本文選題：習(xí)得性無(wú)助 + 大鼠��； 參考：《重慶醫(yī)科大學(xué)》2017年碩士論文

【摘要】：研究背景:抑郁癥(MDD)是一種具有能帶來(lái)巨大危害、自殺率高等特點(diǎn)的常見疾病,是全球衛(wèi)生負(fù)擔(dān)的主要原因。抑郁癥由多種因素致病,其基本分子機(jī)制目前仍不清。盡管已有大量研究探索抑郁癥發(fā)病機(jī)制,提出了多種可能的假說(shuō),但結(jié)論不一,抑郁癥的核心發(fā)病機(jī)制仍無(wú)定論。習(xí)得性無(wú)助(LH)模型是一種較為成熟的抑郁動(dòng)物模型,當(dāng)動(dòng)物重復(fù)置于不可控制且不可預(yù)測(cè)的足底電擊刺激時(shí),會(huì)表現(xiàn)為對(duì)刺激不再逃避的行為。經(jīng)該模型造模后的動(dòng)物顯示出與人類抑郁癥具有高度相似性的行為改變。非靶向代謝組學(xué)是通過(guò)非偏向性測(cè)定組織內(nèi)所有代謝物,通過(guò)識(shí)別疾病和健康兩種狀態(tài)個(gè)體代謝譜差異,而展現(xiàn)其具體機(jī)理。但目前前額葉皮質(zhì)(PFC)代謝譜變化報(bào)道不多。目的:1、采用非靶向的氣相色譜-質(zhì)譜(GC-MS)法,比較LH組與非應(yīng)激對(duì)照(CON)組大鼠PFC代謝分子表達(dá)水平。2、分析LH模型大鼠的差異代謝分子的功能,探討抑郁癥的潛在機(jī)理。方法:1、構(gòu)建LH模型大鼠,經(jīng)慢性足底電擊應(yīng)激造模后,進(jìn)行體重測(cè)量和一系列行為學(xué)測(cè)試。2、采用非靶向的GC-MS方法,測(cè)定10只LH組大鼠及8只CON組大鼠的PFC代謝譜。遴選出LH模型大鼠的差異代謝分子。3、采用IPA對(duì)篩選出的LH模型大鼠的生物標(biāo)志物進(jìn)行通路分析,探討抑郁癥可能的發(fā)病機(jī)制。結(jié)果:1、與CON組相比,LH組大鼠主動(dòng)逃避實(shí)驗(yàn)、糖水偏好實(shí)驗(yàn)、強(qiáng)迫游泳實(shí)驗(yàn)等發(fā)生改變,有統(tǒng)計(jì)學(xué)差異(均p0.05)。而體重稱量、曠場(chǎng)實(shí)驗(yàn)、高架十字迷宮實(shí)驗(yàn)無(wú)差異。提示LH組大鼠有明顯的抑郁表現(xiàn),但無(wú)明顯焦慮表現(xiàn)。2、GC-MS方法發(fā)現(xiàn)兩組PFC組織共有18種差異代謝物,其中9種與氨基酸代謝有關(guān)。3、通過(guò)IPA對(duì)差異代謝物進(jìn)行分子通路和網(wǎng)絡(luò)分析,結(jié)果提示LH組大鼠PFC組織氨基酸代謝出現(xiàn)紊亂,特別是谷氨酸、脯氨酸及甲硫氨酸。此外,脂質(zhì)和葡萄糖代謝亦出現(xiàn)異常。結(jié)論:采用非靶向GC-MS方法,本項(xiàng)目首次探究LH模型大鼠PFC的代謝特征。結(jié)果表明氨基酸代謝,特別是谷氨酸、脯氨酸和甲硫氨酸的紊亂與抑郁癥相關(guān)。
[Abstract]:Background: depression (MDD) is a common disease with the characteristics of great harm and high suicide rate, which is the main cause of global health burden. Depression is caused by many factors, its basic molecular mechanism is still unclear. Although a large number of studies have explored the pathogenesis of depression and put forward a variety of possible hypotheses, there are different conclusions, and the core pathogenesis of depression is still uncertain. The learned helplessness (LH) model is a more mature animal model of depression. When the animal is repeatedly exposed to uncontrollable and unpredictable plantar shock stimulation, it will behave as no longer evading the stimulus. Animals modeled by the model showed highly similar behavioral changes to human depression. Non-target metabonomics measures all metabolites in tissues by non-biases, and reveals the specific mechanism by identifying the difference of individual metabolic spectrum between disease and health. However, there are few reports of metabolic spectrum changes in prefrontal cortex (PFC). Objective to compare the expression level of metabolic molecules of PFC between LH group and control group (Con) by non-targeted gas chromatography-mass spectrometry (GC-MS), and to analyze the function of differentially metabolized molecules in LH model rats, and to explore the potential mechanism of depression. Methods the LH model rats were made by chronic plantar electric shock stress. Body weight measurement and a series of behavioral tests were performed. The PFC metabolic spectra of 10 LH rats and 8 Con rats were measured by non-targeted GC-MS. The differentially metabolized molecules of LH model rats were selected. IPA was used to analyze the biomarkers of LH model rats in order to explore the possible pathogenesis of depression. Results compared with the control group, there were significant changes in the active escape test, sugar water preference test and forced swimming test in LH group compared with those in the Con group (all p0.05). There was no difference in weight weighing, open field test and elevated cross maze test. The results showed that there were 18 different metabolites in PFC tissues of LH group, 9 of which were related to amino acid metabolism. The molecular pathways and networks of differential metabolites were analyzed by IPA. The results suggested that the amino acid metabolism of PFC in LH group was disturbed, especially glutamate, proline and methionine. In addition, lipid and glucose metabolism is also abnormal. Conclusion: the metabolic characteristics of PFC in LH model rats were investigated by non-target GC-MS for the first time. The results showed that disorders of amino acid metabolism, especially glutamate, proline and methionine, were associated with depression.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R749.4

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