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Intrinsic network activity in human brain organoids

View ORCID ProfileTal Sharf, View ORCID ProfileTjitse van der Molen, Elmer Guzman, Stella M.K. Glasauer, Gabriel Luna, Zhouwei Cheng, Morgane Audouard, Kamalini G. Ranasinghe, Kiwamu Kudo, Srikantan S. Nagarajan, Kenneth R. Tovar, Linda R. Petzold, Paul K. Hansma, View ORCID ProfileKenneth S. Kosik
doi: https://doi.org/10.1101/2021.01.28.428643
Tal Sharf
1Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106, USA
2Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA
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Tjitse van der Molen
1Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106, USA
2Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA
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Elmer Guzman
1Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106, USA
2Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA
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Stella M.K. Glasauer
1Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106, USA
2Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA
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Gabriel Luna
1Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106, USA
2Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA
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Zhouwei Cheng
4Department of Computer Science, University of California Santa Barbara, Santa Barbara, CA 93106, USA
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Morgane Audouard
1Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106, USA
2Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA
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Kamalini G. Ranasinghe
5Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA
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Kiwamu Kudo
6Department Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA
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Srikantan S. Nagarajan
6Department Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA
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Kenneth R. Tovar
1Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106, USA
2Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA
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Linda R. Petzold
4Department of Computer Science, University of California Santa Barbara, Santa Barbara, CA 93106, USA
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Paul K. Hansma
1Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106, USA
3Department of Physics, University of California Santa Barbara, Santa Barbara, CA 93106
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Kenneth S. Kosik
1Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106, USA
2Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA
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  • ORCID record for Kenneth S. Kosik
  • For correspondence: kosik@lifesci.ucsb.edu
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Abstract

Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiological behavior of neuronal circuits within organoids remains relatively under-explored. With high-density CMOS microelectrode arrays and shank electrodes, we probed broadband and three-dimensional spontaneous activity of human brain organoids. These recordings simultaneously captured local field potentials (LFPs) and single unit activity. From spiking activity, we estimated a directed functional connectivity graph of synchronous neural network activity which showed a large number of weak functional connections enmeshed within a network skeleton of significantly fewer strong connections. Increasing the intrinsic inhibitory tone with a benzodiazepine altered the functional network graph of the organoid by suppressing the network skeleton. Simultaneously examining the spontaneous LFPs and their phase alignment to spiking showed that spike bursts were coherent with theta oscillations in the LFPs. An ensemble of spikes phase-locked to theta frequency oscillations were strongly interconnected as a sub-network within the larger network in which they were embedded. Our results demonstrate that human brain organoids have self-organized neuronal assemblies of sufficient size, cellular orientation, and functional connectivity to co-activate and generate field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug mechanisms, and the effects of external stimuli upon neuronal networks.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 28, 2021.
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Intrinsic network activity in human brain organoids
Tal Sharf, Tjitse van der Molen, Elmer Guzman, Stella M.K. Glasauer, Gabriel Luna, Zhouwei Cheng, Morgane Audouard, Kamalini G. Ranasinghe, Kiwamu Kudo, Srikantan S. Nagarajan, Kenneth R. Tovar, Linda R. Petzold, Paul K. Hansma, Kenneth S. Kosik
bioRxiv 2021.01.28.428643; doi: https://doi.org/10.1101/2021.01.28.428643
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Intrinsic network activity in human brain organoids
Tal Sharf, Tjitse van der Molen, Elmer Guzman, Stella M.K. Glasauer, Gabriel Luna, Zhouwei Cheng, Morgane Audouard, Kamalini G. Ranasinghe, Kiwamu Kudo, Srikantan S. Nagarajan, Kenneth R. Tovar, Linda R. Petzold, Paul K. Hansma, Kenneth S. Kosik
bioRxiv 2021.01.28.428643; doi: https://doi.org/10.1101/2021.01.28.428643

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