AbstractIn this work, we have analyzed the transcriptomic changes in the brainstem of male Wistar rats 2 h after an acute stress exposure. We performed duplex-specific nuclease normalization of cDNA libraries and compared the results back-to-back for the first time. Based on our RNAseq data, we selected reference genes for RT-qPCR that are best suited for acute stress experiments.

摘要在这项工作中，我们分析了急性应激暴露后2小时雄性Wistar大鼠脑干的转录组变化。我们对cDNA文库进行了双链体特异性核酸酶标准化，并首次背靠背比较了结果。基于我们的RNAseq数据，我们选择了最适合急性应激实验的RT-qPCR参考基因。

Most genes were upregulated. We detected a massive shift in neuropeptide Crh, Trh,Cga, Tshb, Uts2b, Tac4, Lep and neuropeptide receptor Hcrtr1, Sstr5, Bdkrb2, Crhr2 signaling, as well as glutamate Grin3b, Grm2 and GABA Gpr156, acetylcholine Chrm4,Chrne, adrenergic Adra2b receptors expression. A strong increase in the expression of intermediate filaments Krt83/Krt86/Krt80/Krt84/Krt87/Krt4/Krt76 and motor proteins Myo7a, Klc3 was detected.

。我们检测到神经肽Crh，Trh，Cga，Tshb，Uts2b，Tac4，Lep和神经肽受体Hcrtr1，Sstr5，Bdkrb2，Crhr2信号传导以及谷氨酸Grin3b，Grm2和GABA Gpr156，乙酰胆碱Chrm4，Chrne，肾上腺素能Adra2b受体表达发生了巨大变化。检测到中间丝Krt83/Krt86/Krt80/Krt84/Krt87/Krt4/Krt76和运动蛋白Myo7a，Klc3的表达强烈增加。

Remarkably, in the absence of astrocyte activation, we also observed signs of microglial activation at this time point. Both expression of anti-inflammatory cytokines Il13, Ccl24 and pro-inflammatory cytokine receptors Il9r, Il12rb1, Tnfrsf14, Tnfrsf13c, Tnfrsf25, Tnfrsf1b were increased. In the Wnt signaling pathway, we observed increased expression of ligands-receptors Wnt1, Wnt11, Ror2 and also negative regulators Notum, Sfrp5, Sost.

值得注意的是，在没有星形胶质细胞活化的情况下，我们还在这个时间点观察到小胶质细胞活化的迹象。抗炎细胞因子Il13，Ccl24和促炎细胞因子受体Il9r，Il12rb1，Tnfrsf14，Tnfrsf13c，Tnfrsf25，Tnfrsf1b的表达均增加。在Wnt信号通路中，我们观察到配体受体Wnt1，Wnt11，Ror2以及负调节剂Notum，Sfrp5，Sost的表达增加。

RNAseq results after DSN treatment correlated at a high level with RNAseq results without DSN, but there was a proportion of genes that shifted their logFC values. They are mostly rare transcripts TPM 1–10 with higher 0.5–0.9 GC content..

DSN处理后的RNAseq结果与没有DSN的RNAseq结果高度相关，但有一部分基因改变了其logFC值。它们大多是罕见的转录本TPM 1-10，GC含量较高，为0.5-0.9。。

IntroductionAcute stress is an adaptive response by organisms to overcome adverse environmental conditions1,2. Over the course of evolution, the presence of predators has formed a stereotyped behavioral response, usually referred to as “fight or flight.” This behavioral response involves cooperative and fine-tuned neuronal activity in various brain structures.

引言急性应激是生物体克服不利环境条件的适应性反应1,2。在进化过程中，捕食者的存在形成了一种刻板的行为反应，通常被称为“战斗或逃跑”。这种行为反应涉及各种大脑结构中的合作和微调神经元活动。

Notable among these is the brainstem—the structure responsible for autonomic control and reflexive responses to systemic and environmental stressors3. These functions are performed by several neuronal nuclei with different neurotransmitter systems in the brainstem2. Monoamine neuron nuclei are located in this brain structure.

其中值得注意的是脑干，它负责自主控制和对全身和环境压力的反射反应3。这些功能由脑干中具有不同神经递质系统的几个神经元核执行2。单胺神经元核位于这种大脑结构中。

There is evidence that norepinephrine neurons in the locus coeruleus (LC) modulate cognitive functions such as memory and operant conditioning4. In acute stress conditions, the activity of LC norepinephrine neurons participates in the arousal response, along with the action of elevated levels of hormones5.

有证据表明，蓝斑（LC）中的去甲肾上腺素神经元调节认知功能，如记忆和操作条件4。在急性应激条件下，LC去甲肾上腺素神经元的活动参与唤醒反应，以及激素水平升高的作用5。

Excessive increased activity of brainstem neurons causes oxidative stress, which may be a factor in the further development of various psychopathologies6.Whole transcriptome analysis (RNA-seq) could be used to study gene expression changes in the brainstem after acute stress. The sequencing depth varies depending on the library preparation method.

脑干神经元活动过度增加会导致氧化应激，这可能是各种精神病理学进一步发展的一个因素6。全转录组分析（RNA-seq）可用于研究急性应激后脑干的基因表达变化。测序深度取决于文库制备方法。

Reads from ribosomal RNA (rRNA) or highly expressed transcripts make up the majority of the total reads. Getting information about expression changes of rare transcripts requires deep sequencing, which can be expensive. Depletion of rRNA or purification of the polyA fraction is used to overcome this problem.

核糖体RNA（rRNA）或高表达转录本的读数占总读数的大部分。获得有关稀有转录本表达变化的信息需要深度测序，这可能很昂贵。rRNA的消耗或polyA级分的纯化用于克服这个问题。

Another approach that could be used is Duplex Specific Nuclease (DSN) treatment of the double-stranded cDNA library after denaturation and re.

另一种可以使用的方法是变性和re后双链cDNA文库的双链特异性核酸酶（DSN）处理。

Data availibility

可用数据

Raw reads and sorted bam files were deposed to CNGB https://db.cngb.org/ under the project number CNP0004878. Rscript and other findings of the paper are included as supplementary tables. PCR results are also included as supplementary tables. KEGG pathway graphs with overlaid expression information could be founded at https://lda01.shinyapps.io/tr_app2/ as interactive shiny application.

原始读取和排序的bam文件被转储到CNGBhttps://db.cngb.org/项目编号CNP0004878。Rscript和论文的其他发现作为补充表包括在内。PCR结果也包括在补充表中。具有重叠表达信息的KEGG路径图可以在https://lda01.shinyapps.io/tr_app2/作为交互式闪亮应用程序。

Just wait until all information will be loaded on the page.

只需等到所有信息都加载到页面上。

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Download referencesAcknowledgementsStudies was supported by joint research project FWNR-2022-0002. RNA-sequencing was carried out in The Core Facility «Medical genomics»(Tomsk NRMC) and the Tomsk Regional Common Use Center. Bioinformatics analysis was carried out at the Information and Computing Center of Novosibirsk State University.Author informationAuthors and AffiliationsPostgenomics Neurobiology Laboratory, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian FederationDmitriy A.

下载参考文献致谢研究得到了联合研究项目FWNR-2022-0002的支持。。生物信息学分析是在新西伯利亚州立大学信息与计算中心进行的。作者信息作者和附属机构俄罗斯联邦新西伯利亚科学院细胞学和遗传学研究所基因组学神经生物学实验室。

Lanshakov & Ekaterina V. SukharevaNatural Science Department, Novosibirsk State University, Novosibirsk, Russian FederationDmitriy A. Lanshakov & Tatyana S. KalininaFunctional Neurogenomics Laboratory, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian FederationVeta V.

Lanshakov＆Ekaterina V.SukharevaNatural Science Department，新西伯利亚州立大学，新西伯利亚，俄罗斯联邦。

Bulygina & Tatyana S. KalininaLaboratory of Cancer Progression Biology, Tomsk National Research Medical Center, Cancer Research Institute, Russian Academy of Sciences, Tomsk, Russian FederationAnna A. Khozyainova, Tatiana S. Gerashchenko & Evgeny V. DenisovAuthorsDmitriy A. LanshakovView author publicationsYou can also search for this author in.

Bulygina＆Tatyana S.KalininaLaboratory of Cancer Progression Biology，托木斯克国家研究医学中心，俄罗斯科学院癌症研究所，俄罗斯联邦托木斯克Anna A.Khozyainova，Tatiana S.Gerashchenko＆Evgeny V.DenisovAuthorsdmitry A.LanshakovView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsD.A.L. conceived the project, designed, and performed the experiments, and evaluated the data; E.V.S., T.S.K.—RNA isolation, cDNA synthesis for RT-qPCR, qPCR, Mint cDNA libraries preparation, E.V.S., T.S.K., D.A.L., V.V.B.—animal testing, samples collection, D.A.L.—Mint libraries preparations, DSN treatment, D.A.L.—Bioinformatics analysis, A.A.K., T.S.G., E.V.D.—KAPA cDNA library preparation, pooling, and sequencing.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献SD。A、 L.构思项目，设计和执行实验，并评估数据；E、 V.S.，T.S.K.-RNA分离，RT-qPCR的cDNA合成，qPCR，Mint cDNA文库制备，E.V.S.，T.S.K.，D.A.L.，V.V.B.-动物测试，样品收集，D.A.L.-Mint文库制备，DSN处理，D.A.L.-生物信息学分析，A.A.K.，T.S.G.，E.V.D.-KAPA cDNA文库制备，合并和测序。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleLanshakov, D.A., Sukhareva, E.V., Bulygina, V.V. et al. Brainstem transcriptomic changes in male Wistar rats after acute stress, comparing the use of duplex specific nuclease (DSN).

转载和许可本文引用本文Lanshakov，D.A.，Sukhareva，E.V.，Bulygina，V.V。等人。急性应激后雄性Wistar大鼠的脑干转录组变化，比较双链体特异性核酸酶（DSN）的使用。

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KeywordsRNAseqDSNFSTAcute stressBrainstemTranscriptome

关键词RNA序列DSNFST急性压力脑干转录组

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