The PPC neurons modulate memory generalization via NR2B-type NMDA receptors in mice

Generalization, the ability to apply learned rules to novel situations, is a fundamental cognitive process, yet its underlying neural mechanisms remain incompletely understood. The posterior parietal cortex (PPC) is considered a key hub for extracting abstract rules from specific experiences, yet its precise role in generalization requires further elucidation. In this study, we developed a five-hole operant paradigm to demonstrate that mice exhibit robust memory generalization, as reflected by graded success rates across tasks of varying difficulty. Fiber photometry revealed that PPC neurons are selectively activated during correct choices in generalization tasks. Chemogenetic inhibition of PPC neurons significantly impaired this generalization ability, particularly for the most difficult tasks. local infusion of NMDA receptor antagonists into the PPC, but not AMPA or acetylcholine receptor antagonists, specifically disrupted generalization, indicating a critical role for PPC NMDA receptors. Importantly, blockade of the NR2B subunit of NMDA receptors reproduced this impairment, whereas NR2A antagonism had no effect. Together, our findings establish that PPC neurons and NR2B-containing NMDA receptors within the PPC are essential for memory generalization in mice, providing new insights into the circuit and molecular mechanisms underlying adaptive behavior.