目的 探讨运动对出生后多次异氟烷处理不同性别大鼠空间认知功能的影响及其分子学机制。方法 出生后7 d SD大鼠110只,按随机数字表法将大鼠分为正常对照组(n=28)、运动组(n=30)、异氟烷组(n=26)和异氟烷运动组(n=26)。新生大鼠和母鼠单笼饲养,21 d后按雌雄分笼。异氟烷组和异氟烷运动组在生后7、9、11 d进行异氟烷处理。运动组和异氟烷运动组从21 d开始进行规律运动。规律运动6周后,测试雌雄大鼠在八臂迷宮、Morris水迷宫中的表现,随后取大鼠海马组织行免疫组织化学染色及Western Blot分析,测定脑源性神经营养因子(BDNF),Ki-67的阳性表达。结果 各组大鼠在八臂迷宫训练阶段,各组大鼠的总耗时随训练次数增多呈下降趋势,且差异具有统计学意义(P<0.05);组间比较发现:与正常对照组相比,异氟烷组训练次数与总耗时降低趋势的稳定性较差;与非运动组相比,运动两组的下降趋势稳定,总耗时逐渐减少。在八臂迷宫测试阶段,与正常对照组相比,异氟烷组大鼠的参考记忆错误次数增多,总耗时延长,以雌鼠更为明显,差异具有统计学意义(P<0.05);与非运动组雄鼠相比,运动组雄鼠参考记忆错误明显降低(P<0.05);与正常对照组及异氟烷组雄鼠比较:P<0.01,雄鼠运动组总耗时也相应减少,具有显著统计学差异(P<0.05);与异氟烷组雌鼠比较,异氟烷运动雌鼠组总耗时明显缩短(P<0.01)。水迷宫实验中,与正常对照组雌鼠相比,异氟烷组雌鼠目标象限耗时明显减少(P<0.05)。免疫组化结果:与正常对照组相比,异氟烷组大鼠海马组织中BDNF,Ki-67阳性表达明显减少;运动组雄鼠Ki-67阳性表达增多;相比异氟烷组,异氟烷运动组大鼠BDNF阳性表达增多,以雌鼠较为显著(P<0.05)。结论 多次异氟烷处理对大鼠成年后空间认知功能有一定影响,且存在性别差异;雄鼠在长期记忆,而雌鼠在工作记忆方面有一定损害。同时发现,运动促进大鼠空间认知功能的发育,且雄鼠的运动获益更为明显。
Abstract
Objective To investigate the effects of physical activity on spatial cognition and molecular mechanism of postnatal isoflurane exposure in rats of different genders. Methods A total of 110 SD rats were randomly divided into four groups at postnatal 7 days (7 d): group Naive(n=28), Naive+PA(n=30), Iso(n=26) and Iso+PA(n=26). Iso and Iso+PA were exposed to isoflurane for 2 hours in P7, P9 and P11. The rats were separated by genders at 21st day after birth. For groups of Naive+PA and Iso+PA, physical activity was conducted. After 6 weeks, behavioral tests were conducted including radial maze (RAM) and Morris water maze (MWM). After those tests, brain of adult rats was harvested and used to examine the expression of BDNF, Ki-67 by immunohistochemistry and Western blot. Results The total time of each group during the training phase of RAM showed a significant decline with training; compared with group Iso, the performance of adult rats in group Naive was significantly more stable; there was significantly different in PA groups versus non-PA ones. Compared with group Naive, reference memory errors and total time increased in the Iso group, especially in female rats (P<0.05); the reference memory errors of Naive+PA group were significantly less than those of non-PA males (P<0.05); the total time in the PA males was also reduced with a significant difference (group Naive versus Iso in males: P<0.05); Compared with Iso male group, the total time of group Iso+PA became lower significantly (P<0.05). In the water maze test, the duration of target quadrant was significantly reduced in group Iso of females (P<0.05). Compared with group Naive, expressions of BDNF and Ki-67 in the hippocampus of Iso significantly decreased, and expression of Ki-67 increased in the PA male group. Compared with Iso, expression of BDNF in Iso+PA group were higher than group Iso,particularly in females (P<0.05). Conclusions Repeated isoflurane exposure has certain effect on spatial cognition. Spatial memory impairment in males is manifested in long-term memory (reference memory), while females are in short-term memory (working memory). It is also found that physical activity can enhance learning ability and spatial cognitive function,particularly in males.
关键词
运动 /
发育期 /
麻醉药物神经毒性 /
认知 /
性别差异
Key words
physical activity /
postnatal /
anesthesia-induced developmental neurotoxicity /
cognition /
gender difference
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基金
国家自然科学基金(81801884);吴阶平医学基金会临床科研专项资助基金(320.6750.13220)
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