Shaping of Regional Differences in Oligodendrocyte Dynamics by Regional Heterogeneity of the Pericellular Microenvironment

Oligodendrocyte precursor cells (OPCs) are glial cells that differentiate into mature oligodendrocytes (OLs) to generate new myelin sheaths. While OPCs are distributed uniformly throughout the gray and white matter in the developing and adult brain, those in white matter proliferate and differentiate into oligodendrocytes at a greater rate than those in gray matter. There is currently lack of evidence to suggest that OPCs comprise genetically and transcriptionally distinct subtypes. Rather, the emerging view is that they exist in different cell and functional states, depending on their location and age. Contrary to the normal brain, demyelinated lesions in the gray matter of multiple sclerosis brains contain more OPCs and OLs and are remyelinated more robustly than those in white matter. The differences in the dynamic behavior of OL lineage cells are likely to be influenced by their microenvironment. There are regional differences in astrocytes, microglia, the vasculature, and the composition of the extracellular matrix (ECM). We will discuss how the regional differences in these elements surrounding OPCs might shape their phenotypic variability in normal and demyelinated states.

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Quantitative T1 mapping of the normal brain from early infancy to adulthood

Pediatric Radiology ◽

10.1007/s00247-020-04842-7 ◽

2020 ◽

Author(s):

Daniel Gräfe ◽

Jens Frahm ◽

Andreas Merkenschlager ◽

Dirk Voit ◽

Franz Wolfgang Hirsch

Keyword(s):

White Matter ◽

Spatial Resolution ◽

Gray Matter ◽

T1 Mapping ◽

Relaxation Times ◽

Early Infancy ◽

Normal Brain ◽

Regression Equations ◽

T1 Relaxation ◽

Pediatric Brain

Abstract Background Quantitative mapping of MRI relaxation times is expected to uncover pathological processes in the brain more subtly than standard MRI techniques with weighted contrasts. So far, however, most mapping techniques suffer from a long measuring time, low spatial resolution or even sensitivity to magnetic field inhomogeneity. Objective To obtain T1 relaxation times of the normal brain from early infancy to adulthood using a novel technique for fast and accurate T1 mapping at high spatial resolution. Materials and methods We performed whole-brain T1 mapping within less than 3 min in 100 patients between 2 months and 18 years of age with normal brain at a field strength of 3 T. We analyzed T1 relaxation times in several gray-matter nuclei and white matter. Subsequently, we derived regression equations for mean value and confidence interval. Results T1 relaxation times of the pediatric brain rapidly decrease in all regions within the first 3 years of age, followed by a significantly weaker decrease until adulthood. These characteristics are more pronounced in white matter than in deep gray matter. Conclusion Regardless of age, quantitative T1 mapping of the pediatric brain is feasible in clinical practice. Normal age-dependent values should contribute to improved discrimination of subtle intracerebral alterations.

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Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43

10.1101/2021.11.09.467933 ◽

2021 ◽

Author(s):

Dongeun Heo ◽

Jonathan P Ling ◽

Gian C Molina-Castro ◽

Abraham J Langseth ◽

Ari Waisman ◽

...

Keyword(s):

Rna Binding ◽

Morphological Changes ◽

Cell Loss ◽

Adult Brain ◽

Transcriptional Analysis ◽

Myelin Sheaths ◽

Conditional Deletion ◽

Oligodendrocyte Precursor ◽

Specific Control

Generation of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA binding protein TDP-43 occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation of Tardbpin vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43 deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult CNS induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease.

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Clobetasol Attenuates White Matter Injury by Promoting Oligodendrocyte Precursor Cell Differentiation

Pediatric Neurosurgery ◽

10.1159/000509521 ◽

2020 ◽

Vol 55 (4) ◽

pp. 188-196

Author(s):

Xuewen Su ◽

Haifeng Yuan ◽

Yuxin Bai ◽

Junlong Chen ◽

Mingze Sui ◽

...

Keyword(s):

White Matter ◽

Rat Model ◽

Myelin Sheath ◽

White Matter Injury ◽

Neurological Deficits ◽

Treatment Groups ◽

Myelin Sheaths ◽

Neurobehavioral Function ◽

Sheath Formation ◽

Oligodendrocyte Precursor

Introduction: White matter injury (WMI) is the most common brain injury in preterm infants and can result in life-long neurological deficits. The main cause of WMI is damage to the oligodendrocyte precursor cells (OPC) in the brain that results in delayed myelin sheath formation, or the destruction of existing myelin sheaths. OPC undergo highly regulated and strictly timed developmental changes that result in their transformation to mature oligodendrocytes capable of myelin production. Objective: Studies have shown that clobetasol strongly promotes differentiation of OPC into myelin sheaths. Therefore, we hypothesized that clobetasol may be a therapeutic option for the treatment of preterm WMI. Methods: We induced a WMI rat model and observed white matter damage under an optical microscope. Rats subjected to WMI were injected intraperitoneally with clobetasol (2 or 5 mg/kg daily) from day 1 to day 5 in the early treatment groups, or from day 6 to day 10 in the late treatment groups. After 17 days, the rats were sacrificed and the expression of myelin basic protein (MBP) was visualized using immunofluorescence. In addition, we evaluated myelin sheath formation using electron microscopy. The rats were also subjected to the suspension test, ramp test, and open field test to evaluate neurobehavioral functions. Results: A rat model of WMI was successfully induced. It was found that clobetasol significantly induced MBP expression and myelin sheath formation and improved neurobehavioral function in the rats subjected to WMI. Conclusions: Our results indicate that clobetasol attenuates WMI by promoting OPC differentiation, and it may be an effective therapeutic agent for the treatment of preterm WMI.

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White matter and cognition: making the connection

Journal of Neurophysiology ◽

10.1152/jn.00221.2016 ◽

2016 ◽

Vol 116 (5) ◽

pp. 2093-2104 ◽

Cited By ~ 97

Author(s):

Christopher M. Filley ◽

R. Douglas Fields

Keyword(s):

Neural Networks ◽

White Matter ◽

Gray Matter ◽

Chronic Traumatic Encephalopathy ◽

White Matter Lesions ◽

Normal Brain ◽

Brain Structure And Function ◽

And Function ◽

The Brain

Whereas the cerebral cortex has long been regarded by neuroscientists as the major locus of cognitive function, the white matter of the brain is increasingly recognized as equally critical for cognition. White matter comprises half of the brain, has expanded more than gray matter in evolution, and forms an indispensable component of distributed neural networks that subserve neurobehavioral operations. White matter tracts mediate the essential connectivity by which human behavior is organized, working in concert with gray matter to enable the extraordinary repertoire of human cognitive capacities. In this review, we present evidence from behavioral neurology that white matter lesions regularly disturb cognition, consider the role of white matter in the physiology of distributed neural networks, develop the hypothesis that white matter dysfunction is relevant to neurodegenerative disorders, including Alzheimer's disease and the newly described entity chronic traumatic encephalopathy, and discuss emerging concepts regarding the prevention and treatment of cognitive dysfunction associated with white matter disorders. Investigation of the role of white matter in cognition has yielded many valuable insights and promises to expand understanding of normal brain structure and function, improve the treatment of many neurobehavioral disorders, and disclose new opportunities for research on many challenging problems facing medicine and society.

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Microglial Neuropilin-1 trans-regulates oligodendrocyte expansion during development and remyelination

10.1101/2021.01.07.425796 ◽

2021 ◽

Author(s):

Amin Sherafat ◽

Friederike Pfeiffer ◽

Alexander Reiss ◽

William M Wood ◽

Akiko Nishiyama

Keyword(s):

White Matter ◽

Gray Matter ◽

Integral Membrane Protein ◽

Dependent Manner ◽

Oligodendrocyte Precursor Cells ◽

Neuropilin 1 ◽

Oligodendrocyte Precursor ◽

Activity Dependent ◽

Specific Deletion

NG2 glia or oligodendrocyte precursor cells (OPCs) are distributed throughout the gray and white matter and generate myelinating cells. OPCs in white matter proliferate more than those in gray matter in response to platelet-derived growth factor AA (PDGF AA), despite similar levels of its alpha receptor (PDGFRalpha) on their surface. Here we show that the type 1 integral membrane protein Neuropilin-1 (Nrp1) is expressed not on OPCs but on amoeboid and activated microglia in white but not gray matter in an age- and activity-dependent manner. Microglia-specific deletion of Nrp1 compromised developmental OPC proliferation in white matter as well as OPC expansion and subsequent myelin repair after acute demyelination. Exogenous Nrp1 increased PDGF AA-induced OPC proliferation and PDGFRalpha phosphorylation on dissociated OPCs, most prominently in the presence of suboptimum concentrations of PDGF AA. These findings uncover a novel mechanism of regulating oligodendrocyte lineage cell density that involves trans-activation of PDGFRalpha on OPCs via Nrp1 expressed by adjacent microglia.

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FT-IR microspectroscopic analysis of diseased white matter brain tissues

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100141214 ◽

1995 ◽

Vol 53 ◽

pp. 968-969

Author(s):

Steven M. Le Vine ◽

David L. Wetzel

Keyword(s):

White Matter ◽

Gray Matter ◽

Twitcher Mouse ◽

Grid Pattern ◽

Marked Contrast ◽

Spatially Resolved ◽

Ft Ir ◽

Ir Microspectroscopy ◽

Chemical Evidence

In situ FT-IR microspectroscopy has allowed spatially resolved interrogation of different parts of brain tissue. In previous work the spectrrscopic features of normal barin tissue were characterized. The white matter, gray matter and basal ganglia were mapped from appropriate peak area measurements from spectra obtained in a grid pattern. Bands prevalent in white matter were mostly associated with the lipid. These included 2927 and 1469 cm-1 due to CH2 as well as carbonyl at 1740 cm-1. Also 1235 and 1085 cm-1 due to phospholipid and galactocerebroside, respectively (Figs 1and2). Localized chemical changes in the white matter as a result of white matter diseases have been studied. This involved the documentation of localized chemical evidence of demyelination in shiverer mice in which the spectra of white matter lacked the marked contrast between it and gray matter exhibited in the white matter of normal mice (Fig. 3).The twitcher mouse, a model of Krabbe’s desease, was also studied. The purpose in this case was to look for a localized build-up of psychosine in the white matter caused by deficiencies in the enzyme responsible for its breakdown under normal conditions.

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