本文關(guān)鍵詞： 老年焦慮癥 腦源性神經(jīng)營養(yǎng)因子 γ-氨基丁酸能神經(jīng) 神經(jīng)可塑性　出處：《云南中醫(yī)學(xué)院》2015年碩士論文　論文類型：學(xué)位論文

【摘要】：目的:近年來,老年焦慮癥發(fā)病率與日俱增,成為嚴(yán)重影響老年人健康的疾病。γ-氨基丁酸(γ-aminobutyric acid,GABA)能神經(jīng)是調(diào)節(jié)情緒的主要神經(jīng),其功能障礙可導(dǎo)致焦慮行為的發(fā)生。腦源性神經(jīng)營養(yǎng)因子(brain derived neurotrophic factor,BDNF)參與GABA能神經(jīng)可塑性的調(diào)節(jié),并具有改善焦慮相關(guān)行為的作用,其水平隨著年齡的增長而減少。因此,我們提出假設(shè)老年人隨BDNF的減少,導(dǎo)致GABA能神經(jīng)功能障礙,焦慮易感性增加,補充外源性BDNF可通過調(diào)節(jié)GABA能神經(jīng)可塑性發(fā)揮抗焦慮作用。本實驗將探討B(tài)DNF與GABA能神經(jīng)功能與老年焦慮癥的相關(guān)性,以及通過補充BDNF改善GABA能神經(jīng)可塑性治療老年焦慮癥的可行性與有效性,為開發(fā)老年焦慮癥的治療尋找新的藥物靶點。方法:1.第一部分BDNF缺乏-GABA能神經(jīng)功能障礙-焦慮行為相關(guān)性的研究實驗分3組:3月齡陰性對照組(3Mon)、12月齡陰性對照組(12Mon)、12月齡BDNF-LVsh RNA組(12Mon/KD)。通過齒狀回注射BDNF-LVsh RNA敲低老齡小鼠內(nèi)源性BDNF的表達,以高架十字迷宮法(EPM)研究小鼠焦慮程度,以ELISA檢測小鼠海馬、皮層的GABA和BDNF水平。最后進行行為學(xué)和生化指標(biāo)的相關(guān)性分析,研究BDNF缺乏對老齡小鼠GABA能神經(jīng)功能及焦慮行為的影響。2.第二部分外源性BDNF抗老年焦慮的作用與GABA能神經(jīng)可塑性的相關(guān)性研究實驗分4組:3月齡對照組(3Mon)、12月齡對照組(12Mon)、12月齡BDNF組(12Mon/BDNF)、12月齡氟西汀組(12Mon/FXT)。通過給予老齡小鼠外源性BDNF,以EPM研究小鼠焦慮程度;以跳臺法研究小鼠學(xué)習(xí)記憶能力。以ELISA檢測小鼠海馬、皮層的GABA和BDNF水平,利用Western blot法檢測GABAA-Rα1、α2和α5亞基的表達。最后進行行為學(xué)和生化指標(biāo)的相關(guān)性分析,研究外源性BDNF對12月老齡小鼠GABA神經(jīng)可塑性及焦慮行為的改善作用。結(jié)果:1.BDNF缺乏-GABA能神經(jīng)功能障礙-焦慮行為相關(guān)性的研究1.1在EPM行為檢測中,與3Mon組相比,12Mon組和12Mon/KD組進入開臂次數(shù)的百分比(OE%)有降低趨勢。與12Mon組相比,12Mon/KD組進入開臂時間的百分比(OT%)有降低趨勢。1.2與3Mon組相比,12Mon/KD組的皮層BDNF水平明顯降低,差異有統(tǒng)計學(xué)意義(P0.05);12Mon組和12Mon/KD組的海馬BDNF水平明顯降低,差異有統(tǒng)計學(xué)意義(P0.001;P0.01)。與12Mon組相比,12Mon/KD組海馬、皮層的GABA水平有降低趨勢。1.3相關(guān)性分析結(jié)果表明,小鼠的海馬、皮層中GABA水平、BDNF水平與OT%和OE%存在正相關(guān)性(P0.05);小鼠的海馬、皮層中GABA水平和BDNF水平存在正相關(guān)性(P0.05)。2.外源性BDNF抗老年焦慮的作用與GABA能神經(jīng)可塑性的相關(guān)性研究2.1在EPM行為檢測中,與12Mon組相比,12Mon/BDNF組和12Mon/FXT組的OT%和OE%均明顯升高,差異有統(tǒng)計學(xué)意義(P0.05;P0.01);3Mon組的OE%明顯升高,差異有統(tǒng)計學(xué)意義(P0.01)。在跳臺檢測中,與12Mon組相比,第一天學(xué)習(xí)能力測試,12Mon/BDNF組的錯誤潛伏期明顯升高,差異有統(tǒng)計學(xué)意義(P0.05);第二天記憶能力測試,12Mon/BDNF組的錯誤次數(shù)明顯減少,錯誤潛伏期明顯增長,差異有統(tǒng)計學(xué)意義(P0.01;P0.05)。2.2與12Mon組相比,12Mon/FXT組和12Mon/BDNF組的海馬內(nèi)BDNF水平和GABA水平明顯升高,差異有統(tǒng)計學(xué)意義(P0.05;P0.001);皮層內(nèi)BDNF水平和GABA水平有升高趨勢。2.3與12Mon組相比,12Mon/BDNF組的海馬、皮層GABAA-Rα2和α5亞基表達水平均明顯升高,差異有統(tǒng)計學(xué)意義(P0.05)。與3Mon組相比,12Mon組的海馬GABAA-Rα5亞基表達水平明顯降低,差異有統(tǒng)計學(xué)意義(P0.01)。2.4小鼠海馬、皮層中GABA水平和OT%存在正相關(guān)性(P0.05),小鼠海馬中BDNF水平和OE%存在正相關(guān)性(P0.05);小鼠皮層中BDNF水平和OT%存在正相關(guān)性(P0.05)。小鼠海馬、皮層中GABA水平和BDNF水平存在正相關(guān)性(P0.05)。小鼠海馬、皮層中GABAA-Rα2和α5亞基表達水平與BDNF水平存在正相關(guān)性(P0.05)。結(jié)論:1.敲低內(nèi)源性BDNF m RNA可增加老齡小鼠焦慮行為易感性,其作用機制與BDNF水平降低導(dǎo)致GABA能神經(jīng)功能障礙有關(guān)。2.外源性BDNF可改善老齡小鼠的焦慮行為和學(xué)習(xí)記憶功能,其作用機制與改善腦內(nèi)GABA能神經(jīng)可塑性有關(guān)。3.BDNF可能是治療老年焦慮癥潛在藥物靶點。
[Abstract]:Objective: in recent years, the incidence of anxiety disorder in the elderly grow with each passing day become a serious impact on the health of the elderly, the disease. GABA (gamma -aminobutyric acid, GABA) is the main nerve nerve regulating emotions, its dysfunction can lead to anxiety behavior. Brain derived neurotrophic factor (brain derived, neurotrophic factor, BDNF) participate in GABA can regulate neural plasticity, and can improve the anxiety related behavior, its level decreased with age. Therefore, we propose that the elderly with the decrease of BDNF, GABA can cause nerve dysfunction, anxiety and increased susceptibility to exogenous BDNF can be adjusted by the GABA can exert anti neural plasticity the role of anxiety. This experiment will explore BDNF and GABA correlation of nerve function and anxiety disorder in the elderly, and supplemented by BDNF GABA can improve neural plasticity in treating anxiety disorder in the elderly can Feasibility and effectiveness, for the development of treatment of anxiety disorder in the elderly to find new drug targets. Methods: part 1. BDNF lack of -GABA can experimental study on relativity between anxiety behavior - nerve dysfunction were divided into 3 groups: negative control group (3 month old 3Mon 12 month old), negative control group (12Mon), RNA group (12Mon/KD BDNF-LVsh 12 month old). Through the injection of BDNF-LVsh RNA expression in dentate gyrus of knockdown of endogenous BDNF in aged mice, elevated plus maze method (EPM) on mouse anxiety, detected by ELISA in mouse hippocampus cortex, GABA and BDNF levels. Finally, correlation analysis of behavior and biochemical effects of GABA and BDNF, the lack of research on aging mice GABA can the nerve function and anxiety behavior influence.2. second part of exogenous BDNF anti senile anxiety correlation study of neural plasticity were divided into 4 groups: 3 month old control group (3Mon), 12 month old in the control group (12Mon), December At the age of BDNF group (12Mon/BDNF) and fluoxetine group (12Mon/FXT). 12 month old by exogenous BDNF in aged mice, EPM mice in step-down test anxiety; Study on learning and memory ability of mice. ELISA mice were tested, cortex GABA and BDNF level detection using Western blot GABAA-R alpha 1, alpha 2 expression and the alpha 5 subunit. Finally, correlation analysis and biochemical behavior, improve the effect of exogenous BDNF on December aged mice GABA neural plasticity and anxiety behavior. Results: 1.BDNF -GABA lack of nerve dysfunction and anxiety for research on the relationship between the 1.1 in EPM detection, compared with 3Mon group, 12Mon the percentage of group and 12Mon/KD group of open arm entries (OE%) were decreased. Compared with 12Mon group, 12Mon/KD group the percentage of open arm time (OT%) decreased.1.2 compared with 3Mon group, 12Mon/KD group of cortical BDNF levels Decreased obviously, the difference was statistically significant (P0.05); 12Mon group and 12Mon/KD group, the BDNF level in the hippocampus decreased significantly, the difference was statistically significant (P0.001; P0.01). Compared with 12Mon group, 12Mon/KD group, hippocampus, cortex GABA levels had decreased.1.3 correlation analysis results showed that the mice hippocampus, the level of GABA in cortex the level of BDNF and OT% and OE% (P0.05); there is a positive correlation between the hippocampus of mice, GABA and BDNF level in the cortex (P0.05) there is a positive correlation between.2. and GABA effects of exogenous BDNF anti senile anxiety to neural plasticity related research in 2.1 EPM behavior detection, compared with 12Mon group, 12Mon/BDNF group group 12Mon/FXT and OT% and OE% were significantly increased, the difference was statistically significant (P0.05; P0.01); group 3Mon OE% increased significantly, the difference was statistically significant (P0.01). In the step-down test, compared with the 12Mon group, the first day of learning ability test, 12Mon/BDN F group the error latency was significantly increased, the difference was statistically significant (P0.05); the second day memory test, 12Mon/BDNF group significantly reduced the number of errors, error latency significantly increased, the difference was statistically significant (P0.01; P0.05).2.2 compared with 12Mon group, the levels of BDNF and GABA in hippocampus of 12Mon/FXT group and 12Mon/BDNF group obviously increased, the difference was statistically significant (P0.05; P0.001); the levels of BDNF and GABA in cerebral cortex increased.2.3 compared with 12Mon group, in 12Mon/BDNF group, GABAA-R in cerebral cortex of alpha 2 and alpha 5 subunit expression levels were significantly increased, the difference was statistically significant (P0.05). Compared with 3Mon group, 12Mon group hippocampal GABAA-R alpha 5 subunit expression levels were significantly lower, the difference was statistically significant (P0.01) in hippocampus of mice.2.4, GABA level and OT% cortex (P0.05), there is a positive correlation between the level of BDNF and OE% in the hippocampus of mice has a positive correlation (P0.05); The level of BDNF and OT% in the cortex. There is a positive correlation (P0.05) in hippocampus of mice, GABA and BDNF level in the cortex (P0.05). There was a positive correlation between the mouse hippocampus, cortex GABAA-R alpha 2 and alpha 5 subunit expression level and BDNF level has a positive correlation (P0.05). Conclusion: 1. knockdown of endogenous BDNF m RNA can increase the anxiety behavior in aging mice reduced susceptibility, the mechanism and the level of BDNF GABA can lead to anxiety behavior and learning memory function of neural dysfunction.2. exogenous BDNF can improve the aging mice, its mechanism and improvement of GABA in the brain can neural plasticity may be related to the.3.BDNF treatment of elderly patients with anxiety disorder of potential drug targets.

【學(xué)位授予單位】：云南中醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R749.72

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