HIPPOCAMPAL CONSTRAINT OF CORTICAL GENERALIZATION PRESERVES BEHAVIORAL FLEXIBILITY

Generalization enables knowledge acquired in one context to guide behavior in others, but excessive generalization can undermine flexibility when predictive relationships change. How neural circuits support representational reuse while preserving adaptive flexibility remains unclear. Here we show that generalization, temporal stability, and selective ensemble organization together define a unified representational mode in orbitofrontal cortex (OFC) that is normally constrained by hippocampus. Using lesions combined with calcium imaging during an odor–reward association task in mice, we found that removal of hippocampal CA1 biased OFC representations toward enhanced alignment across related associations, increased stability across multiple timescales, and stronger yet more selective functional coupling from highly generalized neurons. This shift supported accurate performance under stable contingencies but incurred a behavioral cost, selectively impairing flexibility when predictive relevance had to be updated. In contrast, OFC lesion produced comparatively modest effects in hippocampus. Together, these findings reveal an asymmetric hippocampus-to-OFC influence that limits excessive cortical generalization and identify controlled destabilization of abstract representations as a key circuit mechanism supporting adaptive flexibility.