Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
School of Life Science and Technology, Chongqing Innovation Institute of China Pharmaceutical University, China Pharmaceutical University, Nanjing, China.
Cell Rep. 2024 Jul 23;43(7):114455. doi: 10.1016/j.celrep.2024.114455. Epub 2024 Jul 9.
The molecular mechanisms underlying multi-brain region origins and sexual dimorphism of anxiety remain unclear. Here, we leverage large-scale transcriptomics from seven brain regions in mouse models of anxiety and extensive experiments to dissect brain-region- and sex-specific gene networks. We identify 4,840 genes with sex-specific expression alterations across seven brain regions, organized into ten network modules with sex-biased expression patterns. Modular analysis prioritizes 86 sex-specific mediators of anxiety susceptibility, including myocyte-specific enhancer factor 2c (Mef2c) in the CA3 region of male mice. Mef2c expression is decreased in the pyramidal neurons (PyNs) of susceptible male mice. Up-regulating Mef2c in CA3 PyNs significantly alleviates anxiety-like behavior, whereas down-regulating Mef2c induces anxiety-like behavior in male mice. The anxiolytic effect of Mef2c up-regulation is associated with enhanced neuronal excitability and synaptic transmission. In summary, this study uncovers brain-region- and sex-specific networks and identifies Mef2c in CA3 PyNs as a critical mediator of anxiety in male mice.
焦虑的多脑区起源和性别二态性的分子机制尚不清楚。在这里，我们利用焦虑症小鼠模型的七个脑区的大规模转录组学和广泛的实验来剖析脑区和性别特异性的基因网络。我们确定了 4840 个在七个脑区具有性别特异性表达改变的基因，这些基因被组织成十个具有性别偏倚表达模式的网络模块。模块化分析优先考虑了 86 个焦虑易感性的性别特异性介质，包括雄性小鼠 CA3 区的肌细胞特异性增强因子 2c（Mef2c）。易感性雄性小鼠 CA3 区的 Mef2c 表达减少。在 CA3 锥体神经元 (PyNs) 中上调 Mef2c 可显著缓解焦虑样行为，而下调 Mef2c 则会导致雄性小鼠出现焦虑样行为。Mef2c 上调的抗焦虑作用与增强的神经元兴奋性和突触传递有关。总之，这项研究揭示了脑区和性别特异性的网络，并确定 CA3 PyNs 中的 Mef2c 是雄性小鼠焦虑的关键介质。
