Human Neural Organoid Microphysiological Systems Show the Building Blocks Necessary for Basic Learning and Memory

Brain Microphysiological Systems including neural organoids derived from human induced pluripotent stem cells offer a unique lens to study the intricate workings of the human brain. This paper investigates the foundational elements of learning and memory in neural organoids, by quantifying immediate early gene expression in response to chemical modulation, input-specific short- and long-term synaptic plasticity, neuronal network dynamics, connectivity, and criticality to demonstrate the utility of these organoids in basic science research. Neural organoids showed synapse formation, glutamatergic and GABAergic receptor expression, immediate early gene expression basally and evoked, functional connectivity, criticality, and synaptic plasticity in response to theta-burst stimulation. In addition, pharmacological interventions on GABAergic and glutamatergic receptors, and input-specific theta-burst stimulation further shed light on the capacity of neural organoids to mirror synaptic modulation, short- and long-term potentiation and depression, demonstrating their potential as tools for studying neurophysiological and neurological processes and informing therapeutic strategies for diseases. Overall design: RNA-seq profiling of neural organoids (Brain Microphysiological Systems) at week 8, 12, and 13 post differentiation.