Maternal Isocaloric Monosaccharide Diets Reorganize Dorsal-Ventral Hippocampal Maturation and Ventral Plasticity in...

Early-life nutrition is increasingly recognized as a key determinant of brain developmental trajectories. Because the dorsal (dHIP) and ventral (vHIP) hippocampus regulate distinct cognitive and emotional functions, understanding how maternal diet shapes maturation along this axis may provide insight into later behavioral vulnerability. However, the impact of maternal diet on the spatial organization of hippocampal maturation along the dorsal-ventral axis remains unclear. Here, we tested whether maternal isocaloric monosaccharide diets containing glucose (GLU) or fructose (FRU) are associated with age-, sex-, and region-dependent molecular remodeling along the dorsal-ventral axis of the hippocampus. In an established Wistar rat cohort, we quantified mRNA expression of genes associated with neuronal maturation and plasticity (Bdnf, Dcx, Gfap, Nes, Rbfox3) and protein levels of DCX, GFAP, and NeuN in the dHIP and vHIP of dams and male and female offspring during adolescence (PND28) and young adulthood (PND63). In dams, FRU exposure was associated with modestly increased Bdnf expression, and both GLU and FRU diets were associated with region-dependent differences in DCX, GFAP, and NeuN protein levels. In offspring, perinatal exposure to GLU or FRU diets induced sex-dependent patterns of hippocampal gene expression. Diet-related molecular differences were more prominent in the dHIP during adolescence, whereas additional vHIP-associated alterations emerged in young adulthood. Several proteins exhibited region-dependent differences, with the vHIP generally displaying higher protein abundance, although diet-induced alterations differed between hippocampal subregions. Guided by PCA and a composite RNA-protein molecular index highlighting persistent molecular remodeling within the vHIP, subsequent analyses focused on the vHIP in male offspring. Targeted analysis of the male vHIP at PND63 revealed that maternal FRU exposure was associated with increased Mc4r expression and elevated MC4R protein levels, whereas both maternal GLU and FRU exposure were associated with increased ARC protein levels. In contrast, maternal monosaccharide exposure was associated with reduced Npas4 expression, and maternal FRU exposure was additionally associated with reduced NPAS4 protein levels. Collectively, maternal monosaccharide diets were associated with age-, sex-, and region-dependent remodeling of hippocampal maturation- and plasticity-related molecular profiles. Subsequent analyses identified persistent alterations in MC4R-, ARC-, and NPAS4-related molecular profiles in the young adult male vHIP.