This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this subproject is to identify the impact of maternal sleep apnea-associated intermittent hypoxia on oligodendrocyte and axon development in offspring CNS. The study will focus on investigating oligodendroglial defects elicited by maternal intermittent hypoxia exposure during gestational period, tracing the destiny of insulted oligodendrocytes and exploring the long-term consequences in mouse embryos and neonates.
Three aims are proposed to characterize the molecular and cellular mechanisms underlying IH-mediated OL injury due to maternal OSA-related IH exposure:
aim 1 : to examine OL generation, proliferation, and differentiation in mouse forebrain and spinal cord at different embryonic stages following IH exposure during gestation (1st-2nd year);
aim 2 : to determine consequences of maternal IH exposure on myelin-forming process and myelin architecture in developing and adult mice, as well as local effects on axonal development that maybe induced or deteriorated by myelin deficit (2nd-3rd year);
aim 3 : to explore signaling molecules invovled in IH-mediated OL injury occurring in maternal sleep apnea during pregnancy (2nd -4th year). Our previous study showed that oligodendrocyte progenitor cells (OPCs) in neural tube decline after 3-day maternal IH exposure during the window of oligodendrogenesis. After the IH insult withdrawn, more Olig2+ progenitors appear in the ventricular zone but less in both gray and white matter, suggesting an increased proliferation or restraint in migration of progenitors. Oligodendrocyte differentiation as well as transcripts of mbp and MAG is inhibited at perinatal stages. These findings indicate that oligodendrogenesis is vulnerable to gestational IH insults, as occurs in OSA during pregnancy. Although early gestational IH exposure leads to 10%~20% decrease of mbp and MAG transcripts in newborns, myelin proteins appear to be normal in the developing offspring. Recently clinical retrospective studies reported that most of OSA occurring in pregnancy is diagnosed in the last trimester and 90% showed severe symptoms. Since oligodendrocyte maturation, myelination, axon sprouting, and synapse formation initiate from the late second and early third trimesters of pregnancy, maternal OSA in the 3rd trimester may result in much severe sequelae in offspring white matter. Thereby, we duplicated a mouse neonatal model of IH insult during the time window that is equivalent to the human 3rd trimester. Based on this model, we explored the differentiation of oligodendrocyte, expression of myelin-related proteins, axonal cytoskeleton and white matter development. A few CC1+/MAG+ mature oligodendrocytes were found in IH-treated spinal cords. The synthesis of myelin-related proteins were dramatically inhibited (40% in brain). In addition, all transcripts of neurofilament subunits (NF-L, M, and H) were significantly decreased with high percentage of NF-L/M components, indicating immaturity of axons. Consistent with these findings, less phosphorylated NFs were detected in IH-exposed developing mice. Furthermore, IH insult resulted in hypoplasia of white matter following IH-induced oligodendroglial-axonal injury.
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