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Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development
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Abstract
Structural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for functional network activity remains unknown, primarily due to experimental inaccessibility of the initial stages of the living human brain. Here, we developed human cortical organoids that dynamically change cellular populations during maturation and exhibited consistent increases in electrical activity over the span of several months. The spontaneous network formation displayed periodic and regular oscillatory events that were dependent on glutamatergic and GABAergic signaling. The oscillatory activity transitioned to more spatiotemporally irregular patterns, and synchronous network events resembled features similar to those observed in preterm human electroencephalography. These results show that the development of structured network activity in a human neocortex model may follow stable genetic programming. Our approach provides opportunities for investigating and manipulating the role of network activity in the developing human cortex.
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“This is in contrast with data obtained using neural organoids in vitro or following transplantation (Mansour et al., 2018, Trujillo et al., 2019), which show highly correlated activity indicative of circuit immaturity.”
From Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits (2019) · cites this paper as Trujillo et al., 2019
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“With their 3D structures and cell components resembling the human brain, these organoids can replicate the complex brain microenvironment better than 2D in vitro models (15–17, 19)”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [17]
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“The cells projected on the UMAP space were annotated using canonical marker genes for neurons, progenitors, intermediate progenitors, astrocytes, other glial cells, and monocytes (17, 84, 85).”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [17]
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“Human brain organoids are 3D cultures derived from human pluripotent stem cells and recapitulate native brain cellular components, cytoarchitecture, and exhibit neural activity.22–24”
From Tubular human brain organoids to model microglia-mediated neuroinflammation (2021) · cites this paper as [24]
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“Human brain organoids are emerging as a scaled-down, three-dimensional model of the human brain, mimicking various developmental features, including generation of new neurons by their conversion from radial glia20 and incorporation into neuronal network21.”
From Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB (2021) · cites this paper as [21]
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Metadata
- Authors
- Trujillo, C. A., Gao, R., Negraes, P. D., Gu, J., Buchanan, J., Preissl, S., Wang, A., Wu, W., Haddad, G. G., Chaim, I. A., Domissy, A., Vandenberghe, M., Devor, A., Yeo, G. W., Voytek, B., & Muotri, A. R.
- Affiliations
- University of California San Diego (US)
- Harvard University (US)
- Corresponding author
- Muotri, Alysson R.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 25
- Issue
- 4
- Pages
- 558-569.e7
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC6778040
- OpenAlex
- W2970454553
- Cited by
- 974
- References
- 80
- Citations by year
- 2026: 131 · 2025: 148 · 2024: 186 · 2023: 110 · 2022: 131 · 2021: 131 · 2020: 98 · 2019: 32
- FWCI
- 57.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- California Institute for Regenerative Medicine (DISC1-08825, DISC2-09649)
- Whitehall Foundation (2017-12-73)
- National Institutes of Health (U19MH1073671, R01MH108528, R01MH109885, R01MH100175, R56MH109587, R01MH094753)
- National Alliance for Research on Schizophrenia and Depression
- Simons Foundation Autism Research Initiative (345469)
- Natural Sciences and Engineering Research Council of Canada
- School of Medicine, University of California, San Diego
- University of California, San Diego
- Foundation for the National Institutes of Health (/NIGMS K12 GM068524, K12 GM068524, U19MH1073671)
- Kavli Institute for Brain and Mind, University of California, San Diego
- Spectrum Pharmaceuticals
- National Science Foundation (1736028)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- cortical organoids, human brain development, network activity, glutamatergic signaling, GABAergic neurotransmission, developmental programming, functional brain networks
- MeSH terms
- Biological Clocks, Cells, Cultured, Cerebellar Cortex, gamma-Aminobutyric Acid, Humans, Nerve Net, Synaptic Transmission, Organoids, Signal Transduction, Neocortex, Gene Expression Profiling, Neurogenesis, Induced Pluripotent Stem Cells, Single-Cell Analysis, Electromagnetic Radiation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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