Electrophysiological Maturation of Cerebral Organoids Correlates with Dynamic Morphological and Cellular Development

Abstract

Summary Cerebral organoids (COs) are rapidly accelerating the rate of translational neuroscience based on their potential to model complex features of the developing human brain. Several studies have examined the electrophysiological and neural network features of COs; however, no study has comprehensively investigated the developmental trajectory of electrophysiological properties in whole-brain COs and correlated these properties with developmentally linked morphological and cellular features. Here, we profiled the neuroelectrical activities of COs over the span of 5 months with a multi-electrode array platform and observed the emergence and maturation of several electrophysiologic properties, including rapid firing rates and network bursting events. To complement these analyses, we characterized the complex molecular and cellular development that gives rise to these mature neuroelectrical properties with immunohistochemical and single-cell transcriptomic analyses. This integrated approach highlights the value of COs as an emerging model system of human brain development and neurological disease.

Microglia orchestrate neuronal activity in brain organoids

“…Finally, a very recent report showed that transplantation of human primary prenatal microglia to brain organoids gave rise to synchronous burst activity 36 (BioRxiv). Synchronous burst has also been reported in the absence of microglia, though in much older organoids, and in conjunction with emerging inhibitory interneurons 16.…”

“…The accumulating body of scientific reports portray brain organoids as a human 3D in vitro platform that achieves remarkable complexity, even resembling its in-vivo counterpart, the embryonic human brain [13][14][15][16][17] . The main cell types of the brain, astrocytes and neurons, spontaneously develop through ectodermal lineage in brain organoids and self-assemble to form cortical layers resembling human brain organization 18 .…”

Electrophysiology Read-Out Tools for Brain-on-Chip Biotechnology

“…MEA recoding is very popular to obtain network-wide information that not only allows detailed network dynamics studies of the 3D tissue per se , it also enables a direct comparison with the human brain electrical patterns [ 141 , 148 , 149 , 158 , 160 , 161 ]. It needs to be mentioned, however, that MEA recording of the intact spheroid or organoid using planar MEAs poses some difficulties in achieving a good electrical contact between the electrodes and the tissue, as the latter does not offer a flat surface that can optimally adhere to the planar MEA substrate.…”

“…In terms of sample processing, one strategy consists of letting the intact tissue sit on the MEA, previously coated with adhesion molecules (poly-(D/L)-lysine, poly(L)-ornithine, polyethylenimine, laminin) for several days or weeks [ 148 , 158 , 160 , 161 ]. However, such a procedure is very likely to induce cell spreading and organoid disaggregation, for which the recorded signal might as well represent the result of secondary 2D network activity, wherein the 2D networks are established upon guidance by the coating biomolecule.…”

Electrophysiological Analysis of Brain Organoids: Current Approaches and Advancements

“…The large-scale recordings provided by MEAs are also amenable to combination with additional data sets or multiplexing with other assays. For example, correlation analysis of MEA activity throughout development with transcriptomics (sc-RNA-seq) and immunohistochemistry has provided mechanistic insight into developmental processes, such as simultaneous astrocyte population growth and neuronal maturation ( Fair et al, 2020 ). Additionally, multiplexing MEA analysis with high content imaging can help offset concerns associated with brain organoid variability by increasing confidence in results reflected across modalities, supporting potential use for drug screening and other high-throughput approaches ( Durens et al, 2020 ).…”