Supplementation of 3′-Sialyllactose During the Growth Period Improves Learning and Memory Development in Mice

3'-Sialyllactose (3'-SL), a major acidic oligosaccharide found in human milk, has been investigated to improve cognitive-enhancing effects with 3 weeks old C57BL/6 mice by administering 3'-SL orally at a dose of 350 mg/kg/day for 6 weeks. Behavioral tests indicated that supplementation with 3'-SL promoted cognitive and memory development in young mice. Through interaction network and coenrichment analysis, nine differentially expressed genes (DEGs) related to memory and cognition were identified and localized in the hippocampal tissue of mice. The intervention of 3'-SL significantly increased the metabolism of sialic acid in mouse hippocampal tissue and promoted the expression of learning-related genes (<i>p</i> < 0.05). Notably, it increased the expression of genes associated with neural cell adhesion molecule (NCAM, <i>p</i> < 0.05), glutamate receptors, and fibroblast growth factor receptor (FGFR, <i>p</i> < 0.05). This suggests that 3'-SL may elevate polysialylated NCAM (PSA-NCAM) levels, which could subsequently interact with FGFR and glutamate receptors, thereby enhancing synaptic growth and plasticity. Additionally, 3'-SL altered the composition of the mouse intestinal microbiota. The synergistic action of gut microbiota and intestinal sialidase promoted the production of free sialic acid, providing essential nutritional elements for the development of the brain's nervous system. In conclusion, our findings provide new insights into the promoting effect of 3'-SL on cognitive development in growing mice and elucidate its molecular mechanisms.