Nested oscillatory dynamics in cortical organoids model early human brain network development
Structural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for functional network activity remains unknown, primarily due to experimental inaccessibility of the initial stages of the living human brain. Here, we developed cortical organoids that spontaneously display periodic and regular oscillatory network events that are dependent on glutamatergic and GABAergic signaling. These nested oscillations exhibit cross-frequency coupling, proposed to coordinate neuronal computation and communication. As evidence of potential network maturation, oscillatory activity subsequently transitioned to more spatiotemporally irregular patterns, capturing features observed in preterm human electroencephalography (EEG). These results show that the development of structured network activity in the human neocortex may follow stable genetic programming, even in the absence of external or subcortical inputs. Our approach provides novel opportunities for investigating and manipulating the role of network activity in the developing human cortex.\n\nHIGHLIGHTSO_LIEarly development of human functional neural networks and oscillatory activity can be modeled in vitro.\nC_LIO_LICortical organoids exhibit phase-amplitude coupling between delta oscillation (2 Hz) and high-frequency activity (100-400 Hz) during network-synchronous events.\nC_LIO_LIDifferential role of glutamate and GABA in initiating and maintaining oscillatory network activity.\nC_LIO_LIDevelopmental impairment of MECP2-KO cortical organoids impacts the emergence of oscillatory activity.\nC_LIO_LICortical organoid network electrophysiological signatures correlate with human preterm neonatal EEG features.\nC_LI\n\neTOCBrain oscillations are a candidate mechanism for how neural populations are temporally organized to instantiate cognition and behavior. Cortical organoids initially exhibit periodic and highly regular nested oscillatory network events that eventually transition to more spatiotemporally complex activity, capturing features of late-stage preterm infant electroencephalography. Functional neural circuitry in cortical organoids exhibits emergence and development of oscillatory network dynamics similar to those found in the developing human brain.