Maternal Hematopoietic TNF, Via Milk Chemokines, Programs Hippocampal Development and Memory

The authors show, in mice, that maternal tumor necrosis factor-α (TNFα) genotype affects postnatal phenotypes in adult offspring. Lack of either one or two copies of the Tnf gene in dams led to reduced levels of chemokines in their milk, increased levels of adult hippocampal neurogenesis and improved spatial memory in offspring. Tumor necrosis factor α (TNF) is a proinflammatory cytokine with established roles in host defense and immune system organogenesis. We studied TNF function and found a previously unidentified physiological function that extends its effect beyond the host into the developing offspring. A partial or complete maternal TNF deficit, specifically in hematopoietic cells, resulted in reduced milk levels of the chemokines IP-10, MCP-1, MCP-3, MCP-5 and MIP-1β, which in turn augmented offspring postnatal hippocampal proliferation, leading to improved adult spatial memory in mice. These effects were reproduced by the postpartum administration of a clinically used anti-TNF agent. Chemokines, fed to suckling pups of TNF-deficient mothers, restored both postnatal proliferation and spatial memory to normal levels. Our results identify a TNF-dependent 'lactrocrine' pathway that programs offspring hippocampal development and memory. The level of ambient TNF is known to be downregulated by physical activity, exercise and adaptive stress. We propose that the maternal TNF–milk chemokine pathway evolved to promote offspring adaptation to post-weaning environmental challenges and competition.