Abstract
SummaryThe cerebrum is a major center for brain function, and its activity is derived from the assembly of activated cells in neural networks. It is currently difficult to study complex human cerebral neuronal network activity. Here, using cerebral organoids, we report self-organized and complex human neural network activities that include synchronized and non-synchronized patterns. Self-organized neuronal network formation was observed following a dissociation culture of human embryonic stem cell-derived cerebral organoids. The spontaneous individual and synchronized activity of the network was measured via calcium imaging, and subsequent analysis enabled the examination of detailed cell activity patterns, providing simultaneous raster plots, cluster analyses, and cell distribution data. Finally, we demonstrated the feasibility of our system to assess drug-inducible dynamic changes of the network activity. The comprehensive functional analysis of human neuronal networks using this system may offer a powerful tool to access human brain function.
Highlights
The cerebrum is the largest and most complex tissue with complexed neural activity (Northcutt and Kaas, 1995)
Recent progress in stem cell technology has enabled the induction of cerebral tissues from human pluripotent stem cells in three dimensions (3D) (Kadoshima et al, 2013; Lancaster et al, 2013; Sasai, 2013a, 2013b)
Since cerebral organoids have the potential to recapitulate at least partially the developmental process of cerebrum formation in 3D, they have enabled the modeling of human cerebral development and cerebrumrelated diseases such as microcephaly, Zika virus infection, glioblastoma, and Timothy syndrome (Birey et al, 2017; Dang et al, 2016; Garcez et al, 2016; Kadoshima et al, 2013; Lancaster et al, 2013; Ogawa et al, 2018; Qian et al, 2016; Quadrato et al, 2017; Watanabe et al, 2017). Despite these recent technical breakthroughs, current cerebral organoid technologies still have significant limitations, especially regarding the functional evaluation of neural network activity, which is indispensable for the examination of human brain function or the modeling of neuropsychiatric disorders
Summary
The cerebrum is the largest and most complex tissue with complexed neural activity (Northcutt and Kaas, 1995). Since cerebral organoids have the potential to recapitulate at least partially the developmental process of cerebrum formation in 3D, they have enabled the modeling of human cerebral development and cerebrumrelated diseases such as microcephaly, Zika virus infection, glioblastoma, and Timothy syndrome (Birey et al, 2017; Dang et al, 2016; Garcez et al, 2016; Kadoshima et al, 2013; Lancaster et al, 2013; Ogawa et al, 2018; Qian et al, 2016; Quadrato et al, 2017; Watanabe et al, 2017) Despite these recent technical breakthroughs, current cerebral organoid technologies still have significant limitations, especially regarding the functional evaluation of neural network activity, which is indispensable for the examination of human brain function or the modeling of neuropsychiatric disorders. Some recent reports have utilized calcium imaging for the characterization of cerebral organoids (Bershteyn et al, 2017; Lancaster et al, 2017; Mansour et al, 2018; Watanabe et al, 2017; Xiang et al, 2017) including the use of high-density silicon microelectrodes to prove network activity in organoids (Mansour et al, 2018; Quadrato et al, 2017), detailed evaluation of the activity in human neural networks has not been achieved
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