NMDAR2和GLAST在慢性心理应激大鼠海马中的表达及枸杞的调控研究
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摘要
目的通过枸杞调节慢性心理应激大鼠海马组织中谷氨酸受体NMDAR2和谷氨酸转运体GLAST表达水平的测定,探讨枸杞对慢性心理应激大鼠的调节及保护作用,进一步探讨慢性心理应激对大鼠中枢海马损伤的分子机制,同时为开发利用我区的特色中药材——枸杞提供科学理论依据。
方法健康成年SD大鼠96只,雌雄各半,体重为180~220g(由西安交通大学医学院实验动物中心提供)。采用慢性复合应激方法(束缚+噪声)制备大鼠慢性心理应激模型,并且以枸杞作为调节因素。随机分为8组,每组12只。①对照组;②慢性心理应激组;③2.0g/kg枸杞组(枸杞低剂量组);④4.0g/kg枸杞组(枸杞中剂量组);⑤6.0g/kg枸杞组(枸杞高剂量组);⑥2.0g/kg枸杞+应激组(枸杞低剂量+应激组);⑦4.0g/kg枸杞+应激组(枸杞中剂量+应激组);⑧6.0g/kg枸杞+应激组(枸杞高剂量+应激组)。采用组织病理学技术和透射电镜技术观察大鼠中枢海马神经细胞的损伤;利用免疫组织化学技术检测海马谷氨酸受体NMDAR2和谷氨酸转运体GLAST的表达水平;运用放射免疫法测定实验大鼠血清皮质醇的含量;通过旷场实验和悬尾实验观察大鼠的行为学变化。
结果(1)各组实验大鼠海马神经元形态CA3区(HE染色)测定结果:与对照组相比,应激组大鼠CA3区锥体细胞数明显减少(P<0.05),光镜下观察细胞间隙增宽,排列不整齐,细胞与周围组织联系疏松,锥体细胞有肿胀,部分胞核固缩呈三角形或不规则形;电镜下观察神经元细胞核膜不清、固缩,核明显固缩,胞质出现空泡样变性,线粒体嵴断裂;与应激组相比,枸杞低剂量+应激组、枸杞中剂量+应激组和枸杞高剂量+应激组大鼠海马CA3区细胞数量明显增加(P<0.05),光镜下观察锥体细胞形态明显优于应激组,偶有染色质边集、胞核固缩呈三角形;电镜下观察偶见线粒体轻度肿胀,粗面内质网轻度扩张、脱颗粒,细胞膜、核膜皱缩等。(2)海马组织谷氨酸受体NMDAR2表达测定结果:与对照组相比,应激组大鼠海马组织CA1区、CA3区和DG区谷氨酸受体NMDAR2表达均明显增加(P<0.05);与应激组相比,枸杞低剂量+应激组、枸杞中剂量+应激组和枸杞高剂量+应激组大鼠海马组织CA1区、CA3区和DG区谷氨酸受体NMDAR2表达均明显降低(P<0.05)。(3)海马组织谷氨酸转运体GLAST表达测定结果:与对照组相比,应激组大鼠海马组织CA1区、CA3区和DG区谷氨酸转运体GLAST表达均明显增加(P<0.05);与应激组相比,枸杞低剂量+应激组、枸杞中剂量+应激组和枸杞高剂量+应激组大鼠海马组织CA1区、CA3区和DG区谷氨酸转运体GLAST表达均明显降低(P<0.05)。(4)体重、血清皮质醇和行为测定结果:与对照组相比,应激组大鼠实验后体重及体重增长量明显降低(P<0.05),血清皮质醇含量明显升高(P<0.05),中央格停留时间和不动时间明显延长(P<0.05),穿格数、直立次数、修饰时间和挣扎次数明显减少(P<0.05);与应激组相比,枸杞中剂量+应激组大鼠体重增长量明显升高(P<0.05),枸杞中剂量+应激组和枸杞高剂量+应激组血清皮质醇含量明显降低(P<0.05),中央格停留时间和不动时间明显缩短(P<0.05),穿格数、直立次数、修饰时间和挣扎次数明显增加(P<0.05)。同时,枸杞和慢性心理应激对大鼠直立次数、血清皮质醇、海马CA3区锥体细胞数、海马CA1区、CA3区和DG区谷氨酸受体NMDAR2和谷氨酸转运体GLAST的表达均存在交互作用。
结论枸杞能够减缓慢性心理应激大鼠海马神经细胞的损伤,使大鼠海马CA1区、CA3区和DG区谷氨酸受体NMDAR2和谷氨酸转运体GLAST表达水平均明显降低,降低慢性心理应激大鼠的血清皮质醇水平,使慢性心理应激大鼠体重增长量明显增加,改善大鼠抑郁样行为,有效减缓心理应激水平。其可能的作用机制是:慢性心理应激通过HPA-Glu -NMDAR途径,损害海马等脑结构。枸杞能够有效地调节下丘脑-垂体-肾上腺皮质(HPA)轴的适应性和神经内分泌功能,使GCs水平下降,促使NMDAR2和GLAST表达水平下降,减缓慢性心理应激损伤海马,对受损伤的神经元具有一定的保护作用。
Objective Apply Lycium Barbarum L.(LBL.) to adjust the N-methyl-D- aspartate receptor-2 (NMDAR2) and Glumatic Acid Transporter(GLAST) in rats’hippocampal apoptosis under chronic psychologic stress, to study the adjustment and protective effect of Lycium Barbarum L. in rats under chronic psychological stress and the molecule mechenism in rats’hippocampal injury. Then provide the scientifical and theoretical basis for exploiting and taking advantage of the Lycium Barbarum L..
Methods Sprague-Dewley(SD)rats,male and femal is half,weighing 220- 260g.Using chronic multiple stress method (bound+noise) to made chronic psychological stress modle,and take the Lycium Barbarum L.as an adjustment factor. Ninty six rats were randomly divided into eight groups:①control group;②chronic psychologic stress group;③2.0g/Kg Lycium Barbarum L. group(LBL. low dose group);④4.0g/Kg Lycium Barbarum L. group(LBL. middle dose group);⑤6.0g/Kg Lycium Barbarum L. group(LBL. high dose group);⑥2.0g/Kg Lycium Barbarum L.+stress group(LBL. low dose+stress group);⑦4.0g/Kg Lycium Barbarum L.+stress group(LBL. middle dose+stress group);⑧6.0g/Kg Lycium Barbarum L.+stress group(LBL. high dose+stress group). Using the organization pathology technology and the transmission electron microscope technology to observe the damage of hippocampal neurons in rats; Using immunohistochemistry technology to observe expression level of the N-methyl-D-aspartate receptor-2 (NMDAR2)and Glumatic Acid Transporter(GLAST); Using the emission immunity method to test the serum cortisol content of the rats; The behavior was observed by the open-field test and the tail-suspension test.
Results (1) Results of morphology and structure of hippocampal neurons of CA3 area(hematoxylin-eosin): Compare with the control group, the quantity of CA3 area pyramid cells were significantly decreased in chronic psychologic stress group(P<0.05),the space of the cells are widen under the light microscope, the arrangement was ataxia, the pyramidal cells were swelling, some cells were the triangle or the irregular shape; Under the electron microscope, observing some nuclear membrane were not clear, shrinking firmly, some appears the vacuole type denaturation in the nucleus and cytoplasm; Compare with the chronic psychologic stress group, the quantity CA3 area cells were significantly increased in LBL. low dose+stress group,LBL. middle dose+stress group and LBL. high dose+stress group(P<0.05), the pyramidal cell shape were superior to the chronic psychologic stress group obviously under the light microscope, some cells are triangle; Under the electron microscope , the degeneration of the mitochodria and the number of their crista decreased, the karyotheca shrinkage and so on.(2)Results the expression of NMDAR2 in the hippocamp: Compare with the control group, the expression of NMDAR2 in the CA1 area, the CA3 area and DG area of the chronic psychologic stress group increased obviously (P<0.05); Compare with the stress group, the expression of NMDAR2 in the CA1 area, the CA3 area and DG area of LBL. low dose+stress group,LBL. middle dose+stress group and LBL. high dose+stress group decreased obviously (P<0.05).(3)Results of the expression of GLAST in the hippocamp: Compare with the control group, the GLAST expression in the CA1 area, the CA3 area and DG area of the chronic psychologic stress group increased obviously (P<0.05);Compare with the chronic psychologic stress group, the GLAST expression in the CA1 area, the CA3 area and DG area of LBL. low dose+stress group,LBL. middle dose+stress group and LBL. high dose+stress group decreased obviously (P<0.05). (4)The results of the weight, behavior and serum cortisol in rats:Compare with the control group, the weights of the rats in chronic psychologic stress group were significantly decreased(P<0.05), serum cortisol levels was significantly increased(P<0.05), the center dwell time and the still time was significantly increased,the frequency of struggling,straighten and modify time were decreased (P<0.05);Compare with the chronic psychologic stress group, the weight of the rats in LBL. middle dose+stress group significantly increased(P<0.05), the serum cortisol levels of LBL. middle dose+stress group and LBL. high dose+stress group significantly decreased(P<0.05), the center dwell time and the still time were significantly decreased,the frequency of struggling,straighten and modify time were increased (P<0.05). In addition, Lycium Barbarum L. and chronic psychological stress were showed interactions between the frequency of straighten, serum cortisol, the number of hippocampal neurons of CA3 area, the NMDAR2 expression and the GLAST expression in the CA1 area, the CA3 area and DG area.
Conclusion Lycium Barbarum L. can slow down the damage in hippocampal neurons of the rats under the chronic psychological stress, causing the NMDAR2 expression and the GLAST expression in the CA1 area, the CA3 area and DG area decreased.the serum cortisol level of rats decreased in chronic psychological stress, increases the weight of rats in chronic psychological stress obviously, improves the depressed behavior of the rats,slows down the psychological stress level effectively.The possible mechanism is: Chronic psychological stress may damage the hippocampal through HPA-Glu-NMDAR way.The Lycium Barbarum L.could improve the adaptation of HPA axis, reduce the excessive release of cortisol, reduce the NMDAR2 expression and the GLAST expression and regulate the level of psychological stress,and protect the impaired hippocampal neurons.
方法健康成年SD大鼠96只,雌雄各半,体重为180~220g(由西安交通大学医学院实验动物中心提供)。采用慢性复合应激方法(束缚+噪声)制备大鼠慢性心理应激模型,并且以枸杞作为调节因素。随机分为8组,每组12只。①对照组;②慢性心理应激组;③2.0g/kg枸杞组(枸杞低剂量组);④4.0g/kg枸杞组(枸杞中剂量组);⑤6.0g/kg枸杞组(枸杞高剂量组);⑥2.0g/kg枸杞+应激组(枸杞低剂量+应激组);⑦4.0g/kg枸杞+应激组(枸杞中剂量+应激组);⑧6.0g/kg枸杞+应激组(枸杞高剂量+应激组)。采用组织病理学技术和透射电镜技术观察大鼠中枢海马神经细胞的损伤;利用免疫组织化学技术检测海马谷氨酸受体NMDAR2和谷氨酸转运体GLAST的表达水平;运用放射免疫法测定实验大鼠血清皮质醇的含量;通过旷场实验和悬尾实验观察大鼠的行为学变化。
结果(1)各组实验大鼠海马神经元形态CA3区(HE染色)测定结果:与对照组相比,应激组大鼠CA3区锥体细胞数明显减少(P<0.05),光镜下观察细胞间隙增宽,排列不整齐,细胞与周围组织联系疏松,锥体细胞有肿胀,部分胞核固缩呈三角形或不规则形;电镜下观察神经元细胞核膜不清、固缩,核明显固缩,胞质出现空泡样变性,线粒体嵴断裂;与应激组相比,枸杞低剂量+应激组、枸杞中剂量+应激组和枸杞高剂量+应激组大鼠海马CA3区细胞数量明显增加(P<0.05),光镜下观察锥体细胞形态明显优于应激组,偶有染色质边集、胞核固缩呈三角形;电镜下观察偶见线粒体轻度肿胀,粗面内质网轻度扩张、脱颗粒,细胞膜、核膜皱缩等。(2)海马组织谷氨酸受体NMDAR2表达测定结果:与对照组相比,应激组大鼠海马组织CA1区、CA3区和DG区谷氨酸受体NMDAR2表达均明显增加(P<0.05);与应激组相比,枸杞低剂量+应激组、枸杞中剂量+应激组和枸杞高剂量+应激组大鼠海马组织CA1区、CA3区和DG区谷氨酸受体NMDAR2表达均明显降低(P<0.05)。(3)海马组织谷氨酸转运体GLAST表达测定结果:与对照组相比,应激组大鼠海马组织CA1区、CA3区和DG区谷氨酸转运体GLAST表达均明显增加(P<0.05);与应激组相比,枸杞低剂量+应激组、枸杞中剂量+应激组和枸杞高剂量+应激组大鼠海马组织CA1区、CA3区和DG区谷氨酸转运体GLAST表达均明显降低(P<0.05)。(4)体重、血清皮质醇和行为测定结果:与对照组相比,应激组大鼠实验后体重及体重增长量明显降低(P<0.05),血清皮质醇含量明显升高(P<0.05),中央格停留时间和不动时间明显延长(P<0.05),穿格数、直立次数、修饰时间和挣扎次数明显减少(P<0.05);与应激组相比,枸杞中剂量+应激组大鼠体重增长量明显升高(P<0.05),枸杞中剂量+应激组和枸杞高剂量+应激组血清皮质醇含量明显降低(P<0.05),中央格停留时间和不动时间明显缩短(P<0.05),穿格数、直立次数、修饰时间和挣扎次数明显增加(P<0.05)。同时,枸杞和慢性心理应激对大鼠直立次数、血清皮质醇、海马CA3区锥体细胞数、海马CA1区、CA3区和DG区谷氨酸受体NMDAR2和谷氨酸转运体GLAST的表达均存在交互作用。
结论枸杞能够减缓慢性心理应激大鼠海马神经细胞的损伤,使大鼠海马CA1区、CA3区和DG区谷氨酸受体NMDAR2和谷氨酸转运体GLAST表达水平均明显降低,降低慢性心理应激大鼠的血清皮质醇水平,使慢性心理应激大鼠体重增长量明显增加,改善大鼠抑郁样行为,有效减缓心理应激水平。其可能的作用机制是:慢性心理应激通过HPA-Glu -NMDAR途径,损害海马等脑结构。枸杞能够有效地调节下丘脑-垂体-肾上腺皮质(HPA)轴的适应性和神经内分泌功能,使GCs水平下降,促使NMDAR2和GLAST表达水平下降,减缓慢性心理应激损伤海马,对受损伤的神经元具有一定的保护作用。
Objective Apply Lycium Barbarum L.(LBL.) to adjust the N-methyl-D- aspartate receptor-2 (NMDAR2) and Glumatic Acid Transporter(GLAST) in rats’hippocampal apoptosis under chronic psychologic stress, to study the adjustment and protective effect of Lycium Barbarum L. in rats under chronic psychological stress and the molecule mechenism in rats’hippocampal injury. Then provide the scientifical and theoretical basis for exploiting and taking advantage of the Lycium Barbarum L..
Methods Sprague-Dewley(SD)rats,male and femal is half,weighing 220- 260g.Using chronic multiple stress method (bound+noise) to made chronic psychological stress modle,and take the Lycium Barbarum L.as an adjustment factor. Ninty six rats were randomly divided into eight groups:①control group;②chronic psychologic stress group;③2.0g/Kg Lycium Barbarum L. group(LBL. low dose group);④4.0g/Kg Lycium Barbarum L. group(LBL. middle dose group);⑤6.0g/Kg Lycium Barbarum L. group(LBL. high dose group);⑥2.0g/Kg Lycium Barbarum L.+stress group(LBL. low dose+stress group);⑦4.0g/Kg Lycium Barbarum L.+stress group(LBL. middle dose+stress group);⑧6.0g/Kg Lycium Barbarum L.+stress group(LBL. high dose+stress group). Using the organization pathology technology and the transmission electron microscope technology to observe the damage of hippocampal neurons in rats; Using immunohistochemistry technology to observe expression level of the N-methyl-D-aspartate receptor-2 (NMDAR2)and Glumatic Acid Transporter(GLAST); Using the emission immunity method to test the serum cortisol content of the rats; The behavior was observed by the open-field test and the tail-suspension test.
Results (1) Results of morphology and structure of hippocampal neurons of CA3 area(hematoxylin-eosin): Compare with the control group, the quantity of CA3 area pyramid cells were significantly decreased in chronic psychologic stress group(P<0.05),the space of the cells are widen under the light microscope, the arrangement was ataxia, the pyramidal cells were swelling, some cells were the triangle or the irregular shape; Under the electron microscope, observing some nuclear membrane were not clear, shrinking firmly, some appears the vacuole type denaturation in the nucleus and cytoplasm; Compare with the chronic psychologic stress group, the quantity CA3 area cells were significantly increased in LBL. low dose+stress group,LBL. middle dose+stress group and LBL. high dose+stress group(P<0.05), the pyramidal cell shape were superior to the chronic psychologic stress group obviously under the light microscope, some cells are triangle; Under the electron microscope , the degeneration of the mitochodria and the number of their crista decreased, the karyotheca shrinkage and so on.(2)Results the expression of NMDAR2 in the hippocamp: Compare with the control group, the expression of NMDAR2 in the CA1 area, the CA3 area and DG area of the chronic psychologic stress group increased obviously (P<0.05); Compare with the stress group, the expression of NMDAR2 in the CA1 area, the CA3 area and DG area of LBL. low dose+stress group,LBL. middle dose+stress group and LBL. high dose+stress group decreased obviously (P<0.05).(3)Results of the expression of GLAST in the hippocamp: Compare with the control group, the GLAST expression in the CA1 area, the CA3 area and DG area of the chronic psychologic stress group increased obviously (P<0.05);Compare with the chronic psychologic stress group, the GLAST expression in the CA1 area, the CA3 area and DG area of LBL. low dose+stress group,LBL. middle dose+stress group and LBL. high dose+stress group decreased obviously (P<0.05). (4)The results of the weight, behavior and serum cortisol in rats:Compare with the control group, the weights of the rats in chronic psychologic stress group were significantly decreased(P<0.05), serum cortisol levels was significantly increased(P<0.05), the center dwell time and the still time was significantly increased,the frequency of struggling,straighten and modify time were decreased (P<0.05);Compare with the chronic psychologic stress group, the weight of the rats in LBL. middle dose+stress group significantly increased(P<0.05), the serum cortisol levels of LBL. middle dose+stress group and LBL. high dose+stress group significantly decreased(P<0.05), the center dwell time and the still time were significantly decreased,the frequency of struggling,straighten and modify time were increased (P<0.05). In addition, Lycium Barbarum L. and chronic psychological stress were showed interactions between the frequency of straighten, serum cortisol, the number of hippocampal neurons of CA3 area, the NMDAR2 expression and the GLAST expression in the CA1 area, the CA3 area and DG area.
Conclusion Lycium Barbarum L. can slow down the damage in hippocampal neurons of the rats under the chronic psychological stress, causing the NMDAR2 expression and the GLAST expression in the CA1 area, the CA3 area and DG area decreased.the serum cortisol level of rats decreased in chronic psychological stress, increases the weight of rats in chronic psychological stress obviously, improves the depressed behavior of the rats,slows down the psychological stress level effectively.The possible mechanism is: Chronic psychological stress may damage the hippocampal through HPA-Glu-NMDAR way.The Lycium Barbarum L.could improve the adaptation of HPA axis, reduce the excessive release of cortisol, reduce the NMDAR2 expression and the GLAST expression and regulate the level of psychological stress,and protect the impaired hippocampal neurons.
引文
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