Traumatic brain injury (TBI) is a leading cause of death and severe morbidity for infants born healthy at term. Despite the high prevalence and incidence of lifelong deficits from infant TBI, no targeted treatment currently exists to actively promote repair. Using a translatable preclinical model of infant TBI, we hypothesized that magnetic resonance imaging (MRI) and touchscreen cognitive testing could be used to quantify outcomes and potential efficacy of the neuro-reparative agent erythropoietin (EPO). Accordingly, controlled cortical impact (CCI) was performed on postnatal day 12 (P12) rats of both sexes. On post-injury day (pid) 1, rats were randomized to intraperitoneal EPO (3000 U/kg/dose) or vehicle (sterile saline) over pid 1-8, and coded. Beginning at P35, rats were trained on a touchscreen operant platform by blinded investigators. Following successful training, rats performed visual discrimination (VD) and reversal tasks to assess executive function and cognitive flexibility (n = 6-8/group). Ex vivo MRI was performed on a 4.7T at P15 and P45. Sham, CCI-veh, and CCIEPO rats were compared using two-way ANOVA with Bonferroni's correction. Results show diffusion tensor imaging (DTI) of ipsilateral and contralateral regions in CCI-veh P45 rats have widespread bilateral injury and significant abnormalities of functional anisotropy (FA), mean diffusivity (MD), axial (AD) and radial diffusivity (RD). Treatment with EPO reversed changes in MD, AD and RD. EPO treatment also ameliorated deficits in cognitive flexibility on a touchscreen platform, including error reduction and perseveration (all p < 0.05). In conclusion, in our model of moderate-severe infantile TBI, EPO, administered in an extended dosing paradigm congruent with its mechanisms of action, proved efficacious in reversing microstructural and functional impairment in developing rats. To our knowledge, this is the first demonstration using the highly translatable, touchscreen platform of cognitive assessment for TBI. These data support the use of ageappropriate preclinical models with human clinical trial-compatible imaging biomarkers and outcome measures. [ABSTRACT FROM AUTHOR]