慢性復(fù)合應(yīng)激對學(xué)習(xí)記憶功能的影響及神經(jīng)顆粒素在其機(jī)制中的作用
發(fā)布時間：2019-06-18 11:51
【摘要】： 應(yīng)激是機(jī)體在內(nèi)外環(huán)境劇變的刺激下所產(chǎn)生的綜合應(yīng)答狀態(tài),包括精神、神經(jīng)、內(nèi)分泌和免疫等方面的反應(yīng)。當(dāng)機(jī)體接受某種應(yīng)激原刺激時,其下丘腦-垂體-腎上腺(Hypothalamus-pituitary-adrenal gland,HPA)軸的興奮性增強(qiáng),腎上腺分泌應(yīng)激激素,使血液中糖皮質(zhì)激素(GC)水平升高,最終產(chǎn)生一系列的非特異性適應(yīng)反應(yīng)。應(yīng)激對機(jī)體的影響取決于應(yīng)激模式、應(yīng)激強(qiáng)度和持續(xù)時間以及機(jī)體的反應(yīng)性等因素。其中,應(yīng)激對認(rèn)知功能的影響更為復(fù)雜。目前,大多數(shù)研究結(jié)果顯示慢性應(yīng)激損傷動物的學(xué)習(xí)和記憶功能,但也有少數(shù)實(shí)驗(yàn)結(jié)果表明慢性應(yīng)激可增強(qiáng)動物的學(xué)習(xí)和記憶功能。 中樞神經(jīng)系統(tǒng)的海馬腦區(qū)富含糖皮質(zhì)激素受體(GR),是中樞GR含量最高的腦區(qū),因而是HPA軸應(yīng)激反應(yīng)的高位調(diào)節(jié)中樞和應(yīng)激激素的主要靶區(qū)。而且,由于海馬的解剖位置和它與多個腦區(qū)之間的纖維聯(lián)系,使得海馬成為學(xué)習(xí)與記憶的重要腦區(qū)。神經(jīng)顆粒素(Neurogranin,Ng)是一種78個氨基酸組成的神經(jīng)元特異性蛋白,主要分布于大腦皮層、海馬和嗅球等腦區(qū)。作為Calpacitin蛋白家族中的一員,它不僅是蛋白激酶C(Protein kinase C, PKC)的天然作用底物,還是突觸后鈣調(diào)蛋白(CaM)結(jié)合蛋白。在生理狀態(tài)下,Ng與CaM結(jié)合成CaM-Ng復(fù)合體,而當(dāng)Ng被PKC磷酸化或被氧化劑氧化或細(xì)胞內(nèi)的Ca2+濃度升高時,Ng與CaM的親和力下降,CaM-Ng復(fù)合體解離,釋放出游離的CaM,從而實(shí)現(xiàn)對CaM及Ca2+/CaM依賴性蛋白激酶和蛋白酶等活性的調(diào)節(jié)。同時,這些酶大多參與長時程增強(qiáng)(LTP)的誘導(dǎo)。LTP是突觸傳遞效能持續(xù)增強(qiáng)的一種表現(xiàn)形式,是突觸可塑性的一個重要功能性指標(biāo),而突觸可塑性則是中樞神經(jīng)系統(tǒng)可塑性這一學(xué)習(xí)和記憶的重要機(jī)制的基礎(chǔ)。因此,Ng可能在學(xué)習(xí)和記憶的神經(jīng)系統(tǒng)可塑性等生理性變化中具有重要作用。 本實(shí)驗(yàn)采用4種應(yīng)激原組成的復(fù)合應(yīng)激,將應(yīng)激時間持續(xù)6周,以模擬現(xiàn)代社會人類面臨的復(fù)雜的生存環(huán)境,如競爭、經(jīng)濟(jì)、人際關(guān)系等所產(chǎn)生的慢性社會心理應(yīng)激,處理實(shí)驗(yàn)動物,制作動物模型,探討慢性復(fù)合應(yīng)激對動物學(xué)習(xí)與記憶功能的影響和Ng在此影響機(jī)制中的作用。實(shí)驗(yàn)將成年雄性Wistar大鼠隨機(jī)分為2組:(1)對照組:平行接受常規(guī)喂養(yǎng),不作任何處理;(2)慢性復(fù)合應(yīng)激組:每天無規(guī)律交替暴露于水池中睡眠剝奪、金屬網(wǎng)籠中捆綁、垂直旋轉(zhuǎn)器垂直旋轉(zhuǎn)、和夜間間歇性光照4種應(yīng)激原組成的復(fù)合應(yīng)激環(huán)境中,持續(xù)6周。觀察慢性復(fù)合應(yīng)激對大鼠體重和行為的影響;應(yīng)激結(jié)束后,用Morris水迷宮測試大鼠的空間學(xué)習(xí)與記憶成績;采用免疫組織化學(xué)方法觀察大鼠海馬各亞區(qū)Ng表達(dá)水平的變化;同時應(yīng)用RT-PCR技術(shù)分析各組大鼠海馬Ng mRNA水平的變化。結(jié)果顯示: 1、慢性復(fù)合應(yīng)激組動物警惕性增高,呈現(xiàn)攻擊性增強(qiáng)的趨勢,且排泄物增多; 2、慢性復(fù)合應(yīng)激組大鼠的體重增長幅度明顯小于對照組(p0.05); 3、Morris水迷宮測試提示,應(yīng)激前兩組大鼠尋找隱蔽平臺的潛伏期無明顯差別,應(yīng)激后慢性復(fù)合應(yīng)激組大鼠的空間學(xué)習(xí)記憶能力(潛伏期:14.19s)明顯好于對照組(潛伏期:18.89s)(p0.05); 4、分析免疫組織化學(xué)實(shí)驗(yàn)結(jié)果,海馬DG區(qū)和CA3區(qū)Ng的蛋白表達(dá)水平明顯高于對照組(p0.05),而兩組海馬CA1區(qū)的Ng的免疫反應(yīng)性無顯著差別; 5、與對照組相比,慢性復(fù)合應(yīng)激組動物的Ng mRNA水平亦明顯上調(diào)。實(shí)驗(yàn)結(jié)果提示,慢性復(fù)合應(yīng)激可增強(qiáng)海馬依賴的學(xué)習(xí)與記憶功能,而Ng蛋白在海馬中的表達(dá)和Ng mRNA轉(zhuǎn)錄水平的增高,則說明Ng參與了該增強(qiáng)機(jī)制。
[Abstract]:Stress is the comprehensive response state of the body under the stimulation of the change of the internal and external environment, including the reaction of the spirit, the nerve, the endocrine and the immunity. The hypothalamic-pituitary-adrenal gland (HPA) of the hypothalamus-pituitary-adrenal gland (HPA) of the body increases the excitability of the shaft of the hypothalamus-pituitary-adrenal gland (HPA), and the adrenal gland secretes the stress hormone to increase the level of the glucocorticoid (GC) in the blood, resulting in a series of non-specific adaptation reactions. The effect of stress on the body depends on the stress pattern, the stress intensity and the duration, and the reactivity of the body. The effect of stress on cognitive function is more complicated. At present, most of the results show that the learning and memory function of the animals with chronic stress damage, but a few experimental results show that the chronic stress can enhance the learning and memory function of the animals. The brain region of the central nervous system is rich in the glucocorticoid receptor (GR), which is the brain region with the highest central GR content, and is thus the high-level regulation center and the stress-induced stress response of the HPA axis stress reaction. In addition, due to the anatomical location of the hippocampus and the fiber connection between it and a plurality of brain regions, the hippocampus becomes a learning and a memory. Neurogranin (Ng) is a neuron-specific protein composed of 78 amino acids, which is mainly distributed in the cerebral cortex and the hippocampus. As a member of the family of Calpacitin, it is not only a natural active substrate of protein kinase C (PKC), or postsynaptic calmodulin (Ca M) Binding protein. In physiological state, Ng and CaM are combined into CaM-Ng complex, and when Ng is phosphorylated by PKC or oxidized by the oxidizing agent or the concentration of Ca 2 + in the cell increases, the affinity of Ng and CaM decreases, and the CaM-Ng complex is dissociated and released. Free CaM for CaM and Ca2 +/ CaM-dependent protein kinases and proteases At the same time, most of these enzymes are involved in long-term potentiation (L The induction of TP is an expression of the continuous enhancement of synaptic transmission, which is an important functional index of the synaptic plasticity, and the plasticity of the synapse is the core of the study and memory of the plasticity of the central nervous system. The foundation of the mechanism. Therefore, Ng may be in physiological changes, such as learning and memory neuroplasticity. The invention has the important effect. The experiment adopts four stress original compound stress, and the stress time is continued for 6 weeks, so as to simulate the complex living environment of the modern society human, such as the chronic social psychological stress caused by the competition, the economy, the human relationship and the like, To study the effect of chronic compound stress on the learning and memory function of animals and (2) the chronic composite stress group: the daily irregular exposure to the sleep deprivation in the pool, the metal mesh cage, The vertical rotation of the vertical rotator and the intermittent illumination at night are composed of four stress sources. The effects of chronic compound stress on body weight and behavior of rats were observed in a complex stress environment. After the stress, the space and memory of the rats were tested by Morris water maze. Changes of the expression level of Ng in each subzone of the horse, and the simultaneous application of RT-PCR to the analysis of each group of rats Hippocampus Ng m The change of RNA level. The results showed that:1. The vigilance of the animals in the chronic compound stress group to increase, to present a trend of aggression enhancement, and to increase the amount of excretion;2. Chronic complex The weight gain of the rats in the combined stress group was obviously small. In the control group (p0.05),3, Morris water maze test suggested that there was no significant difference in the latency of the two groups of rats before the stress, and the spatial learning and memory ability of the rats after the stress (incubation period) : 14.19 s) was better than the control group (incubation period: 18.89 s) (p0.05);4. Analysis of the results of the immunohistochemical study, the protein tables of the hippocampal DG region and the CA3 region Ng. The level of Ng in the CA1 region of the two groups was significantly higher than that in the control group (p0.05). There was no significant difference in reactivity.5. The level of Ng mRNA in the chronic compound stress group was also up-regulated in comparison with the control group. The results suggested that the chronic compound stress could enhance the dependence of the hippocampus.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2006
【分類號】：R33
本文編號：2501466
[Abstract]:Stress is the comprehensive response state of the body under the stimulation of the change of the internal and external environment, including the reaction of the spirit, the nerve, the endocrine and the immunity. The hypothalamic-pituitary-adrenal gland (HPA) of the hypothalamus-pituitary-adrenal gland (HPA) of the body increases the excitability of the shaft of the hypothalamus-pituitary-adrenal gland (HPA), and the adrenal gland secretes the stress hormone to increase the level of the glucocorticoid (GC) in the blood, resulting in a series of non-specific adaptation reactions. The effect of stress on the body depends on the stress pattern, the stress intensity and the duration, and the reactivity of the body. The effect of stress on cognitive function is more complicated. At present, most of the results show that the learning and memory function of the animals with chronic stress damage, but a few experimental results show that the chronic stress can enhance the learning and memory function of the animals. The brain region of the central nervous system is rich in the glucocorticoid receptor (GR), which is the brain region with the highest central GR content, and is thus the high-level regulation center and the stress-induced stress response of the HPA axis stress reaction. In addition, due to the anatomical location of the hippocampus and the fiber connection between it and a plurality of brain regions, the hippocampus becomes a learning and a memory. Neurogranin (Ng) is a neuron-specific protein composed of 78 amino acids, which is mainly distributed in the cerebral cortex and the hippocampus. As a member of the family of Calpacitin, it is not only a natural active substrate of protein kinase C (PKC), or postsynaptic calmodulin (Ca M) Binding protein. In physiological state, Ng and CaM are combined into CaM-Ng complex, and when Ng is phosphorylated by PKC or oxidized by the oxidizing agent or the concentration of Ca 2 + in the cell increases, the affinity of Ng and CaM decreases, and the CaM-Ng complex is dissociated and released. Free CaM for CaM and Ca2 +/ CaM-dependent protein kinases and proteases At the same time, most of these enzymes are involved in long-term potentiation (L The induction of TP is an expression of the continuous enhancement of synaptic transmission, which is an important functional index of the synaptic plasticity, and the plasticity of the synapse is the core of the study and memory of the plasticity of the central nervous system. The foundation of the mechanism. Therefore, Ng may be in physiological changes, such as learning and memory neuroplasticity. The invention has the important effect. The experiment adopts four stress original compound stress, and the stress time is continued for 6 weeks, so as to simulate the complex living environment of the modern society human, such as the chronic social psychological stress caused by the competition, the economy, the human relationship and the like, To study the effect of chronic compound stress on the learning and memory function of animals and (2) the chronic composite stress group: the daily irregular exposure to the sleep deprivation in the pool, the metal mesh cage, The vertical rotation of the vertical rotator and the intermittent illumination at night are composed of four stress sources. The effects of chronic compound stress on body weight and behavior of rats were observed in a complex stress environment. After the stress, the space and memory of the rats were tested by Morris water maze. Changes of the expression level of Ng in each subzone of the horse, and the simultaneous application of RT-PCR to the analysis of each group of rats Hippocampus Ng m The change of RNA level. The results showed that:1. The vigilance of the animals in the chronic compound stress group to increase, to present a trend of aggression enhancement, and to increase the amount of excretion;2. Chronic complex The weight gain of the rats in the combined stress group was obviously small. In the control group (p0.05),3, Morris water maze test suggested that there was no significant difference in the latency of the two groups of rats before the stress, and the spatial learning and memory ability of the rats after the stress (incubation period) : 14.19 s) was better than the control group (incubation period: 18.89 s) (p0.05);4. Analysis of the results of the immunohistochemical study, the protein tables of the hippocampal DG region and the CA3 region Ng. The level of Ng in the CA1 region of the two groups was significantly higher than that in the control group (p0.05). There was no significant difference in reactivity.5. The level of Ng mRNA in the chronic compound stress group was also up-regulated in comparison with the control group. The results suggested that the chronic compound stress could enhance the dependence of the hippocampus.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2006
【分類號】：R33
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