biostudies-literatureMeyer KNIA NIH HHSNIMH NIH HHSThe Ludwig Foundation, The Robert and Renee Belfer Family FoundationU.S. Department of Health & Human Services | NIH | National Institute of Mental HealthU.S. Department of Health & Human Services | National Institutes of Health153-164https://www.ebi.ac.uk/biostudies/studies/S-EPMC11964151biostudies-literatureUnknown29(1)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 ameliorateMolecular psychiatryImpaired neural stress resistance and loss of REST in bipolar disorder.PMC11964151R01 MH113279R21 MH093958P50 MH106933RF1-AG048029R01 AG069042RO1MH113279RF1 AG048029U24 MH068457Yankner BATam JMLing KHSpathopoulou AMeyer KDrake DChoi JYeo PLChurch GMAron LGarcia-Corral MPerlis RHTsai LHKo TLee EAfalseImpaired neural stress resistance and loss of REST in bipolar disorder.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 ameliorate2024-01-01T00:00:00Z2024 Jan2026-06-02T06:50:51.64Z2025-07-12T03:04:37.955ZS-EPMC119641513793876710.1038/s41380-023-02313-7