Abstract
Defining the relationship between vascular development and the expression of hypoxia-inducible factors (Hifs) and vascular endothelial growth factor (Vegf) in the auditory brainstem is important to understand how tissue hypoxia caused by oxygen shortage contributes to sensory deficits in neonates. In this study, we used histology, molecular labeling, confocal microscopy and 3D image processing methods to test the hypothesis that significant maturation of the vascular bed in the medial nucleus of the trapezoid body (MNTB) occurs during the postnatal period that precedes hearing onset. Isolectin-B4 histochemistry experiments suggested that the MNTB vasculature becomes more elaborate between P5 and P10. When combined with a cell proliferation marker and immunohistochemistry, we found that vascular growth coincides with a switch in the localization of proliferating cells to perivascular locations, and an increase in the density of microglia within the MNTB. Furthermore, microglia were identified as perivascular cells with proliferative activity during the period of vascular maturation. Lastly, combined in situ hybridization and immunohistochemistry experiments showed distinct profiles of Hif1a and Vegf mRNA localization in microglia, astrocytes and MNTB principal neurons. These results suggest that different cells of the neuro-glio-vascular unit are likely targets of hypoxic insult in the auditory brainstem of neonate rats.
Highlights
Perinatal asphyxia is a major factor responsible for severe injury in preterm and term neonates
We found that the numbers of anti-Iba1 labeled cells in IN and OUT regions of interest (ROI), respectively, were 2.2 ± 1.4, and 8.6 ± 3.7 at P1 (p = 0.0297), 7.1 ± 2.0, and 8.5 ± 2.0 at P5 (p > 0.9999), and 31.0 ± 5.8, and 21.0 ± 8.0 at P10 (p > 0.9999)
Microglia ratios were 0.3 ± 0.2 at P1, 0.9 ± 0.3 at P5, and 1.7 ± 0.8 at P10, which showed statistically significantly differences from each other (Figure 3L; Kruskal–Wallis statistic (3, 52) = 35.81, p < 0.0001). These results show that subtle changes in the number of medial nucleus of the trapezoid body (MNTB) microglia occur at P1, and that more robust changes in the number of MNTB microglia occur between P5 and P10
Summary
Perinatal asphyxia is a major factor responsible for severe injury in preterm and term neonates. Human neonates who experience asphyxia may develop hearing loss and poor speech discrimination [1], while rats exposed to controlled anoxia at birth show deficits that are consistent with slower neural processing of sound [2]. The molecular factors and the cellular populations that are affected by oxygen shortage in the auditory brain of neonates have not been fully identified. The vascular system is at the interface between an environmental oxygen challenge and the local tissue response. The vascular supply to the brain consists of blood vessels that carry out gas exchange, nutrient delivery, and immune support to meet local tissue metabolic requirements and maintain homeostasis [3].
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