Behavioural and brain morphological analysis of non-inflammatory and inflammatory Rat models of preterm birth

Abstract

Despite their inherent limitations, investigations using preclinical models of preterm birth have much contributed, together with human neuropathological studies, for advances in our understanding of brain injury in premature infants. Here, we addressed the question of whether the neurodevelopmental and behavioral consequences of preterm birth evaluated using an inflammatory, prenatal transient hypoxia/ischemia (TSHI) model would differ from those observed after actual preterm birth induced by mifepristone (non-inflammatory model). Pregnant Wistar rats were either injected with mifepristone, and pups were delivered on embryonic day 21 (ED21 group), or laparotomized on the 18th day of gestation for 60 minutes of uterine artery occlusion. Rat pups were tested postnatally for characterization of developmental milestones and, after weaning, they were behaviorally tested for anxiety and for spatial learning and memory. One month later, brains were processed for quantification of doublecortin (DCX)- and neuropeptide Y (NPY)-immunoreactive cells, and cholinergic varicosities in the hippocampus. ED21 rats did not differ from controls with respect to neonatal developmental milestones, anxiety, learning and memory functions, and neurochemical parameters. Conversely, in TSHI rats the development of neonatal reflexes was delayed, the levels of anxiety were reduced and spatial learning and memory was impaired; in the hippocampus, the density of DCX and NPY cells was increased and the density of cholinergic varicosities was reduced. These results suggest that preterm birth, by itself, does not induce significant changes in neonatal developmental and adult neurologic outcome and that external noxae seem to be important contributing factors of the lesions observed in premature brains.