MICROVASCULAR REWIRING DURING PREGNANCY CONTRIBUTES TO THE ESTABLISHMENT OF MATERNAL BEHAVIOR

The contribution of the neurovascular system to this brain plasticity has however seldomly been considered. We used 3D whole-brain clearing, light-sheet imaging, and data analysis with our unbiased whole-brain vascular mapping technique TubeMap, to reconstruct the evolution of the brain vasculature throughout pregnancy at the capillary level. We found an increase in the vascularization of several brain regions throughout pregnancy. This increase was found in particular in the preoptic region of the hypothalamus, involved in pregnancy regulation and maternal behavior, and in cortical areas, such as the somatosensory cortex. In the hypothalamic pre-optic area, the vascularization was associated with the presence of endothelial tip cells, confirming active vascular remodeling in the region. Blood flow was also impacted in the region, as confirmed with fast ultrasound analyses. Steroid hormonal implants of estradiol or progesterone in virgin females recapitulated the increase in hypothalamic vascularization and vascular remodeling seen in pregnant dams. Using 3D whole brain fluorescent in situ hybridization, we measured in pregnant dams an increase in Vegfa expression levels in the brain regions having increased blood vessel numbers. Vegfa downregulation by shRNA in the preoptic area blocked the pregnancy-induced vascular densification, and disturbed maternal behavior post-birth. These data suggest that vascular remodeling in the hypothalamic pre-optic region is regulated by high levels of circulating estradiol during pregnancy and likely via the action of VEGF-A. Our data suggest an active role of vascular remodeling in shaping pregnancy- and maternal behaviors-related neuronal functions, proving the importance of vascular remodeling in healthy brains.