Genetic susceptibility and environmental factors (such as stress) can interact to affect the likelihood of developing a mood disorder. Stress-induced changes in the hippocampus have been implicated in mood disorders, and mutations in several genes have now been associated with increased risk, such as brain-derived neurotrophic factor (BDNF). The hippocampus has important anatomical subdivisions, and pyramidal neurons of the vulnerable CA3 region show significant remodeling after chronic stress, but the mechanisms underlying their unique plasticity remain unknown. This study characterizes stress-induced changes in the in vivo translating mRNA of this cell population using a CA3-specific enhanced green fluorescent protein (EGFP) reporter fused to the L10a large ribosomal subunit (EGFPL10a). RNA-sequencing after isolation of polysome-bound mRNAs allows for cell-type-specific, genome-wide characterization of translational changes after stress. The data demonstrate that acute and chronic stress produce unique translational profiles and that the stress history of the animal can alter future reactivity of CA3 neurons. CA3-specific EGFPL10a mice were then crossed to the stress-susceptible BDNF Val66Met mouse line to characterize how a known genetic susceptibility alters both baseline translational profiles and the reactivity of CA3 neurons to stress. Not only do Met allele carriers exhibit distinct levels of baseline translation in genes implicated in ion channel function and cytoskeletal regulation, but they also activate a stress response profile that is highly dissimilar from wild-type mice. Closer examination of genes implicated in the mechanisms of neuroplasticity, such as the NMDA and AMPA subunits and the BDNF pathway, reveal how wild-type mice upregulate many of these genes in response to stress, but Met allele carriers fail to do so. These profiles provide a roadmap of stress-induced changes in a genetically homogenous population of hippocampal neurons and illustrate the profound effects of gene-environment interactions on the translational profile of these cells.

中文翻译：

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BDNF Val66Met小鼠CA3锥体神经元中应激诱导的神经可塑性的翻译谱。

遗传易感性和环境因素（例如压力）可能相互作用，从而影响患上情绪障碍的可能性。应激引起的海马体改变与情绪障碍有关，并且几种基因的突变现在与增加的风险相关，例如脑源性神经营养因子（BDNF）。海马具有重要的解剖结构，在慢性应激后，脆弱的CA3区的锥体神经元显示出明显的重塑，但其独特可塑性的机制仍不清楚。这项研究使用融合到L10a大核糖体亚基（EGFPL10a）的CA3特异性增强型绿色荧光蛋白（EGFP）报告基因表征了应激诱导的该细胞群体体内翻译mRNA的变化。分离结合多核糖体的mRNA后进行RNA测序，可以对应激后的翻译变化进行细胞类型特异性，全基因组表征。数据表明，急性和慢性应激会产生独特的翻译谱，并且动物的应激史可以改变CA3神经元的未来反应性。然后将CA3特异性EGFPL10a小鼠与易受压力的BDNF Val66Met小鼠品系杂交，以表征已知的遗传易感性如何改变基线翻译谱和CA3神经元对压力的反应性。Met等位基因携带者不仅在涉及离子通道功能和细胞骨架调控的基因中表现出不同水平的基线翻译，而且还激活了与野生型小鼠完全不同的应激反应谱。仔细检查涉及神经可塑性机制的基因，例如NMDA和AMPA亚基以及BDNF途径，揭示了野生型小鼠如何在应激反应中上调许多这些基因，但Met等位基因携带者却不能。这些概况提供了海马神经元的遗传同质种群中应激诱导的变化的路线图，并说明了基因-环境相互作用对这些细胞的翻译概况的深远影响。