Circuit inhibition promotes the dynamic reorganization of prefrontal task encoding to support cognitive flexibility

The mammalian prefrontal cortex encodes variables related to goal-directed behavior, and enables flexibility during environmental changes, making it critical to understand how the dynamic updating vs. stable maintenance of different encodings contribute to behavioral adaptation. We addressed this by comparing prefrontal encoding during successful adaptation vs. maladaptive perseveration. Specifically, we studied mutant (Dlx5/6+/-) mice, which have dysfunctional parvalbumin-expressing inhibitory interneurons and perseverate in a rule shifting task. We measured mPFC activity patterns using microendoscopic calcium imaging, then used linear classifiers and neural networks to compare representational geometries in wild-type mice and Dlx5/6+/- mutants before, during, and after benzodiazepine treatment, which persistently rescues their rule shift learning. The encoding of correct vs. incorrect trial outcomes rapidly shifts as mice successfully learn new cue-reward associations, but becomes more stable when mutant mice perseverate. We also find activity patterns that normally distinguish learning of the initial association vs. rule shift, but become diminished during perseveration. Finally, during perseveration, outdated representations are inappropriately reinstated, not just passively maintained. These results reveal prefrontal contributions to flexible behavior driven by the dynamic reorganization of abstract rule representations, rather than stable reinforcement signals.