Abstract
Lactation is a crucial phase of brain development, and the events and nutrients during this period have long-term consequences for the occurrence of depression. This study investigated the effect and mechanism of lactoferrin (LF) deficiency during lactation on depression in adulthood. Lactation LF-deficient mice were established by nursing wild-type mice using LF systemic knockout mother mice. Additionally, 14-day-old mice were injected with lipopolysaccharide (LPS) and subjected to chronic unpredictable mild stress when they reached 6 weeks of age. The results show that lactation lactoferrin deficiency increases depression-like behavior in adult mice, and the mechanism is associated with heightened neuronal damage, abnormal microglial activation, and decreased BDNF in the hippocampus. In contrast, recombinant human lactoferrin promotes neuronal proliferation by upregulating ERK 1 and 2 phosphorylation and attenuates LPS-induced neuronal injury and microglial activation by inhibiting the activation of Toll-like receptor 4-nuclear factor-kappa B pathway in vitro. Our findings suggest that lactoferrin intake during lactation protects neurons by regulating microglial activation, thereby effectively reducing depressive symptoms in adults.