Transcriptomic Signatures of Hippocampal Subregions and Neuronal Nuclei in Active Place Avoidance Memory Maintenance

Abstract

The gene expression changes associated with memory acquisition, consolidation and reconsolidation, all active epochs in memory formation, have been well characterized in the rodent hippocampus. Less is known, however, of the changes in gene expression supporting the maintenance of memory, particularly when it remains undisturbed or offline days after the memory experience. In this study, we used a combination of spatial transcriptomic and single nuclear RNA sequencing (snRNA-seq) to measure the gene expression changes in the dorsal hippocampus during an early phase of offline memory maintenance, 3 days after the post-training retention test of an active place avoidance memory. Through spatial transcriptomics we identified spatially regionalized differential gene expression and biological process enrichment, with CA1, CA3, and DG exhibiting differential expression of genes involved in post-synaptic function, synaptic vesicle transport, and neuronal differentiation, respectively. Notably, through snRNA-seq, differentially expressed genes detected in clusters of hippocampal neurons from the trained animal were largely defined by their down regulation of genes involved in ATP synthesis and cytoplasmic translation. With both techniques we also examined the gene expression changes in a putative subset of memory-associated neurons through the detection of eYFP mRNA in the Arc-Cre/flox-eYFP double transgenic mouse line. Amongst this population of cells, we detected a limited number of differentially expressed genes unique to each subregional population and associated with synaptic plasticity and post-synaptic signaling. Our results suggest that two overarching transcriptomic patters contribute to the functional changes in hippocampal cells during offline memory maintenance: a regional distribution of pathways linked to synaptic functions, and a reduction of metabolic activity across hippocampal sub-regions and memory-associated neuronal ensembles.