美国西奈山伊坎医学院Rachel Yehuda，Kristen J. Brennand和美国纽约干细胞基金会研究所Daniel Paull合作，近期取得重要工作进展，他们研究利用人类神经元对PTSD基因和环境相互作用进行建模，揭示了诊断特异性糖皮质激素诱导的基因表达。相关论文2022年10月20日在线发表于《自然—神经科学》杂志上。

研究人员比较了人类诱导多能干细胞（hiPSC）来源的谷氨酸神经元和外周血单核细胞（PBMCs），对氢化可的松（hydrocortisone）暴露的转录反应，这些细胞来自患有PTSD的退伍军人（n=19 hiPSC和n=20 PBMC捐赠者）和对照组（n=20 hiPSC和n=20 PBMC捐赠者）。仅在神经元中，研究人员观察到诊断特异性糖皮质激素诱导的基因表达变化，与人类死后大脑中发现的PTSD特异性转录组模式相对应。

他们观察到创伤后应激障碍神经元的糖皮质激素过敏，并确定了有助于这种创伤后应激障碍依赖糖皮质激素反应的基因。他们发现创伤后应激障碍中存在转录因子的共同调节网络，介导糖皮质激素的高反应性。这些发现表明，诱导神经元为研究PTSD的分子机制、识别应激反应的生物标志物，以及进行药物筛选以确定新的治疗方法提供了平台。

据介绍，创伤后应激障碍（PTSD）可在严重创伤后发生，但基因和环境风险因素对个体临床结果的影响程度尚不清楚。

附：英文原文

Title: Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression

Author: Seah, Carina, Breen, Michael S., Rusielewicz, Tom, Bader, Heather N., Xu, Changxin, Hunter, Christopher J., McCarthy, Barry, Deans, P. J. Michael, Chattopadhyay, Mitali, Goldberg, Jordan, Desarnaud, Frank, Makotkine, Iouri, Flory, Janine D., Bierer, Linda M., Staniskyte, Migle, Noggle, Scott A., Huckins, Laura M., Paull, Daniel, Brennand, Kristen J., Yehuda, Rachel

Issue&Volume: 2022-10-20

Abstract: Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown. Here, we compared transcriptional responses to hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD (n=19 hiPSC and n=20 PBMC donors) and controls (n=20 hiPSC and n=20 PBMC donors). In neurons only, we observed diagnosis-specific glucocorticoid-induced changes in gene expression corresponding with PTSD-specific transcriptomic patterns found in human postmortem brains. We observed glucocorticoid hypersensitivity in PTSD neurons, and identified genes that contribute to this PTSD-dependent glucocorticoid response. We find evidence of a coregulated network of transcription factors that mediates glucocorticoid hyper-responsivity in PTSD. These findings suggest that induced neurons represent a platform for examining the molecular mechanisms underlying PTSD, identifying biomarkers of stress response, and conducting drug screening to identify new therapeutics.

DOI: 10.1038/s41593-022-01161-y

Source: https://www.nature.com/articles/s41593-022-01161-y