急慢性应激对小鼠自发行为和空间学习记忆功能的影响及其机制
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摘要
本研究分别采用单因素急性应激动物模型(足底电击)和多因素慢性不可预知应激动物模型(拥挤、冷/热刺激、白噪声、高台、足底电击,28天),研究了急、慢性应激条件下小鼠自发行为和空间学习记忆能力的变化及其脑内c-fos表达的变化情况。旨在探讨不同应激条件对小鼠自发行为和空间学习记忆能力的影响及其作用机制。以开场实验检测小鼠新异环境下的自发行为；采用Morris水迷宫测试小鼠的空间学习记忆能力；以酶联免疫法测定小鼠血清皮质酮含量,通过HE染色观察小鼠海马、前脑皮层及下丘脑室旁核神经元的形态学变化；并运用免疫组织化学方法检测小鼠海马、前脑皮层和下丘脑室旁核的c-fos表达。
研究结果如下：
1.急性应激后,与对照组小鼠比较,应激组小鼠的水平穿越格数、直立次数、粪便粒数均明显减少,中央格停留时间显著延长,但修饰次数无显著变化；慢性应激后,与对照组小鼠比较,应激组小鼠的水平穿越格数、直立次数、修饰次数均明显减少,中央格停留时间显著延长,粪便粒数明显增多。
2.急性应激后,与对照组小鼠比较,应激组小鼠寻找平台的逃避潜伏期明显缩短,且在空间搜索实验中,其在目标象限停留时间明显延长；慢性应激后,与对照组小鼠比较,应激组小鼠寻找平台的逃避潜伏期明显延长,且在空间搜索实验中,其在目标象限停留时间明显缩短。
3.急、慢性应激后,与对照组小鼠比较,应激组小鼠血清皮质酮含量均明显增加,但急性应激增加的程度更强。
4.急性应激后,与对照组小鼠比较,应激组小鼠的神经元形态结构没有明显变化；慢性应激后,与对照组小鼠比较,应激组小鼠海马、前脑皮层及下丘脑室旁核神经元数量明显减少,细胞萎缩变性,呈现不同程度的损伤现象。
5.急性应激后,与对照组小鼠比较,应激组小鼠海马、前脑皮层及下丘脑室旁核c-fos阳性细胞数明显增多,平均目标灰度值明显降低；慢性应激后,与对照组小鼠比较,应激组小鼠海马、前脑皮层及下丘脑室旁核c-fos阳性细胞数明显减少,平均目标灰度值明显增高。
研究结论如下：
1.急、慢性应激均减少小鼠的开场行为活动,但在慢性应激条件下更为明显。
2.急性应激明显增强小鼠的空间学习记忆能力；慢性应激则明显损害小鼠的空间学习记忆能力。
3.急性应激对小鼠神经元形态结构无明显影响；慢性应激则导致小鼠海马、前脑皮层和下丘脑室旁核神经元发生明显的形态学变化。
4.急性应激可使小鼠海马、前脑皮层及下丘脑室旁核c-fos表达明显上调；慢性应激则使小鼠海马区、前脑皮层及下丘脑室旁核神经元中c-fos表达明显下调。
研究结果表明,急性应激导致小鼠自发行为和空间学习记忆能力的变化可能与与血清皮质酮的急剧上升及脑海马、前脑皮层和下丘脑室旁核c-fos的大量表达有关；而慢性应激导致小鼠自发行为抑制和空间学习记忆能力受损亦可能与长期高水平皮质酮,脑海马、前脑皮层和下丘脑室旁核神经元的损害及c-fos表达的明显下调密切相关。
This study using animal model of single-factor acute stress (foot shock) and multivariate chronic unpredictable stress (crowding, cold/hot stimulation, flat noise, hathpace, foot shock, 28days), we examined the spontaneous behavior and the changes of spatial learning memory ability in mice, and the changes of the expression of c-fos in the brain. This study aims to investigate the effects of acute and chronic stress on the spontaneous behavior and ability of spatial learning-memory in mice and its mechanism. In the present study, we examined the spontaneous behavior of mice in new environment using open field test, and the ability of spatial learning memory of mice using Morris water maze; The corticosterone levels in blood serum of mice were measured using ELISA. the morphologic changes in hippocampus (HP)、prefrontal cortex (PFC) and Hypothalamic paraventricular nucleus (PVN) of brain were observed using HE dye, and the expression of c-fos in HP、PFC and PVN of mice brain were examined using immunohistochemical method.
The results of this study are as follows:
1. After acute stress, compared with the control group mice, the square crossing, rearing and defecation of the stress mice were remarkably decreased, and the central cell residence time was significantly increased; after chronic stress, compared with the control group mice, the square crossing, rearing and grooming of the stress mice were remarkably decreased, the central cell residence time and defecation were significantly increased.
2. After acute stress, compared with the control group mice, the escape latency to find platform of the stress group mice were markedly decreased, and in the space exploration test, the resident time in target quadrant remarkable increased in the stress group mice. After the chronic stress, compared with the control group mice, the escape latency to find platform of the stress group mice were significantly increased, and in the space exploration test, the swimming time in target quadrant remarkably decreased.
3. After acute and chronic stress, compared with the control group mice, the corticosterone levels of the stress group were remarkably increased, and that the corticosterone levels in acute stress mice the increased was stronger.
4. After acute stress, compared with the control group mice, there was no remarkable change in the neuron morphology of the stress group mice. After chronic stress, compared with the control group mice, the number of neurons in HP、PFC and hypothalamic PVN of the stress group mice brain were observably decreased, and cells shrivel and degeneration in theirs, showed varying degrees of damage.
5. After acute stress, compared with the control group mice, the number of positive cells in HP、PFC and hypothalamic PVN of the stress group mice brain were remarkably increased, and the average target gray value was significantly decreased. After chronic stress, compared with the control group mice, the number of positive cells in HP、PFC and hypothalamic PVN of the stress group mice brain were remarkably decreased, and the average target gray value was remarkably increased.
Conclusion:
1. The acute and chronic stress different treatments reduced the spontaneous behavior of mice in open field test, and it is more evident under conditions of chronic stress.
2. The acute stress treatments can prominently enhance the spatial learning-memory ability of mice; and the chronic stress can significantly damage the spatial learning-memory ability of mice.
3. The acute stress treatments has no significant effect on neuronal morphology of mice; and the chronic stress cause obvious morphological changes of neurons in HP、PFC and hypothalamic PVN of mice brain.
4. The acute stress treatments cause obvious increase of c-fos expression in HP、PFC and hypothalamic PVN of mice brain. The chronic stress induce obvious reduction of c-fos expression in HP、PFC and hypothalamic PVN of mice brain.
In the present study, the results suggested that the decrease of the spontaneous behavior and the increase of the spatial learning-memory ability of mice caused by acute stress, and it may be related to the rapid rise of the serum corticosterone and a large number of c-fos expression in HP、PFC and hypothalamic PVN of mice brain. The spontaneous behavioral inhibition and the spatial learning and memory impairment caused by chronic stress may be related to the damage of HP、PFC and hypothalamic PVN neurons in long-time high level corticosterone and the obvious reduction of c-fos expression.
研究结果如下：
1.急性应激后,与对照组小鼠比较,应激组小鼠的水平穿越格数、直立次数、粪便粒数均明显减少,中央格停留时间显著延长,但修饰次数无显著变化；慢性应激后,与对照组小鼠比较,应激组小鼠的水平穿越格数、直立次数、修饰次数均明显减少,中央格停留时间显著延长,粪便粒数明显增多。
2.急性应激后,与对照组小鼠比较,应激组小鼠寻找平台的逃避潜伏期明显缩短,且在空间搜索实验中,其在目标象限停留时间明显延长；慢性应激后,与对照组小鼠比较,应激组小鼠寻找平台的逃避潜伏期明显延长,且在空间搜索实验中,其在目标象限停留时间明显缩短。
3.急、慢性应激后,与对照组小鼠比较,应激组小鼠血清皮质酮含量均明显增加,但急性应激增加的程度更强。
4.急性应激后,与对照组小鼠比较,应激组小鼠的神经元形态结构没有明显变化；慢性应激后,与对照组小鼠比较,应激组小鼠海马、前脑皮层及下丘脑室旁核神经元数量明显减少,细胞萎缩变性,呈现不同程度的损伤现象。
5.急性应激后,与对照组小鼠比较,应激组小鼠海马、前脑皮层及下丘脑室旁核c-fos阳性细胞数明显增多,平均目标灰度值明显降低；慢性应激后,与对照组小鼠比较,应激组小鼠海马、前脑皮层及下丘脑室旁核c-fos阳性细胞数明显减少,平均目标灰度值明显增高。
研究结论如下：
1.急、慢性应激均减少小鼠的开场行为活动,但在慢性应激条件下更为明显。
2.急性应激明显增强小鼠的空间学习记忆能力；慢性应激则明显损害小鼠的空间学习记忆能力。
3.急性应激对小鼠神经元形态结构无明显影响；慢性应激则导致小鼠海马、前脑皮层和下丘脑室旁核神经元发生明显的形态学变化。
4.急性应激可使小鼠海马、前脑皮层及下丘脑室旁核c-fos表达明显上调；慢性应激则使小鼠海马区、前脑皮层及下丘脑室旁核神经元中c-fos表达明显下调。
研究结果表明,急性应激导致小鼠自发行为和空间学习记忆能力的变化可能与与血清皮质酮的急剧上升及脑海马、前脑皮层和下丘脑室旁核c-fos的大量表达有关；而慢性应激导致小鼠自发行为抑制和空间学习记忆能力受损亦可能与长期高水平皮质酮,脑海马、前脑皮层和下丘脑室旁核神经元的损害及c-fos表达的明显下调密切相关。
This study using animal model of single-factor acute stress (foot shock) and multivariate chronic unpredictable stress (crowding, cold/hot stimulation, flat noise, hathpace, foot shock, 28days), we examined the spontaneous behavior and the changes of spatial learning memory ability in mice, and the changes of the expression of c-fos in the brain. This study aims to investigate the effects of acute and chronic stress on the spontaneous behavior and ability of spatial learning-memory in mice and its mechanism. In the present study, we examined the spontaneous behavior of mice in new environment using open field test, and the ability of spatial learning memory of mice using Morris water maze; The corticosterone levels in blood serum of mice were measured using ELISA. the morphologic changes in hippocampus (HP)、prefrontal cortex (PFC) and Hypothalamic paraventricular nucleus (PVN) of brain were observed using HE dye, and the expression of c-fos in HP、PFC and PVN of mice brain were examined using immunohistochemical method.
The results of this study are as follows:
1. After acute stress, compared with the control group mice, the square crossing, rearing and defecation of the stress mice were remarkably decreased, and the central cell residence time was significantly increased; after chronic stress, compared with the control group mice, the square crossing, rearing and grooming of the stress mice were remarkably decreased, the central cell residence time and defecation were significantly increased.
2. After acute stress, compared with the control group mice, the escape latency to find platform of the stress group mice were markedly decreased, and in the space exploration test, the resident time in target quadrant remarkable increased in the stress group mice. After the chronic stress, compared with the control group mice, the escape latency to find platform of the stress group mice were significantly increased, and in the space exploration test, the swimming time in target quadrant remarkably decreased.
3. After acute and chronic stress, compared with the control group mice, the corticosterone levels of the stress group were remarkably increased, and that the corticosterone levels in acute stress mice the increased was stronger.
4. After acute stress, compared with the control group mice, there was no remarkable change in the neuron morphology of the stress group mice. After chronic stress, compared with the control group mice, the number of neurons in HP、PFC and hypothalamic PVN of the stress group mice brain were observably decreased, and cells shrivel and degeneration in theirs, showed varying degrees of damage.
5. After acute stress, compared with the control group mice, the number of positive cells in HP、PFC and hypothalamic PVN of the stress group mice brain were remarkably increased, and the average target gray value was significantly decreased. After chronic stress, compared with the control group mice, the number of positive cells in HP、PFC and hypothalamic PVN of the stress group mice brain were remarkably decreased, and the average target gray value was remarkably increased.
Conclusion:
1. The acute and chronic stress different treatments reduced the spontaneous behavior of mice in open field test, and it is more evident under conditions of chronic stress.
2. The acute stress treatments can prominently enhance the spatial learning-memory ability of mice; and the chronic stress can significantly damage the spatial learning-memory ability of mice.
3. The acute stress treatments has no significant effect on neuronal morphology of mice; and the chronic stress cause obvious morphological changes of neurons in HP、PFC and hypothalamic PVN of mice brain.
4. The acute stress treatments cause obvious increase of c-fos expression in HP、PFC and hypothalamic PVN of mice brain. The chronic stress induce obvious reduction of c-fos expression in HP、PFC and hypothalamic PVN of mice brain.
In the present study, the results suggested that the decrease of the spontaneous behavior and the increase of the spatial learning-memory ability of mice caused by acute stress, and it may be related to the rapid rise of the serum corticosterone and a large number of c-fos expression in HP、PFC and hypothalamic PVN of mice brain. The spontaneous behavioral inhibition and the spatial learning and memory impairment caused by chronic stress may be related to the damage of HP、PFC and hypothalamic PVN neurons in long-time high level corticosterone and the obvious reduction of c-fos expression.
引文
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