Modeling forebrain regional development and connectivity by human brain organoids

Brain organoids are powerful research tools with a wide range of applications, including disease modeling, drug development, and biological computing 1, 2. Human brain organoids, as 3D in vitro neural cultures, are constructed based on neuroectodermal developmental principles, exhibit high physiological, functional, and structural similarity to actual human tissue, and can be advantageous over animal models in studying human-specific developmental program and function 3, 4. Organoid protocols provide a readily available source of samples that would otherwise be ethically challenging to obtain, leading to a paradigm shift in developmental neurobiology research. Region-specific organoids derived from human pluripotent stem cells (hPSCs) have accelerated detailed studies of telencephalic and diencephalic development. These consist of genetic and environmental mechanisms that regulate forebrain development, such as cortical layer formation, neuronal migration, projections, and synapse formation. Brain organoids offer an innovative approach to investigate pathogenesis of forebrain-related neurodevelopmental and neurodegenerative disorders, including autism spectrum disorder, schizophrenia, and Alzheimer’s disease 5, 6, 7, 8, 9•, 10, 11•, 12, 13. This review highlights the current status and future directions in understanding developmental processes and diseases related to the brain, with a focus on forebrain regional development and inter-regional communication.

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