Andrea C Ewald, Tracy L Baker and Jyoti J Watters Department of Comparative Biosciences, University of Wisconsin-Madison
The in utero environment is well-known to influence CNS development and microglial function, effects that can last into adulthood. However, fetal brain reprogramming has never been evaluated in the context of sleep disordered breathing (SDB) during pregnancy, despite its alarming increase in recent years and detrimental consequences to the newborn. Here, we tested the hypothesis that SDB during pregnancy reprograms the developing CNS, enhancing the adult neuroinflammatory response in CNS regions important for respiratory control. To test this hypothesis, we developed a rat model of gestational intermittent hypoxia (GIH), a hallmark of SDB during pregnancy. Pregnant dams received intermittent hypoxia (2 min alternating 10.5%/21% O2) or normoxia (2 min alternating 21% O2/21% O2) for 8 hrs/day from gestational days 10-21. Adult male and female offspring (8-12 wks old) were challenged with vehicle (HBSS) or lipopolysaccharide (LPS; 1mg/kg, 3h), then brainstem and cervical spinal cord tissues were dissected for immunomagnetic microglial isolation. Inflammatory gene expression was analyzed by qRT-PCR in tissue homogenates and isolated microglia. Adult male, but not female, offspring exhibited increased basal inflammatory gene expression in brainstem and spinal cord tissue homogenates, suggesting that males have chronic basal neuroinflammation in brain regions important in respiratory control. By contrast, female, but not male, GIH offspring exhibited increased basal inflammatory gene expression in isolated microglia, suggesting that the inflammation in male homogenates is not due to microglia. Further, the normal CNS immune response to LPS challenge also differed by gene, sex, and CNS region in GIH offspring. Thus, SDB during pregnancy can have complex, long-lasting consequences on neuroinflammation in respiratory control regions of adult offspring, potentially contributing to sex differences in respiratory and CNS disease. (NS085226 and HL105511).
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