OUP accepted manuscript

The fatty acid amides (FAMs) are present in breast milk. Oleamide (ODA), a member of the FAM family, has been reported to affect learning and memory-related abilities in animal experiments.This study aimed to characterize the temporal changes of FAMs in human milk, and sought to examine the effect of ODA supplementation during suckling on post-weaning cognitive performance in mice.FAMs were measured in human milk (postpartum 1-24 weeks) by UPLC-TQ-MS analysis. We supplemented neonatal C57BL/6J mice of both sexes with vehicle (control), 5 mg/(kg ∙ day) ODA (L-ODA) or 25 mg/(kg ∙ day) ODA (H-ODA) throughout suckling by oral gavage. After weaning, Morris water maze test and novel object recognition test were performed. Neurogenesis, spinal morphogenesis in the DG region and hippocampal expression of synaptic markers were analyzed. Data were analyzed by ANOVA and repeated-measures ANOVA.ODA (0.566-1.31 mg/L) was the most abundant FAMs in breast milk, followed by palmitamide (0.135-0.269 mg/L) and linoleamide (0.046-0.242 mg/L). Compared to the control group, the H-ODA group demonstrated shorter escape latency, shorter travel distance, 113% more platform crossing times and 48% greater discrimination index in behavioral tests (P < 0.05). Additionally, the H-ODA group showed higher density of EdU+ and EdU+&DCX+ cells (62% and 53%, respectively), 52% greater spine density in DG region than the control group (P < 0.05). The synaptic markers, PSD95 and SYP, were upregulated in the H-ODA group compared to the control group (P < 0.05). The L-ODA group also showed shorter escape latency in behavioral tests and 27% greater spine density in DG region than the control group (P < 0.05).ODA is the most common FAMs in human milk. ODA supplementation during suckling promotes learning and memory-related abilities in adolescent mice by augmenting hippocampal neuronal proliferation and boosting synaptic plasticity.