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Fluctuating hyperoxia (ΔO2) impairs cortical growth and Cux1 expression in a preterm model of intrauterine growth restriction

Presented at the Neonatal Society 2011 Autumn Meeting.

Woodrow E1, Georgala PA2, Wade J1, Gillespie T2, Becher JC1

1 Jennifer Brown Research Laboratory, MRC Centre for Reproductive Health, Queen‟s Medical Research Institute, University of Edinburgh
2 Centre for Integrative Physiology, University of Edinburgh

Background: Preterm infants with growth restriction are at increased risk of respiratory morbidity and neurological sequelae including reduced cortical volume at term and adverse neurodevelopment in childhood (1). Higher oxygen saturation targeting in preterm infants improves survival but both hyperoxia and oxygen fluctuations are associated with markers of cortical injury (2). The neurons of the superficial cortical laminae are late born and undergo critical growth and maturation from 24 weeks gestation, a process controlled by key transcription factors (3). We hypothesise that IUGR and postnatal fluctuating hyperoxia (ΔO2) impair cortical growth with a preferential effect on the neurons of the superficial layers.

Methods: Sprague-Dawley rat dams received 18% or 9% protein diet from E15 to P7. Litters were reared in air or fluctuating hyperoxia (circa 10kPa) from birth until P7. Brains were weighed and sections through the motor cortex were stained with cresyl violet. The thickness of the superficial (IV-II) and deep (VI-V) cortical layers was measured using ImageJ analysis. Staining for gene expression of transcription factors specific to neuronal subtypes (Tbr1, Ctip2, Satb2 and Cux1) was performed using immunofluorescence and cell numbers were quantified and analysed by 2 way ANOVA.

Results: IUGR pups had smaller brain weights than normally grown pups at P7 (p<0.001) but cortical thickness was preserved. ΔO2 did not affect brain weight at P7 in either group but did result in a decrease in cortical thickness in both normally grown (p<0.05) and IUGR groups (p<0.001). Cortical thinning was observed primarily in the late born superficial cortical layers but was also observed in the deep layers in pups with growth restriction (p<0.001). Thinning was observed in the context of preserved cell density signifying ΔO2 leads to a loss in neuron numbers. When measured, ΔO2 did not affect numbers of callosal, corticothalamic or corticospinal neurons but did result in a reduction of superficial neurons expressing Cux1, a key transcription factor intrinsic to dendritic branching and synapse formation (p<0.01).

Conclusion: Postnatal ΔO2, a modifiable factor in neonatal care, may impair cortical growth and development in preterm infants with a preferential disadvantage to the late born superficial layers generated during the third trimester. Specific effects on neurons intrinsic to cortical circuitry in the context of growth restriction suggest such infants may be particulary vulnerable to oxygen induced injury.

Corresponding author: elaine.woodrow@ed.ac.uk

1. Zaw et al. Pediatrics. 2003 Jun;11:1273-7.
2. Boardman et al. Annals of Neurology. 2007 Aug;62(2):185-92.
3. Molyneaux et al. Nature Reviews – Neuroscience. 2007 Jun;8(6):427-37

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