Abstract: Objective To identify differentially expressed genes (DEGs) and their expression patterns and regulatory mechanisms in the hippocampus of male rat offsprings with depression-like behavior induced by prenatal stress (PS). Methods SD rats were selected to establish a chronic restrained stress model from March to October 2022. Sucrose preference test was implemented for measurement of susceptibility to prenatal stress in offsprings (PS-S).Open field test, forced swimming test, tail hanging test were used to verify the validity of animal model and the efficacy of the screening method, respectively. High-throughput sequencing-based transcriptomic approaches were applied as powerful tools to identify and characterize gene regulatory networks in hippocampus of PS-S offspring rats in this study. After data processing and quality control, bioinformatics analysis was performed to screen and classify DEGs. Results Totally 486 DEGs were identified between PS-S group and control group, of which 230 were up-regulated genes enriched in 20 GO terms, while 256 were down-regulated genes enriched in 17 GO terms. Go terms, such as "gas transport", "hemoglobin complex", "oxygen transport", "oxygen carrier activity", were ranked highest in DEGs. Seven GO terms including "glutamate 5-kinase activity","response to oxygen-containing compound" and "retinol metabolic process" were significantly enriched both in up- and down-regulated genes. KEGG pathway analysis showed that DEGs were mainly enriched in signal pathway such as "tryptophan metabolism", "phagosome", "protein digestion and absorption", "neuroactive ligand-receptor interaction" and "fructose and mannose metabolism". These findings suggested that significant differences in gene expression of TTR, CRABP2, FABP5, AANAT and TPH1 might played a critical role in PS induced depressive-like behavior in offspring rats. Conclusion DEGs involved in retinol metabolic process, retinoid and tryptophan metabolism pathways may contribute to the pathogenesis of prenatal stress-induced depression-related behavioral alterations in rat models.

Key words: prenatal stress, depressive-like behavior, hippocampus, transcriptome

摘要： 目的 研究产前应激(PS)诱导的抑郁样子代大鼠大脑海马体的差异表达基因(DEG)及其表达规律和调节机制。方法 2020年3—10月选择SD大鼠建立慢性束缚应激模型进行研究。使用糖水偏好实验测试子代大鼠PS易感性(PS-S),分别采用旷场实验、强迫游泳实验、悬尾实验验证PS模型和糖水偏好实验筛选个体对应激反应的有效性。应用基于高通量测序的转录组学方法来表征PS-S子代大鼠海马体中的基因网络。在数据处理和质量控制之后,使用生物信息学分析筛选差异表达基因并进行分类。结果 鉴定出486个差异表达基因,其中230个上调,256个下调。GO功能富集分析显示,上调的基因中鉴别出20个GO注释,下调的基因中鉴别出17个GO注释。诸如“气体运输”、“血红蛋白复合物”、“氧气运输”、“氧载体活性”等 GO 注释在DEG中排名靠前。包括“谷氨酸与激酶活性”、“对含氧化合物的反应”和“视黄醇代谢过程”等7个GO注释可同时富集在上调和下调的DEG集。KEGG富集分析表明,这些DEG主要富集于色氨酸代谢、吞噬体、蛋白消化吸收、神经活性配体受体相互作用、果糖和甘露糖代谢等信号通路。分析发现TTR、CRABP2、FABP5、AANAT和TPH1等基因的表达差异可能在 PS 诱导的子代大鼠抑郁样行为中起关键作用。结论 视黄醇代谢过程、视黄酸代谢和色氨酸代谢通路相关基因的差异表达可能参与PS致子代抑郁行为的发病机制。

关键词: 产前应激, 抑郁样行为, 海马体, 转录组学