| 摘要 | 抑郁症（Major Depressive Disorder, MDD）是一种以显著、持久的情绪低 落为主要临床特征的常见情感类精神疾病，在严重危害病人身心健康的同时也 给家庭和社会带来了极大的心理压力和经济负担。尽管大量的科学研究探索了 抑郁症的发病机制，并提出来了各种机制假说，但抑郁症一个明确的发病机制 尚不清楚，进而使得市面上大多抗抑郁药存在疗效有限且不良反应多的现象。 为了进一步探索不同抑郁症亚型的内在机制，可以通过分析抑郁症在特定动物 模型中表现出的一些核心症状来模拟人类抑郁发生发展，并据此用来进行抗抑郁药评估和筛选。
因此在本课题中，我们通过慢性社交挫败应激模型（Chronic Social Defeat Stress Model, CSDS）来构建抑郁模型，采用动物行为学方法来研究慢性社交 挫败应激下所产生的抑郁样行为以及膜脂对小鼠抑郁样行为的影响。为深入研究膜质调控与抑郁症的关系，开发创新型抗抑郁药物，我们通过代谢组学分析 技术，采用定量脂质组学技术检测海马脂质成分的变化，找到有重要生物学意义和统计学显著差异的脂质，进一步探究膜脂类化合物及相关代谢途径对小鼠 抑郁样行为影响的分子机制。
我们发现慢性社交挫败应激下小鼠表现出快感缺失、行为绝望和社交回避等抑郁样行为，喂食磷脂酰丝氨酸（Phosphatidylserine, PS）和鞘磷脂（Sphingomyelin, SM）可以逆转社交挫败小鼠类似抑郁样的行为。定量脂质组学分析显 示 BMP（16:0/20:2）、PI（14:0/18:1）和 TAG（49:0）_FA17:0 在 CSDS 小鼠中 显著上调，然而喂食 PS 和 SM 又能逆转 BMP（16:0/20:2）、PI（14:0/18:1）和 T AG（49:0）_FA17:0 在海马中的变化，提示体内半单磷酸甘油酯（Bis（monoac ylglycero）phosphate, BMP）、磷脂酰肌醇（Phosphatidylinositol, PI）等甘油磷脂 类和甘油三酯（Triacylglycerol, TAG）等甘油酯类代谢的紊乱可能影响着抑郁的 发生和发展。进一步分析发现海马内神经酰胺（Ceramide, Cer）系统可能在抑 郁症中扮演重要角色，低水平的 Cer 具有营养和保护作用，Cer 及相关酶所参与 的生物学过程也可能是抑郁症的一个重要发病机制。此外我们也找到显著差异 代谢物 TAG、磷脂酰胆碱（Phosphatidylcholine, PC）和甘油二酯（Diacylglycerol, DAG）所富集的癌症中胆碱代谢、脂肪消化和吸收以及脂肪细胞中脂肪分解 调节等代谢通路的改变。这些发现不仅有助于深入理解抑郁症的致病机制，而 且也提示体内脂质化合物可能成为抑郁症潜在的诊断和预后标记物，以及抗 抑郁药的潜在治疗靶点，为开发靶向脂质及脂质代谢的抗抑郁药物提供新思路。 |
| 其他摘要 | Major Depressive Disorder (MDD) is a common affective psychiatric disorder characterized by significant and persistent depressed mood, which seriously jeopardizes the physical and mental health of patients and also brings great psychological pressure and economic burden to families and society. Although a large number of scientific studies have explored the pathogenesis of depression and proposed various mechanism hypotheses, a clear pathogenesis of depression is still unclear, which in turn makes most antidepressants on the market have limited efficacy and many adverse effects. In order to further explore the underlying mechanisms of different depression subtypes, human depression can be simulated by analyzing some core symptoms of depression in specific animal models, and accordingly used for antidepressant evaluation and screening.
Therefore, in this study, we constructed a depression model by using the Chronic Social Defeat Stress Model (CSDS), and adopted animal behavioral methods to study the depression-like behaviors under chronic social defeat stress and the effects of mem brane lipids on depression-like behaviors in mice. In order to investigate the relationship between membrane lipid regulation and depression and to develop innovative amide pressant drugs, we used quantitative lipid omics to detect the changes in hippocampal 1ipid composition through metabolomics analysis, to find biologically significant and statistically significant differences in lipids, and to further investigate the molecular mechanism of the effects of membrane lipids and related metabolic pathways on the depressive behaviors of mice.
We found that mice under chronic social defeat stress exhibited depressive-like behaviors such as pleasure deficit, behavioral despair, and social avoidance, and that feeding phosphatidylserine (PS) and sphingomyelin (SM) reversed the depression-like behaviors in socially defeated mice. Quantitative lipidomic analysis revealed that BMP (16:0/20:2), PI (14:0/18:1) and TAG (49:0)_ FA17:0 were significantly up-regulated in CSDS mice, yet feeding PS and SM reversed BMP (16:0/20:2), PI (14:0/18:1) and TAG (49:0)_ FA17:0 changes in the hippocampus. changes in the hippocampus, suggesting that in vivo disturbances in the metabolism of glycerophospholipids such as Bis (monoacylglycero)phosphate (BMP), phosphatidylinositol (PI), and glycerides such as triacylglycerol (TAG) might influence the the onset and development of depression. Further analysis revealed that the Ceramide (Cer) system in the hippocampus may play an important role in depression, and that low levels of Cer have trophic and protective effects, and that the biological processes in which Cer and related enzymes are involved may also be an important pathogenesis of depression. In addition, we found significant differences in metabolic pathways such as choline metabolism, fat digestion and absorption, and regulation of lipolysis in adipocytes in cancers enriched for the metabolites TAG, phosphatidylcholine (PC), and di-glycerol (DAG). These findings not only contribute to an in-depth understanding of the pathogenic mechanisms of depression, but also suggest that lipid compounds in vivo may be potential diagnostic and prognostic markers of depression, as well as potential therapeutic targets for antidepressants, providing new ideas for the development of antidepressant drugs targeting lipids and lipid metabolism. |
修改评论