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Single-cell transcriptomics reveals Sox6 positive interneurons enriched in the prefrontal cortex of female mice vulnerable to chronic social stress

Molecular Psychiatry (2025)Cite this article

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Abstract

Major depressive disorder (MDD) is a prevalent mental illness that significantly impacts global health, with women showing twice the prevalence of men. This study employed the chronic social defeat stress (CSDS) model in female mice to investigate cellular and molecular changes in the prefrontal cortex (PFC) associated with depressive-like behaviors. Using single-nucleus RNA sequencing (snRNA-Seq), we examined transcriptomic alterations across various cell types in the PFC. Our results revealed that interneurons exhibited the most significant transcriptomic changes among all analyzed cell types. Notably, we found the Sox6+ interneurons (Sox6+Int) were enriched in the CSDS susceptible group. This enrichment was associated with enhanced inflammatory and immune responses, as well as alterations in synaptic function and mitochondrial pathways. Furthermore, we observed significant changes in cell-cell communication patterns, particularly between Sox6+Int and oligodendrocyte precursor cells (OPC). Weighted gene co-expression network analysis (WGCNA) identified several gene modules in Sox6+Int associated with specific depressive-like behaviors, implicating pathways related to inflammation, autophagy, and synaptic function. In particular, specific knockdown of Sox6 in neurons reversed the depressive-like behaviors. These findings provide novel insights into the cellular and molecular mechanisms underlying MDD in females, highlighting the potential role of Sox6+Int in stress-induced depression. Our study not only extends our understanding of the neurobiological basis of depression but also identifies potential therapeutic targets for sex-specific interventions in MDD treatment.

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Fig. 1: Construction of the CSDS model.
Fig. 2: Identification of cell types.
Fig. 3: Cell type-specific DEGs changes and enrichment pathways.
Fig. 4: Interneuron (Int) subtypes identification and specific functions.
Fig. 5: The hub of Sox6+Int in the CSDS model.
Fig. 6: Specifically knocked down Sox6 in neurons ameliorated depressive-like behaviors.

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Data availability

All data reported in this paper will be shared by the lead contact upon request. All raw sequencing data generated by this study are available in the Gene Expression Omnibus (GEO) repository under the accession number GSE291951.

Code availability

Code reported in this paper will be shared by the lead contact upon request.

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Acknowledgements

This work was supported by the National Key R&D Program of China (STI2030-Major Projects 2021ZD0202400, STI2030-Major Projects 2021ZD0200600), the Natural Science Foundation Project of China (82171523, 82471545, 82401784, 32400850, 82401523, 82201688), National Reserve Talent Project in the Health and Wellness Sector of Chongqing (HBRC202410, HBRC202417), China Postdoctoral Science Foundation (2024MD754023), Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJZD-K202400404).

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  1. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Guojing Ma, Jing Wu, Yiyuan Wu, Jie Yang, Jianping Zhang, Yu Huang, Ruimin Tian, Xingyu Zhou, Xunmin Tan, Yifan Li, Ping Liu, Minghao Yuan, Xiaodong Song & Peng Zheng

  2. Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China

    Guojing Ma, Jing Wu, Yiyuan Wu, Jie Yang, Jianping Zhang, Yu Huang, Ruimin Tian, Xingyu Zhou, Xunmin Tan, Yifan Li, Ping Liu, Minghao Yuan, Xiaodong Song & Peng Zheng

  3. Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, China

    Guojing Ma, Jing Wu, Yiyuan Wu, Jie Yang, Jianping Zhang, Yu Huang, Ruimin Tian, Xingyu Zhou, Xunmin Tan, Yifan Li, Ping Liu, Minghao Yuan, Xiaodong Song & Peng Zheng

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

    Ma-Li Wong & Julio Licinio

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Contributions

PZ designed experiments. GJM, JW, JY and XYZ performed analysis and computation. GJM, YH and XMT performed all experiments. GJM, RMT and YYW constructed the animal model. GJM and JPZ created figures and drafted the manuscript. PZ, JW, JPZ, YH and XDS provided the fundings. YFL, PL and MHY performed data quality control. PZ, MLW and JL revised the manuscript for intellectual content. All authors reviewed and revised the final manuscript before submitting the manuscript.

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Correspondence to Peng Zheng.

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All animal studies and experimental procedures were approved by the Animal Care and Use Committee of Chongqing Medical University (IACUC-CQMU-2023-0145), all methods were carried out in accordance with the relevant guidelines and regulations.

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Ma, G., Wu, J., Wu, Y. et al. Single-cell transcriptomics reveals Sox6 positive interneurons enriched in the prefrontal cortex of female mice vulnerable to chronic social stress. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03088-9

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