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

Abstract

AbstractIntrauterine hypoxia is a common cause of brain injury in children with a wide spectrum of long-term neurodevelopmental sequela. Even an insult that does not result in significant neuroanatomical injury in perinatal brain imaging can lead to lifelong disabilities. Commonly used postnatal HIE models are not able to directly study the effects of pregnancy risk factors that contribute to outcomes of hypoxia in children. Large animal models suggest that transient prenatal hypoxia alone is sufficient to lead to significant functional impairment to the developing brain but published rodent prenatal hypoxia models are complex (requiring prolonged [days] hypoxic exposure or difficult surgical procedures) and can be difficult to replicate. Thus, to further understand the mechanisms underlying hypoxic injury seen in children affected by mild intrauterine hypoxia, murine models that are simple to reproduce and phenocopy the lack of neuroanatomic injury but have significant functional deficits are needed. Here we characterized the effect of late gestation (embryonic day 17.5) transient prenatal hypoxia on long-term anatomical and neurodevelopmental outcomes. Late gestation transient prenatal hypoxia increased hypoxia-inducible factor 1 alpha protein levels (a marker of hypoxic exposure) in the fetal brain but did not result in any difference in gestational age at birth, litter size at birth, or pup survival. In addition, there were no differences in 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 had abnormalities in repetitive behaviors, hindlimb strength, and decreased seizure threshold. Males demonstrated increased anxiety. Females had deficits 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.