Organoid Modeling of Human Cortical Microcircuits

Neurological diseases are among the most debilitating medical conditions affecting millions of people worldwide. Few effective treatments exist in part because we know little about the underlying causes of these conditions. Moreover, drug discovery efforts have been hampered by our reliance on animal models that fail to recapitulate salient features of human disease. In our project, we have developed innovative technologies to create and study 3D human brain-like structures termed organoids or “mini-brains” from patient-derived human pluripotent stem cells. Our studies show that neurons within the organoids are active and interconnect to form functional networks. This feature provides us with an unprecedented opportunity to listen in on their conversation and ask how and why neural communication differs in various disease states. In the first stage of our project, we generated organoids representing different regions of the brain and assembled these units to form more complete brain-like structures. We also developed a means for measuring neural network activities in the composite organoids, which revealed the existence of intricate oscillatory neural activities similar to what is seen in the neonatal and adult human brain. We lastly evaluated neural network activities in brain organoids derived from patients afflicted with Rett Syndrome, an incurable genetic disorder that leads to problems with language, motor functions, cognition, and seizures. In Rett organoids, we found marked differences in neural network functions including loss of oscillatory activities seen in control organoids and appearance of high-frequency activity bursts reminiscent of brainwaves associated with epileptic seizures. Our studies collectively demonstrate the complexity of brainwave activities that can be achieved with our brain organoid system and its utility for modeling human neurological disorders to better understand the root causes of these conditions and develop novel therapies.