Differential Contributions of Glutamatergic Hippocampal→Retrosplenial Cortical Projections to the Formation and Persistence of Context Memories

Abstract

Learning to associate stressful events with specific environmental contexts depends on excitatory transmission in the hippocampus, but how this information is transmitted to the neocortex for lasting memory storage is unclear. We identified dorsal hippocampal (DH) projections to the retrosplenial cortex (RSC), which arise mainly from the subiculum and contain either the vesicular glutamate transporter 1 (vGlut1) or vGlut2. Both vGlut1+ and vGlut2+ axons strongly excite and disynaptically inhibit RSC pyramidal neurons in superficial layers, but vGlut2+ axons trigger greater inhibition that spreads to deep layers, indicating that these pathways engage RSC circuits via partially redundant, partially differentiated cellular mechanisms. Using contextual fear conditioning in mice to model contextual associative memories, together with chemogenetic axonal silencing, we found that vGlut1+ projections are principally involved in processing recent context memories whereas vGlut2+ projections contribute to their long-lasting storage. Thus, within the DH→RSC pathway, engagement of vGlut1+ and vGlut2+ circuits differentially contribute to the formation and persistence of fear-inducing context memories.

Keywords: context fear conditioning; hippocampus; retrosplenial cortex; vGlut1; vGlut2.