枳菊解郁汤对抑郁模型小鼠行为学的影响及其机制
摘要
本研究采用多因素慢性不可预知应激源(电击足底、拥挤、拥挤+热刺激、冷水刺激、禁水、禁食、通宵照明,21天),建立抑郁动物模型,并给予动物不同剂量中药复方枳菊解郁汤处理。将健康昆明品系小白鼠随机分为对照组,模型组,阳性药物(氟西汀)组,枳菊解郁汤低、中、高剂量组。采用开场实验、悬尾实验和Morris水迷宫实验,检测小鼠自发活动和探究行为、情绪行为变化以及空间学习记忆能力的变化；检测小鼠海马及前脑皮层SOD活性和MDA含量的改变；应用HE染色法从形态学角度观察小鼠海马和前脑皮层神经元的改变；采用免疫组化法检测c-fos在小鼠海马各区和前脑皮层的表达情况,旨在探讨慢性应激对小鼠行为学的影响以及中药复方枳菊解郁汤的抗抑郁作用及其机制。研究结果：
1.与对照组小鼠相比,模型组小鼠穿越格数、直立次数、修饰次数均显著减少,中央格停留时间明显延长,排便粒数显著增多。与模型组小鼠相比,氟西汀组、枳菊解郁汤中剂量小鼠开场行为有显著性差异,高剂量组穿越格数、直立次数、中央格停留时间均有明显差异。
2.与对照组小鼠相比,模型组小鼠悬尾行为中第一次静止不动时间(不动潜伏期)和后4分钟累积不动时间均显著增加。与模型组小鼠相比,氟西汀组小鼠第一次静止不动时间和后4分钟累积不动时间均显著减少,各药物组小鼠的第一次静止不动时间亦都显著减少,中剂量组小鼠后4分钟累积不动时间显著减少。
3.与对照组小鼠相比,模型组小鼠在定位航行实验中寻找平台的逃避潜伏期明显延长,在空间搜索实验中,模型组小鼠在目标象限停留时间明显缩短。与模型组相比,在定位航行实验中氟西汀组、中药中剂量组小鼠的逃避潜伏期均显著缩短,在空间搜索实验中各药物组小鼠在目标象限停留的时间明显延长,在中药复方中剂量组小鼠尤为明显。
4.与对照组小鼠相比,模型组小鼠脑组织SOD活性显著降低、MDA的含量显著增加；与模型组小鼠相比,各药物组小鼠脑内SOD活性明显升高,MDA的含量明显减少。
5.对照组、氟西汀组和枳菊解郁汤中、高剂量组小鼠海马CA1、CA3与DG区神经元数量多,细胞完整,排列整齐,层次紧密,边缘清晰,细胞核染色较深,位于细胞中央。前脑皮层神经元形态规整,染色清晰均一。枳菊解郁汤低剂量组小鼠细胞排列稀疏、松散,数量有所减少,有少量三角形及梭形细胞,细胞间隙大,且染色较浅。
模型组小鼠海马与前脑皮层神经元变形,有的出现萎缩现象,胞核固缩,且细胞数量减少,细胞间隙大,形态不规则,可见较多的三角形及梭形细胞,排列疏松不齐,有中断现象,且细胞淡染,着色不匀。
6.与对照组小鼠相比,模型组小鼠脑海马及前脑皮层c-fos阳性细胞数明显减少,平均目标灰度值明显增大；与模型组小鼠相比,枳菊解郁汤中剂量和高剂量组小鼠海马及前脑皮层c-fos阳性细胞数明显增加,平均目标灰度值明显降低。
研究结论：
1.枳菊解郁汤可明显改善慢性应激致抑郁模型小鼠行为学的改变,表现出一定的抗抑郁作用。
2.枳菊解郁汤可提高慢性应激致抑郁模型小鼠脑内SOD的活性并降低MDA的含量,通过对抗脑组织的脂质过氧化,清除体内超氧自由基,减轻其对神经细胞的损伤而实现抗抑郁效应。
3.枳菊解郁汤可对抗慢性应激致抑郁模型小鼠海马各区和前脑皮层神经元c-fos表达的减少,降低各脑区神经元损伤。枳菊解郁汤具有一定的抗抑郁作用,其机制可能与引起海马和前脑皮层神经元c-fos的表达上调有关。
This study using depression model mice induced by multivariate chronic unpredictable stressors (foot shock, crowding, crowding+hot stimulation, cold water stimulation, water deprivation, food deprivation and all-night lighting, unexpectedly given to mice, one method each day in 21 days), and give the animal different doses of Chinese Medical prescription of Zhijujieyu-tang. Healthy Kunming mice were randomly divided into six groups:the control group, the model group, the positive control (fluoxetine) group, the low, medium and high concentration of Zhijujieyu-tang groups. We examined the spontaneous activity, emotional behavior change and spatial learning memory ability changes in mice by using Open-field、Tail-suspension and Morris water maze tests, and examined the changes of SOD activity and MDA content in hippocampus (HP) and prefrontal cortex (PFC). The changes of morphological structure in HP and PFC of mice brain were observed by HE dye. The expression of c-fos in HP and PFC of mice brain were examined using immunohistochemical method. This study aims to investigate the effects of chronic stress on the behavior in mice and the mechanism of Chinese Medical prescription of Zhijujieyu-tang.
The results of this study are as follows:
1. Compared with the control group mice, the square crossing, rearing and grooming of the model group mice were remarkably decreased, and the central cell residence time and defecation were significantly increased in model group mice. Compared with the model group mice, the behavior of Open-field test in the fluoxetine and medium concentration of Zhijujieyu-tang group mice existed remarkable difference, and the square crossing, rearing and the central cell residence time in the high concentration of Zhijujieyu-tang group mice existed significant variation.
2. Compared with the control group mice, the latency immobility (first immobile time) and immobility time (latter 4 minutes immobile time) of Tail-suspension test were significantly increased in model group mice. Compared with the model group mice, the latency immobility and immobility time were remarkably decreased in fluoxetine group and medium concentration group mice, and the latency immobility were remarkably decreased in the low and high concentration group mice,
3. Compared with the control group mice, the escape latency to find platform of the model group mice were markedly increased, and the resident time in target quadrant remarkable decreased in the model group mice. Compared with the model group mice, the escape latency to find platform of the fluoxetine, medium concentration group of Zhijujieyu-tang mice were remarkably decreased, and the resident time in target quadrant remarkable increased in the different medicinal dosages group mice, the medium concentration group of Zhijujieyu-tang mice was very remarkably.
4. Compared with the control group mice, the SOD activity were significantly decreased, and MDA content were markedly increased in the brain tissue of model group mice. Compared with the model group mice, the SOD activity were markedly increased, and MDA content were significantly decreased in the different medicinal dosages group mice.
5. In the control, fluoxetine, medium and high concentration groups mice of Zhijujieyu-tang, there are lots of neurons in CA1, CA3 areas and Dentate gyrus(DG) area of HP, they arrange tidily, administrative levels is compact. Cell nucleus was dyed deep colour, and located at the center of cells. The neurons in PFC have tidy shape, they arranged orderly, and they are dyed even. In low concentration group mice of Zhijujieyu-tang, the morphological results showed that cells arrange still less, and its number has decreased, they are dyed lightly. Their shape is untidy.
In the model group mice of Zhijujieyu-tang, the nerve cell are irregular in shape, and arrange untidily and laxly in in HP and PFC. The layers decreased obviously. Some cells show putrescence, some swollen. They are dyed uneven.
6. Compared with the control group mice, the number of c-fos positive cells in HP and PFC of the model group mice brain were remarkably decreased, and the average target gray value were significantly increased. Compared with the model group mice, the number of c-fos positive cells in HP and PFC of the medium, high concentration group mice of Zhijujieyu-tang were markedly increased, and the average target gray value were markedly decreased.
Conclusions are as follows:
1. Zhijujieyu-tang could markedly improve the changes of behavior induced by chronic stress in mice. It suggested that it have a certain effects of anti-depression.
2. Zhijujieyu-tang could increase the SOD activity, and decrease MDA content in chronic stress induced-depression model mice brain. With the inhibition of lipid peroxidation and the scavenging of superoxide free radical, so that lighten damage of nerve cell, that may be the one of possible mechanisms of the anti-depression of Zhijujieyu-tang.
3. Zhijujieyu-tang could resist the decrease of c-fos neurons in HP and PFC of depressive model mice brain, and reduce the damage of neuron in different areas of mice brain. The mechanism of antidepressant-like effects of Zhijujieyu-tan may be closely related to the up-regulation of c-fos expression in HP and PFC.
1.与对照组小鼠相比,模型组小鼠穿越格数、直立次数、修饰次数均显著减少,中央格停留时间明显延长,排便粒数显著增多。与模型组小鼠相比,氟西汀组、枳菊解郁汤中剂量小鼠开场行为有显著性差异,高剂量组穿越格数、直立次数、中央格停留时间均有明显差异。
2.与对照组小鼠相比,模型组小鼠悬尾行为中第一次静止不动时间(不动潜伏期)和后4分钟累积不动时间均显著增加。与模型组小鼠相比,氟西汀组小鼠第一次静止不动时间和后4分钟累积不动时间均显著减少,各药物组小鼠的第一次静止不动时间亦都显著减少,中剂量组小鼠后4分钟累积不动时间显著减少。
3.与对照组小鼠相比,模型组小鼠在定位航行实验中寻找平台的逃避潜伏期明显延长,在空间搜索实验中,模型组小鼠在目标象限停留时间明显缩短。与模型组相比,在定位航行实验中氟西汀组、中药中剂量组小鼠的逃避潜伏期均显著缩短,在空间搜索实验中各药物组小鼠在目标象限停留的时间明显延长,在中药复方中剂量组小鼠尤为明显。
4.与对照组小鼠相比,模型组小鼠脑组织SOD活性显著降低、MDA的含量显著增加；与模型组小鼠相比,各药物组小鼠脑内SOD活性明显升高,MDA的含量明显减少。
5.对照组、氟西汀组和枳菊解郁汤中、高剂量组小鼠海马CA1、CA3与DG区神经元数量多,细胞完整,排列整齐,层次紧密,边缘清晰,细胞核染色较深,位于细胞中央。前脑皮层神经元形态规整,染色清晰均一。枳菊解郁汤低剂量组小鼠细胞排列稀疏、松散,数量有所减少,有少量三角形及梭形细胞,细胞间隙大,且染色较浅。
模型组小鼠海马与前脑皮层神经元变形,有的出现萎缩现象,胞核固缩,且细胞数量减少,细胞间隙大,形态不规则,可见较多的三角形及梭形细胞,排列疏松不齐,有中断现象,且细胞淡染,着色不匀。
6.与对照组小鼠相比,模型组小鼠脑海马及前脑皮层c-fos阳性细胞数明显减少,平均目标灰度值明显增大；与模型组小鼠相比,枳菊解郁汤中剂量和高剂量组小鼠海马及前脑皮层c-fos阳性细胞数明显增加,平均目标灰度值明显降低。
研究结论：
1.枳菊解郁汤可明显改善慢性应激致抑郁模型小鼠行为学的改变,表现出一定的抗抑郁作用。
2.枳菊解郁汤可提高慢性应激致抑郁模型小鼠脑内SOD的活性并降低MDA的含量,通过对抗脑组织的脂质过氧化,清除体内超氧自由基,减轻其对神经细胞的损伤而实现抗抑郁效应。
3.枳菊解郁汤可对抗慢性应激致抑郁模型小鼠海马各区和前脑皮层神经元c-fos表达的减少,降低各脑区神经元损伤。枳菊解郁汤具有一定的抗抑郁作用,其机制可能与引起海马和前脑皮层神经元c-fos的表达上调有关。
This study using depression model mice induced by multivariate chronic unpredictable stressors (foot shock, crowding, crowding+hot stimulation, cold water stimulation, water deprivation, food deprivation and all-night lighting, unexpectedly given to mice, one method each day in 21 days), and give the animal different doses of Chinese Medical prescription of Zhijujieyu-tang. Healthy Kunming mice were randomly divided into six groups:the control group, the model group, the positive control (fluoxetine) group, the low, medium and high concentration of Zhijujieyu-tang groups. We examined the spontaneous activity, emotional behavior change and spatial learning memory ability changes in mice by using Open-field、Tail-suspension and Morris water maze tests, and examined the changes of SOD activity and MDA content in hippocampus (HP) and prefrontal cortex (PFC). The changes of morphological structure in HP and PFC of mice brain were observed by HE dye. The expression of c-fos in HP and PFC of mice brain were examined using immunohistochemical method. This study aims to investigate the effects of chronic stress on the behavior in mice and the mechanism of Chinese Medical prescription of Zhijujieyu-tang.
The results of this study are as follows:
1. Compared with the control group mice, the square crossing, rearing and grooming of the model group mice were remarkably decreased, and the central cell residence time and defecation were significantly increased in model group mice. Compared with the model group mice, the behavior of Open-field test in the fluoxetine and medium concentration of Zhijujieyu-tang group mice existed remarkable difference, and the square crossing, rearing and the central cell residence time in the high concentration of Zhijujieyu-tang group mice existed significant variation.
2. Compared with the control group mice, the latency immobility (first immobile time) and immobility time (latter 4 minutes immobile time) of Tail-suspension test were significantly increased in model group mice. Compared with the model group mice, the latency immobility and immobility time were remarkably decreased in fluoxetine group and medium concentration group mice, and the latency immobility were remarkably decreased in the low and high concentration group mice,
3. Compared with the control group mice, the escape latency to find platform of the model group mice were markedly increased, and the resident time in target quadrant remarkable decreased in the model group mice. Compared with the model group mice, the escape latency to find platform of the fluoxetine, medium concentration group of Zhijujieyu-tang mice were remarkably decreased, and the resident time in target quadrant remarkable increased in the different medicinal dosages group mice, the medium concentration group of Zhijujieyu-tang mice was very remarkably.
4. Compared with the control group mice, the SOD activity were significantly decreased, and MDA content were markedly increased in the brain tissue of model group mice. Compared with the model group mice, the SOD activity were markedly increased, and MDA content were significantly decreased in the different medicinal dosages group mice.
5. In the control, fluoxetine, medium and high concentration groups mice of Zhijujieyu-tang, there are lots of neurons in CA1, CA3 areas and Dentate gyrus(DG) area of HP, they arrange tidily, administrative levels is compact. Cell nucleus was dyed deep colour, and located at the center of cells. The neurons in PFC have tidy shape, they arranged orderly, and they are dyed even. In low concentration group mice of Zhijujieyu-tang, the morphological results showed that cells arrange still less, and its number has decreased, they are dyed lightly. Their shape is untidy.
In the model group mice of Zhijujieyu-tang, the nerve cell are irregular in shape, and arrange untidily and laxly in in HP and PFC. The layers decreased obviously. Some cells show putrescence, some swollen. They are dyed uneven.
6. Compared with the control group mice, the number of c-fos positive cells in HP and PFC of the model group mice brain were remarkably decreased, and the average target gray value were significantly increased. Compared with the model group mice, the number of c-fos positive cells in HP and PFC of the medium, high concentration group mice of Zhijujieyu-tang were markedly increased, and the average target gray value were markedly decreased.
Conclusions are as follows:
1. Zhijujieyu-tang could markedly improve the changes of behavior induced by chronic stress in mice. It suggested that it have a certain effects of anti-depression.
2. Zhijujieyu-tang could increase the SOD activity, and decrease MDA content in chronic stress induced-depression model mice brain. With the inhibition of lipid peroxidation and the scavenging of superoxide free radical, so that lighten damage of nerve cell, that may be the one of possible mechanisms of the anti-depression of Zhijujieyu-tang.
3. Zhijujieyu-tang could resist the decrease of c-fos neurons in HP and PFC of depressive model mice brain, and reduce the damage of neuron in different areas of mice brain. The mechanism of antidepressant-like effects of Zhijujieyu-tan may be closely related to the up-regulation of c-fos expression in HP and PFC.
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