Intrinsic Network Activity in Human Brain Organoids

Abstract

Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, neurophysiology within organoids remains relatively under-explored. With high-density CMOS microelectrode arrays and shank electrodes, we probed broadband and three-dimensional activity of human brain organoids. From spiking activity, we estimated a directed functional connectivity graph of neural network activity which showed a large number of weak functional connections enmeshed within a network skeleton of significantly fewer strong connections. Increasing the intrinsic inhibitory tone with a benzodiazepine suppressed the network skeleton of the functional network. We further demonstrate that human brain organoids have self-organized neuronal assemblies of sufficient size, cellular orientation, and functional connectivity to generate local field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug mechanisms, and the effects of external stimuli upon neuronal networks.