Regina Armstrong

In multiple sclerosis, microglia/macrophage activation and astrocyte reactivity are important components of the lesion environment that can impact remyelination. The current study characterizes these glial populations relative to expression of candidate regulatory molecules in cuprizone demyelinated corpus callosum. Importantly, periods of recovery after acute or chronic cuprizone demyelination are examined to compare conditions of efficient versus limited remyelination, respectively. Microglial activation attenuates after early demyelination. In contrast, astrocyte reactivity persists throughout demyelination and a 6-week recovery period following either acute or chronic demyelination. This astrocyte reaction is characterized by (a) early proliferation, (b) increased expression of GFAP (glial fibrillary acidic protein), Vim (vimentin), Fn1 (fibronectin) and CSPGs (chondroitin sulphate proteoglycans) and (c) elaboration of a dense network of processes. Glial processes elongated in t...

The dysembryoplastic neuroepithelial tumor (DNT) is an uncommon lesion characterized by a heterogeneous population of neurons, astrocytes, and oligodendroglia-like cells (OLCs). The basic nature of the DNT and its constituent cells, particularly the OLCs, remains unresolved; some authors favor a neuronal origin, and others propose a glial or mixed origin for these cells. We examined 11 DNTs with antibodies to myelin oligodendrocyte glycoprotein, a marker of mature oligodendrocytes. All DNTs studied (7 from males, 4 from females; age range of patients, 2-37 years) were composed of varying proportions of neurons, astrocytes, and OLCs. Membrane or cytoplasmic immunoreactivity for myelin oligodendrocyte glycoprotein was found in many OLCs in 9 of 11 cases. The number of myelin oligodendrocyte glycoprotein-positive OLCs was variable: >75% of the OLCs were positive in 5 cases, 25% to 75% of the OLCs were positive in 2 cases, and <25% of the OLCs were positive in 2 cases. These findi...

We have analyzed the role of glutamate and its receptors (GluRs) in regulating the development of oligodendrocytes. Activation of AMPA-preferring GluRs with selective agonists inhibited proliferation of purified cortical oligodendrocyte progenitor (O-2A) cells cultured with different mitogens, as measured by [3H]thymidine incorporation or bromodeoxyuridine staining. In contrast, activation of GABA or muscarinic receptors did not affect O-2A proliferation. Cell viability and apoptosis assays demonstrated that the inhibition of O-2A proliferation was not attributable to a cytotoxic action of GluR agonists, and was reversible. Activation of GluRs prevented lineage progression from the O-2A (GD3+/nestin+) stage to the prooligodendroblast (O4+) stage, but did not affect O-2A migration. Additional experiments examined the membrane ionic channels mediating these GluR activation effects. We found that proliferating O-2A cells expressed functional delayed rectifier K+ channels, which were ab...

Radioactive glycerol, ethanolamine, or choline injected into the vicinity of the cell bodies of rat sciatic nerve sensory fibers is incorporated into phospholipid. Some newly synthesized ethanolamine and choline phosphoglycerides are subsequently committed to transport down the sciatic nerve axons at a rate of several hundred millimeters per day. Most labeled choline phosphoglycerides move uniformly down the axons; in contrast, the crest of moving ethanolamine phosphoglycerides is continually attenuated. These data, as well as differences in the clearance of these phospholipids distal to a nerve ligature, suggest that various classes of labeled phospholipids are differentially unloaded from the transport vector (possibly by exchange with unlabeled lipid in stationary axonal structures) during movement down the axons. The extent of unloading appears to be defined by the base moiety; both diacyl and plasmalogen species of ethanolamine phosphoglycerides exchange extensively with statio...

Regenerated and remyelinated nerve fibers have shorter internodes and thus more nodes than normal mature fibers. This requires either a decrease in the number of sodium channels per node or an increase in the number of channels per fiber or both. The purpose of this investigation was to determine what happens to sodium channel number, as estimated by 3H-saxitonin (STX) binding, in regenerated fibers and to relate this to nodal number. Five adult cats underwent cryoaxotomy of ventral root levels L5, L6, L7, and S1 on the left side. After regeneration for 16-45 weeks, binding parameters were determined. On the right (control) side, binding was consistent with that in unoperated animals (b = 1.3, Bmax = 10.2 +/- 0.4 fmol/mg wet, Kd = 0.6 +/- 0.1 nM). However, the regenerated nerves showed a 3.5-fold increase in maximal binding (b = 1.3, Bmax = 36.1 +/- 0.5, Kd = 0.45 +/- 0.4). Computer-aided histologic analysis of the regenerated roots revealed a decrease in fiber size; a significant d...

This study takes advantage of fibroblast growth factor 2 (FGF2) knock-out mice to determine the contribution of FGF2 to the regeneration of oligodendrocytes in the adult CNS. The role of FGF2 during spontaneous remyelination was examined using two complementary mouse models of experimental demyelination. The murine hepatitis virus strain A59 (MHV-A59) model produces focal areas of spinal cord demyelination with inflammation. The cuprizone neurotoxicant model causes extensive corpus callosum demyelination without a lymphocytic cell response. In both models, FGF2 expression is upregulated in areas of demyelination in wild-type mice. Surprisingly, in both models, oligodendrocyte repopulation of demyelinated white matter was significantly increased in FGF2 -/- mice compared with wild-type mice and even surpassed the oligodendrocyte density of nonlesioned mice. This dramatic result indicated that the absence of FGF2 promoted oligodendrocyte regeneration, possibly by enhancing oligodendro...

Previously, we tested the prediction that axonal damage results in decreased axial diffusivity (lambda(parallel)) while demyelination leads to increased radial diffusivity (lambda(perpendicular)). Cuprizone treatment of C57BL/6 mice was a highly reproducible model of CNS white matter demyelination and remyelination affecting the corpus callosum (CC). In the present study, six C57BL/6 male mice were fed 0.2% cuprizone for 12 weeks followed by 12 weeks of recovery on normal chow. The control mice were fed normal chow and imaged in parallel. Biweekly in vivo DTI examinations showed transient decrease of lambda(parallel) in CC at 2-6 weeks of cuprizone treatment. Immunostaining for nonphosphorylated neurofilaments demonstrated corresponding axonal damage at 4 weeks of treatment. Significant demyelination was evident from loss of Luxol fast blue staining at 6-12 weeks of cuprizone ingestion and was paralleled by increased lambda(perpendicular) values, followed by partial normalization during the remyelination phase. The sensitivity of lambda(perpendicular) to detect demyelination may be modulated in the presence of axonal damage during the early stage of demyelination at 4 weeks of cuprizone treatment. Our results suggest that lambda(parallel) and lambda(perpendicular) may be useful in vivo surrogate markers of axonal and myelin damage in mouse CNS white matter.

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Moderate to severe traumatic brain injury (TBI) in humans and rats induces measurable metabolic changes, including a sustained depression in cerebral glucose uptake. However, the effect of a mild TBI on brain glucose uptake is unclear, particularly in rodent models. This study aimed to determine the glucose uptake pattern in the brain after a mild lateral fluid percussion (LFP) TBI. Briefly, adult male rats were subjected to a mild LFP and positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)FDG), which was performed prior to injury and at 3 and 24 h and 5, 9, and 16 days post-injury. Locomotor function was assessed prior to injury and at 1, 3, 7, 14, and 21 days after injury using modified beam walk tasks to confirm injury severity. Histology was performed at either 10 or 21 days post-injury. Analysis of function revealed a transient impairment in locomotor ability, which corresponds to a mild TBI. Using reference region normalization, PET imaging revealed that mild LFP-induced TBI depresses glucose uptake in both the ipsilateral and contralateral hemispheres in comparison with sham-injured and naïve controls from 3 h to 5 days post-injury. Further, areas of depressed glucose uptake were associated with regions of glial activation and axonal damage, but no measurable change in neuronal loss or gross tissue damage was observed. In conclusion, we show that mild TBI, which is characterized by transient impairments in function, axonal damage, and glial activation, results in an observable depression in overall brain glucose uptake using (18)FDG-PET.

The establishment and operation of the nervous system requires genetic regulation by a network of DNA-binding proteins, among which is the zinc finger superfamily of transcription factors. We have cloned and characterized a member of the unusual Cys-Cys-His-Cys (also referred to as Cys2HisCys, CCHC, or C2HC) class of zinc finger proteins in the developing nervous system. The novel gene, Myt1-like (Myt1l), is highly homologous to the original representative of this class, Myelin transcription factor 1 (Myt1) (Kim and Hudson, 1992). The MYT1 gene maps to human chromosome 20, while MYT1L maps to a region of human chromosome 2. Both zinc finger proteins are found in neurons at early stages of differentiation, with germinal zone cells displaying intense staining for MyT1. Unlike Myt1, Myt1l has not been detected in the glial lineage. Neurons that express Myt1l also express TuJ1, which marks neurons around the period of terminal mitosis. The Myt1l protein resides in distinct domains within the neuronal nucleus, analogous to the discrete pattern previously noted for Myt1 (Armstrong et al.: 14:303-321, 1995). The developmental expression and localization of these two multifingered CCHC proteins suggests that each may play a role in the development of neurons and oligodendroglia in the mammalian central nervous system.

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We have examined the potential roles of intracellular Ca2+ regulation and of multiple cytoskeletal elements in control of the directed migration of cultured oligodendrocyte progenitor cells (OPs). OPs were found to migrate in response to platelet-derived growth factor (PDGF) or to a lesser extent to basic fibroblast growth factor (FGF) in a non-additive manner. This response was inhibited by chelation of intracellular Ca2+ by using BAPTA-AM. OP migration was not evoked by the neurotransmitter agonists phenylephrine or methacholine, which elevate OP Ca2+ levels. Inhibition of the MAP kinase pathway with PD 098059 did not affect OP migration to PDGF. Within growth cone-like leading edges of migratory OP processes, monomeric and filamentous actin were found to be colocalized with myosin and filamentous actin was prominent in filopodia extending beyond the leading edge. Tubulin was distributed throughout OP processes and cell bodies. Inhibition of actin or tubulin polymerization, by using cytochalasin B or nocodazole, respectively, altered OP morphology and markedly impaired migration. Inhibition of the myosin ATPase by BDM, which prevents force-generating actin/myosin interactions, greatly inhibited the chemotaxic response at concentrations that did not disrupt cell morphology. These results indicate that growth factors stimulate OP migration by activating pathways which include intracellular Ca2+ regulation, and characterize the distribution of multiple cytoskeletal elements involved in the generation of directed OP movement.

... Axonal transport through nodes of Ranvier. Regina Armstrong 1 , 2 , Arrel D. Toews 1 , 3 and Pierre Morell Corresponding Author Contact Information , 1 , 2 , 3. ... In this pathologi-cal tissue, heminodes form between a myelinated in-ternode and an adjacent demyelinated region. ...

Childhood ataxia with diffuse central nervous system hypomyelination syndrome (CACH) is a recently described leukodystrophy of unknown etiology. To characterize the neuropathological features and gain insight as to the pathogenesis of this disorder, we studied cerebral tissue from six patients with the CACH syndrome. Evaluation of toluidine blue-stained, semithin sections of white matter from CACH patients disclosed unusual cells with "foamy" cytoplasm, small round nuclei and fine chromatin. Electron microscopy (EM) revealed cells in the white matter with abundant cytoplasm containing many mitochondria and loosely clustered, membranous structures, but lacking the lysosomal structures seen in macrophages. Further analysis of tissue sections with antibodies and special stains demonstrated that the abnormal cells with abundant cytoplasm labeled with oligodendroglial markers, but did not react with macrophage or astrocytic markers. Double immunolabeling with macrophage and oligodendroglial markers clearly distinguished macrophages from the "foamy" oligodendroglial cells (FODCs). Proteolipid protein (PLP) mRNA in situ hybridization demonstrated PLP mRNA transcripts in a high proportion of oligodendrocytes in CACH patients compared to control patients, and PLP mRNA transcript signal in cells, morphologically consistent with FODCs. Normal and pathological brain control tissues did not contain FODCs. These neuropathological findings will be useful pathological identifiers of CACH, and may provide clues to the pathogenesis of this disorder.