Newborn brain injury is a major health concern with lifelong consequences. Encephalopathy of prematurity (EoP) and pediatric traumatic brain injury (TBI) are among the most common forms and are characterized by a harmful neuroinflammatory response driven by microglia. Despite their central role, no effective clinical therapies currently exist to modulate microglia or neonatal neuroinflammation. Interestingly, non-pharmacological interventions used in the neonatal intensive care unit (NICU)—such as skin-to-skin care, music exposure, and environmental enrichment—improve brain development and are associated with increased endogenous oxytocin levels. Yet this association and its underlying mechanisms remain largely elusive.

In this doctoral thesis, we examined the neuroprotective effects of early-life oxytocin in mouse models of EoP and TBI. Using chemogenetic activation of oxytocinergic neurons to mimic physiological oxytocin release, we assessed microglial cellular and transcriptomic responses during acute inflammation and evaluated long-term brain development through imaging, histology, and behavioral analyses. Oxytocin reduced acute microglial activation, promoted gene expression linked to brain developmental support, and suppressed pro-inflammatory pathways, with injury-specific effects across models. Long-term outcomes included improved white-matter development, neurovascular recovery, functional connectivity, and rescued social behavior, likely mediated by enhanced microglial support of oligodendrocyte maturation. Sex-specific and glial crosstalk–dependent effects were also observed.

This translational work provides the first mechanistic evidence that endogenous oxytocin enhances brain development by modulating microglia, with lasting effects following a brief treatment window. These findings support broader implementation of oxytocin-inducing interventions in neonatal care and suggest relevance for a wide range of perinatal brain injuries characterized by neuroinflammation.