Thalamocortical regulation of prefrontal stability enables abstract rule generalization

Our ability to generalize abstract rules to new situations is a cognitive hallmark, yet its neural basis is unclear. We identified a thalamocortical circuit essential for this process in mice. During a cross-modal rule transfer task, medial prefrontal cortex (mPFC) neurons encoded task rules across sensory modalities to enable generalization. Crucially, mediodorsal thalamus (MD) projections to mPFC were causally required: Inhibiting this pathway destabilized mPFC representations and impaired rule transfer, whereas enhancing it improved performance. Without MD input, mPFC recruited distinct populations for each task, losing cross-context stability. Direct mPFC excitation impaired generalization, underscoring the specificity of thalamic regulation. Thus, the MD stabilizes mPFC activity for flexible rule transfer—a mechanism with implications for cognitive disorders and artificial intelligence.