Neuroprotective effect of lipopolysaccharides in a dual-hit rat pup model of preterm hypoxia-ischemia.

The combination of lipopolysaccharide (LPS) and hypoxia-ischemia (HI) has been used to model the brain injury sustained by sick pre-term infants in order to study the pathological conditions of diffuse white matter injury, which is a major cause of preterm morbidity. Prior studies have shown that the timing and dose of LPS administration will determine whether the injury is reduced or exacerbated. Here we show that administering a single injection of LPS (0.

Cholesterol biosynthesis defines oligodendrocyte precursor heterogeneity between brain and spinal cord.

Brain and spinal cord oligodendroglia have distinct functional characteristics, and cell-autonomous loss of individual genes can result in different regional phenotypes. However, a molecular basis for these distinctions is unknown. Using single-cell analysis of oligodendroglia during developmental myelination, we demonstrate that brain and spinal cord precursors are transcriptionally distinct, defined predominantly by cholesterol biosynthesis.

mTOR Signaling Regulates Metabolic Function in Oligodendrocyte Precursor Cells and Promotes Efficient Brain Remyelination in the Cuprizone Model.

In demyelinating diseases, such as multiple sclerosis, primary loss of myelin and subsequent neuronal degeneration throughout the CNS impair patient functionality. While the importance of mechanistic target of rapamycin (mTOR) signaling during developmental myelination is known, no studies have yet directly examined the function of mTOR signaling specifically in the oligodendrocyte (OL) lineage during remyelination. Here, we conditionally deleted from adult oligodendrocyte precursor cells (OPCs) using in male adult mice to test its function in new OLs responsible for remyelination.

Mechanistic Target of Rapamycin Regulates the Oligodendrocyte Cytoskeleton during Myelination.

During differentiation, oligodendrocyte precursor cells (OPCs) extend a network of processes that make contact with axons and initiate myelination. Recent studies revealed that actin polymerization is required for initiation of myelination whereas actin depolymerization promotes myelin wrapping. Here, we used primary OPCs in culture isolated from neonatal rat cortices of both sexes and young male and female mice with oligodendrocyte-specific deletion of mechanistic target of rapamycin (mTOR) to demonstrate that mTOR regulates expression of specific cytoskeletal targets and actin reorganization in oligodendrocytes during developmental myelination.

Loss of Tuberous Sclerosis Complex1 in Adult Oligodendrocyte Progenitor Cells Enhances Axon Remyelination and Increases Myelin Thickness after a Focal Demyelination.

Although the mammalian target of rapamycin (mTOR) is an essential regulator of developmental oligodendrocyte differentiation and myelination, oligodendrocyte-specific deletion of tuberous sclerosis complex (TSC), a major upstream inhibitor of mTOR, surprisingly also leads to hypomyelination during CNS development. However, the function of TSC has not been studied in the context of remyelination. Here, we used the inducible Cre-lox system to study the function of TSC in the remyelination of a focal, lysolecithin-demyelinated lesion in adult male mice.

Heterogeneity in oligodendroglia: Is it relevant to mouse models and human disease?

There are many lines of evidence indicating that oligodendrocyte progenitor cells and oligodendrocyte populations in the central nervous system (CNS) are heterogeneous based on their developmental origins as well as from morphological and molecular criteria. Whether these distinctions reflect functional heterogeneity is less clear and has been the subject of considerable debate. Recent findings, particularly from knockout mouse models, have provided new evidence for regional variations in myelination phenotypes, particularly between brain and spinal cord.