Prefrontal multistimulus integration within a dedicated disambiguation circuit guides interleaving contingency judgment learning

Understanding how cortical network dynamics support learning is a challenge. This study investigates the role of local neural mechanisms in the prefrontal cortex during contingency judgment learning (CJL). To better understand brain network mechanisms underlying CJL, we introduce ambiguity into associative learning after fear acquisition, inducing a generalized fear response to an ambiguous stimulus sharing nontrivial similarities with the conditioned stimulus. Real-time recordings at single-neuron resolution from the prelimbic (PL) cortex show distinct PL network dynamics across CJL phases. Fear acquisition triggers PL network reorganization, led by a disambiguation circuit managing spurious and predictive relationships during cue-danger, cue-safety, and cue-neutrality contingencies. Mice with PL-targeted memory deficiency show malfunctioning disambiguation circuit function, while naive mice lacking unconditioned stimulus exposure lack the disambiguation circuit. This study shows that fear conditioning induces prefrontal cortex cognitive map reorganization and that subsequent CJL relies on the disambiguation circuit's ability to learn predictive relationships.