Depression is one of the most common psychiatric diseases and the prevalence of depressive symptoms in women is almost twice compared to men, although the reasons of this gender difference are not fully understood yet. Recently, soluble amyloid beta (Aβ)1-42 peptide has been receiving great importance in the development of depression, also considering that depression is highly comorbid with Alzheimer's disease and other neurodegenerative illnesses. The central role played by Aβ in the development of depressive-like symptoms in rodents has been evidenced in environmental rodent model of depression. Indeed, we have previously found that lifelong exposure to n-3 polyunsaturated fatty acids (PUFA) deficient diet in female rats at 8 weeks of life leads to depressive like- symptoms and higher susceptibility to stress associated with increased Aβ levels. In order to understand if such effects were maintained over time, rats were exposed to the same diet regimen until 6 or 21 weeks of life. We found that both timepoints of exposure to n-3 PUFA deficient diet lead to depressive-like phenotype. Furthermore, a significant alteration in brain neurochemistry was retrieved. In particular, in hippocampal area a significant reduction in serotonin (5-HT) and noradrenaline (NA) content was evidenced. Considering the prominent role of NA in counterbalancing neuroinflammatory state, we quantified in the same brain area kynurenine levels, a metabolite of tryptophan implicated in inflammatory state and brought to the fore for its implication in depression. Interestingly, kynurenine levels were significantly increased in hippocampus (HIPP) of female rats exposed to such diet. In addition, lifelong deficiency in n-3 PUFA dietary intake led to systemic increase of corticosterone, hence hypothalamic pituitary adrenal (HPA) axis hyperactivation, and higher proinflammatory cytokine production. Increased production of kynurenine, along with HPA axis hyperactivation, have been associated with immune system modulation, particularly through Toll-like receptor type 2 (TLR2) and Toll-like receptor type 4 (TLR4) involvement. In addition, it has been shown that soluble forms of Aβ1-42 can induced depressive like-phenotype in consequence to a crosstalk between TLR4 and 5-HTergic system. Thus, considering that in this model we have previously reported increased plasma Aβ1-42 level, we quantified TRL2 and 4 expression in HIPP of treated rats. We found that chronic exposure to a diet characterized by very low n-3 PUFA content led to higher expression of TLR2 and TLR4 in HIPP of female treated rats, indicating an activation of the immune system and was accompanied by increased expression of oligomeric Aβ. Taken together, our data indicate that the pro-depressive effects induced by a diet poor in n-3 PUFA can be attributable to a shift of hippocampal tryptophan metabolism toward inflammatory metabolite ultimately corresponding to altered immune response and increased Aβ oligomerization.

中文翻译：

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雌性大鼠终生营养 omega-3 缺乏引起的抑郁样表型：犬尿氨酸、Toll 样受体和淀粉样蛋白 β 寡聚体之间的串扰

抑郁症是最常见的精神疾病之一，女性抑郁症状的患病率几乎是男性的两倍，尽管这种性别差异的原因尚不完全清楚。最近，可溶性淀粉样蛋白 β (Aβ)1-42 肽在抑郁症的发展中受到了极大的重视，还考虑到抑郁症与阿尔茨海默病和其他神经退行性疾病高度共存。Aβ 在啮齿动物抑郁样症状的发展中发挥的核心作用已在抑郁的环境啮齿动物模型中得到证实。确实，我们之前已经发现，雌性大鼠在 8 周龄时终生暴露于缺乏 n-3 多不饱和脂肪酸 (PUFA) 的饮食会导致抑郁样症状和与 Aβ 水平升高相关的更高的压力敏感性。为了了解这种影响是否会随着时间的推移而保持，大鼠在生命的 6 或 21 周之前都接受相同的饮食方案。我们发现暴露于 n-3 PUFA 缺乏饮食的两个时间点都会导致抑郁样表型。此外，还检索到脑神经化学的显着变化。特别是，在海马区，证实了血清素 (5-HT) 和去甲肾上腺素 (NA) 含量的显着减少。考虑到 NA 在平衡神经炎症状态中的突出作用，我们在相同的大脑区域量化了犬尿氨酸水平，色氨酸的一种代谢物，与炎症状态有关，并因其与抑郁症的关系而备受关注。有趣的是，暴露于这种饮食的雌性大鼠的海马体 (HIPP) 中犬尿氨酸水平显着增加。此外，n-3 PUFA 膳食摄入量的终生缺乏会导致皮质酮的全身增加，从而导致下丘脑垂体肾上腺 (HPA) 轴过度激活，以及更高的促炎细胞因子产生。犬尿氨酸的产生增加以及 HPA 轴过度激活与免疫系统调节有关，特别是通过 Toll 样受体 2 型 (TLR2) 和 Toll 样受体 4 型 (TLR4) 参与。此外，已经表明，由于 TLR4 和 5-HTergic 系统之间的串扰，Aβ1-42 的可溶性形式可以诱导抑郁样表型。因此，考虑到在该模型中我们之前曾报道血浆 Aβ1-42 水平升高，我们量化了治疗大鼠 HIPP 中的 TRL2 和 4 表达。我们发现长期暴露于以非常低的 n-3 PUFA 含量为特征的饮食导致雌性治疗大鼠的 HIPP 中 TLR2 和 TLR4 的更高表达，表明免疫系统的激活并伴随着寡聚 Aβ 的表达增加。总之，我们的数据表明，n-3 PUFA 含量低的饮食引起的促抑郁作用可归因于海马色氨酸代谢向炎性代谢物的转变，最终对应于免疫反应的改变和 Aβ 寡聚化的增加。我们发现长期暴露于以非常低的 n-3 PUFA 含量为特征的饮食导致雌性治疗大鼠的 HIPP 中 TLR2 和 TLR4 的更高表达，表明免疫系统的激活并伴随着寡聚 Aβ 的表达增加。总之，我们的数据表明，n-3 PUFA 含量低的饮食引起的促抑郁作用可归因于海马色氨酸代谢向炎性代谢物的转变，最终对应于免疫反应的改变和 Aβ 寡聚化的增加。我们发现长期暴露于以非常低的 n-3 PUFA 含量为特征的饮食导致雌性治疗大鼠的 HIPP 中 TLR2 和 TLR4 的更高表达，表明免疫系统的激活并伴随着寡聚 Aβ 的表达增加。总之，我们的数据表明，n-3 PUFA 含量低的饮食引起的促抑郁作用可归因于海马色氨酸代谢向炎性代谢物的转变，最终对应于免疫反应的改变和 Aβ 寡聚化的增加。