Cholinergic modulation enables scalable action selection learning in a computational model of the striatum González-Redondo, Álvaro Garrido Alcázar, Jesús Alberto Hellgren Kotaleski, Jeanette Grillner, Sten Ros, Eduardo Dopamine Acetylcholine Spiking neural network The striatum plays a central role in action selection and reinforcement learning, integrating cortical inputs with dopaminergic signals encoding reward prediction errors. While dopamine modulates synaptic plasticity underlying value learning, the mechanisms that enable selective reinforcement of behaviorally relevant stimulus-action associations–the structural credit assignment problem–remain poorly understood, especially in environments with multiple competing stimuli and actions. Here, we present a computational model in which acetylcholine (ACh), released by striatal cholinergic interneurons, acts as a channel-specific gating signal that restricts plasticity to brief temporal windows following action execution. The model implements a biologically plausible three-factor learning rule requiring presynaptic activity, postsynaptic depolarization, and phasic dopamine, with plasticity gated by cholinergic pauses that temporally align with behaviorally relevant events. This mechanism ensures that only synapses involved in the selected behavior are eligible for modification. Through systematic evaluation across tasks with distractors and contingency reversals, we show that AChgated learning promotes synaptic specificity, suppresses cross-channel interference, and yields increasingly competitive performance relative to Q-learning in complex tasks, reflecting the scalability of the proposed learning mechanism. Moreover, the model reveals distinct roles for striatal pathways: direct pathway (D1) neurons maintain stimulus-specific responses, while indirect pathway (D2) neurons are progressively recruited to suppress outdated associations during policy adaptation. These findings provide a mechanistic account of how coordinated cholinergic and dopaminergic signaling can support scalable and efficient reinforcement learning in the striatum, consistent with experimental observations of pathway-specific plasticity. 2025-10-22T08:21:33Z 2025-10-22T08:21:33Z 2025-10-07 journal article González-Redondo, Á., Garrido, J.A., Hellgren Kotaleski, J. et al. Cholinergic modulation enables scalable action selection learning in a computational model of the striatum. Sci Rep 15, 34902 (2025). https://doi.org/10.1038/s41598-025-18776-3 https://hdl.handle.net/10481/107283 10.1038/s41598-025-18776-3 eng info:eu-repo/grantAgreement/H2020/945539 info:eu-repo/grantAgreement/H2020/101147319 info:eu-repo/grantAgreement/H2020/101137289 http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional Nature Publishing Group