Sex differences in the benefits of rehabilitative training during adolescence following neonatal hypoxia–ischemia in rats

Much effort and many resources are being devoted to rehabilitative programs for children with disabilities caused by neonatal hypoxic–ischemic encephalopathy without clear evidence of the efficacy of such programs. We recently reported that rehabilitative training tasks during adolescence improve spatial learning impairment following neonatal hypoxic–ischemic injury in rats without histological improvement. In the present study we focused on sex differences. Wister rat pups were exposed to a unilateral hypoxic–ischemic insult at 7 days of age. Six weeks after hypoxia–ischemia, rehabilitative training tasks were started. The tasks consisted of the plus maze, the eight-arm radial maze, and the choice reaction time task. Sixteen weeks after the insult, the water maze task was performed to evaluate spatial learning ability. Afterwards, we morphologically examined brain injury. Our rehabilitative training significantly improved swimming time and length in females (P < 0.01) but not in males. Likewise, the training ameliorated infarct areas in the injured cerebral hemisphere in females but not in males (P < 0.01). These results suggest that it may be important to develop and evaluate cognitive rehabilitation programs for children with brain injury on the basis of gender.

Research Highlights
► Rehabilitative training during adolescence following neonatal hypoxia–ischemia.
► The training improved spatial learning in female but not in male rats.
► The training histologically ameliorated the brain injury in females but not in males.
► Sex stratification is important in rehabilitation programs for brain injury.