Distinct Hippocampal Neuronal Reactions Reveal Different Neuronal Codes for Memory Generalization

To survive in an ever-changing world we need to learn and memorize associations of environmental stimuli and generalize them to new situations. Both memory and generalization critically rely on the hippocampus, but it is unclear how hippocampal neuronal activities represent memory and generalization, and if a conserved hippocampal mechanism serves these functions. Here we compared neuronal activities in hippocampal CA1 region of two sub-strains of the widely used C57BL/6 mice, C57BL/6J (B6J) and C57BL/6NCrl (B6NCrl), in contextual fear conditioning. Both sub-strains learnt well but differed in freezing and generalization. They displayed distinct early-late bi-phasic reactions to the unconditioned stimulus. While in both sub-strains the neurons showing late-phase reactions were preferentially engaged in memory representation, the neuronal activity feature that correlated with generalization level differed in the two sub-strains: in B6NCrl, these neurons activity level during learning negatively correlated with the generalization level; in B6J, functional coupling of these late-phase neurons with other neurons positively correlated with the generalization level. We further found that the distinct neuronal reactions were accompanied by distinct GABAb receptor-mediated inhibition but not by differences in the major synaptic inputs or neuronal excitability of the CA1. Therefore, this comparative study reveals two signature neuronal activity features in learning that can predict generalization levels. The results also demonstrate that differences in hippocampal network properties lead to diverse hippocampal mechanisms in memory encoding and generalization.