Hypoxia-ischemia (HI) is a significant cause of disability and mortality in neonates. HI is characterized by acute energetic failure and secondary inflammatory response. The primary therapeutic intervention is hypothermia, which presents limited neuroprotective effects. Environmental approaches, such as skin-to-skin contact, have been highlighted for their benefits in brain development. Oxytocin (OT) is a neuropeptide with roles in parturition and social behavior, but it also modulates the microglial inflammatory responses. Therefore, the study of OT signaling can be helpful to bridge the gap between clinical outcomes and a mechanistic approach.We used a lineage of C57B6 mice expressing the Gq activating DREADD construct specifically in OT neurons, which is activated by its ligand CNO (Clozapine-N-Oxide). Mice were submitted to neonatal HI at P9 (permanent occlusion of the right common carotid artery followed by 60’ at 8% O2 hypoxic environment. HI animals received intraperitoneal CNO (10mg/kg) injections (HI + CNO) or vehicle (HI) four times between P9 (after HI) and P11. Sham animals were submitted to all procedures except artery ligation and hypoxia. At P11, mice were euthanized 1-hour after the last CNO injection, and the right hemisphere was collected for mRNA analysis. RT-qPCR (n=5-7) for the following genes related to inflammatory response (Arg1, lgals3, Cxc3r, Il10, and TNF-alpha) were assessed. 48h after HI, inflammatory markers were significantly increased in HI animals compared to control littermates, whereas activation of OT neurons partially reversed this effect. Our preliminary data encourage the study of oxytocin signalling in perinatal brain injury.Approval GE337