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Demyelination-Induced Inflammation Attracts Newly Born Neurons to the White Matter

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Abstract

There is compelling evidence that microglial activation negatively impacts neurogenesis. However, microglia have also been shown to promote recruitment of newly born neurons to injured areas of the gray matter. In the present study, we explored whether demyelination-triggered inflammation alters the process of neurogenesis in the white matter. A 2-μl solution of 0.04 % ethidium bromide was stereotaxically injected into the corpus callosum of adult male rats. Brain inflammation was dampened by daily injections of progesterone (5 mg/kg, s.c.) for 14 days. Control rats received oil (s.c.). Newly born neurons (DCX and Tbr2), microglia (Iba-1), astrocytes (vimentin or GFAP), oligodendrocyte progenitor cells (OPCs; NG2), and mature oligodendrocytes (CC-1) were monitored in the vicinity of demyelination site using immunofluorescent staining. Western blot was used to explore microglial polarization using M1 (iNOS) and M2 (arginase-1) markers. Focal demyelination elicited strong microglial and astroglial activation and reduced the number of OPCs at the site of demyelination. This inflammatory response was associated with enhanced number of newly born neurons in the white matter and the subventricular zone (SVZ). A proportion of newly born neurons within the white matter showed features of OPCs. Interestingly, blunting brain inflammation led to reduced neurogenesis around the demyelination area and in the SVZ. These data suggest that the white matter inflammation creates a conducive environment for the recruitment of newly born neurons. The fact that a sizable fraction of these newly born neurons adopt OPC features suggests that they could contribute to the remyelination process.

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Acknowledgments

This work was supported by Kuwait University Research Grant No. YM11/11 to A.M. Confocal imaging was performed in The Research Unit for Genomics, Proteomics, and Cellomics Sciences supported by Research Project No. SRUL02/13. The authors thank Dr. Willias Masocha for the critical reading of this manuscript.

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Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Health Sciences Centre, Kuwait University, P.O. Box 24923, 13110, Safat, Kuwait

    Samah Kalakh & Abdeslam Mouihate

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  1. Samah Kalakh
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  2. Abdeslam Mouihate
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Correspondence to Abdeslam Mouihate.

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All experimental procedures were performed in accordance with guidelines on the humane handling of experimental animals as established by the Canadian Council on Animal Care. Experiments performed were approved by the Kuwait University Health Sciences Center Animal Research Ethics committee.

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The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary data 1

Local distribution of microglia and astrocytes at the demyelination lesion area. Microglia (Iba1+, green) and astrocytes (GFAP+, red) were co-detected in the vicinity of the demyelination lesion. Microglia were mostly found at the center of the lesion in both oil-treated (EB-O) and progesterone administered (EB-Prog) rat groups. However, astrocytes were found both at the center and the edge of the demyelination lesion. Administration of progesterone resulted in reduced number of microglia (left panel). CC: corpus callosum. (GIF 193 kb)

High resolution image (TIFF 1605 kb)

Supplementary data 2

Detection of NeuN and NG2 in the cerebral cortex. Immunofluorescent detection of NeuN+ cells (green), NG2+ cells (red) in the cerebral cortex of both EB-O (upper panel) and EB-Prog (lower panel). No co-localization was observed between NeuN and NG2 stainings in the cerebral cortex of either EB-O or EB-Prog groups. Scale bar =50 μm. CTX: cortex. (GIF 165 kb)

High resolution image (TIFF 1116 kb)

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Kalakh, S., Mouihate, A. Demyelination-Induced Inflammation Attracts Newly Born Neurons to the White Matter. Mol Neurobiol 54, 5905–5918 (2017). https://doi.org/10.1007/s12035-016-0127-5

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