Transient late gestation prenatal hypoxic insult results in functional deficits but not gross neuroanatomic deficits in mice

Intrauterine hypoxia is a common cause of brain injury in children with a wide spectrum of long-term neurodevelopmental sequela even after milder injury that does not result in significant neuroanatomical injury. Published prenatal hypoxia models generally require many days of modest hypoxia or are invasive, difficult to replicate surgery to ligate the uterine artery. Postnatal models of neonatal hypoxic brain injury are not able to study the effects of antenatal risk factors that contribute to outcomes of hypoxia to the developing brain. In addition, the most common postnatal hypoxia models induce significant cell death and large focal neuroanatomic injury through unilateral ischemia, which is not a common pattern of injury in children. Large animal models suggest that brief transient prenatal hypoxia alone is sufficient to lead to significant functional impairment to the developing brain. Thus, to further understand the mechanisms underlying hypoxic injury to the developing brain, it is vital to develop murine models that are simple to reproduce and phenocopy the lack of neuroanatomic injury but significant functional injury seen in children affected by mild intrauterine hypoxia. Here we characterized the effect of late gestation (embryonic day 17.5) transient prenatal hypoxia on long-term anatomical and neurodevelopmental outcomes. Prenatal hypoxia induced hypoxia inducible factor 1 alpha in the fetal brain. There was no difference in gestational age at birth, litter size at birth, survival, fetal brain cell death, or long-term changes in gray or white matter between offspring after normoxia and hypoxia. However, there were several long-term functional consequences from prenatal hypoxia, including sex-dichotomous changes. Both males and females have abnormalities in repetitive behaviors, hindlimb strength, and decreased seizure threshold. Males demonstrated increased anxiety. Females have deficit in social interaction. Hypoxia did not result in motor or visual learning deficits. This work demonstrates that transient late gestation prenatal hypoxia is a simple, clinically-relevant paradigm for studying putative environmental and genetic modulators of the long-term effects of transient hypoxia on the developing brain.