Modular Platform for Rapidly Investigating Long‐Distance Propagation of Human Neural Network Activity

Biological neural networks exhibit synchronized activity within and across interconnected regions of the central nervous system. Understanding how these coordinated networks are established and maintained may reveal therapeutic targets for neurodegeneration. However, current experimental human cellular models of long-distance networks are lacking. Here, we address this issue by testing the influence of astrocytes upon synchronous network activity using human pluripotent stem cell-derived bioengineered neural organoids. This study revealed that astrocytes significantly facilitate global activity within and across numerous rapidly merged organoids via combinatorial mechanisms. Treatment with amyloid-beta oligomer protein to mimic the neurodegenerative microenvironment inhibited synchronous activity initiation, yet this could be restored by propagating activity from neighboring networks, suggesting neuromodulation strategies can influence distant diseased networks. Altogether, this study identifies critical contributions of human astrocytes to biological neural networks and delivers a rapid model for investigating long-range functional communication of the nervous system in both healthy and disease states.