Neural and vascular development in a rat model for diseases of prematurity : the influence of intermittent hyperoxia-hypoxia and growth retardation on brain microstructure and retinal vasculature
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Preterm born infants are at high risk of periventricular leukomalacia, a distinct form of white matter damage, and retinopathy of prematurity, a disease affecting the retinal vasculature. Further, they often suffer from breathing disorders and thus require supplemental oxygen therapy. In addition, pretermbirth is often associated with poor postnatal weight gain. The aim of this thesis was to investigate the influence of oxygen fluctuations, growth retardation and their combined effect on brain maturation and retinal vasculature by means of a neonatal rat model. Rat pups were held in intermittent hyperoxia-hypoxia (IHH, n = 52) or room air (n = 32) for the first 14 postnatal days. Litter size was manipulated to 8, 12 or 16 pups per litter to induce variations in weight gain. Diffusion tensor imaging (DTI) was performed on postnatal day 15 and 28 and fractional anisotropy, mean, axial and radial diffusivity were measured. Rat pups were euthanized after the second scan, the left retina dissected and its vasculature stained. White matter structures were differentially affected by IHH exposure. The fractional anisotropy, a measure for whitematter maturation, increased in all structures over time independent of oxygen condition. In limbic fibers, this increase was higher in the IHH compared to the room air group. Conversely, the fractional anisotropy of pups exposed to IHH increased less in commisural, projection and association fibers. Presumably, this was due to varying development time and maturation-dependent vulnerability of these regions. In grey matter, exposure to IHH led to a less increase in fractional anisotropy, and a less decrease in mean, axial and radial diffusivity over time than in room air controls. Weight gain was positively correlated with mean, axial and radial diffusivity at P28, possibly reflecting higher brain water content. Hence, these DTI parameters are poor measures of brain maturation per se, as they highly depend on weight. Arteries and veins showed abnormal dilation in the mid-periphery of the retina after IHH exposure, but there was no difference in vessel tortuosity comparing oxygen groups. Interestingly, even though exposure to IHH affected both, the brain microstructure and retinal vasculature, DTI parameters were not associated with measures of abnormal retinal vascularization. Concluding, exposure to IHH led to subtle microstructural alterations inwhite and greymatter, and dilated vessels in the retina. Consequently, supplemental oxygen treatment must be applied cautiously to avoid severe hyperoxic-hypoxic fluctuations in pretermborn infants.