Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
The Razavi Newman Integrative Genomics and Bioinformatics Core (IGC), The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA.
Transl Psychiatry. 2021 Nov 30;11(1):608. doi: 10.1038/s41398-021-01733-9.
Major depressive disorder (MDD) is a prevalent psychiatric disorder, and exposure to stress is a robust risk factor for MDD. Clinical data and rodent models have indicated the negative impact of chronic exposure to stress-induced hormones like cortisol on brain volume, memory, and cell metabolism. However, the cellular and transcriptomic changes that occur in the brain after prolonged exposure to cortisol are less understood. Furthermore, the astrocyte-specific contribution to cortisol-induced neuropathology remains understudied. Here, we have developed an in vitro model of "chronic stress" using human induced pluripotent stem cell (iPSC)-derived astrocytes treated with cortisol for 7 days. Whole transcriptome sequencing reveals differentially expressed genes (DEGs) uniquely regulated in chronic cortisol compared to acute cortisol treatment. Utilizing this paradigm, we examined the stress response transcriptome of astrocytes generated from MDD patient iPSCs. The MDD-specific DEGs are related to GPCR ligand binding, synaptic signaling, and ion homeostasis. Together, these data highlight the unique role astrocytes play in the central nervous system and present interesting genes for future study into the relationship between chronic stress and MDD.
重度抑郁症（MDD）是一种常见的精神疾病，而暴露于压力是 MDD 的一个强有力的风险因素。临床数据和啮齿动物模型表明，长期暴露于应激激素（如皮质醇）会对大脑体积、记忆和细胞代谢产生负面影响。然而，皮质醇长期暴露后大脑中发生的细胞和转录组变化还不太清楚。此外，星形胶质细胞对皮质醇诱导的神经病理学的特定贡献仍研究不足。在这里，我们使用皮质醇处理 7 天的人诱导多能干细胞（iPSC）衍生的星形胶质细胞开发了一种“慢性应激”的体外模型。全转录组测序揭示了与急性皮质醇处理相比，慢性皮质醇处理中独特调控的差异表达基因（DEGs）。利用这一范例，我们检查了来自 MDD 患者 iPSC 产生的星形胶质细胞的应激反应转录组。MDD 特异性 DEGs 与 GPCR 配体结合、突触信号和离子稳态有关。总之，这些数据突出了星形胶质细胞在中枢神经系统中的独特作用，并为进一步研究慢性应激与 MDD 之间的关系提供了有趣的基因。
