Cell Type-Specific Remodelling of the Rat Hippocampus by Parity and Age

Abstract

BackgroundThe hippocampus undergoes extensive cellular remodelling throughout life. Parity, the experience of pregnancy and motherhood, triggers profound hormonal changes which modulate brain plasticity in the short and long term. Signatures of past parity are seen in the middle-aged hippocampus in humans and rodents, but how parity shapes cellular composition long-term after pregnancy have not been systematically examined using quantitative, cell-type-specific approaches. MethodsWe performed cell type deconvolution on bulk RNA-sequencing data from female rat hippocampus, comparing nulliparous and parous females across age (7 or 13 months either 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. ResultsAge emerged as the dominant factor, significantly altering six cell types, particularly somatostatin (SST) and parvalbumin/Vip interneurons. Regional effects (dorsal and ventral hippocampus) affected nine cell types, while age x region 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. ConclusionsOur 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 aging research.