02185nas a2200349   4500000000100000000000100001008004100002260001500043653002400058653002200082653002400104100003000128700002300158700001800181700002400199700001900223700001700242700002500259700001600284700001600300700001800316700002000334700001900354700001900373700001800392245011800410856005500528300000900583490000600592520122300598022001401821       2025                            d  c2025-08-1610aLearning and memory10aNeural Stem Cells10aSynaptic plasticity1 aDowlette-Mary Alam El Din1 aLeah Moenkemoeller1 aAlon Loeffler1 aForough Habibollahi1 aJack Schenkman1 aAmitav Mitra1 aTjitse van der Molen1 aLixuan Ding1 aJason Laird1 aMaren Schenke1 aErik C. Johnson1 aBrett J. Kagan1 aThomas Hartung1 aLena Smirnova00aHuman neural organoid microphysiological systems show the building blocks necessary for basic learning and memory  uhttps://www.nature.com/articles/s42003-025-08632-5  a12370 v83 aBrain 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.  a2399-3642