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

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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, Ma-Li Wong, Julio Licinio, Peng Zheng
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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.

单细胞转录组学显示,易受慢性社会压力影响的雌性小鼠前额叶皮层中富集了Sox6阳性中间神经元
重度抑郁症(MDD)是一种严重影响全球健康的普遍精神疾病,女性的患病率是男性的两倍。本研究采用雌性小鼠慢性社会失败应激(CSDS)模型,研究与抑郁样行为相关的前额叶皮层(PFC)的细胞和分子变化。利用单核RNA测序(snRNA-Seq),研究人员检测了pfc中不同细胞类型的转录组变化。结果显示,在所有分析的细胞类型中,中间神经元表现出最显著的转录组变化。值得注意的是,我们发现Sox6+中间神经元(Sox6+Int)在CSDS易感组中富集。这种富集与炎症和免疫反应增强以及突触功能和线粒体通路的改变有关。此外,我们观察到细胞间通信模式的显著变化,特别是在Sox6+Int和少突胶质前体细胞(OPC)之间。加权基因共表达网络分析(WGCNA)确定了Sox6+Int中与特定抑郁样行为相关的几个基因模块,暗示了与炎症、自噬和突触功能相关的途径。特别是,神经元中Sox6的特异性敲低逆转了类似抑郁的行为。这些发现为女性MDD的细胞和分子机制提供了新的见解,强调了Sox6+Int在应激性抑郁症中的潜在作用。我们的研究不仅扩展了我们对抑郁症的神经生物学基础的理解,而且还确定了在重度抑郁症治疗中性别特异性干预的潜在治疗靶点。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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