Investigating milk-derived extracellular vesicles as mediators of maternal stress and environmental intervention

Parental communication signals are transmitted through nursing and critically shape neurodevelopmental trajectories. Mirroring some well characterized effects of gestational challenges in rodents, maternal immune activation (MIA) during the lactational period disrupts maternal physiology, decreases milk quality, and is associated with adverse neurobehavioral outcomes in offspring. This occurs without MIA significantly affecting maternal care. While gestational MIA models are responsive to environmental interventions, which beneficially alter maternal milk composition and associated offspring outcomes, the milk-borne mediators underlying resilience remain poorly understood. Given their ability to transport and deposit biologically active cargos, we propose that milk-derived extracellular vesicles (MEVs) are vehicles that deliver environmental programming signals (e.g., miRNAs) from nursing mothers to their offspring. Using a rat model, we show that lactational MIA altered MEV miRNA cargo and expression of hippocampal miRNAs in offspring. Several miRNAs in MEVs were also found in the hippocampus of matching offspring. Remarkably, the miRNA dysregulation observed in MEVs and hippocampus was rescued when dams were raised in an enriched environment, suggesting environmental enrichment protected from the effects of MIA, as also observed in the behavioral phenotype. RNA-seq of adult offspring hippocampus showed long-term transcriptional changes associated with the gene targets of early-life regulated miRNAs. Our results position MEV miRNA cargos as dynamic programming signals by which maternal experience is communicated to offspring, encoding both stress-induced and protective cues that influence development. This suggests that breastfeeding interventions can regulate the genetic cargo of the milk, programming the life of developing infants.