BACKGROUND Acutely stressful experiences can trigger neuropsychiatric disorders and impair cognitive processes by altering hippocampal function. Although the intrinsic organization of the hippocampus is highly conserved throughout its long dorsal-ventral axis, the dorsal (anterior) hippocampus mediates spatial navigation and memory formation, whereas the ventral (posterior) hippocampus is involved in emotion regulation. To understand the molecular consequences of stress, detailed genome-wide screens are necessary and need to distinguish between dorsal and ventral hippocampal regions. While transcriptomic screens have become a mainstay in basic and clinical research, proteomic methods are rapidly evolving and hold even greater promise to reveal biologically and clinically relevant biomarkers. METHODS Here, we provide the first combined transcriptomic (RNA sequencing) and proteomic (sequential window acquisition of all theoretical mass spectra [SWATH-MS]) profiling of dorsal and ventral hippocampus in mice. We used three different acute stressors (novelty, swim, and restraint) to assess the impact of stress on both regions. RESULTS We demonstrated that both hippocampal regions display radically distinct molecular responses and that the ventral hippocampus is particularly sensitive to the effects of stress. Separately analyzing these structures greatly increased the sensitivity to detect stress-induced changes. For example, protein interaction cluster analyses revealed a stress-responsive epigenetic network around histone demethylase Kdm6b restricted to the ventral hippocampus, and acute stress reduced methylation of its enzymatic target H3K27me3. Selective Kdm6b knockdown in the ventral hippocampus led to behavioral hyperactivity/hyperresponsiveness. CONCLUSIONS These findings underscore the importance of considering dorsal and ventral hippocampus separately when conducting high-throughput molecular analyses, which has important implications for fundamental research as well as clinical studies.

中文翻译：

---

背侧和腹侧海马中不同的蛋白质组学、转录组学和表观遗传应激反应

背景 急性压力经历可通过改变海马功能引发神经精神障碍并损害认知过程。尽管海马体的内在组织在其长的背腹轴上高度保守，但背侧（前）海马体介导空间导航和记忆形成，而腹侧（后）海马体参与情绪调节。为了了解压力的分子后果，详细的全基因组筛选是必要的，需要区分背侧和腹侧海马区域。虽然转录组筛选已成为基础和临床研究的中流砥柱，但蛋白质组学方法正在迅速发展，并且在揭示生物学和临床相关的生物标志物方面有着更大的希望。方法在这里，我们提供了首次对小鼠背侧和腹侧海马体的转录组学（RNA 测序）和蛋白质组学（所有理论质谱的顺序窗口采集 [SWATH-MS]）组合分析。我们使用了三种不同的急性压力源（新奇、游泳和克制）来评估压力对这两个区域的影响。结果 我们证明，两个海马区域都显示出截然不同的分子反应，并且腹侧海马对压力的影响特别敏感。单独分析这些结构大大提高了检测应力引起的变化的灵敏度。例如，蛋白质相互作用聚类分析揭示了围绕组蛋白去甲基化酶 Kdm6b 的应激反应表观遗传网络仅限于腹侧海马，急性应激降低了其酶靶点 H3K27me3 的甲基化。腹侧海马体中的选择性 Kdm6b 敲低导致行为过度活跃/反应过度。结论 这些发现强调了在进行高通量分子分析时分别考虑背侧和腹侧海马的重要性，这对基础研究和临床研究具有重要意义。