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Thalamocortical regulation of prefrontal stability enables abstract rule generalization

Xu, Jinghong1; Wang, Zheng1; Liu, Jingchen1; Liu, Hao1; Li, Mengwei1; Liu, Zili1; Zheng, Beilin1; Zhao, Yulan1; Zhang, Jiping1; Yu, Liping1

Published Feb 11, 2026 on Dryad. https://doi.org/10.5061/dryad.44j0zpcth

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Abstract

The ability to generalize abstract rules to novel contexts is a hallmark of intelligent behavior, yet its neural mechanisms remain poorly understood. Here, we identify a thalamocortical circuit essential for abstract rule generalization in mice. Using a cross-modal delayed match-to-sample task, we find that mice generalize learned rules from auditory to visual domains, with the same medial prefrontal cortex (mPFC) neurons encode task rules across sensory modalities to enable generalization. Pathway-specific manipulations revealed that mediodorsal thalamus (MD) projections to the mPFC are causally required for generalization: optogenetic inhibition of MD-to-mPFC projections disrupts rule transfer by destabilizing mPFC representations, while enhancing this pathway improved performance. Strikingly, without MD input, mPFC recruits distinct neuronal populations for each task, abolishing cross-context stability. Conversely, direct mPFC excitation impairs generalization, highlighting the specificity of thalamic regulation. These findings demonstrate that the MD stabilizes mPFC activity to enable the flexible transfer of abstract rules – a mechanism with broad implications for cognitive disorders and artificial intelligence.