Experience‐Dependent Reorganization of Hippocampal CA3 Neuronal Ensembles Associates With Memory Generalization

ABSTRACT Memory generalization is essential for adaption to novel circumstances through experiential learning, leading to behavioral flexibility and survival capability. However, its underlying neural mechanisms remain to be elucidated. This study designed 8‐arm‐maze‐based tasks to reveal how the hippocampal CA3 associates with the generalization of spatial working memory. Mice successfully transferred the learned rule to novel task configurations, but the efficiency was inversely correlated with task difficulty. In vivo electrophysiological recordings of the CA3 showed that single‐unit and population activity in the CA3 reflected this behavioral transition. On testing day 1, neuronal firing and population trajectories robustly distinguished in relatively simple tasks, but not in more difficult tasks. On testing day 2, as behavioral performance improved, the representational differences of the CA3 neuronal population across different tasks gradually decreased. Decoding analysis revealed that task discriminability based on population activity decreased over time, indicating CA3 neural coding is shifting toward a more generalized pattern. Feature elimination analysis further demonstrated that CA3 neurons employ a sparse but redundant coding scheme to support generalization. Together, the observed neural and behavioral changes are consistent with the emergence of generalized task representations, indicating experience‐dependent reorganization of CA3 population activity during memory generalization across task configurations.