Hypoxic ischemic encephalopathy (HIE) affects 1.5 in 1000 infants and results in a range of neurodevelopmental delays. At the present time, therapeutic hypothermia is the recommended treatment for late preterm to term (>35 weeks gestational age, GA) infants. HIE occurs with a higher frequency in preterm infants (<35 weeks GA); however, there are no approved therapeutic treatments for this age group. As such, caffeine is a potential pharmaceutical treatment for HIE in preterm infants. Caffeine is an existing therapy for apnea of prematurity in preterm infants, but it is not routinely used for infants >32 weeks GA. Caffeine can reduce cerebral palsy risk in the preterm population thus garnering support for its neuroprotective properties. In preclinical term HIE animal models, caffeine treatment has been shown to have anti-inflammatory properties and improves neurobehavioral outcomes. Caffeine is a non-selective adenosine receptor antagonist; however, the mechanism underlying its neuroprotective effects is unknown, presenting a major knowledge gap in translating its use for HIE in preterm infants. Thus, the main objective of this project is to investigate the biologic mechanisms of caffeine in the developing brain of the preterm HIE infant using a preclinical (rat) model. The immediate impact of this proposal is in its translational value to advance the use of caffeine as a potential treatment for HIE in <35 weeks GA preterm infants.