Behavioral and brain morphological analysis of non-inflammatory and inflammatory rat models of preterm brain injury.

Investigations using preclinical models of preterm birth have much contributed, together with human neuropathological studies, for advances in our understanding of preterm brain injury. Here, we evaluated whether the neurodevelopmental and behavioral consequences of preterm birth induced by a non-inflammatory model of preterm birth using mifepristone would differ from those after inflammatory prenatal transient hypoxia-ischemia (TSHI) 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 min of uterine arteries 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 total number of DCX and NPY cells was increased, and the density of cholinergic varicosities was reduced. With these results we suggest that a preterm birth, in a non-inflammatory prenatal environment, does not significantly change neonatal development and adult neurologic outcome. On other hand, prenatal hypoxia and ischemia (inflammation) modifies developmental trajectory, learning and memory, neurogenesis, and NPY GABAergic and cholinergic brain systems.