Gaining insight into psychiatric disease by engineering piece by piece the human brain in vitro

ABSTRACT The inaccessibility of human brain tissue at the molecular and cellular level has hindered therapeutic development for psychiatric disorders. Our laboratory has developed neural organoids mimicking specific brain regions from stem cells and pioneered neural assembloids to study interneuron migration and circuit formation. However, in vitro models lack the in vivo interactions and inputs necessary for complex neuropsychiatric disease modeling. We now propose generating assembloids within the in vivo rodent cortex to enhance neuronal maturation and behavioral readouts. Specifically, we will expand transplantation models by integrating glutamatergic and GABAergic neurons to model excitation-inhibition imbalances and early cortical circuit formation. We will establish transplanted forebrain assembloids, characterize their integration and functionality, and apply this model to study severe neurodevelopmental disorders caused by genetic mutations.