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Alternative splicing in mouse brains affected by psychological stress is enriched in the signaling, neural transmission and blood-brain barrier pathways

Molecular Psychiatry volume 28, pages 4707–4718 (2023)Cite this article

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Abstract

Psychological stress increases the risk of major psychiatric disorders. Psychological stress on mice was reported to induce differential gene expression (DEG) in mice brain regions. Alternative splicing is a fundamental aspect of gene expression and has been associated with psychiatric disorders but has not been investigated in the stressed brain yet. This study investigated changes in gene expression and splicing under psychological stress, the related pathways, and possible relationship with psychiatric disorders. RNA-seq raw data of 164 mouse brain samples from 3 independent datasets with stressors including chronic social defeat stress (CSDS), early life stress (ELS), and two-hit stress of combined CSDS and ELS were collected. There were more changes in splicing than in gene expression in the ventral hippocampus and medial prefrontal cortex, but stress-induced changes of individual genes by differential splicing and differential expression could not be replicated. In contrast, pathway analyses produced robust findings: stress-induced differentially spliced genes (DSGs) were reproducibly enriched in neural transmission and blood-brain barrier systems, and DEGs were reproducibly enriched in stress response-related functions. The hub genes of DSG-related PPI networks were enriched in synaptic functions. The corresponding human homologs of stress-induced DSGs were robustly enriched in AD-related DSGs as well as BD and SCZ in GWAS. These results suggested that stress-induced DSGs from different datasets belong to the same biological system throughout the stress response process, resulting in consistent stress response effects.

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Fig. 1: Overview of the study.
Fig. 2: Top enriched biological processes for DSGs and the enriched KEGG pathways for DSGs.
Fig. 3: The hub genes in DSG-related PPI networks and their functional annotations.
Fig. 4: Functional annotations for hub genes in DEG-related PPI networks.
Fig. 5: Enrichment of DSGs in psychiatric disorder-related candidate genes and GWAS genes.
Fig. 6: The enrichment of CSDS-induced DSGs in tight junction pathway from different datasets in vHIP.

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Code availability

The code of this work is provided at https://github.com/Fefe-W/Psychological-stress.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grants Nos. 82022024, 31970572, 31871276), the National Key R&D Project of China (Grants No. 2016YFC1306000 and 2017YFC0908701), Innovation-driven Project of Central South University (Grant Nos. 2020CX003), The science and technology innovation Program of Hunan Province (2021RC4018, 2021RC5027). NIH grants U01 MH122591, 1U01MH116489, 1R01MH110920, R01MH126459. This work was supported in part by the High Performance Computing Center of Central South University. We thank Richard F. Kopp for revising.

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  1. Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China

    Feiran Wang, Xiuju Yang, Zongyao Ren, Chao Chen & Chunyu Liu

  2. National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, China

    Chao Chen

  3. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China

    Chao Chen

  4. Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, 13210, USA

    Chunyu Liu

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CC and CL designed the study and interpreted the results. FW, XY, and ZR collected the datasets. FW preprocessed the datasets and performed all the analyses in this study. All authors read and approved the final version.

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Wang, F., Yang, X., Ren, Z. et al. Alternative splicing in mouse brains affected by psychological stress is enriched in the signaling, neural transmission and blood-brain barrier pathways. Mol Psychiatry 28, 4707–4718 (2023). https://doi.org/10.1038/s41380-023-02103-1

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