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Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of cognitive impairment in children. Clinically, male infants are more sensitive to the ischemic insult and have worse long-term deficits than girls. The mechanism underlying the sex difference remains elusive. Our previous study using an HIE animal model on post-natal day 10 (P10) mice has revealed that male animals exhibited worse outcomes than females, corresponding to an increased microglial activation that initiates post-ischemia immune responses. CX3CL1/CX3CR1 axis is an endogenous inhibitory signaling pathway that keeps microglia quiescent in normal brains. Whether the CX3CL1/CX3CR1 axis is sex-differently expressed in neonatal brains to cause the sexually dimorphic phenotypes of HIE is not known.Hypothesis: We hypothesize that neonatal female brains are protected against HIE due to a more robust CX3CL1/CX3CR1 signaling compared to males and that manipulation of CX3CL1/CX3CR1 axis has sex-specific effects on HIE.Methods: C57BL6 P10 mice (WT) of both sexes were subjected to a 45-min Rice-Vanucci model (RVM) to induce HIE. CX3CR1 expression, microglial activation, and the infiltration of peripheral leukocytes were examined by flow cytometry. CX3CR1 knockout mice were also used to evaluate the effect of genetic deletion of CX3CL1/CX3CR1 signaling.Results: WT females had a better outcome after neonatal HIE. In addition, WT females have significantly higher expression of CX3CR1 on microglia at baseline than males, measured by CX3CR1 MFI with flow cytometry. Importantly, the majority of the CX3CR1+ microglia co-expressed CD206, a marker of anti-inflammatory phenotype for phagocytes. CX3CR1 KO females lost the resistance to ischemic damage as the knockout of CX3CR1 gene led to exacerbate HIE outcomes only in females.Conclusions: The high expression of CX3CR1 primes female brains to resist inflammatory responses to HIE and has beneficial effects, though the protective mechanism is not sufficient in male brains. Sex differences seen in neonatal HIE are at least in part ascribed to the sexually dimorphic CX3CL1/CX3CR1 signaling.Funding: R01: NS093042 and R21: NS091794 to Fudong Liu.