Present and Future Modeling of Human Psychiatric Connectopathies With Brain Organoids

Brain organoids derived from human pluripotent stem cells are emerging as a powerful tool to model cellular aspects of neuropsychiatric disorders, including alterations in cell proliferation, differentiation, migration, and lineage trajec-tory. To date, most contributions in the field have focused on modeling cellular impairment of the cerebral cortex, with few studies probing dysfunction in local network connectivity. However, it is increasingly more apparent that these psychiatric disorders are connectopathies involving multiple brain structures and the connections between them. Therefore, the lack of reproducible anatomical features in these 3-dimensional cultures represents a major bottleneck for effectively modeling brain connectivity at the micro(cellular) level and at the macroscale level between brain re-gions. In this perspective, we review the use of current organoid protocols to model neuropsychiatric disorders with a specific emphasis on the potential and limitations of the current strategies to model impairments in functional con-nectivity. Finally, we discuss the importance of adopting interdisciplinary strategies to establish next-generation, multiregional organoids that can model, with higher fidelity, the dysfunction in the development and functionality of long-range connections within the brain of patients affected by psychiatric disorders.