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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Prenatal Hypoxia in Different Periods of Embryogenesis Differentially Affects Cell Migration, Neuronal Plasticity,
Dmitrii S Vasilev1, Nadezhda M Dubrovskaya1, Natalia L Tumanova2
1I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of SciencesSaint Petersburg, Russia; Research Center, Saint-Petersburg State Pediatric Medical UniversitySaint Petersburg, Russia.
Insights
Prenatal hypoxia on embryonic day 14 (E14) disrupts cortical neuron development and behavior, leading to lasting deficits. Hypoxia on embryonic day 18 (E18) has minimal long-term effects on the developing rat cortex.
Area of Science:
- Neuroscience
- Developmental Biology
- Perinatal Medicine
Background:
- Prenatal hypoxia, a condition of insufficient oxygen supply during pregnancy, can significantly impact fetal development.
- The developing brain, particularly the cerebral cortex, is highly sensitive to oxygen deprivation during critical developmental windows.
- Understanding the specific timing of hypoxic insult is crucial for predicting long-term neurological consequences.
Purpose of the Study:
- To investigate the long-term effects of prenatal hypoxia on cortical development and function.
- To compare the impact of hypoxia exposure at two distinct embryonic stages (E14 and E18) on neuronal development and behavior.
- To elucidate the specific cellular and behavioral deficits induced by prenatal hypoxia.
Main Methods:
- Prenatal hypoxia was induced in rats on embryonic days E14 or E18.
- 5-ethynyl-2'-deoxyuridine (EdU) was administered to label newly generated neurons.
- Postnatal analysis included counting and localizing cortical neurons, assessing dendritic spine density, and evaluating parietal cortex-dependent behaviors.
Main Results:
- Hypoxia on E14 reduced total cortical neurons, increased scattered neurons in superficial layers, and decreased pyramidal neurons and dendritic spine density.
- Hypoxia on E18 also decreased total cortical neurons but increased scattered neurons in deeper layers, with less impact on overall structure.
- Only E14 hypoxia led to impaired whisker-placing reactions and reduced forepaw reaching ability, indicating functional deficits.
Conclusions:
- Prenatal hypoxia on E14 significantly disrupts cortical cytoarchitecture, neuronal plasticity, and behavior, leading to long-term cortical dysfunction.
- Prenatal hypoxia on E18 has a less pronounced effect on cortical structure and associated behaviors.
- The timing of hypoxic insult during prenatal development critically determines the severity and nature of long-term neurological consequences.
Abstract:
Long-term effects of prenatal hypoxia on embryonic days E14 or E18 on the number, type and localization of cortical neurons, density of labile synaptopodin-positive dendritic spines, and parietal cortex-dependent behavioral tasks were examined in the postnatal ontogenesis of rats. An injection of 5'ethynyl-2'deoxyuridine to pregnant rats was used to label neurons generated on E14 or E18 in the fetuses. In control rat pups a majority of cells labeled on E14 were localized in the lower cortical layers V-VI while the cells labeled on E18 were mainly found in the superficial cortical layers II-III. It was shown that hypoxia both on E14 and E18 results in disruption of neuroblast generation and migration but affects different cell populations. In rat pups subjected to hypoxia on E14, the total number of labeled cells in the parietal cortex was decreased while the number of labeled neurons scattered within the superficial cortical layers was increased. In rat pups subjected to hypoxia on E18, the total number of labeled cells in the parietal cortex was also decreased but the number of scattered labeled neurons was higher in the lower cortical layers. It can be suggested that prenatal hypoxia both on E14 and E18 causes a disruption in neuroblast migration but with a different outcome. Only in rats subjected to hypoxia on E14 did we observe a reduction in the total number of pyramidal cortical neurons and the density of labile synaptopodin-positive dendritic spines in the molecular cortical layer during the first month after birth which affected development of the cortical functions. As a result, rats subjected to hypoxia on E14, but not on E18, had impaired development of the whisker-placing reaction and reduced ability to learn reaching by a forepaw. The data obtained suggest that hypoxia on E14 in the period of generation of the cells, which later differentiate into the pyramidal cortical neurons of the V-VI layers and form cortical minicolumns, affects formation of cortical cytoarchitecture, neuronal plasticity and behavior in postnatal ontogenesis which testify to cortical dysfunction. Hypoxia on E18 does not significantly affect cortical structure and parietal cortex-dependent behavioral tasks.
