Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Sep 3

PMID 31474560

Citations 345

Authors

Cleber A Trujillo

Richard Gao

Priscilla D Negraes

Jing Gu

Justin Buchanan

Sebastian Preissl

Allen Wang

Wei Wu

Gabriel G Haddad

Isaac A Chaim

Alain Domissy

Matthieu Vandenberghe

Anna Devor

Gene W Yeo

Bradley Voytek

Alysson R Muotri

Affiliations

Soon will be listed here.

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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References

Schevon C, Weiss S, McKhann Jr G, Goodman R, Yuste R, Emerson R . Evidence of an inhibitory restraint of seizure activity in humans. Nat Commun. 2012; 3:1060. PMC: 3658011. DOI: 10.1038/ncomms2056. View

Pasca S . The rise of three-dimensional human brain cultures. Nature. 2018; 553(7689):437-445. DOI: 10.1038/nature25032. View

Farahany N, Greely H, Hyman S, Koch C, Grady C, Pasca S . The ethics of experimenting with human brain tissue. Nature. 2018; 556(7702):429-432. PMC: 6010307. DOI: 10.1038/d41586-018-04813-x. View

Zerbino D, Achuthan P, Akanni W, Amode M, Barrell D, Bhai J . Ensembl 2018. Nucleic Acids Res. 2017; 46(D1):D754-D761. PMC: 5753206. DOI: 10.1093/nar/gkx1098. View

Kelava I, Lancaster M . Stem Cell Models of Human Brain Development. Cell Stem Cell. 2016; 18(6):736-748. DOI: 10.1016/j.stem.2016.05.022. View

Tolonen M, Palva J, Andersson S, Vanhatalo S . Development of the spontaneous activity transients and ongoing cortical activity in human preterm babies. Neuroscience. 2007; 145(3):997-1006. DOI: 10.1016/j.neuroscience.2006.12.070. View

Tang X, Kim J, Zhou L, Wengert E, Zhang L, Wu Z . KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Proc Natl Acad Sci U S A. 2016; 113(3):751-6. PMC: 4725523. DOI: 10.1073/pnas.1524013113. View

Tetzlaff C, Okujeni S, Egert U, Worgotter F, Butz M . Self-organized criticality in developing neuronal networks. PLoS Comput Biol. 2010; 6(12):e1001013. PMC: 2996321. DOI: 10.1371/journal.pcbi.1001013. View

Camp J, Badsha F, Florio M, Kanton S, Gerber T, Wilsch-Brauninger M . Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci U S A. 2015; 112(51):15672-7. PMC: 4697386. DOI: 10.1073/pnas.1520760112. View

10.

Voytek B, Kayser A, Badre D, Fegen D, Chang E, Crone N . Oscillatory dynamics coordinating human frontal networks in support of goal maintenance. Nat Neurosci. 2015; 18(9):1318-24. PMC: 4551604. DOI: 10.1038/nn.4071. View

11.

Henriques J, Davidson R . Left frontal hypoactivation in depression. J Abnorm Psychol. 1991; 100(4):535-45. DOI: 10.1037//0021-843x.100.4.535. View

12.

Fries P . A mechanism for cognitive dynamics: neuronal communication through neuronal coherence. Trends Cogn Sci. 2005; 9(10):474-80. DOI: 10.1016/j.tics.2005.08.011. View

13.

Mukamel R, Gelbard H, Arieli A, Hasson U, Fried I, Malach R . Coupling between neuronal firing, field potentials, and FMRI in human auditory cortex. Science. 2005; 309(5736):951-4. DOI: 10.1126/science.1110913. View

14.

Pasca A, Sloan S, Clarke L, Tian Y, Makinson C, Huber N . Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods. 2015; 12(7):671-8. PMC: 4489980. DOI: 10.1038/nmeth.3415. View

15.

Yoon S, Elahi L, Pasca A, Marton R, Gordon A, Revah O . Reliability of human cortical organoid generation. Nat Methods. 2018; 16(1):75-78. PMC: 6677388. DOI: 10.1038/s41592-018-0255-0. View

16.

Buzsaki G, Logothetis N, Singer W . Scaling brain size, keeping timing: evolutionary preservation of brain rhythms. Neuron. 2013; 80(3):751-64. PMC: 4009705. DOI: 10.1016/j.neuron.2013.10.002. View

17.

Buzsaki G . Large-scale recording of neuronal ensembles. Nat Neurosci. 2004; 7(5):446-51. DOI: 10.1038/nn1233. View

18.

Blankenship A, Feller M . Mechanisms underlying spontaneous patterned activity in developing neural circuits. Nat Rev Neurosci. 2009; 11(1):18-29. PMC: 2902252. DOI: 10.1038/nrn2759. View

19.

Uhlhaas P, Singer W . Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci. 2010; 11(2):100-13. DOI: 10.1038/nrn2774. View

20.

Lancaster M, Knoblich J . Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc. 2014; 9(10):2329-40. PMC: 4160653. DOI: 10.1038/nprot.2014.158. View