期刊
NATURE NEUROSCIENCE
卷 24, 期 10, 页码 1488-1500出版社
NATURE PORTFOLIO
DOI: 10.1038/s41593-021-00906-5
关键词
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资金
- California Institute for Regenerative Medicine (CIRM) [DISC1-08819]
- National Institute of Health [R01NS089817, R01DA051897, K08NS119747, K99HD096105, R01MH123922, R01MH121521, P50HD103557, R01GM099134, R01NS103788, R01NS088571, R01NS030549, R01AG050474]
- UCLA Jonsson Comprehensive Cancer Center
- BSCRC Ablon Scholars Program
- BSCRC Innovation Program
- UCLA BSCRC Steffy Brain Aging Research Fund
- UCLA Clinical and Translational Science Institute
- Paul Allen Family Foundation Frontiers Group
- March of Dimes Foundation
- Simons Foundation Autism Research Initiative Bridge
- UCLA/NINDS Translational Neuroscience Training Grant [R25NS065723]
- American Epilepsy Society
- CURE Epilepsy
- UCLA BSCRC
- UCLA BSCRC Rose Hills Foundation Graduate Scholarship Training Program
- Uehara Memorial Foundation
- UCLA-California State University Northridge CIRM-Bridges training program [EDUC2-08411]
- Semel Institute of Neuroscience at UCLA
- NICHD [U54HD087101, P50HD10355701]
- Quantitative and Computational Biosciences Collaboratory Postdoctoral Fellowship
This paper explores neural network and cellular complexity within human cortical and subcortical fusion organoids, revealing network dysfunction associated with Rett syndrome. The findings demonstrate the potential of brain organoids in modeling human neurological diseases and the utility in therapeutic discovery.
This paper explores neural network and cellular complexity within human cortical and subcortical fusion organoids. The platform is used to model network dysfunction associated with Rett syndrome and to identify new therapeutic candidates. Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network-level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-alpha. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.
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