Effect of neonatal hyperoxia followed by concentrated ambient ultrafine particle exposure on cumulative learning in C57Bl/6J mice

Hyperoxia during treatment for prematurity may enhance susceptibility to other risk factors for adverse brain development, such as air pollution exposure, as both of these risk factors have been linked to a variety of adverse neurodevelopmental outcomes. This study investigated the combined effects of neonatal hyperoxia followed by inhalation of concentrated ambient ultrafine particles (CAPS, <100 nm in aerodynamic diameter) on learning. C57BL/6 J mice were birthed into 60% oxygen until postnatal day (PND) 4 and subsequently exposed to filtered air or to CAPS using the Harvard University Concentrated Ambient Particle System (HUCAPS) from PND 4-7 and 10-13. Behavior was assessed on a fixed interval (FI) schedule of reinforcement in which reward is available only after a fixed interval of time elapses, as well as expected reductions in behavior during an extinction procedure when reward was withheld. Both produce highly comparable behavioral performance across species. Performance measures included rate of responding, response accuracy, and temporal control (quarter life). Exposure to hyperoxia or CAPS resulted in lower mean quarter life values, an effect that was further enhanced in males by combined exposure, findings consistent with delayed learning of the FI schedule. Females also initially exhibited greater reductions in quarter life values following the combined exposure to hyperoxia and CAPS and delayed reductions in response rates during extinction. Combined hyperoxia and CAPS produced greater learning deficits than either risk factor alone, consistent with enhanced neurodevelopmental toxicity, findings that could reflect a convergence of both insults on common neurobiological systems. The basis for sex differences in outcome warrants further research. This study highlights the potential for heightened risk of adverse neurodevelopment outcomes in individuals born preterm in regions with higher levels of ultrafine particle (UFP) air pollution, in accord with the multiplicity of risk factors extant in the human environment.