Oligodendrocyte pathology following Traumatic Brain Injury : Experimental and clinical studies
Abstract: 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.
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