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Myelin loss and oligodendrocyte pathology in white matter tracts following traumatic brain injury in the rat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. (Neurosurgery)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. (Neurosurgery)
2013 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 38, no 1, 2153-2165 p.Article, review/survey (Refereed) Published
Abstract [en]

Axonal injury is an important contributor to the behavioral deficits observed following traumatic brain injury (TBI). Additionally, loss of myelin and/or oligodendrocytes can negatively influence signal transduction and axon integrity. Apoptotic oligodendrocytes, changes in the oligodendrocyte progenitor cell (OPC) population and loss of myelin were evaluated at 2, 7 and 21 days following TBI. We used the central fluid percussion injury model (n = 18 and three controls) and the lateral fluid percussion injury model (n = 15 and three controls). The external capsule, fimbriae and corpus callosum were analysed. With Luxol Fast Blue and RIP staining, myelin loss was observed in both models, in all evaluated regions and at all post-injury time points, as compared with sham-injured controls (P ≤ 0.05). Accumulation of β-amyloid precursor protein was observed in white matter tracts in both models in areas with preserved and reduced myelin staining. White matter microglial/macrophage activation, evaluated by isolectin B4 immunostaining, was marked at the early time points. In contrast, the glial scar, evaluated by glial fibrillary acidic protein staining, showed its highest intensity 21 days post-injury in both models. The number of apoptotic oligodendrocytes, detected by CC1/caspase-3 co-labeling, was increased in both models in all evaluated regions. Finally, the numbers of OPCs, evaluated with the markers Tcf4 and Olig2, were increased from day 2 (Olig2) or day 7 (Tcf4) post-injury (P ≤ 0.05). Our results indicate that TBI induces oligodendrocyte apoptosis and widespread myelin loss, followed by a concomitant increase in the number of OPCs. Prevention of myelin loss and oligodendrocyte death may represent novel therapeutic targets for TBI.

Place, publisher, year, edition, pages
2013. Vol. 38, no 1, 2153-2165 p.
Keyword [en]
apoptosis; central fluid percussion; lateral fluid percussion; myelin damage; Olig2; Tcf4
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:uu:diva-198321DOI: 10.1111/ejn.12179ISI: 000321205000012OAI: oai:DiVA.org:uu-198321DiVA: diva2:615780
Available from: 2013-04-11 Created: 2013-04-11 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Oligodendrocyte pathology following Traumatic Brain Injury: Experimental and clinical studies
Open this publication in new window or tab >>Oligodendrocyte pathology following Traumatic Brain Injury: Experimental and clinical studies
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic brain injury (TBI) caused by traffic and fall accidents, sports-related injuries and violence commonly results in life-changing disabilities. Cognitive impairments following TBI may be due to disruption of axons, stretched by the acceleration/deceleration forces of the initial impact, and their surrounding myelin in neuronal networks. The primary injury, which also results in death to neuronal and glial cells, is followed by a cascade of secondary injury mechanisms including a complex inflammatory response that will exacerbate the white matter injury.

Axons are supported and protected by the ensheathing myelin, ensuring fast conduction velocity. Myelin is produced by oligodendrocytes (OLs), a cell type vulnerable to many of the molecular processes, including several inflammatory mediators, elicited by TBI. Since one OL extends processes to several axons, the protection of OLs is an important therapeutic target post-TBI.  During development, OLs mature from oligodendrocyte progenitor cells (OPCs), also present in the adult brain.

The aim of this thesis was to investigate white matter pathology, with a specific focus on the OL population, in experimental and clinical TBI. Since the inflammatory response may contribute to OL cell death and OPC proliferation, neutralization of interleukin-1β (IL-1β) was investigated.

The lateral and central fluid percussion injury models were used in mice and rats where memory, learning and complex behaviors were investigated by two functional tests. Brain tissue, surgically resected due to life-threatening brain swelling or hemorrhage, from TBI patients was also investigated. Axonal injury, myelin damage, microglia alterations and OPCs and OL cell death were investigated by immunohistochemical techniques. In focal and diffuse experimental TBI, OL cell death was observed in important white matter tracts. OL cell death was accompanied by myelin damage, axonal injury and presence of microglia as well as an increased number of OPCs in both the experimental and human setting. OPCs were found to proliferate in diffuse TBI in mice where both complex behavioral changes and impaired memory were observed. Neutralization of IL-1β normalized and improved these behavioral alterations and also lead to a preserved number of mature OLs although without influencing OPC proliferation.

The results provided in this thesis indicate that white matter pathology is a key component of the pathophysiology of TBI. The OPC proliferation may influence regeneration post-injury and might be an important future therapeutic targets for TBI. The present studies also suggest that treatment strategies targeting neuroinflammation may positively influence behavioral outcome and OL cell death in TBI.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1311
Keyword
Traumatic brain injury, oligodendrocytes, oligodendrocyte progenitor cells, interleukin 1-β, central fluid percussion injury
National Category
Natural Sciences
Research subject
Neurosurgery; Neurosurgery
Identifiers
urn:nbn:se:uu:diva-316401 (URN)978-91-554-9846-7 (ISBN)
Public defence
2017-05-05, Hedstrandsalen, Akademiska Sjukhuset, Uppsala, 09:00 (English)
Opponent
Supervisors
Note

(Faculty of Medicine)

Available from: 2017-04-11 Created: 2017-03-07 Last updated: 2017-04-21

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Flygt, JohannaMarklund, Niklas

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