Editors' ChoiceORGANOIDS

From mini-brains to neural networks

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Science Translational Medicine  10 Jul 2019:
Vol. 11, Issue 500, eaay3570
DOI: 10.1126/scitranslmed.aay3570

Abstract

Cells dissociated from cerebral organoids self-organize into two-dimensional neuronal networks with relatively advanced functionality.

The cerebrum is the largest part of our brain and performs many complex functions, ranging from motor control to memory. Over the last several years, researchers have generated three-dimensional cerebrum-like tissues in a dish by exposing aggregates of human pluripotent stem cells to specific cocktails of molecules. These cerebral organoids grow to a few millimeters in diameter and can be used to study some basic principles of brain development and disease. However, a major hurdle is that the dense, three-dimensional structure of organoids impedes detailed analysis of the communication between neurons and the activity of the entire neuronal network. This information is essential for understanding how neurons in the cerebrum work together to achieve complex functions. Sakaguchi et al. recently addressed this limitation by dissociating human cerebral organoids into single cells and plating them onto two-dimensional surfaces so that they could easily image calcium activity, a proxy for neuronal firing. Over the course of one month, the neurons self-organized into clusters connected by bundles of neurites and began firing synchronously, indicative of relatively mature synaptic connections. The researchers could also modulate network activity with drugs that blocked specific receptors in neurons, demonstrating how this approach could be used to identify new drugs that modulate neuronal activity in the cerebrum.

This method could potentially be used to understand how patterns of neuronal network activity are affected by pathologies that affect the cerebrum, including cerebral palsy, neurodegenerative diseases, psychiatric diseases, and Zika virus infection. Although organoids have many features that mimic native cerebral tissue, both three-dimensional organoids and two-dimensional neuronal networks have relatively random architecture and lack full maturity. These issues limit their relevance, especially for modeling diseases that affect older patients. Organoids are also relatively low-throughput because they take several weeks or months to grow, possibly, hindering their integration into the drug development pipeline. Despite these limitations, these recent results highlight how organoids recapitulate relatively complex behaviors and can be implemented to unlock new understanding of the human brain.

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