Thalamocortical regulation of prefrontal stability enables abstract rule generalization

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.