基于海马 PPARγ及其天然激动剂的抗抑郁机制研究
文献类型：学位论文
| 作者 | 李洁 |
| 答辩日期 | 2024-06 |
| 文献子类 | 硕士 |
| 授予单位 | 中国科学院大学 |
| 授予地点 | 中国科学院心理研究所 |
| 其他责任者 | 郭建友 |
| 关键词 | PPARγ 抑郁症 转录组学分析 天然激动剂 木犀草素 |
| 学位名称 | 理学硕士 |
| 学位专业 | 健康心理学 |
| 其他题名 | Study of antidepressive mechanisms based on hippocampal PPARγ and its natural stimulants |
| 中文摘要 | As one of the most serious and prevalent mental disorders globally, depression manifests itself as a persistent and severe depressed state of mind, and it takes the most significant loss of lifespan globally. In China, depression has become one of the major disease burdens, with the number of patients now exceeding 95 million. Depressed patients usually have a prolonged course of illness, which seriously affects their psychosocial functioning and quality of life. Although there are many hypotheses about the pathogenesis of depression, the specific molecular mechanisms are still inconclusive. In recent years, scholars have begun to focus on the relationship between depression and metabolism. Studies have shown that there is a significant association between depression and metabolic syndrome, and the both may share some pathophysiological mechanisms, such as alterations in the stress system, including the HPA axis, the autonomic nervous system, and the immune system, etc. PPARγ is considered one of the major therapeutic targets for the treatment of metabolic disorders, which plays a key role in energy homeostasis and metabolism, and is associated with almost all aspects of the metabolic syndrome. At the same time, PPARγ is also widely distributed in the nervous system, where it is highly activated during stress and acts as an anti-inflammatory agent as well as a neuroprotective agent in the central nervous system. Based on the criticality of PPARγ in regulating energy homeostasis and metabolism, and its anti-inflammatory and neuroprotective effects in the nervous system, PPARγ may have some antidepressant potential. However, experimental confirmation of its exact role in depression is still lacking. Therefore, further studies could help to explore the potential and mechanism of PPARγ in depression treatment in more depth. This project contains the following two studies: study I, firstly, the animal depression model was established using the Chronic Unpredictable Mild Stress (CUMS) model, and after modeling, the anxiety-depression level of the animals was assessed using the sucrose preference, forced swimming, open field, and elevated plus maze test; the pathways with significant differences in effects were obtained by transcriptomics analysis of the hippocampal tissues of the rats; and finally, by the western blot experiments to verify the changes in the content of target proteins PPARγ and mTOR. The results of the study showed that the CUMS model successfully induced anxiety-depression-like behaviors in the animals; the mTOR pathway was significantly up-regulated in the model group compared with the control group through transcriptomic analysis; western blot showed that the mTOR pathway in the hippocampus was over-activated under the stimulation of CUMS, which was in line with the results of the transcriptomic analysis, while the expression of PPARγ was significantly inhibited. For study II, the same CUMS modeling was used and the PPARγ natural small molecule agonist, luteolin, was used for the intervention. The antidepressant efficacy of luteolin was tested at the end of modeling using sucrose preference, forced swimming, open field and elevated plus maze tests to test the anxiety and depression levels of the animals; ELISA was used to examine the levels of inflammatory factors in the serum of the animals, and western bolt to validate the protein content of PPARγ and mTOR. The results of the study showed that after the intervention of PPARγ natural agonist luteolin, the anxiety and depression-like behaviors of rats in the administered group were significantly improved, the level of inflammatory factors in the serum was significantly reduced, the expression of PPARγ in the hippocampus was significantly increased, and the expression of mTOR was significantly reduced. The above results suggest that the activation of PPARγ target can improve depression-like behaviors and has the potential to be a new target for depression treatment, and that the natural agonist of PPARγ, luteolin, may have antidepressant effects by activating PPARγ and thereby decreasing the expression of mTOR and the level of inflammatory factors. Depression has a huge impact on people's lives and mental health, and exploring new drug targets by studying the pathological overlap between depression and co-morbid diseases has become a positive strategy. In-depth study of PPARγ targets can improve the understanding of depression mechanisms and facilitate the development of novel antidepressant drugs characterized by "metabolic inertia" or improve the metabolic status of depressed patients. |
| 英文摘要 | 抑郁症作为全球范围内最严重和最为普遍的精神障碍之一，表现为持续严 重的心境低落，在全球范围内，抑郁症对寿命造成的损失最为显著。在中国， 抑郁症已经成为主要的疾病负担之一，目前患者数量已超过 9500 万。抑郁症患 者通常病程较长，严重影响了他们的社会心理功能和生活质量。尽管关于抑郁 症发病机制的假说很多，但具体的分子机制尚无定论。近年来，学者们开始关 注抑郁症与代谢的关系。研究表明，抑郁症与代谢综合征之间存在显著关联， 两者可能共享一些病理生理机制，例如应激系统的改变，包括 HPA 轴、自主神 经系统和免疫系统等。PPARγ被认为是治疗代谢紊乱的主要治疗靶点之一，它 在能量稳态和代谢中发挥关键作用，几乎与代谢综合症的所有方面有关。与此 同时，PPARγ也广泛分布于神经系统，它在应激期间会被高度激活，并在中枢 神经系统中起到一种抗炎剂以及神经保护的作用。基于 PPARγ在调节能量稳 态和代谢中的关键性，及其在神经系统中发挥的抗炎和神经保护作用，PPARγ 可能具有一定的抗抑郁潜力。然而，目前仍缺乏实验证实其在抑郁症中的确切 作用。因此，进一步的研究有助于更深入地探索 PPARγ在抑郁症治疗中的潜 力和机制。 本课题包含了以下两个研究：研究一，首先使用慢性温和不可预知刺激 （CUMS）模型建立动物抑郁模型，造模结束后，采用糖水偏好、强迫游泳、 旷场和高架十字迷宫实验评估动物的焦虑-抑郁程度；通过对大鼠海马组织进行 转录组学分析得到差异显著的影响通路；最后通过 western blot 实验，验证靶点 蛋白 PPARγ和 mTOR 的含量变化。研究结果显示，CUMS 模型成功诱导出动 物的焦虑抑郁样行为；通过转录组学分析，筛选得到模型组相比于控制组显著 上调的 mTOR 通路；western blot 检测发现海马内 mTOR 通路在 CUMS 的刺激 下呈现过度激活状态，与转录组学结果一致，PPARγ的表达则被显著抑制。 研究二，同样使用 CUMS 模型，并使用 PPARγ天然小分子激动剂，木犀草素，进行干预。造模结束后采用糖水偏好、强迫游泳、旷场和高架十字迷宫实验测试动物的焦虑抑郁水平，检测木犀草素的抗抑郁药效；采用 ELISA 检测 动物血清中炎症因子水平，以及 western bolt 验证 PPARγ和 mTOR 的蛋白含量。研究结果显示，在给予 PPARγ天然激动剂木犀草素进行干预之后，给药组大 鼠的焦虑抑郁样行为得到明显改善，血清中炎症因子水平显著降低，海马内PPARγ表达显著升高，而 mTOR 的表达则显著降低。 以上结果提示 PPARγ靶点的激活可以改善抑郁样行为，具有成为抑郁治疗新靶点的潜力，且 PPARγ天然激动剂，木犀草素，可能通过激活 PPARγ进而降低 mTOR 表达和炎症因子水平发挥抗抑郁效果。抑郁症对人们的生活和心理健康产生巨大影响，通过研究抑郁症与共病疾病的病理重叠，探索新的药物 靶点成为一种积极策略。深入研究 PPARγ靶点，可以增进对抑郁机制的理解， 促进开发具有“代谢惰性”特征的新型抗抑郁药物或改善抑郁患者的代谢状态。 |
| 语种 | 中文 |
| 源URL | [http://ir.psych.ac.cn/handle/311026/47944]  |
| 专题 | 心理研究所_健康与遗传心理学研究室 |
| 推荐引用方式 GB/T 7714 | 李洁. 基于海马 PPARγ及其天然激动剂的抗抑郁机制研究[D]. 中国科学院心理研究所. 中国科学院大学. 2024. |
入库方式： OAI收割
来源：心理研究所
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