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Abstract

Brain organoids develop self-organizing neural networks that can be used to model neurodevelopment and disease. Here we introduce PULSE, a foundation model developed using over 900 hours of high-density microelectrode array recordings of in vitro and ex vivo neural tissue. We show that this single model can address two open questions: how disease-associated variants alter network development, and how naive circuits encode information. PULSE revealed accelerated network maturation in held-out human 16p11.2-deletion organoids. It also revealed a change in network coordination shared with SHANK3 deficiency. Because organoids develop without sensory input, they let us ask how circuits encode information before any representation is learned. Closed-loop control of a virtual inverted pendulum engaged existing spontaneous activity patterns rather than creating new ones. PULSE provides a common reference frame for neural circuits across genotypes, protocols and tasks.

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