Transcriptomic profiles of susceptibility and resilience to stress in the amygdala and hippocampus of male rats

Traumatic experiences elicit a wide range of cognitive responses in both humans and animals, leading to diverse outcomes such as enhanced performance, cognitive impairment, or the development of mood and anxiety disorders like posttraumatic stress disorder (PTSD). A key challenge in understanding these varied responses is to decipher the underlying biological mechanisms that contribute to individual variability in trauma resilience or susceptibility. The purpose of this study was to elucidate the molecular bases for these differences, focusing on the amygdala and hippocampus—brain regions integral to stress responses. We exposed adult, male rats to an acute, severe stressor and profiled persistent anxiety-like behavior outcomes 7 days later. We investigated the transcriptional signatures in the basolateral amygdala and hippocampal dentate gyrus via bulk RNA sequencing from animals with behavioral outcomes indicative of stress resilience or vulnerability. Our results suggest that the basolateral amygdala and dentate gyrus display distinct transcriptomic changes following acute, severe stress. Furthermore, we identified specific region-dependent genes related to insulin signaling, neural plasticity, and stress responses that correlate with each phenotype. Notably, a larger number of genes separated stress-resilient animals from both control and stress-susceptible animals, underscoring that an active molecular response, particularly in the hippocampus, facilitates protection from the long-term consequences of severe stress. These findings provide novel insight into the mechanisms that engender individual variability in the behavioral responses to stress and offer new targets for the advancement of therapies for stress-induced neuropsychiatric disorders.创伤性经历可在人类与动物体内引发广泛的认知反应，进而催生多样化结局，包括认知表现提升、认知损伤，或是出现情绪与焦虑障碍，例如创伤后应激障碍（posttraumatic stress disorder, PTSD）。理解这类多样化反应的核心挑战，在于破译驱动创伤韧性与易感性个体差异的潜在生物学机制。本研究旨在阐明此类差异的分子基础，重点关注参与应激反应的核心脑区——杏仁核与海马体。我们将成年雄性大鼠暴露于急性重度应激原，并于7天后对其持续类焦虑行为结局进行表征分析。我们通过批量RNA测序（bulk RNA sequencing），对表现出应激韧性或易感性行为表型的动物的基底外侧杏仁核与海马齿状回的转录特征展开研究。研究结果显示，急性重度应激后，基底外侧杏仁核与齿状回呈现出截然不同的转录组变化。此外，我们鉴定出与胰岛素信号通路、神经可塑性及应激反应相关的特定区域依赖性基因，这类基因与对应行为表型存在显著关联。值得注意的是，有更多基因可将应激韧性动物与对照组及应激易感动物区分开来，这进一步表明，主动的分子应答（尤其是在海马体中）可助力机体抵御重度应激带来的长期不良后果。本研究结果为阐释应激行为反应个体差异的潜在机制提供了全新视角，并为应激诱导的神经精神障碍的治疗手段开发提供了新靶点。