Chemogenetic activation of oxytocinergic neurons rescues neural correlates of encephalopathy of prematurity in mice

Every year, 15 million babies are born preterm, putting them at increased risk of encephalopathy of prematurity (EoP). EoP is characterized by microglia-induced neuroinflammation, which can aggravate injury mechanisms leading to neuronal disorders, myelination delay, and subsequent functional consequences. While effective neuroprotective strategies in the preterm brain remain elusive, interventions such as skin-to-skin, developmental care, and music therapy have a positive impact on newborn brain development, potentially related to the oxytocinergic system. Endogenous oxytocin is recognized as a regulator of maternal-child social bonding, but its neuroprotective effect in the injured brain remains to be elucidated. Here, we investigated the effects of chemogenetic activation of oxytocinergic neurons on the neural correlates of EoP. Using a well-established mouse model of systemic interleukin-1β to induce EoP, we showed that neonatal chemogenetic activation of oxytocinergic neurons has anti-inflammatory effects in microglia, improving microstructural development of the corpus callosum and motor cortex, and rescuing typical social behavior. These neuroprotective effects were more pronounced in females, who showed a greater reduction in microgliosis and improved social behavior compared to males. This study provides a biological explanation for how developmental care and early interventions, linked to the oxytocinergic system, may induce neuroprotection in the developing brain.