Absence of 6’Sialyllactose during lactation impairs cognitive capabilities and modulates gene expression

Aims: Human milk is the ideal source of nutrition for the new-born, promoting the development of cognitive capabilities. However, which components of maternal milk are involved in the proper development of executive functions has remained elusive. We hypothesized that the maturation of attention, cognitive flexibility, and memory depends on the neonatal bioavailability of a specific human milk oligosaccharide (HMOs), sialyl(alpha2,6)lactose (6’SL). Methods: To test this hypothesis, we evaluated the aforementioned cognitive capabilities in adult mice that received maternal milk containing different concentrations of 6’SL. To modulate the availability of 6’SL during lactation, we leveraged a genetically engineered mouse (C57BL/6-St6gal1tm1.1Jxm/J, KO), that provides milk without 6‘SL. Specifically, we performed a cross-fostering study in which wild-type (WT) mice were reared to either KO or WT dams. During lactation, maternal behaviour was analysed for potential effects of maternal care on offspring. Adult subjects were tested for spatial memory, working memory and sensorimotor gating. To understand the underpinning molecular mechanisms of potential effect, we performed an RNA-seq analysis on PFC and hippocampal samples. Furthermore, we addressed ex vivo long-term potentiation (LTP, an electrophysiological correlate of memory performance) in hippocampal slices. Results: Mice that received 6’SL deficient milk showed an impoverishment of spatial reference memory, working memory and attentional capabilities compared to control. Furthermore, this group showed an altered regulation in the expression of genes involved in PFC development and an alteration in LTP. Conclusions: These findings show that absence of 6’SL in maternal milk impairs cognitive functions, such as memory and attention.