Single-cell map of the female brain across reproductive transitions

Ovarian hormone shifts enable reproduction and are associated with substantial brain plasticity and disease risks. While imaging studies provide (micro)structural insights into brain changes across the ovarian cycle and pregnancy, the high resolution, single-cell map of the brain across reproductive transitions is missing. Here, we performed multiome (gene expression and chromatin accessibility) analysis of the mouse ventral hippocampus (vHIP) across sex, estrous cycle, and peripartum period at single cell resolution. We identify dynamic changes in vHIP cellular composition across the estrous cycle and pregnancy, including in the neural stem cells of the dentate gyrus (DG), enabling hormone-driven neurogenesis. Major gene expression changes are neuronal function-relevant, cell type-specific, and found in excitatory neurons of CA1, CA3, and DG subfields, across sex and reproductive transitions. In contrast, chromatin accessibility changes are more extensive and found across cell types, likely driven by estrogen level shifts in both within-female and between-sex comparisons. We show that chromatin remodeling during the estrous cycle primes the genome for gene expression changes during pregnancy and is also enriched for brain disease-relevant genes. Finally, we reveal a thyroid hormone transporter (Transthyretin, Ttr) gene as the major candidate gene that drives structural and behavioral changes across the estrous cycle and pregnancy. Our study provides an extensive cellular and molecular view of how reproductive transitions shape the brain and opens the possibility to target downstream targets of estrogen, including thyroid hormone signaling, as a treatment option for hormone-sensitive periods in women.