Early-Life Stress Induces Depression-Like Behavior and Synaptic-Plasticity Changes in a Maternal Separation Rat Model: Gender Difference and Metabolomics Study
Early-Life Stress Induces Depression-Like Behavior and Synaptic-Plasticity Changes in a Maternal Separation Rat Model: Gender Difference and Metabolomics Study
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早年压力在母体分离大鼠模型中诱发抑郁样行为和突触可塑性变化：性别差异和代谢组学研究
DOI：
10.3389/fphar.2020.00102
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发表时间：
2020-02-26
影响因子：
5.6
通讯作者：
Zhang, Rong
中科院分区：
文献类型：
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作者：
Cui, Yongfei;Cao, Kerun;Zhang, Rong
全球有3亿多人患有抑郁症。据报道，处于早期生活压力（ELS）下的人在成年后容易患抑郁症，突触可塑性可能是这种抑郁症的分子机制。在此，我们模拟ELS通过使用一个母亲分离（MS）模型，并评估了行为检查，包括蔗糖偏好，强迫游泳，和开放领域的测试在成年期的SD大鼠的行为。行为学测试显示，MS组SD大鼠比非MS（NMS）组更易出现抑郁和焦虑样行为。尼氏染色结果显示MS组大鼠前额叶皮层和海马CA 1、CA 2、CA 3、DG区神经元数量明显减少。免疫组化结果显示，与NMS组相比，MS组前额叶皮层和海马（包括CA 1、CA 2、CA 3和DG区）脑片突触素阳性面积百分比显著减少。Western印迹分析用于评估突触可塑性蛋白标志物，包括突触后密度95、突触体蛋白和生长相关结合蛋白43在皮质和海马中的蛋白表达。结果显示，MS组中这3种蛋白的表达水平均显著低于NMS组。LC-MS/MS分析显示性激素及其代谢产物（包括雌二醇、睾酮、雄烯二酮、雌酮、雌三醇和5β-二氢睾酮）的峰面积无显著差异。通过应用非靶向代谢组学对差异代谢物进行全面分析，途径富集结果显示了精氨酸和脯氨酸代谢、泛酸和CoA生物合成、谷胱甘肽代谢以及苯丙氨酸、酪氨酸和色氨酸生物合成途径的重要性。总之，MS模型导致成年SD大鼠易患抑郁症，这可能通过精氨酸和脯氨酸代谢、泛酸和CoA生物合成、谷胱甘肽代谢以及苯丙氨酸、酪氨酸和色氨酸生物合成来调节突触可塑性。
More than 300 million people suffer from depressive disorders globally. People under early-life stress (ELS) are reportedly vulnerable to depression in their adulthood, and synaptic plasticity can be the molecular mechanism underlying such depression. Herein, we simulated ELS by using a maternal separation (MS) model and evaluated the behavior of Sprague–Dawley (SD) rats in adulthood through behavioral examination, including sucrose preference, forced swimming, and open-field tests. The behavior tests showed that SD rats in the MS group were more susceptible to depression- and anxiety-like behaviors than did the non-MS (NMS) group. Nissl staining analysis indicated a significant reduction in the number of neurons at the prefrontal cortex and hippocampus, including the CA1, CA2, CA3, and DG regions of SD rats in the MS group. Immunohistochemistry results showed that the percentages of synaptophysin-positive area in the prefrontal cortex and hippocampus (including the CA1, CA2, CA3, and DG regions) slice of the MS group significantly decreased compared with those of the NMS group. Western blot analysis was used to assess synaptic-plasticity protein markers, including postsynaptic density 95, synaptophysin, and growth-associated binding protein 43 protein expression in the cortex and hippocampus. Results showed that the expression levels of these three proteins in the MS group were significantly lower than those in the NMS group. LC–MS/MS analysis revealed no significant differences in the peak areas of sex hormones and their metabolites, including estradiol, testosterone, androstenedione, estrone, estriol, and 5β-dihydrotestosterone. Through the application of nontargeted metabolomics to the overall analysis of differential metabolites, pathway-enrichment results showed the importance of arginine and proline metabolism; pantothenate and CoA biosyntheses; glutathione metabolism; and the phenylalanine, tyrosine, and tryptophan biosynthesis pathways. In summary, the MS model caused adult SD rats to be susceptible to depression, which may regulate synaptic plasticity through arginine and proline metabolism; pantothenate and CoA biosyntheses; glutathione metabolism; and phenylalanine, tyrosine, and tryptophan biosyntheses.