本文選題：杏仁核 + 恐懼記憶消散��； 參考：《華中科技大學(xué)》2015年博士論文

【摘要】：第一部分SKF83959對小鼠恐懼記憶消散的作用及機(jī)制 目的：SKF83959可被視為Gq蛋白偶聯(lián)多巴胺受體的一種激動劑,其已被證明具有抗抑郁、幫助改善帕金森病(Parkinson's disease,PD)動物模型的PD癥狀等多種有益作用。目前為止,尚不清楚SKF83959是否對動物的恐懼記憶消散會產(chǎn)生一定的影響。有鑒于此,我們在此研究了SKF83959對恐懼記憶消散的作用。 方法：采用fear conditioning行為學(xué)實驗方法研究SKF83959對小鼠恐懼記憶消散的影響；應(yīng)用曠場實驗方法研究SKF83959對小鼠自發(fā)活動及基礎(chǔ)焦慮水平的影響;運(yùn)用腦區(qū)套管埋置、腦區(qū)注射給藥方法結(jié)合fear conditioning行為學(xué)實驗方法研究SKF83959促進(jìn)小鼠恐懼記憶消散作用的發(fā)揮是否有賴于杏仁核腦區(qū)磷脂酶C/肌醇三磷酸/鈣離子(phospholipase C/inositol triphosphate/Ca2+, PLC/IP3/Ca2+)信號通路的激活。 結(jié)果：(1)Fear conditioning開始之前SKF83959腹腔注射給藥(每天1次,1mg/kg/day,為期7天)顯著促進(jìn)小鼠恐懼記憶的消散,對恐懼記憶的自發(fā)性恢復(fù)(spontaneous recovery)、續(xù)新(renewal)及復(fù)燃(reinstatement)等現(xiàn)象亦具有顯著的抑制作用：在記憶的自發(fā)性恢復(fù)實驗中,SKF83959可使小鼠的僵直率由60.9±5.1%降至44.2±4.4%(n=7-8/group,p0.05vs vehicle):在記憶的續(xù)新實驗中,SKF83959可使小鼠的僵直率由78.4±3.2%降至67.5±3.2%(n=8-10/group,p0.05vs vehicle)；在記憶的復(fù)燃實驗中,SKF83959可使小鼠的僵直率由95.2±0.7%降至78.3±2.3%(n=10-13/group,p0.01vs vehicle).同樣地,feaur conditioning結(jié)束之后SKF83959腹腔注射給藥(每天1次,1mg/kg/day,為期7天)亦具有上述作用：在記憶的續(xù)新實驗中,SKF83959可使小鼠的僵直率由52.0±7.0%降至28.9±5.4%(n=7/group,p0.05vs vehicle)；在記憶的復(fù)燃實驗中,SKF83959可使小鼠的僵直率由90.9±3.1%降至71.0±7.1%(n=11/group,p0.05vs vehicle).(2)SKF83959腹腔注射給藥(每天1次,1mg/kg/day,為期7天)并不影響小鼠的自發(fā)活動及基礎(chǔ)焦慮水平。(3)SKF83959通過激活杏仁核腦區(qū)的PLC/IP3/Ca2+信號通路促進(jìn)小鼠恐懼記憶的消散。 結(jié)論：SKF83959具有顯著的恐懼記憶消散促進(jìn)作用,這一作用的發(fā)揮有賴于動物杏仁核腦區(qū)PLC/IP3/Ca2+信號通路的激活。 第二部分IGF2對慢性社會挫敗應(yīng)激所致小鼠抑郁樣行為的作用 目的：胰島素樣生長因子2(insulin-like growth factor2,IGF2)是胰島素樣多肽家族(insulin-like peptide family)的重要一員。盡管最近剛有研究指出IGF2具有顯著的抗抑郁作用,不過,對于中樞神經(jīng)系統(tǒng)內(nèi)由IGF2所介導(dǎo)的信號通路在動物抑郁樣行為的產(chǎn)生過程中所起的作用仍有待做進(jìn)一步的挖掘。有鑒于此,我們開展了相關(guān)研究,力爭使我們對中樞神經(jīng)系統(tǒng)內(nèi)由IGF2所介導(dǎo)的信號通路對動物抑郁樣行為的調(diào)控作用有一個更好的認(rèn)識。 方法：建立小鼠慢性社會挫敗應(yīng)激(chronic social defeat stress,CSDS)抑郁模型；利用western blotting實驗方法對慢性社會挫敗應(yīng)激抑郁模型小鼠海馬腦區(qū)IGF2的蛋白表達(dá)水平進(jìn)行檢測;在應(yīng)用shRNA介導(dǎo)的基因干擾技術(shù)對小鼠海馬腦區(qū)的IGF2基因進(jìn)行沉默(knockdown)的基礎(chǔ)上,應(yīng)用強(qiáng)迫游泳行為學(xué)實驗方法及閾下社會挫敗應(yīng)激模式對小鼠在抑郁樣行為及其對不良應(yīng)激的易感性方面所發(fā)生的改變進(jìn)行測定；應(yīng)用腦區(qū)套管埋置及腦區(qū)注射給藥技術(shù)研究海馬腦區(qū)給予外源性IGF2對小鼠強(qiáng)迫游泳行為及CSDS所致小鼠抑郁樣行為的影響。 結(jié)果：(1)接受過CSDS處理的小鼠其海馬腦區(qū)IGF2的蛋白表達(dá)水平與其所表現(xiàn)出的抑郁樣行為的嚴(yán)重程度密切相關(guān)。具有越嚴(yán)重的抑郁樣行為的小鼠其海馬腦區(qū)IGF2的蛋白表達(dá)水平越低。(2)對小鼠海馬腦區(qū)的IGF2基因進(jìn)行沉默可誘發(fā)小鼠抑郁樣行為的產(chǎn)生,這一作用具體表現(xiàn)在：海馬腦區(qū)IGF2基因沉默可使小鼠的強(qiáng)迫游泳不動時間由131±26s增至222±34s(n=13-15/group,p0.05vs control).與此同時,海馬腦區(qū)IGF2基因沉默亦可使小鼠對閾下社會挫敗應(yīng)激的易感性得到顯著增加。在社會接觸行為學(xué)實驗中,海馬腦區(qū)IGF2基因沉默可使小鼠在target階段的社會接觸時間由51.4±8.0s減少為29.5±6.7s(n=11-13/group,p0.05vs control)；在糖水偏好實驗中,海馬腦區(qū)IGF2基因沉默可使小鼠的糖水偏好水平由89.8±2.6%降至71.3±6.4%(n=11-13/group,p0.05vs control).(3)小鼠海馬腦區(qū)給予IGF2具有抗抑郁作用,具體表現(xiàn)在：海馬腦區(qū)急性給予IGF2(2.5ng/side)可顯著減少小鼠的強(qiáng)迫游泳不動時間,具體而言,IGF2可使動物的強(qiáng)迫游泳不動時間由94±11s減少為49±12s(PBS:n=21；IGF2(2.5ng/side):n=14:p0.05vs PBS)；海馬腦區(qū)多次重復(fù)給予IGF2(250ng/side,為期7天)可逆轉(zhuǎn)CSDS所致小鼠抑郁樣行為的產(chǎn)生。在社會接觸行為學(xué)實驗中,IGF2可使CSDS易感鼠在target階段的社會接觸時間由14.6±4.1s增至38.8±5.4s(CSDS susceptible-PBS:n=10；CSDS susceptible-IGF2(250ng/side): n=10；p0.05vs CSDS susceptible-PBS)；在糖水偏好實驗中,IGF2可使CSDS易感鼠的糖水偏好水平由64.2±3.2%增至85.7±3.0%(CSDS susceptible-PBS:n=9；CSDS susceptible-IGF2(250ng/side):n:9；p0.01vs CSDS susceptible-PBS)。IGF2抗抑郁作用的發(fā)揮有賴于海馬腦區(qū)的IGF2受體而非IGF1受體的激活。 結(jié)論：小鼠海馬腦區(qū)由IGF2/IGF2受體所介導(dǎo)的信號通路在小鼠抑郁樣行為的產(chǎn)生過程中扮演重要角色。下調(diào)海馬腦區(qū)IGF2的表達(dá)水平可增加小鼠對應(yīng)激的易感性,相反,小鼠海馬腦區(qū)給予IGF2則可通過激活海馬腦區(qū)內(nèi)的IGF2受體而非IGF1受體產(chǎn)生抗抑郁作用。
[Abstract]:Part one: the effect and mechanism of SKF83959 on mice's fear memory dissipation.
Objective: SKF83959 can be considered as an agonist of the Gq protein coupled dopamine receptor, which has been proved to be antidepressant and helps to improve the PD symptoms of Parkinson's disease (Parkinson's disease, PD) animal models. So far, it is not clear whether SKF83959 will have a certain effect on the dissipation of fear memory in animals. In view of this, we studied the effect of SKF83959 on fear memory dissipation.
Methods: the effect of SKF83959 on the dissipation of fear memory in mice was studied by fear conditioning behavior test, and the effect of SKF83959 on spontaneous activity and basic anxiety level of mice was studied by using open field experiment. The method of using brain area cannula, brain area injection and fear conditioning behavior study method to study SKF8 3959 whether to promote the effect of fear memory dissipation in mice depends on the activation of the signal pathway of the phospholipase C/ inositol three phosphate / calcium ion (phospholipase C/inositol triphosphate/Ca2+, PLC/IP3/Ca2+) in the amygdala brain region.
Results: (1) SKF83959 intraperitoneal injection of SKF83959 before the beginning of conditioning (1 times a day, 1mg/kg/day for 7 days) significantly promoted the dissipation of fear memory in mice, and also had a significant inhibitory effect on the spontaneous recovery of fear memory (spontaneous recovery), continued new (renewal) and reignition (reinstatement) and other phenomena: the spontaneity of memory. In the recovery experiment, SKF83959 can reduce the rigidity of mice from 60.9 + 5.1% to 44.2 + 4.4% (n=7-8/group, p0.05vs vehicle). In the new experiment of memory, SKF83959 can reduce the rigidity of mice from 78.4 + 3.2% to 67.5 + 3.2% (n=8-10/group, p0.05vs vehicle). In memory reburning experiment, SKF83959 can make the rigidity of mice by 95.2 + 0 .7% was reduced to 78.3 + 2.3% (n=10-13/group, p0.01vs vehicle). Similarly, SKF83959 intraperitoneal injection after feaur conditioning (1 times a day, 1mg/kg/day, 7 days) also had the above effect: in the new experiment of memory, SKF83959 could reduce the rigidity of mice from 52 + 7% to 28.9 + 5.4% (n=7/group, p0.05vs vehicle); In the reburning experiment of memory, SKF83959 can reduce the rigidity of mice from 90.9 + 3.1% to 71 + 7.1% (n=11/group, p0.05vs vehicle). (2) SKF83959 intraperitoneal injection (1 times a day, 1mg/kg/day, for 7 days) does not affect the spontaneous activity and basic anxiety level of mice. (3) SKF83959 through the activation of PLC/IP3/Ca2+ signaling pathway in the brain region of the amygdala. Promote the dissipation of fear memory in mice.
Conclusion: SKF83959 plays a significant role in promoting fear memory dissipation, which depends on activation of PLC/IP3/Ca2+ signaling pathway in amygdala brain region.
The second part is the effect of IGF2 on depressive behavior of mice induced by chronic social frustration.
Objective: insulin like growth factor 2 (insulin-like growth FACTOR2, IGF2) is an important member of the insulin like polypeptide family (insulin-like peptide family). Although recent studies have pointed out that IGF2 has a significant antidepressant effect, the signal pathway mediated by IGF2 in the central nervous system is depressive behavior in animals. The role of the production process remains to be further explored. In the light of this, we have carried out a study to make a better understanding of the role of IGF2 mediated signaling pathways in the regulation of animal depressive behavior in the central nervous system.
Methods: the chronic social defeat stress (CSDS) depression model of mice was established, and the protein expression level of IGF2 in the hippocampus of the chronic social frustration stress depression model mice was detected by Western blotting test, and the IGF2 gene of the hippocampus brain region of mice was applied by the shRNA mediated gene interference technique. On the basis of silence (knockdown), the experimental method of forced swimming behavior and the model of subthreshold social frustration stress were used to determine the changes in the behavior of depressive like and the susceptibility to adverse stress in mice. The application of brain area cannula embedding and brain region injection to study the hippocampus of the hippocampus was given to exogenous IGF2. Forced swimming behavior and CSDS induced depressive behavior in mice.
Results: (1) the protein expression level of IGF2 in the hippocampus of mice treated with CSDS was closely related to the severity of the depressive behavior. The lower the protein expression level of IGF2 in the hippocampus of the mice with the more severe depressive behavior was lower. (2) the silence of the IGF2 gene in the hippocampus of the mice could induce mice. The effect of depressive behavior is manifested in the following: IGF2 gene silencing in the hippocampus can increase the time of forced swimming in mice from 131 + 26S to 222 + 34S (n=13-15/group, p0.05vs control). At the same time, the IGF2 gene silencing in the hippocampus can also increase the susceptibility of mice to subthreshold social frustration stress. In the contact behavior experiment, the IGF2 gene silencing in the hippocampus could reduce the social contact time of the mice from 51.4 + 8.0s to 29.5 + 6.7s (n=11-13/group, p0.05vs control) in the target stage. In the sugar water preference experiment, the silencing of IGF2 gene in the hippocampus could reduce the sugar water preference level from 89.8 + 2.6% to 71.3 + 6.4% (n=11-13/group) in the hippocampus. P0.05vs control) (3) (3) the hippocampal brain area of the mice has antidepressant effect, which is manifested in the acute administration of IGF2 (2.5ng/side) in the hippocampus of the hippocampus, which can significantly reduce the time of forced swimming in mice. Specifically, IGF2 can reduce the time of forced swimming of animals from 94 + 11S to 49 + 12s (PBS:n=21; IGF2 (2.5ng/side)): n=14:p0.05 Vs PBS); IGF2 (250ng/side, 7 days) can reverse the production of depressive behavior in mice caused by CSDS in the hippocampus. In social contact behavior experiments, IGF2 can increase the social contact time of CSDS susceptible mice from 14.6 + 4.1s to 38.8 + 5.4s (CSDS susceptible-PBS:n=10). E: n=10; p0.05vs CSDS susceptible-PBS). In the sugar water preference experiment, IGF2 can increase the sugar water preference of CSDS susceptible mice from 64.2 + 3.2% to 85.7 + 3% (CSDS susceptible-PBS:n=9; CSDS susceptible-IGF2 (250ng/side)). The activation of the body is not the IGF1 receptor.
Conclusion: the signal pathway mediated by IGF2/IGF2 receptor in the hippocampus of mice plays an important role in the production of depressive behavior in mice. Down regulation of the expression level of IGF2 in the hippocampus can increase the susceptibility to stress in mice. On the contrary, the IGF2 in the hippocampus of the mice can be activated by activating the IGF2 receptor in the hippocampal brain instead of IGF1. The body produces antidepressant effect.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R749.5

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