Din, D. a. E., et al. (2025).
Communications Biology, 8(1).
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-speci c 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-speci c theta-burst stimulation further shed light on the capacity of neural organoids to
mirror synaptic modulation, speci cally short- and long-term potentiation and depression,
demonstrating their potential as tools for studying neurophysiological and neurological processes and
informing therapeutic strategies for diseases.
Here are some thoughts:
This study demonstrates that human neural organoids grown in a microphysiological system develop key functional properties necessary for basic learning and memory. Over a maturation period of up to 14 weeks, the organoids exhibit increasingly synchronized neural network activity, with evidence of progressing toward a "critical state"—a hallmark of efficient brain function—shown by power-law-distributed neuronal avalanches and fractal avalanche shapes. Critically, the organoids display synaptic plasticity, the fundamental mechanism of learning, as they respond to theta-burst stimulation with long-term potentiation (LTP) and long-term depression (LTD) in specific neuronal units. The organoids also express immediate-early genes like FOS, EGR1, ARC, and NPAS4, which are rapidly activated during learning processes in the human brain. Their neural activity is modulated by pharmacological agents targeting glutamate, GABA, and dopamine receptors, confirming biological relevance and potential for disease modeling. Overall, these findings establish human neural organoids as a sophisticated model system that recapitulates essential building blocks of human brain function, with significant implications for neuroscience research, drug development, and the emerging field of organoid intelligence.
