神经发育变化和应激抵抗力受损与双相情感障碍（BD）的发病机制有关，但潜在的调节机制尚未解决。在这里，我们描述了 BD 的人类大脑类器官模型，该模型表现出神经发育改变、神经网络活动升高以及转录组的重大变化。这些表型变化在不同实验室的 iPS 细胞系生成的大脑类器官中得到了重现。 BD 大脑类器官转录组显示转录抑制因子 REST 的基因靶标高度显着富集。这与核 REST 和 REST 与靶基因识别位点的结合减少有关。将类器官培养物中的氧浓度降低至生理范围可改善发育表型并恢复 REST 表达。这些效果可以通过锂处理来模拟。在 BD 患者的前额皮质中也观察到核 REST 减少和 REST 靶基因去抑制。因此，BD 脑类器官中细胞应激反应受损会导致神经发育改变以及与 REST 下调相关的转录失调。这些发现为探索 BD 的分子基础提供了新的模型和概念框架。© 2023。作者，获得 Springer Nature Limited 的独家许可。

Neurodevelopmental changes and impaired stress resistance have been implicated in the pathogenesis of bipolar disorder (BD), but the underlying regulatory mechanisms are unresolved. Here we describe a human cerebral organoid model of BD that exhibits altered neural development, elevated neural network activity, and a major shift in the transcriptome. These phenotypic changes were reproduced in cerebral organoids generated from iPS cell lines derived in different laboratories. The BD cerebral organoid transcriptome showed highly significant enrichment for gene targets of the transcriptional repressor REST. This was associated with reduced nuclear REST and REST binding to target gene recognition sites. Reducing the oxygen concentration in organoid cultures to a physiological range ameliorated the developmental phenotype and restored REST expression. These effects were mimicked by treatment with lithium. Reduced nuclear REST and derepression of REST targets genes were also observed in the prefrontal cortex of BD patients. Thus, an impaired cellular stress response in BD cerebral organoids leads to altered neural development and transcriptional dysregulation associated with downregulation of REST. These findings provide a new model and conceptual framework for exploring the molecular basis of BD.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.