INTRODUCTION: Early-life exposure to dietary monosaccharides can shape neurodevelopmental trajectories and activity-dependent plasticity within limbic circuits of the offspring. However, the long-term consequences for ventral hippocampal plasticity remain insufficiently defined. Our previous studies using the same maternal dietary model demonstrated anxiety-like behavioral alterations in male offspring and dorsal–ventral reorganization of hippocampal neurodevelopment following maternal fructose exposure.

AIM(S): We investigated whether maternal isocaloric glucose or fructose intake programs molecular pathways of synaptic plasticity in the ventral hippocampus during adolescence and young adulthood.

METHOD(S): Male Wistar offspring were evaluated at adolescence (PND28) and young adulthood (PND63) after perinatal maternal exposure to isocaloric control, glucose, or fructose diets. Ventral hippocampal expression of melanocortin-4 receptor (Mc4r), activity-regulated cytoskeleton-associated protein (Arc), brain-derived neurotrophic factor (Bdnf), and neuronal PAS domain protein 4 (Npas4) was quantified at the mRNA level by RT-qPCR and at the protein level by Western blotting.

RESULTS: Adolescence was characterized by limited and dissociated molecular alterations. In contrast, young adulthood revealed a coordinated plasticity profile defined by increased MC4R and ARC protein abundance together with reduced NPAS4 expression, with the strongest and most consistent effects observed in fructose-exposed offspring, while BDNF levels remained largely unchanged. These findings indicate selective remodeling of activity-dependent signaling rather than generalized neurotrophic activation.

CONCLUSIONS: Maternal monosaccharide exposure is associated with a male-specific molecular signature of ventral hippocampal plasticity converging on the MC4R–ARC–NPAS4 axis, providing a plausible mechanistic substrate for previously observed behavioral vulnerability.

FINANCIAL SUPPORT: This study was supported by the research grant UMO-2023/49/N/NZ1/03606 from the National Science Centre (Kraków, Poland) to Kacper Witek.