Human neural organoid microphysiological systems show the building blocks necessary for basic learning and memory
Dowlette‐Mary Alam El Din, Leah S. Mönkemöller, Alon Loeffler, Forough Habibollahi, Jack Schenkman, Amitav Mitra, Tjitse van der Molen, Lixuan Ding, Jason Laird, Maren Schenke, Erik C. Johnson, Brett J Kagan, Thomas Härtung, Lena Smirnova
Abstract
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, specifically short- and long-term potentiation and depression, demonstrating their potential as tools for studying neurophysiological and neurological processes and informing therapeutic strategies for diseases. Neural organoids exhibit key aspects of learning and memory, including input-specific synaptic plasticity, basal and evoked immediate early gene expression, and critical network dynamics, highlighting their value in modeling human neurophysiology.