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。
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.
关键词
产前应激 /
抑郁样行为 /
海马体 /
转录组学
Key words
prenatal stress /
depressive-like behavior /
hippocampus /
transcriptome
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] Goldstein Z, Rosen B, Howlett A, et al. Interventions for paternal perinatal depression:A systematic review[J]. J Affect Disord, 2020, 265:505-510.
[2] Van Niel MSPayne JL. Perinatal depression:A review[J]. Cleve Clin J Med, 2020, 87(5):273-277.
[3] Mathers CDLoncar D. Projections of global mortality and burden of disease from 2002 to 2030[J]. PLoS Med, 2006, 3(11):e442.
[4] Charil A, Laplante DP, Vaillancourt C, et al.Prenatal stress and brain development[J]. Brain Res Rev, 2010, 65(1):56-79.
[5] Haq SU, Bhat UAKumar A. Prenatal stress effects on offspring brain and behavior:Mediators, alterations and dysregulated epigenetic mechanisms[J]. J Biosci, 2021, 46:34.
[6] Weinstock M. Prenatal stressors in rodents:Effects on behavior[J]. Neurobiol Stress, 2017, 6:3-13.
[7] Lautarescu A, Craig MCGlover V. Prenatal stress:Effects on fetal and child brain development[J]. Int Rev Neurobiol, 2020, 150:17-40.
[8] Zhang H, He W, Huang Y, et al. Hippocampal metabolic alteration in rat exhibited susceptibility to prenatal stress[J]. J Affect Disord, 2019, 259:458-467.
[9] Wang S, Ishima T, Zhang J, et al. Ingestion of lactobacillus intestinalis and lactobacillus reuteri causes depression- and anhedonia-like phenotypes in antibiotic-treated mice via the vagus nerve[J]. Journal of neuroinflammation, 2020, 17(1):241-241.
[10] Li C, Wang F, Miao P, et al. Mir-138 increases depressive-like behaviors by targeting sirt1 in hippocampus[J]. Neuropsychiatr Disease Treat, 2020, 16:949-957.
[11] Fan C, Long Y, Wang L, et al. N-acetylcysteine rescues hippocampal oxidative stress-induced neuronal injury via suppression of p38/jnk signaling in depressed rats[J]. FrontCell Neurosci, 2020, 14:554613-554613.
[12] Tingting Q, Fang F, Meiting S, et al. Umbelliferone reverses depression-like behavior in chronic unpredictable mild stress-induced rats by attenuating neuronal apoptosis via regulating rock/akt pathway[J]. Behav Brain Res, 2017, 317:147-156.
[13] Encinas M, Iglesias M, Liu Y, et al. Sequential treatment of sh-sy5y cells with retinoic acid and brain-derived neurotrophic factor gives rise to fully differentiated, neurotrophic factor-dependent, human neuron-like cells[J]. J Neurochem, 2000, 75(3):991-1003.
[14] Bonhomme D, Minni AM, Alfos S, et al. Vitamin a status regulates glucocorticoid availability in wistar rats:Consequences on cognitive functions and hippocampal neurogenesis?[J]. Front Behav Neurosci, 2014, 8:20.
[15] Lenz M, Eichler A, Kruse P, et al. All-trans retinoic acid induces synaptopodin-dependent metaplasticity in mouse dentate granule cells[J]. Elife, 2021, 10:e71983.
[16] Sullivan GM, Mann JJ, Oquendo MA, et al. Low cerebrospinal fluid transthyretin levels in depression:Correlations with suicidal ideation and low serotonin function[J]. BiolPsychiatry, 2006, 60(5):500-506.
[17] Kang J, Kim W, Seo H, et al. Radiation-induced overexpression of transthyretin inhibits retinol-mediated hippocampal neurogenesis[J]. Sci Rep, 2018, 8(1):8394.
[18] Hu P, van Dam AM, Wang Y, et al. Retinoic acid and depressive disorders:Evidence and possible neurobiological mechanisms[J]. Neurosci Biobehav Rev, 2020, 112:376-391.
[19] Melo MCA, Abreu RLC, Linhares Neto VB, et al. Chronotype and circadian rhythm in bipolar disorder:A systematic review[J]. Sleep Med Rev, 2017, 34:46-58.
[20] Maffei ME. 5-hydroxytryptophan (5-htp):Natural occurrence, analysis, biosynthesis, biotechnology, physiology and toxicology[J]. Int J Mol Sci, 2020, 22(1):181.
[21] Chen Y, Xu H, Zhu M, et al. Stress inhibits tryptophan hydroxylase expression in a rat model of depression[J]. Oncotarget, 2017, 8(38):63247-63257.
基金
陕西省自然科学基金基础研究计划(2022JM-585)
PDF(29754 KB)
