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

Trujillo, Cleber A.; Gao, Richard; Negraes, Priscilla D.; Gu, Jing; Buchanan, Justin; Preißl, Sebastian; Wang, Allen; Wu, Weiqiang; Haddad, Gabriel G.; Chaim, Isaac A.; Domissy, Alain; Vandenberghe, Matthieu; Devor, Anna; Yeo, G; Voytek, Bradley; Muotri, Alysson R.

doi:10.1016/j.stem.2019.08.002

Cited by 618 publications

(722 citation statements)

References 63 publications

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“…Collectively, these experiments demonstrate the existence of highly sophisticated physiological activities within Cx+GE organoids, congruent with their cytoarchitectural and cellular complexity. These results stand in agreement with findings recently reported by Trujillo et al, who have also observed the emergence of neural oscillations in cortical organoids cultured for prolonged time periods using a different recording approach 40 . Our studies here further demonstrate that the emergence of higher order network activities such as multi-frequency oscillations requires functional integration of inhibitory interneurons into the excitatory network framework as permitted by the organoid fusion technique, since no oscillations were apparent without them.…”

Section: Discussionsupporting

confidence: 94%

Identification of neural oscillations and epileptiform changes in human brain organoids

Samarasinghe

Miranda

Buth

et al. 2019

Preprint

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Human brain organoids represent a powerful tool for the study of human neurological diseases particularly those that impact brain growth and structure. However, many neurological diseases lack obvious anatomical abnormalities, yet significantly impact neural network functions, raising the question of whether organoids possess sufficient neural network architecture and 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 oscillatory network behaviors reminiscent of intact brain preparations. We further demonstrate strikingly abnormal epileptiform network activity in organoids derived from a Rett Syndrome patient despite only modest anatomical differences from isogenically matched controls, and rescue with an unconventional neuromodulatory drug Pifithrin-a. Together, these findings provide an essential foundation for the utilization of human brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

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Section: Discussionsupporting

confidence: 94%

Identification of neural oscillations and epileptiform changes in human brain organoids

Samarasinghe

Miranda

Buth

et al. 2019

Preprint

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“…The estimated connectivity ( Figure 5) combined with quantitative analyses, such as graph-theory approaches ( Figure 6), enabled us to describe the developmental progress of the cultures, thus demonstrating the capability of detecting basic neuronal features such as the increased synaptic connectivity and the formation of few, highly connected network hubs. These latter are both indexes of more mature neuronal circuits and agree well with higher spiking frequencies and network burst generation observed in mature neuronal cultures [63].…”

Section: Discussionsupporting

confidence: 84%

Super-selective reconstruction of causal and direct connectivity with application toin-vitroiPSC neuronal networks

Puppo

PrÐ

Bang

et al. 2020

Preprint

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Despite advancements in the development of cell-based in-vitro neuronal network models, the lack of appropriate computational tools limits their analyses. Methods aimed at deciphering the effective connections between neurons from extracellular spike recordings would increase utility of in-vitro local neural circuits, especially for studies of human neural development and disease based on induced pluripotent stem cells (hiPSC). Current techniques allow statistical inference of functional couplings in the network but are fundamentally unable to correctly identify indirect and apparent connections between neurons, generating redundant maps with limited ability to model the causal dynamics of the network. In this paper, we describe a novel mathematically rigorous, model-free method to map effective -direct and causal -connectivity of neuronal networks from multi-electrode array data. The inference algorithm uses a combination of statistical and deterministic indicators which, first, enables identification of all existing functional links in the network and then, reconstructs the directed and causal connection diagram via a super-selective rule enabling highly accurate classification of direct, indirect and apparent links. Our method can be generally applied to the functional characterization of any in-vitro neuronal networks. Here, we show that, given its accuracy, it can offer important insights into the functional development of in-vitro iPSC-derived neuronal cultures by reconstructing their effective connectivity, thus facilitating future efforts to generate predictive models for neurological disorders, drug testing and neuronal network modeling.

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“…4F), consistent with the role of microglia in synaptic remodeling (49,50). In addition, we explored whether presence of microglia might influence functional network maturation that is known to occur in organoids (51). We recorded spontaneous neural activity using multi-electrode arrays in neuroimmune and control organoids at 5 weeks after transplantation and found increased synchronization and frequency of oscillatory bursts in neuroimmune organoids compared to control ( Fig.…”

Section: Introductionsupporting

confidence: 65%

Human microglia upregulate cytokine signatures and accelerate maturation of neural networks

Schmunk

et al. 2020

Preprint

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Microglia are the resident macrophages of the brain that emerge in early development and play vital role disease states, as well as in normal development. Many fundamental questions about microglia diversity and function during human brain development remain unanswered, as we currently lack cellular-resolution datasets focusing on microglia in developing primary tissue, or experimental strategies for interrogating their function. Here, we report an integrative analysis of microglia throughout human brain development, which reveals molecular signatures of stepwise maturation, as well as human-specific cytokine-associated subtype that emerges around the onset of neurogenesis. To demonstrate the utility of this atlas, we have compared microglia across several culture models, including cultured primary microglia, pluripotent stem cell-derived microglia. We identify gene expression signatures differentially recruited and attenuated across experimental models, which will accelerate functional characterization of microglia across perturbations, species, and disease conditions. Finally, we identify a role for human microglia in development of synchronized network activity using a xenotransplantation model of human microglia into cerebral organoids.

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

Cited by 618 publications

References 63 publications

Identification of neural oscillations and epileptiform changes in human brain organoids

Identification of neural oscillations and epileptiform changes in human brain organoids

Super-selective reconstruction of causal and direct connectivity with application toin-vitroiPSC neuronal networks

Human microglia upregulate cytokine signatures and accelerate maturation of neural networks

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