健康与遗传心理学研究室知识库

目的：抑郁症是一种常见的精神疾病，但其发病机制目前仍不清楚，大量的研究表明抑郁症与免疫系统异常相关，其中炎症反应是其重要病因之一。部分抑郁症患者体内的炎症水平显著高于正常人，而炎症又可以诱发 人和 实验动物产生抑郁样行为。尽管细胞和分子机制尚不明确，其仍然启示免疫调节有可能是治疗抑郁症的关键途径之一。多年来 n-3系 多不饱和脂肪酸 n-3 polyunsaturated fatty acids, n-3 PUFAs 一直作为一种心血管系统的保健品而被广泛使用，而近年来的研究发现其对神经系统同样有益。 大量研究结果 显示长期服用 n-3 PUFAs不仅可以改善情绪，对于多种精神疾病也有治疗效果。其中 n-3 PUFAs对抑郁症的影响得到越来越多的关注， 大量证据显示 n-3 PUFAs可以改善抑郁症状，但其中的机制目前并不明确， 而 对免疫系统的调控作用 有可能是 其作用途径之一。然而目前还没有研究对 n-3 PUFAs的免疫调节特性在抑郁症中的影响进行详细 阐述 。因此，本研究的目的是探索 n-3 PUFAs对抑郁样行为的改善作用及其调控机制。

方案：本研究主要由五个实验组成。实验一通过检验中枢侧脑室连续注射LPS 是否可以引发大鼠中枢炎性免疫激活，探索建立炎症诱发抑郁模型的可行性。实验二通过糖精水偏好测试、旷场测试和悬尾测试等一系列行为测试，检验中枢侧脑室连续注射LPS是否可以引发动物产生抑郁样行为，确定炎症诱发抑郁模型的稳定性。实验三则检测了n-3 PUFAs中两种主要的多不饱和脂肪酸——二十二碳六烯酸（Docosahexaenoic Acid, DHA）和二十碳五烯酸（Eicosapentaenoic Acid, EPA）对中枢侧脑室连续注射LPS引发的大鼠抑郁样行为的影响，明确n-3 PUFAs是否对LPS诱发的抑郁样行为具有改善效应。最后，实验四和实验五通过检测n-3 PUFAs对中枢神经系统炎症状态下大鼠中枢免疫激活状态以及相关信号通路的影响，探索n-3 PUFAs通过免疫调节途径改善LPS引发的抑郁样行为的调控机制。

结果：实验一结果显示中枢侧脑室连续注射 LPS能 够导致大鼠海马中 促炎性细胞因子 肿瘤坏死因子 -α Tumor necrosis factor-α, TNF-α 表达水平升高 。此外， 中枢侧脑室连续注射 LPS还可以导致大鼠海马和缰核中小胶质细胞数量显著增加，说明LPS引发了中枢神经系统炎症。实验二结果显示中枢侧脑室连续注射LPS能够导致大鼠产生包括糖精水偏好下降，绝望情绪，自发活动和探索活动减少在内的一系列抑郁样症状，说明LPS导致大鼠产生了明显的抑郁样行为。实验三结果显示连续摄入EPA可以显著改善中枢侧脑室连续注射LPS引发的抑郁样行为，而DHA则对行为无改善效应。实验四在检测了大鼠海马和缰核中促炎性细胞因子TNF-α的表达水平和小胶质细胞的数量后发现与DHA相比，只有EPA可以抑制中枢侧脑室连续注射LPS引起的中枢神经系统炎症。实验五结果显示与DHA相比，只有EPA可以逆转LPS对MAPK信号通路中细胞外调节蛋白激酶（Extracellular regulated protein kinase1/2, ERK1/2），c-Jun氨基末端激酶（c-Jun N-terminal kinase, JNK），p38以及转录因子核因子κB（nuclear factor κB, NFκB）磷酸化水平的影响。

结论：本研究结果表明多不饱和脂肪酸分子EPA可以通过调控MAPK信号通路中ERK1/2，JNK，p38以及转录因子NFκB的活性并影响中枢神经系统炎症状态来改善LPS引发的抑郁样行为。本研究为解释n-3 PUFAs的抗抑郁机制提供了新的实验证据，并为改善和治疗中枢炎症导致的抑郁症带来启示。

Depression is a common mental illness, but its pathogenesis is still unclear. A large amount of studies has shown that depression is associated with abnormal immune system function, and inflammation is one of its important causes. The inflammation level in the blood of patients with depression is much higher than that of normal people, and inflammation can trigger depressive like behaviors in animals and humans. Although the molecular mechanism is still unclear, it still suggests that immunomodulation maybe one of the potential pathways to treat depression. N-3 PUFAs have been widely used as a kind of health care products for cardiovascular system for many years. However, recent studies have found that n-3 PUFAs are also beneficial to nervous system. There are evidences that long-term use of n-3 PUFAs can not only improve mood, but also exert therapeutic effects on a variety of mental disorders. Recent years the effects of n-3 PUFAs on depression have received more and more attention. There is evidence that n-3 PUFAs can improve the symptoms of depression, whereas the mechanism is still unclear. However, studies show that its immunomodulatory properties may play a role in its therapeutic effect on depression. Therefore, the purpose of this study is to explore the effects of n-3 PUFAs on depressive-like behaviors and the behind regulatory mechanisms.

Five experiments were carried out in the investigation. Experiments 1 examined whether central LPS injections can induce CNS inflammation on rats. Experiments 2 examined whether central injection of LPS can induce depressive-like behaviors in animals through a series of behavioral tests including saccharin preference test, open field test, and tail suspension test. Experiments 3 examined the effects of two major polyunsaturated fatty acids of n-3 PUFAs, DHA and EPA, on the depressive-like behaviors induced by central injections of LPS, respectively. Finally, experiments 4 and 5 examined the effects of n-3 PUFAs on the CNS inflammation induced by central injection of LPS and explored related MAPK signaling pathways including ERK1/2, P38 and JNK.

The results of experiment 1 showed that central injection of LPS not only increased the expression of pro-inflammatory cytokine TNF-α, but also increased the number of microglial cells in hippocampus and habenula of rats, indicating that LPS induced CNS inflammation. The results of experiment 2 showed that central injection of LPS resulted in decreased saccharin preference, spontaneous activity, exploration activity and increased desperation symptom, indicating that CNS inflammation caused significant depressive-like behaviors in rats. The results of experiment 3 showed that continuous intake of EPA, not DHA, for 3 weeks can significantly improve the depressive-like behaviors induced by central injection of LPS. The results of experiments 4 showed that EPA, not DHA, reversed the increase of TNF-α expression and number of microglial cells in hippocampus and habenula induced by central injection of LPS. Further, the results of experiment 5 showed that EPA, not DHA, reversed the effect of LPS on phosphorylation level of ERK1/2, JNK and p38 of MAPK signaling pathway and transcription factor NFκB.

In conclusion, the results of this study indicate that EPA, a polyunsaturated fatty acid molecule, can ameliorate depressive-like behaviors through regulating MAPK signaling pathway and CNS inflammation. This study offered new evidences for the antidepressant effect of n-3 PUFAs and provided a potential new strategy for the treatment of depression caused by CNS inflammation.