Multi-omics analysis reveals chromatin and transcriptomic remodeling in hippocampal CA1 following adolescent social isolation

Social isolation (SI) during adolescence is associated with long-term vulnerability to psychiatric disorders; however, its effect on the hippocampal epigenome and transcriptome remains unclear. Here, we performed integrative ATAC-seq and RNA-seq of the hippocampal CA1 region using an adolescent mouse SI model, combined with single-cell RNA-seq reference mapping and cell type deconvolution. ATAC-seq identified SI-associated alterations in chromatin accessibility, including an increase in enhancer-associated regions linked to calcium transport and a decrease in promoter regions related to synaptic organization. Motif enrichment analysis highlighted that the activator protein 1 (AP-1) motif within these regions exhibited reduced accessibility. RNA-seq identified 106 differentially expressed genes, including the upregulation of Fosl2 and Hdac9 and the downregulation of Fbxw7, along with the enrichment of myelination-related pathways. Although global concordance between chromatin accessibility and transcriptional changes is limited, integrative multi-omics revealed locally coordinated shifts across a subset of differentially expressed genes. Cell type-oriented analyses suggested that SI-downregulated transcriptional signatures were preferentially linked to excitatory neurons, whereas SI-upregulated signatures were enriched in non-neuronal populations, particularly oligodendrocytes. Consistent with this finding, deconvolution indicated an increased representation of oligodendrocytes along with a reduction in excitatory neurons in isolated mice. Together, these findings suggest that adolescent SI drives selective epigenomic and transcriptional remodeling within the hippocampal CA1 circuits, accompanied by divergent adaptive responses across neuronal and glial populations.