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Identification of neural oscillations and epileptiform changes in human brain organoids.

ABSTRACT: Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network 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 network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-α. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

SUBMITTER: Samarasinghe RA

PROVIDER: S-EPMC9070733 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Over the last decade, scientists have begun to model CNS development, function, and disease in vitro using human pluripotent stem cell (hPSC)-derived organoids. Using traditional protocols, these 3D tissues are generated by combining the innate emergent properties of differentiating hPSC aggregates with a bioreactor environment that induces interstitial transport of oxygen and nutrients and an optional supportive hydrogel extracellular matrix (ECM). During extended culture, the hPSC-derived neural organoids (hNOs) obtain millimeter scale sizes with internal microscale cytoarchitectures, cellular phenotypes, and neuronal circuit behaviors mimetic of those observed in the developing brain, eye, or spinal cord. Early studies evaluated the cytoarchitectural and phenotypical character of these organoids and provided unprecedented insight into the morphogenetic processes that govern CNS development. Comparisons to human fetal tissues revealed their significant similarities and differences. While hNOs have current disease modeling applications and significant future promise, their value as anatomical and physiological models is limited because they fail to form reproducibly and recapitulate more mature in vivo features. These include biomimetic macroscale tissue morphology, positioning of morphogen signaling centers to orchestrate appropriate spatial organization and intra- and inter-connectivity of discrete tissue regions, maturation of physiologically relevant neural circuits, and formation of vascular networks that can support sustained in vitro tissue growth. To address these inadequacies scientists have begun to integrate organoid culture with bioengineering techniques and methodologies including genome editing, biomaterials, and microfabricated and microfluidic platforms that enable spatiotemporal control of cellular differentiation or the biochemical and biophysical cues that orchestrate organoid morphogenesis. This review will examine recent advances in hNO technologies and culture strategies that promote reproducible in vitro morphogenesis and greater biomimicry in structure and function.

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Identification of neural oscillations and epileptiform changes in human brain organoids.

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