Milk-derived extracellular vesicles are functional mediators of postnatal neuroimmune rescue

Early parental experiences can be translated into biological signals that are transmitted to offspring. These signals influence developmental trajectories to both increase offspring vulnerability following adverse experiences or promote resilience when environments are supported and enriched. Among the potential routes of parental-offspring communication, milk-derived extracellular vesicles (EVs) transferred through nursing are particularly interesting because they carry bioactive molecular cargos capable of influencing recipient cells. Previously, we found that milk-derived EV cargo is remodeled by both adverse and positive experiences and that environmental enrichment (EE) can rescue adversity-associated effects, including EV-miRNA cargo changes. Environmental programming of EVs during lactation may therefore have functional consequences on offspring development and adaptability. Here, we tested whether milk-derived EVs from our rat EE model are sufficient to rescue offspring outcomes following maternal immune activation (MIA). Milk-derived EVs isolated from donor EE dams were administered directly to MIA-exposed pups, mitigating MIA-associated reductions in social behavior. EE-EV administration also promoted social behavior in non-MIA exposed male offspring. To investigate microglia as a cellular target, EE-EVs were administered to LPS-activated BV2 microglial cells. EE-EV exposure attenuated LPS-associated transcriptional alterations across inflammatory pathways, including cytokine, chemokine, and NF-ĸB signaling, while modulating genes associated with cellular homeostasis and metabolic responses. Together, these results 1) support milk-derived EVs as a biologically active interface through which environmental experience may be communicated to offspring, and 2) identify microglial transcriptional responses as a potential cellular pathway underlying these effects.