Abstract：
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.
摘要：
多脑区域起源和焦虑性二态的分子机制尚不清楚。这里,我们利用小鼠焦虑模型中7个脑区的大规模转录组学和广泛的实验来解剖脑-区域和性别特异性基因网络.我们确定了4,840个基因在七个大脑区域具有性别特异性表达改变，组织成十个具有性别偏见表达模式的网络模块。模块化分析优先考虑86种性别特异性焦虑易感性介质，包括雄性小鼠CA3区域中的肌细胞特异性增强因子2c(Mef2c)。在易感雄性小鼠的锥体神经元(PyNs)中,Mef2c表达降低。在CA3Pyns中上调Mef2c可显着缓解焦虑样行为，而下调Mef2c在雄性小鼠中诱导焦虑样行为。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,这项研究揭示了大脑区域和性别特异性网络，并确定了CA3PyNs中的Mef2c是雄性小鼠焦虑的关键介质。
