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  • Book
    Sonia R. Mayoral.
    Digital2012
    Male sex is a well-established clinical risk factor for poor neurodevelopmental outcome following preterm birth. The mechanisms responsible for this sex-related difference are unknown. The damage associated with prematurity can be mimicked in rodents by prolonged exposure to sublethal, postnatal hypoxia. This chronic, sublethal hypoxia (CSH) leads to anatomical changes in mice that strongly resemble the loss of volume, decreased myelination and ventriculomegaly seen in preterm newborns. However, no sex differences have been previously explored in this rodent model. We hypothesized that sex comparisons in hypoxic mice would show sex-related differences in the brain's response to the same degree of hypoxic insult. The hippocampal formation is a brain region that is notably affected in clinical studies and we found in mice that the male hippocampus, normally larger than the female, undergoes a greater volume loss compared to females. Myelination, generally greater in males, was significantly disrupted by hypoxia in neonatal male forebrain. The numbers of oligodendrocytes were significantly reduced in male hippocampus by the end CSH treatment. Females also experienced oligodendrocyte losses, but these occurred earlier than in males and numbers recovered to normal by the end of treatment. Sex-specific oligodendrocyte losses could not be attributed to caspase-dependent cell death or to differences in proliferation. Sex hormones play a complex role in the oligodendrocyte losses, leading us to hypothesize a differential effect of estrogen and testosterone on male versus female brain. We conclude that males show greater vulnerability to myelin loss and that females show greater resilience and recovery following the initial damage. Together, these results 1) illustrate at least two mechanisms that contribute to sex differences in neurological outcome; 2) support the use of this rodent model to investigate the basis of sex-related susceptibility to brain damage, and 3) provide insights into the cellular and hormonal mechanisms that may play a role in producing sex bias in neonatal brain injury.