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1.
Brain Res ; 1228: 20-6, 2008 Sep 04.
Article in English | MEDLINE | ID: mdl-18616932

ABSTRACT

Recent studies have shown that neuroblasts migrate from the subventricular zone (SVZ) into the injured area after ischemic brain insults. However, it is not well understood which mechanism mediates this ectopic migration and which types of cells migrate into the damaged region from the SVZ. The present study was designed to investigate the characteristics of the migration of nestin-positive neural stem cells toward the region of ischemic injury after focal cortical ischemia. Nestin-eGFP transgenic mice were used to effectively model the migration of SVZ cells. Photothrombotic ischemia was induced by injection of rose bengal (30 mg/kg) and exposure to cold light. Migration of nestin-positive cells was examined using 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) and bromodeoxyuridine (BrdU) labeling. The number of nestin-positive cells was increased significantly in the peri-infarct area at 5 and 7 days after photothrombosis. A subset of nestin-positive cells was co-labeled with DiI or BrdU. Some of the nestin-positive cells co-expressed doublecortin (DCX) and only a few nestin-positive cells co-labeled with anti-epidermal growth factor receptor (EGFr) antibody. However, no nestin-positive cells were immunoreactive for glial fibrillary acidic protein (GFAP). The inhibition of matrix metalloproteinases (MMPs) using the MMP inhibitor, FN-439, decreased nestin-positive cells in the peri-infarct region at 7 days after photothrombosis. Although MMP-9 was not co-expressed in the nestin-positive cells in the peri-infarct cortex, MMP-9 did co-localize with GFAP-positive astrocytes. These results suggest that nestin-positive neural progenitor cells migrate into the peri-infarct cortex after photothrombotic ischemia and that MMP-9 is involved in the migration.


Subject(s)
Brain Ischemia/physiopathology , Cell Movement/drug effects , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase Inhibitors , Oligopeptides/pharmacology , Animals , Brain Infarction/metabolism , Brain Infarction/physiopathology , Brain Ischemia/metabolism , Bromodeoxyuridine/chemistry , Bromodeoxyuridine/metabolism , Carbocyanines/chemistry , Carbocyanines/metabolism , Doublecortin Domain Proteins , Doublecortin Protein , ErbB Receptors/metabolism , Glial Fibrillary Acidic Protein/metabolism , Green Fluorescent Proteins/genetics , Hydroxamic Acids/administration & dosage , Immunohistochemistry , Intermediate Filament Proteins/genetics , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Transgenic , Microinjections , Microtubule-Associated Proteins/metabolism , Nerve Tissue Proteins/genetics , Nestin , Neuroglia/drug effects , Neuroglia/metabolism , Neuroglia/pathology , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Neuropeptides/metabolism , Oligopeptides/administration & dosage , Rose Bengal/chemistry , Rose Bengal/metabolism , Stem Cells/cytology , Stem Cells/drug effects , Stem Cells/metabolism
2.
J Comp Neurol ; 505(2): 190-208, 2007 Nov 10.
Article in English | MEDLINE | ID: mdl-17853439

ABSTRACT

Neuroblasts migrate long distances in the postnatal subventricular zone (SVZ) and rostral migratory stream (RMS) to the olfactory bulbs. Many fundamental features of SVZ migration are still poorly understood, and we addressed several important questions using two-photon time-lapse microscopy of brain slices from postnatal and adult eGFP(+) transgenic mice. 1) Longitudinal arrays of neuroblasts, so-called chain migration, have never been dynamically visualized in situ. We found that neuroblasts expressing doublecortin-eGFP (Dcx-eGFP) and glutamic acid decarboxylase-eGFP (Gad-eGFP) remained within arrays, which maintained their shape for many hours, despite the fact that there was a wide variety of movement within arrays. 2) In the dorsal SVZ, neuroblasts migrated rostrocaudally as expected, but migration shifted to dorsoventral orientations throughout ventral regions of the lateral ventricle. 3) Whereas polarized bipolar morphology has been a gold standard for inferring migration in histologic sections, our data indicated that migratory morphology was not predictive of motility. 4) Is there local motility in addition to long distance migration? 5) How fast is SVZ migration? Unexpectedly, one-third of motile neuroblasts moved locally in complex exploratory patterns and at average speeds slower than long distance movement. 6) Finally, we tested, and disproved, the hypothesis that all motile cells in the SVZ express doublecortin, indicating that Dcx is not required for migration of all SVZ cell types. These data show that cell motility in the SVZ and RMS is far more complex then previously thought and involves multiple cell types, behaviors, speeds, and directions.


Subject(s)
Cell Differentiation/physiology , Cell Movement/physiology , Lateral Ventricles/cytology , Neurons/physiology , Nonlinear Dynamics , Stem Cells/physiology , Animals , Animals, Newborn , Cell Migration Assays/methods , Cell Movement/genetics , Doublecortin Domain Proteins , Doublecortin Protein , Glial Fibrillary Acidic Protein/metabolism , Glutamate Decarboxylase/genetics , Green Fluorescent Proteins/genetics , Imaging, Three-Dimensional/methods , Intermediate Filament Proteins/metabolism , Mice , Mice, Transgenic , Microscopy, Electron, Transmission/methods , Microtubule-Associated Proteins/genetics , Nerve Tissue Proteins/metabolism , Nestin , Neural Cell Adhesion Molecule L1/metabolism , Neurons/classification , Neurons/cytology , Neurons/ultrastructure , Neuropeptides/genetics , Photomicrography/methods , Sialic Acids/metabolism , Time Factors
3.
Neurosci Lett ; 425(2): 83-8, 2007 Sep 25.
Article in English | MEDLINE | ID: mdl-17723276

ABSTRACT

Neural progenitor cells (NPCs) in the subventricular zone (SVZ) travel a long distance along the rostral migratory stream (RMS) to give rise to interneurons in the olfactory bulb (OB). Using the multiphoton microscope and time-lapse recording techniques we here report the behavior of NPCs in the RMS under both intact and ischemic conditions in living brain slices. The NPCs were visualized in 3-week-old transgenic mice that carry the reporter gene, green fluorescent protein (GFP), driven by the nestin promoter. Cortical brain ischemia was induced by permanent occlusion of the right common carotid artery and the middle cerebral artery. We observed that the RMS contained two populations of NPCs: nonmigrating cells (bridge cells) and migrating cells. Bridge cells enabled migrating cells to travel and also produced new cells in the RMS. The direction of NPC migration in the RMS was bidirectional in both intact and ischemic conditions. Cortical ischemia impeded NPC travel in the RMS next to the lesion area during the early period of ischemia. Cell-cell contact was a prominent feature affecting NPC translocation and migratory direction. These data suggest that behavior and function of nestin-positive NPCs in the RMS are variable. Cell-cell contacts and microenvironmental changes influence NPC behavior in the RMS. This study may provide insights to help in understanding NPC biology.


Subject(s)
Brain Ischemia/physiopathology , Cell Movement/physiology , Microscopy, Fluorescence, Multiphoton/methods , Neurons/cytology , Stem Cells/cytology , Telencephalon/embryology , Animals , Biomarkers/analysis , Biomarkers/metabolism , Cell Communication/physiology , Cell Differentiation/physiology , Cerebral Ventricles , Genes, Reporter , Green Fluorescent Proteins , Immunohistochemistry , Infarction, Middle Cerebral Artery/physiopathology , Intermediate Filament Proteins/metabolism , Male , Mice , Mice, Transgenic , Microscopy, Fluorescence, Multiphoton/instrumentation , Nerve Regeneration/physiology , Nerve Tissue Proteins/metabolism , Nestin , Neuronal Plasticity/physiology , Neurons/physiology , Organ Culture Techniques , Stem Cells/physiology , Telencephalon/cytology , Telencephalon/physiology , Time Factors
4.
J Korean Med Sci ; 19(3): 419-25, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15201510

ABSTRACT

Neuronal migration disorders (NMDs) constitute the main pathologic substrate of medically intractable epilepsy in human. This study is designed to investigate the changes in expression of glutamate receptor subtypes on radiation-induced NMD in rats. The lesion was produced by intrauterine irradiation (240 cGy) on E17 rats, and then 10 weeks old rats were used for the study. The pathologic and immuno-histochemical findings for glutamate receptor subunit proteins on NMD cortex were correlated with development of behavioral seizures and EEG abnormality. Spontaneous seizures uncommonly occurred in NMD rats (5%); however, clinical stages of seizures were significantly increased in NMD rats by an administration of kainic acid. Brains taken from irradiated rats revealed gross and histopathologic features of NMD. Focal cortical dysplasia was identified by histopathology and immunohistochemistry with neurofilament protein (NF-M/H). Significantly strong NR1 and NR2A/B immunoreactivities were demonstrated in cytomegalic and heterotopic neurons of NMD rats. The results of the present study indicate that epileptogenesis of NMD might be caused by upregulation of glutamate receptor expression in dysplastic neurons of the rat cerebral cortex with NMDs.


Subject(s)
Cerebral Cortex/metabolism , Neurons/metabolism , Receptors, N-Methyl-D-Aspartate/biosynthesis , Up-Regulation , Animals , Cell Movement , Electroencephalography , Glutamic Acid/metabolism , Immunohistochemistry , Kainic Acid/pharmacology , Neurons/pathology , Rats , Rats, Wistar , Receptors, Glutamate/metabolism , Time Factors
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