Neural organoids have the potential to improve our understanding of human brain development and neurological disorders. However, it remains to be seen whether these tissues can model circuit formation with functional neuronal output. Here we have adapted air–liquid interface culture to cerebral organoids, leading to improved neuronal survival and axon outgrowth. The resulting thick axon tracts display various morphologies, including long-range projection within and away from the organoid, growth-cone turning, and decussation. Single-cell RNA sequencing reveals various cortical neuronal identities, and retrograde tracing demonstrates tract morphologies that match proper molecular identities. These cultures exhibit active neuronal networks, and subcortical projecting tracts can innervate mouse spinal cord explants and evoke contractions of adjacent muscle in a manner dependent on intact organoid-derived innervating tracts. Overall, these results reveal a remarkable self-organization of corticofugal and callosal tracts with a functional output, providing new opportunities to examine relevant aspects of human CNS development and disease.
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The data that support the findings of this study are included in the Supplementary Information with the paper. All scRNA-seq data has been deposited on GEO, accession number GSE124174. Raw data (for example, raw images and electrophysiological recordings) is available upon request from the corresponding author.
Journal peer review information: Nature Neuroscience thanks Alexander Jaworski and other anonymous reviewer(s) for their contribution to the peer review of this work.
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The authors would like to thank members of the Lancaster lab for helpful discussions and D. Jabaudon for insightful comments, as well as members of the LMB mouse facility for help with timed matings and tissue collections. We also thank members of the H. McMahon laboratory for plasmids and the LMB light microscopy facility, in particular B. Sutcliffe, for assistance with imaging. We are grateful to P. Coupland and S. Ballereau (Cancer Research UK) for technical assistance and to M. Galardini and P. Beltrao (European Bioinformatics Institute) for helping with computing resources. This work was supported by the Medical Research Council MC_UP_1201/9 (to M.A.L.), European Research Council ERC STG 757710 (to M.A.L.), Medical Research Council MR/P008658/1 (to A.L.), Wellcome Trust ISSF_RRZC/115_RG89529 (to A.L.), Newton Trust RRZC/115_RG89305 (to A.L.), MRC Clinician Scientist Fellowship (to A.L.), grants from the Biotechnology and Biological Sciences Research Council (BBSRC) (to O.P.), Medical Research Council MC_UP_1201/2 (to M.T.), European Research Council ERC Starting Grant, STG 677029 (to M.T.), ERANET-NEURON Micronet consortium (to M.T.), Medical Research Council MC_UP_1201/13 (to E.D.), and HFSP CDA (to E.D.).