Neurodevelopmental impairment following neonatal hyperoxia in the mouse
Highlights
► Adult mice exposed to hyperoxia in the newborn period had impaired spatial and recognition memory. ► Adult hyperoxia- and hypoxia-exposed mice had smaller hippocampi by MRI and histology ► Adult mice exposed to hyperoxia in the newborn period had reduced cerebellar area but performance on the Rotorod test was not affected. ► Neonatal hyperoxia exposure increased exploratory behavior and decreased anxiety in adult mice.
Introduction
Extremely low birth weight infants are at high risk (~ 40%) for neurodevelopmental impairment (NDI) even in the absence of known intracranial complications of prematurity such as intraventricular hemorrhage or periventricular leukomalacia (Broitman et al., 2007, Laptook et al., 2005, Neubauer et al., 2008). The etiology for NDI in the absence of such obvious intracranial pathology is not clear, and there are no animal models to simulate neurodevelopmental outcomes of prematurity. Preterm infants are often exposed to supraphysiological levels of oxygen supplementation, sometimes alternating with periods of hypoxemia, that are known to affect normal lung and retinal development (Auten et al., 2009, Dorfman et al., 2008, Londhe et al., 2011). Impairment of lung development (bronchopulmonary dysplasia) or abnormal retinal development (retinopathy of prematurity) in extremely preterm infants are associated with an increased risk of NDI (Anderson and Doyle, 2006, Hintz et al., 2005a, Schmidt et al., 2003). It is important to determine if oxygen supplementation also alters developmental programming of brain development, leading to neurodevelopmental impairment and alterations in neurobehavior. Our objective in this project was to test the hypothesis that exposure of newborn mice to chronic hypoxia or hyperoxia during the first two postnatal weeks would lead to permanent impairment of brain development and function, when assessed in adult life.
Section snippets
Materials and methods
All protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of UAB, and were consistent with the PHS policy on Humane Care and Use of Laboratory Animals (Office of Laboratory Animal Welfare, Aug 2002) and the Guide for the Care and Use of Laboratory Animals (National Research Council, National Academy Press, 1996). All experiments, unless otherwise specified, were done with a minimum of six mice of either gender from at least two litters for each experimental
Neurobehavioral studies
As described previously by Van Groen (Handattu et al., 2009, Perry et al., 2010) and others (Rogers et al., 1999, Rogers et al., 2001), a modified comprehensive phenotyping protocol (SHIRPA) was used at 12 weeks of age. Mice were assessed for locomotor activity (Open field test), balance and coordination (Rotarod test) anxiety (Elevated Plus Maze), spatial learning and memory (Novel Object Recognition test, Morris Water Maze Task), and vision (Cliff test). All the behavioral tests described
Neonatal hyperoxia exposure decreased adult spatial learning and memory in adult mice
Air- and hypoxia-exposed mice were able to find the submerged platform in the Morris water maze task in a comparable reduced amount of time with successive trials. However, neonatal hyperoxia markedly impaired the ability of mice to find the platform (Fig. 1). Neonatal hyperoxia also decreased performance in the novel object recognition, with less time spent on exploring the new objects compared to air-exposed mice (Fig. 2A).
Neonatal hyperoxia exposure increased exploratory behavior and decreased anxiety in adult mice
In the elevated plus maze test, hyperoxia-exposed (but not
Discussion
The present study is the first to determine the effect of neonatal exposure to chronic hypoxia or hyperoxia on adult neurobehavior and brain structure in a mouse model. The major finding of our study was that exposure of newborn mice to chronic hyperoxia led to deficits in spatial and recognition memory associated with smaller hippocampi in adult mice. This finding is important and highly clinically relevant as human preterm infants, despite a relatively uncomplicated neonatal intensive care
Conclusions
In conclusion, neonatal exposure to chronic hyperoxia leads to impaired spatial learning and memory deficits associated with reduced hippocampal size in adult mice. Neonatal exposure to chronic hypoxia also reduces hippocampal size, and may lead to more subtle neurological effects. These mouse models may be useful to investigate the mechanisms underlying abnormal neurodevelopment in preterm infants who are often exposed to hyperoxia or have hypoxemic episodes.
Disclosure
None.
Conflict of interest statement
None.
Acknowledgments
This work was partially funded by NIH P30 NS47466, NIH R01 HL092906, NIH C06 RR15490, IKARIA, and Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
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