Transcriptomic signatures of hippocampal active place avoidance memory maintenance

While the molecular mechanisms of memory acquisition and consolidation are well-documented, the transcriptomic state of the hippocampus during the "offline" maintenance phase—the period between initial consolidation and long-term storage—remains poorly understood. This study investigates the gene expression patterns in the dorsal hippocampus of mice three days after they were trained in an active place avoidance (APA) task, specifically focusing on the neuronal ensembles active during memory retention.

Researchers used Arc-Cre/flox-eYFP transgenic mice to permanently label neurons that were active during a memory retention test. Three days after this test, they performed both spatial transcriptomics and single-nucleus RNA sequencing (snRNA-seq) on the dorsal hippocampus. By comparing trained mice to untrained controls, the authors sought to identify transcriptomic signatures associated with the maintenance of the memory trace without triggering active recall.

Surprisingly, the researchers found relatively few differentially expressed genes (DEGs) within the specific neuronal ensembles tagged by the Arc-eYFP system. However, broader analysis of hippocampal subregions revealed distinct patterns. Spatial transcriptomics showed that CA1, CA3, and the dentate gyrus (DG) each exhibited unique regional gene expression profiles related to post-synaptic function, synaptic vesicle transport, and neuronal differentiation, respectively.

Perhaps most notably, snRNA-seq revealed a widespread, sub-regional downregulation of genes involved in ATP synthesis and cytoplasmic translation across hippocampal neurons in trained animals. The authors suggest that this metabolic and translational suppression may represent a mechanism for energy conservation or a state of "engrammatic pruning," where the memory trace is stabilized and muted during the offline maintenance phase, effectively poising the neurons for future reactivation.