and the PD exercise group was significantly decreased (P<0.01), compared with the PD group, the radio of the touching by the left forelimb of the PD exercise group significantly increased (P<0.05, P<0.05, P<0.01, P<0.01), and the improvement effect of the rats in the PD+6Ex and PD+8Ex group was the more significant. The grid test results showed that compared with the Control group, the latency of PD and PD exercise rats on the grid was significantly prolonged (P<0.01); compared with the PD group, The motor latency on the grid of the PD+6Ex and PD+8Ex groups were significantly shorter (P<0.01, P<0.01). 3. Immunohistochemistry results showed that compared with the Control group, TH assay in the PD and PD exercise group rats’ striatum was reduced significantly (P<0.01); compared with the PD group, The expression of TH in the striatum of PD+Pre,PD+4Ex, PD+6Ex and PD+8Ex group rats was increased significantly (P<0.05, P<0.05, P<0.01, P<0.01). The Western blot results showed that the TH of the striatum in each group was consistent with the immunohistochemical results. 4.Correlation analysis showed that there was a high correlation between the change of TH expression in the striatum and the improvement of limb asymmetry between PD+6Ex and PD+8Ex group (r=0.787, r=0.807); The expression of TH in the striatum of PD+Pre and PD+4Ex groups was associated with a lower level of motor performance (r=0.752, r=0.741). There was a high correlation between the expression of TH in the striatum and the improvement of the movement latency in rats of the PD+6Ex and PD+8Ex (r = 0.769, r = 0.779). There was a low correlation of PD + Pre and PD + 4Ex group rats between changes in TH expression levels and changes in motor performance (r=0.692, r=0.682). Conclusion: 1.Compared with PD rats, Pre-exercise and4 weeks,6 weeks and 8 weeks moderate exercise intensity both can improve PD model rats’ sensory motor function and 4 weeks,6 weeks and 8 weeks exercise has time-series characteristics. 2.Moderate treadmill exercise can significantly up-regulate TH expression in striatum, and 4 weeks,6 weeks and 8 weeks exercise has time-series characteristics. The neuroprotection and time effect may be related to the enhancement of TH expression and the protection of DA neurons. Key words: PD model rats ,striatum dopamine, exercise time,Sensorimotor function.