习得性无助模型大鼠前额叶皮质的代谢组学研究

发布时间：2018-07-06 09:51

本文选题：习得性无助 + 大鼠　；参考：《重庆医科大学》2017年硕士论文

【摘要】：研究背景:抑郁症(MDD)是一种具有能带来巨大危害、自杀率高等特点的常见疾病,是全球卫生负担的主要原因。抑郁症由多种因素致病,其基本分子机制目前仍不清。尽管已有大量研究探索抑郁症发病机制,提出了多种可能的假说,但结论不一,抑郁症的核心发病机制仍无定论。习得性无助(LH)模型是一种较为成熟的抑郁动物模型,当动物重复置于不可控制且不可预测的足底电击刺激时,会表现为对刺激不再逃避的行为。经该模型造模后的动物显示出与人类抑郁症具有高度相似性的行为改变。非靶向代谢组学是通过非偏向性测定组织内所有代谢物,通过识别疾病和健康两种状态个体代谢谱差异,而展现其具体机理。但目前前额叶皮质(PFC)代谢谱变化报道不多。目的:1、采用非靶向的气相色谱-质谱(GC-MS)法,比较LH组与非应激对照(CON)组大鼠PFC代谢分子表达水平。2、分析LH模型大鼠的差异代谢分子的功能,探讨抑郁症的潜在机理。方法:1、构建LH模型大鼠,经慢性足底电击应激造模后,进行体重测量和一系列行为学测试。2、采用非靶向的GC-MS方法,测定10只LH组大鼠及8只CON组大鼠的PFC代谢谱。遴选出LH模型大鼠的差异代谢分子。3、采用IPA对筛选出的LH模型大鼠的生物标志物进行通路分析,探讨抑郁症可能的发病机制。结果:1、与CON组相比,LH组大鼠主动逃避实验、糖水偏好实验、强迫游泳实验等发生改变,有统计学差异(均p0.05)。而体重称量、旷场实验、高架十字迷宫实验无差异。提示LH组大鼠有明显的抑郁表现,但无明显焦虑表现。2、GC-MS方法发现两组PFC组织共有18种差异代谢物,其中9种与氨基酸代谢有关。3、通过IPA对差异代谢物进行分子通路和网络分析,结果提示LH组大鼠PFC组织氨基酸代谢出现紊乱,特别是谷氨酸、脯氨酸及甲硫氨酸。此外,脂质和葡萄糖代谢亦出现异常。结论:采用非靶向GC-MS方法,本项目首次探究LH模型大鼠PFC的代谢特征。结果表明氨基酸代谢,特别是谷氨酸、脯氨酸和甲硫氨酸的紊乱与抑郁症相关。
[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.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.4

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