No abstract

Intrauterine hypoxia is a common cause of brain injury in children resulting in a broad spectrum of long-term neurodevelopmental sequela, including life-long disabilities that can occur even in the absence of severe neuroanatomic damage. Postnatal hypoxia-ischemia rodent models are commonly used to understand the effects of ischemia and transient hypoxia on the developing brain. Postnatal models, however, have some limitations. First, they do not test the impact of placental pathologies on outcomes from hypoxia. Second, they primarily recapitulate severe injury because they provoke substantial cell death, which is not seen in children with mild hypoxic injury. Lastly, they do not model preterm hypoxic injury. Prenatal models of hypoxia in mice may allow us to address some of these limitations to expand our understanding of developmental brain injury. The published rodent models of prenatal hypoxia employ multiple days of hypoxic exposure or complicated surgical procedures, making these models challenging to perform consistently in mice. Furthermore, large animal models suggest that transient prenatal hypoxia without ischemia is sufficient to lead to significant functional impairment to the developing brain. However, these large animal studies are resource-intensive and not readily amenable to mechanistic molecular studies. Therefore, here we characterized the effect of late gestation (embryonic day 17.5) transient prenatal hypoxia (5% inspired oxygen) on long-term anatomical and neurodevelopmental outcomes in mice. Late gestation transient prenatal hypoxia increased hypoxia-inducible factor 1 alpha protein levels (a marker of hypoxic exposure) in the fetal brain. Hypoxia exposure predisposed animals to decreased weight at postnatal day 2, which normalized by day 8. However, hypoxia did not affect gestational age at birth, litter size at birth, or pup survival. No differences in fetal brain cell death or long-term gray or white matter changes resulted from hypoxia. Animals exposed to prenatal hypoxia did have several long-term functional consequences, including sex-dichotomous changes. Hypoxia exposure was associated with a decreased seizure threshold and abnormalities in hindlimb strength and repetitive behaviors in males and females. Males exposed to hypoxia had increased anxiety-related deficits, whereas females had deficits in social interaction. Neither sex developed any motor or visual learning deficits. This study demonstrates that late gestation transient prenatal hypoxia in mice is a simple, clinically relevant paradigm for studying putative environmental and genetic modulators of the long-term effects of hypoxia on the developing brain.

No abstract

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.