Cognitive flexibility deficits in male mice exposed to neonatal hyperoxia followed by concentrated ambient ultrafine particles

Abstract

Epidemiological evidence indicates an association between early-life exposure to air pollution and preterm birth. Thus, it is essential to address the subsequent vulnerability of preterm infants, who are exposed to unique factors at birth including hyperoxia, and subsequently to air pollution. Health effects of air pollution relate to particle size and the ultrafine particulate component (<100 nm) is considered the most reactive. We previously reported neonatal mice exposed to hyperoxia (60% oxygen), mimicking preterm oxygen supplementation, for the first 4 days of life, followed by exposure to concentrated ambient ultrafine particles (CAPS) from postnatal day (PND) 4–7 and 10–13 exhibited deficits in acquisition of performance on a fixed interval (FI) schedule of reinforcement, a behavioral paradigm rewarding the first response at the end of a fixed interval of time. Specifically, mice exposed to hyperoxia followed by CAPS continued to respond earlier in the interval than controls, suggesting deficits in acquisition of timing of the interval. To further examine the extent of cognitive deficits produced by hyperoxia and CAPs exposures, performance under an intra- extradimensional shift discrimination paradigm was implemented, requiring the ability to respond to shifting rules for reward. Under these conditions, developmental exposure to hyperoxia and CAPS increased errors on both the reversal and extradimensional (ED) tasks in males but not females. Furthermore it altered the ratio of glutamate and GABA neurotransmitters in the frontal cortex, a region known to mediate cognitive flexibility, were observed immediately following neonatal hyperoxia and CAPS exposure on post-natal day 14 but not following behavioral experience. Collectively, the findings from this study suggests that combined developmental exposures to hyperoxia and CAPS leads to protracted and enhanced learning deficits consistent with cognitive inflexibility in males exclusively.