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Transcriptomic Signatures of Hippocampal Active Place Avoidance Memory Maintenance [scRNA-Seq]

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 during the offline maintenance of memory. In this study, we measured the gene expression changes in the dorsal hippocampus of four mice three days after consolidation of an active place avoidance memory. We examined gene expression changes in a putative subset of memory-associated neurons by leveraging the immediate early gene in vivo tagging system of the Arc-Cre/flox- eYFP transgenic mouse line. Through spatial transcriptomics we found that memory trained animals exhibited spatially regionalized expression of genes involved in post-synaptic function in CA1, synaptic vesicle transport in CA3, and neuronal differentiation in DG. Surprisingly, these gene expression enrichments were not observed in eYFP mRNA positive spatial spots. To gain granularity into this finding, we carried out single nuclear RNA sequencing, which confirmed enrichment of differentially expressed genes associated with synaptic plasticity and post-synaptic signaling unique to each subregion in trained animals, but not from their eYFP mRNA positive nuclei. Notably, nuclei of hippocampal neurons were largely characterized by their down regulation of genes involved in ATP synthesis and cytoplasmic translation. Our results suggest that two overarching transcriptomic patterns contribute to the functional changes in hippocampal cells during offline memory maintenance: regionally distributed expression of genes linked to synaptic functions (with concomitant sparseness of memory-associated neuronal ensembles) and a reduction of metabolic activity related genes across hippocampal sub-regions.

ORGANISM(S): Mus musculus

PROVIDER: GSE330161 | GEO | 2026/05/06

REPOSITORIES: GEO

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Project description:The purpose of this study was to determine whether there were differences in gene expression in the hippocampus, a part of the brain involved in memory consolidation, between male mice with age-related memory deficits (SAMP8 mice) and control mice with no age-related memory deficits. The senescence-accelerated mouse (SAMP8) strain exhibits decreased learning and memory and increased amyloid beta peptide (Aβ) accumulation at 12 months compared to 4 months. To detect differences in gene expression in SAMP8 mice, we used a Control mouse that was a 50% cross between SAMP8 and CD-1 mice and which showed no memory deficits (50% SAMP8 mouse). We then compared gene expression in the hippocampus of 4 month and 12 month old SAMP8 and Control mice using Affymetrix gene arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the Long Term Potentiation (LTP) (6 genes), Phosphatidylinositol Signaling (6 genes), and Endocytosis (10 genes) pathways. The changes in LTP included MAPK signaling (N-ras, CREB binding protein, protein phosphatase inhibitor 1) and Ca-dependent signaling (PI receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through PI3-kinase, and Western blotting revealed phosphorylation changes in AKT and 70S6K. Changes in the Endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered genes expression in three SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways may provide new therapeutic targets in addition to targeting Aβ metabolism itself. Global differential profiling of hippocampal gene expression (4 month and 12 month old SAMP8 and Control mice) was performed using Affymetrix GeneChip® Mouse Genome 430 2.0 Arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the Long Term Potentiation (LTP) (6 genes), Phosphatidylinositol Signaling (6 genes), and Endocytosis (10 genes) pathways. The changes in LTP included MAPK signaling (N-ras, CREB binding protein, protein phosphatase inhibitor 1) and Ca-dependent signaling (PI receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through PI3-kinase, and Western blotting revealed phosphorylation changes in AKT and 70S6K. Changes in the Endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered genes expression in three SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways may provide new therapeutic targets in addition to targeting Aβ metabolism itself. 2-way ANOVA (2 x 2 conditions, n=4). First variable was age (4 and 12 months) and second variable was mouse strain (Control and SAMP8). This results in 4 groups: Control-4 month, Control-12 month, SAMP8-4 month, and SAMP8-12 month. Each group had 4 biological replicates (4 mice). The ”Control” mice were a 50% backcross of the SAMP8 mice with CD-1 mice (50% SAMP8 mice). These mice were closely related to SAMP8 mice but exhibited no memory deficits at 4 or 12 months. The SAMP8 mice had memory deficits at 12 months but not at 4 months.

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Transcriptomic Signatures of Hippocampal Active Place Avoidance Memory Maintenance [scRNA-Seq]

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