REM期睡眠剥夺与药物干预对大鼠认知行为及海马突触可塑性的影响
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摘要
目的通过观察不同程度快速眼动(REM)期睡眠剥夺和恢复及中枢性兴奋药莫达非尼(modafinil)干预后大鼠大鼠认知功能和海马突触可塑性变化,探讨REM期睡眠剥夺引起认知功能下降的机制及改善方法。方法成年雄性SD大鼠随机分为REM期睡眠剥夺组、空白对照组(CC)和环境对照组(TC),REM睡眠剥夺组又分非药物空白对照组(control Group,CG),助溶剂CMC组(CMC), modafinil干预组(modafinil),每组分为剥夺1天(SD1d)、SD3d、SD5d、恢复睡眠6h(RS6h)和RS12h,共5个时间点;采用改良多平台水环境REM期睡眠剥夺法(MMPM)进行REM期睡眠剥夺,利用Y迷宫测定大鼠空间学习记忆能力,运用蛋白质免疫印记(Western Blot)技术对大鼠海马synapsinⅠ蛋白作选择性半定量分析,运用免疫组织化学(IHC)的方法分析大鼠海马CA3区突触素SynapsinⅠ的表达,同时应用电镜技术观察海马CA3区辐射层突触的形态结构变化,观察突触可塑性。结果CC组与TC组的EN及TRT均无明显差别(p>0.05),与CC比较CG组大鼠EN在SD3d、SD5d时明显增加(p<0.05),TRT无变化(p>0.05),在SD1d、SD3d、SD5d时modafinil组与CG组比较EN减少(p<0.05),TRT无差别。免疫组化结果显示与CC组比较各睡眠剥夺时间点海马CA3区synapsinⅠ表达均减少(p<0.05),在SD1d、SD3d和RS6h、RS12h各时间点,modafinil组synapsinⅠ表达比CG组增加(p<0.05),Western Blot结果与之一致。电镜下观察SD1d时,未用药大鼠突触前膜囊泡数量减少,活性区长度减小,突触后致密物变薄,modafinil干预后突触前膜囊泡数量增加,活性区增长,突触后致密物增厚。结论不同程度的REM期睡眠剥夺均会造成认知功能下降,引起大鼠海马CA3区synapsinⅠ表达变化,而莫达非尼可以使睡眠剥夺后synapsinⅠ的表达减少改善,诱导大鼠海马突触可塑性变化,对REM睡眠剥夺后的认知行为下降有改善作用。
Objective To investigate the change of cognition and synaptic plasiticity in rats’hippocampus after various degrees of sleep deprivation and sleep revival and modafinil intervention. Methods All the male SD rats were divided into 3 groups randomly: cage control group (CC), tank control group (TG) and REM sleep deprivation and revival group. REM sleep deprivation group was divided into control group (CG), CMC auxiliary solvent group (CMC) and modafinil administration group (modafinil). Animals in REM sleep deprivation and revival group were sacrificed at the end of 1d, 3d, 5d sleep deprivation periods respectively and at the end of 6h, 12h sleep revival after 5d sleep deprivation. The modified multiple platform method(MMPM)was used to establish sleep deprivation model, The cognitive function was tested by Y-type maze, Western blot technique was specially used to analysis the quantitative level of synapsinⅠinvolved in the hippocampus, immunohistochemistry was used to observe the synapsinⅠexpression and distribution in the CA3 hippocampus, and electron microscope techniques was used to investigate the changes of morphosis in stratum radiatum of CA3 hippocampus. Results There were no statistically significant differences(p>0.05)in error reaction numbers (EN) and total reaction time (TRT) between CC and TC. Compared with CC, EN of CG was increased in SD3d and SD5d (p<0.05), Compared with CG, EN of modafinil group decreased in SD1d, SD3d and SD5d (p<0.05). Compared with CC, synapsinⅠexpressions in every time point was decreased (p<0.05) by immunohistochemistry, Compared with CG, synapsinⅠexpressions in modafinil group were increased in SD1d, SD3d and RS6h (p<0.05), same results were gotten in Western Blot. Under the electron microscope, numbers of synaptic vesicles, active zones in presynaptic membrane and postsynaptic density were decreased compared with control group in SD1d, but by administrating modafinil, numbers of synaptic vesicles, active zones in presynaptic membrane and postsynaptic density were all increased in SD1d. Conclusion Sleep deprivation, no matter mild or severe, both could have adverse effects on cognitive function and synapsinⅠexpression, modafinil may improve the cognitive disorder after sleep deprivation and regulate synaptic plasiticity.
Objective To investigate the change of cognition and synaptic plasiticity in rats’hippocampus after various degrees of sleep deprivation and sleep revival and modafinil intervention. Methods All the male SD rats were divided into 3 groups randomly: cage control group (CC), tank control group (TG) and REM sleep deprivation and revival group. REM sleep deprivation group was divided into control group (CG), CMC auxiliary solvent group (CMC) and modafinil administration group (modafinil). Animals in REM sleep deprivation and revival group were sacrificed at the end of 1d, 3d, 5d sleep deprivation periods respectively and at the end of 6h, 12h sleep revival after 5d sleep deprivation. The modified multiple platform method(MMPM)was used to establish sleep deprivation model, The cognitive function was tested by Y-type maze, Western blot technique was specially used to analysis the quantitative level of synapsinⅠinvolved in the hippocampus, immunohistochemistry was used to observe the synapsinⅠexpression and distribution in the CA3 hippocampus, and electron microscope techniques was used to investigate the changes of morphosis in stratum radiatum of CA3 hippocampus. Results There were no statistically significant differences(p>0.05)in error reaction numbers (EN) and total reaction time (TRT) between CC and TC. Compared with CC, EN of CG was increased in SD3d and SD5d (p<0.05), Compared with CG, EN of modafinil group decreased in SD1d, SD3d and SD5d (p<0.05). Compared with CC, synapsinⅠexpressions in every time point was decreased (p<0.05) by immunohistochemistry, Compared with CG, synapsinⅠexpressions in modafinil group were increased in SD1d, SD3d and RS6h (p<0.05), same results were gotten in Western Blot. Under the electron microscope, numbers of synaptic vesicles, active zones in presynaptic membrane and postsynaptic density were decreased compared with control group in SD1d, but by administrating modafinil, numbers of synaptic vesicles, active zones in presynaptic membrane and postsynaptic density were all increased in SD1d. Conclusion Sleep deprivation, no matter mild or severe, both could have adverse effects on cognitive function and synapsinⅠexpression, modafinil may improve the cognitive disorder after sleep deprivation and regulate synaptic plasiticity.
引文
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