Multi-omics characterization of chronic social defeat stress recall-activated nuclei in Arc-GFP mice

Susceptibility to chronic social stressors often results in the development of mental health disorders including major depressive and anxiety disorders. In contrast, some individuals remain resilient even after repeated stress exposure. Understanding the molecular drivers underlying these divergent phenotypic outcomes is crucial. However, previous studies using the chronic social defeat (CSD) stress model have been limited by the use of bulk tissues investigating single omics domains. To overcome these limitations, here, we applied the CSD mouse model to Arc-GFP mice for investigating the mechanistic divergence between susceptibility and resilience, specifically in stress recall-activated nuclei. By conducting an in-depth analysis of the less-known differential methylome landscape in the ventral hippocampus, we noted unique phenotype-specific alterations in multiple biological processes with an overrepresentation of GTPase-related mechanisms. Interestingly, the differentially methylated regions were enriched in ETS transcription factor binding sites (TFBSs), important targets of the Ras-ETS signaling pathway. This differential methylation in the ETS TFBSs could form the basis of persisting stress effects long after stressor exposure. Furthermore, by integrating the methylome modifications with transcriptomic alterations, we resolved the GTPase-related mechanisms differentially activated in the resilient and susceptible phenotypes with alterations in endocytosis overrepresented in the susceptible phenotype. Overall, our findings reveal novel insights underlying the divergence of resilience versus susceptibility.

个体对慢性社会应激源的易感性常可导致精神健康障碍的发生，包括重性抑郁障碍与焦虑障碍。与之相反，部分个体在反复应激暴露后仍能保持心理韧性。阐明驱动这两种截然不同表型结局的分子机制，具有重要意义。然而，既往基于慢性社会挫败（chronic social defeat, CSD）应激模型的研究，多采用整体组织样本开展单一组学维度的分析，存在一定局限性。为克服上述不足，本研究将CSD小鼠模型应用于Arc基因绿色荧光蛋白（Arc-GFP）小鼠，以探究应激回忆激活的细胞核中，易感性与韧性表型的机制差异。通过对腹侧海马体中尚少被关注的差异甲基化组谱进行深入分析，我们发现不同表型在多种生物学过程中存在独特的改变，且GTP酶相关机制的富集程度显著升高。有趣的是，差异甲基化区域在ETS家族转录因子结合位点（ETS transcription factor binding sites, TFBSs）中显著富集，而后者是Ras-ETS信号通路的重要靶点。上述ETS结合位点的差异甲基化，或可成为应激暴露后长期持续存在的应激效应的分子基础。此外，通过将甲基化组修饰与转录组变化进行整合分析，我们明确了韧性与易感表型中差异激活的GTP酶相关机制，其中易感表型的胞吞作用富集程度显著升高。综上，本研究为韧性与易感性的表型分化机制提供了全新的见解。