Early Neuropathological and Neurobehavioral Consequences of Preterm Birth in a Rabbit Model

Preterm birth is the most significant problem in contemporary obstetrics accounting for 5-18% of worldwide deliveries. Encephalopathy of prematurity encompasses the multifaceted diffuse brain injury resulting from preterm birth. Current animal models exploring the underlying pathophysiology of encephalopathy of prematurity employ significant insults to generate gross central nervous system abnormalities. To date the exclusive effect of prematurity was only studied in a non-human primate model. Therefore, we aimed to develop a representative encephalopathy of prematurity small animal model only dependent on preterm birth. Time mated New-Zealand white rabbit does were either delivered on 28 (pre-term) or 31 (term) postconceptional days by caesarean section. Neonatal rabbits underwent neurobehavioral evaluation on 32 days post conception and then were transcardially perfuse fixed. Neuropathological assessments for neuron and oligodendrocyte quantification, astrogliosis, apoptosis and cellular proliferation were performed. Lastly, ex-vivo high-resolution Magnetic Resonance Imaging was used to calculate T1 volumetric and Diffusion Tensor Imaging derived fractional anisotropy and mean diffusivity. Preterm birth was associated with a motoric (posture instability, abnormal gait and decreased locomotion) and partial sensory (less pain responsiveness and failing righting reflex) deficits that coincided with global lower neuron densities, less oligodendrocyte precursors, increased apoptosis and less proliferation. These region-specific histological changes corresponded with Magnetic Resonance Diffusion Tensor Imaging differences. The most significant differences were seen in the hippocampus, caudate nucleus and thalamus of the preterm rabbits. In conclusion this model of preterm birth, in the absence of any other contributory events, resulted in measurable neurobehavioral deficits with associated brain structural and Magnetic Resonance Diffusion Tensor Imaging findings.