Cell Type-Specific Remodelling of the Female Hippocampus by Reproductive Experience and Age

The hippocampus undergoes extensive cellular remodelling throughout life. Aging affects hippocampal structure, contributing to cognitive decline and neurodegenerative disease risk. Parity, as the experience of pregnancy and motherhood, triggers profound hormonal and metabolic changes which modulate brain plasticity in the short and long term. Signatures of past parity are seen in the hippocampus in humans and rodents, but how parity shapes cellular composition in the short and long-term after pregnancy have not been systematically examined using quantitative, cell-type-specific approaches. We performed cell type deconvolution on bulk RNA-sequencing data from female rat hippocampus, comparing nulliparous and parous females across ages (7 or 13 months; parous animals studied 30 days or 7 months after parturition). We harmonized 349 cell type annotations from three single-cell reference datasets into 27 biologically coherent categories using female-only data. Three-way ANOVA identified independent and interactive effects, while complementary analyses (random forest, PCA, DESeq2) identified parity-associated transcriptional signatures. Cell-specific functional enrichment employed weighted gene set meta-analysis across multiple pathway databases. Age emerged as the dominant factor, significantly altering six cell types, particularly somatostatin and parvalbumin/Vip interneurons. Regional effects (dorsal and ventral hippocampus) affected nine cell types, while agexregion interactions identified two cell types. Parity independently affected three populations: dorsal CA3 pyramidal neurons, SST interneurons, and astrocytes. Cell-type-specific pathway analysis revealed distinct mechanisms including protein degradation in CA3 neurons, stress-response regulation in astrocytes, and disrupted GPCR/signalling-receptor programs in SST interneurons. Our study shows that parity selectively remodels hippocampal cellular architecture through distinct, cell-type-specific molecular programs operating independently of age and region, establishing parity as a critical biological variable in neuroscience and aging research.