产前应激致子代大鼠抑郁样行为的海马体转录组学变化

Transcriptomic alterations in the hippocampus of offspring rats with depression-like behavior induced by prenatal stress

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。

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 230were up-regulated genes enriched in 20GO terms,while 256were down-regulated genes enriched in 17GO 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,AANATand TPH1might 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.