The impact of chronic stress on the PFC transcriptome: a bioinformatic meta-analysis of publicly available RNA-sequencing datasets

Figures & data

Table 1. List and details of studies used in the meta-analysis.

Bioproject	Reference	Study title	Stress paradigm	Housing	Duration	Age	Substrain	Sex	Phenotype	Time of sacrifice	Number of samples	Sequencing
PRJNA293822^a	Bagot et al. (2016)	Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility.	Chronic social defeat	Single	10 days	8 weeks	C57BL/6J	Male	Control, resilient, susceptible	2 days, 28 days after last defeat	9	Single-end, 100 bp
PRJNA398031^b	Labonté et al. (2017)	Sex-specific transcriptional signatures inhuman depression.	Chronic variable stress	Grouped	3 weeks	8 weeks	C57BL/6J	Male/Female	Control, stress	Day after last stressor	19	Paired-end, 50 bp
PRJNA323485^c	Bondar et al. (2018)	Molecular adaptations to social defeat stress and induced depression in mice.	Chronic social defeat	Single	10 days, 30 days	10–12 weeks	C57BL/6J	Male	Control, stress	2 days after last defeat	13	Paired-end, 100 bp
PRJNA430409	Laine et al. (2018)	Genetic control of myelin plasticity after chronic psychosocial stress.	Chronic social defeat	Single	10 days	7 weeks	C57BL/6NCrl	Male	Control, resilient, susceptible	6–8 days after last defeat	18	Single-end, 96 bp
PRJNA415948	Cheng et al. (2018)	10–11 translocation proteins modulate the response to environmental stress in mice.	Chronic restraint stress	Grouped	2 h/day for 2 weeks	7–8 weeks	C57BL/6J	Male	Control, stress	After last restraint	6	Single-end, 100 bp
PRJNA525440	Wang et al. (2019)	RNA-sequencing and bioinformatics analysis of long noncoding RNAs and mRNAs in the prefrontal cortex of mice following repeated social defeat stress.	Chronic social defeat	Grouped	6 days	6–8 weeks	C57BL/6NCrl	Male	Control, stress	After last behavioral test	6	Paired-end, 100 bp
PRJNA625244	Weger et al. (2020)	Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress.	Multimodal chronic restraint	Grouped	3 weeks	6 weeks	C57BL/6J	Male	Control, stress	2 days after behavioral testing	30	Single-end, 70 bp

^a Dataset from mice culled 2 days after last defeat was used.

^b Sequencing carried out on samples from non-behavioral cohort. Data from males were analyzed.

^c Dataset from mice subjected to 10 day protocol was used.

Figure 1. Analysis of RNA-seq datasets from studies which have used chronic stress protocols in male mice to examine the impact on the PFC transcriptome. (A) Pearson correlation plot of average gene expression across all the seven studies that were the included in this study. (B) Heatmaps indicating degree of fold-change and the number of differentially expressed genes in each study and in the combined analysis (bottom row) for stress vs control mice. (C) UpSet plot of overlaps between the various datasets that were analyzed. The vertical lines which connect black circles indicate intersecting sets of genes between studies. The y-axis of the histogram indicates the number of intersecting genes and the bar plot on the right-hand side indicates the number of genes in each set. (D–G) EnrichR analysis of differentially expressed genes in the combined analysis for stress vs control mice. (H) Predicted upstream regulators of the differentially expressed genes in the combined analysis as determined using IPA.

Figure 2. Analysis of RNA-seq datasets from studies which have used chronic social defeat stress to examine the impact on the PFC transcriptome in male mice classified as resilient or susceptible. (A) Heatmaps indicating degree of fold-change and the number of differentially expressed genes in each study and in the combined analysis (bottom row) for susceptible vs control and resilient vs control mice. (B) UpSet plot of overlaps between the various datasets that were analyzed. (C–E) EnrichR analysis for differentially expressed genes that were common in the combined analysis and metaRNAseq analysis for susceptible vs control mice. (F) Predicted upstream regulators of the differentially expressed genes that were common in the combined analysis and metaRNAseq analysis for susceptible vs control mice.

Bagot, R. C., Cates, H. M., Purushothaman, I., Lorsch, Z. S., Walker, D. M., Wang, J., Huang, X., Schlüter, O. M., Maze, I., Peña, C. J., Heller, E. A., Issler, O., Wang, M., Song, W. M., Stein, J. L., Liu, X., Doyle, M. A., Scobie, K. N., Sun, H. S., … Nestler, E. J. (2016). Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility. Neuron, 90(5), 969–983. https://doi.org/10.1016/j.neuron.2016.04.015

 PubMed Web of Science ®Google Scholar

Labonté, B., Engmann, O., Purushothaman, I., Menard, C., Wang, J., Tan, C., Scarpa, J. R., Moy, G., Loh, Y.-H E., Cahill, M., Lorsch, Z. S., Hamilton, P. J., Calipari, E. S., Hodes, G. E., Issler, O., Kronman, H., Pfau, M., Obradovic, A. L. J., Dong, Y., … Nestler, E. J. (2017). Sex-specific transcriptional signatures in human depression. Nature Medicine, 23(9), 1102–1111. https://doi.org/10.1038/nm.4386

 PubMed Web of Science ®Google Scholar

Bondar, N., Bryzgalov, L., Ershov, N., Gusev, F., Reshetnikov, V., Avgustinovich, D., Tenditnik, M., Rogaev, E., & Merkulova, T. (2018). Molecular adaptations to social defeat stress and induced depression in mice. Molecular Neurobiology, 55(4), 3394–3407. https://doi.org/10.1007/s12035-017-0586-3

 PubMed Web of Science ®Google Scholar

Laine, M. A., Trontti, K., Misiewicz, Z., Sokolowska, E., Kulesskaya, N., Heikkinen, A., Saarnio, S., Balcells, I., Ameslon, P., Greco, D., Mattila, P., Ellonen, P., Paulin, L., Auvinen, P., Jokitalo, E., & Hovatta, I. (2018). Genetic control of myelin plasticity after chronic psychosocial stress. eNeuro, 5(4), ENEURO.0166-18.2018. https://doi.org/10.1523/ENEURO.0166-18.2018

 Google Scholar

Cheng, Y., Sun, M., Chen, L., Li, Y., Lin, L., Yao, B., Li, Z., Wang, Z., Chen, J., Miao, Z., Xin, N., Huang, L., Allen, E. G., Wu, H., Xu, X., & Jin, P. (2018). Ten-eleven translocation proteins modulate the response to environmental stress in mice. Cell Reports, 25(11), 3194–3203.e4. https://doi.org/10.1016/j.celrep.2018.11.061

 PubMed Web of Science ®Google Scholar

Wang, X., Ma, S., Mao, M., Li, C., Shen, X., Xu, S., & Yang, J. (2019). RNA-sequencing and bioinformatics analysis of long noncoding RNAs and mRNAs in the prefrontal cortex of mice following repeated social defeat stress. BioMed Research International, 2019, 7505260.

 PubMed Web of Science ®Google Scholar

Weger, M., Alpern, D., Cherix, A., Ghosal, S., Grosse, J., Russeil, J., Gruetter, R., de Kloet, E. R., Deplancke, B., & Sandi, C. (2020). Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress. Scientific Reports, 10(1), 18308. https://doi.org/10.1038/s41598-020-75326-9

 PubMed Web of Science ®Google Scholar

Data availability statement

All data generated or analyzed during this study are freely available on the NCBI GEO website. Accession details have been included in Table 1. Scripts for analysis of data are available on request.