Molecular mechanisms governing the oligodendrocyte response to mild traumatic brain injury
Creators: name: Adams, Alexandra A.
Publisher: name: No Publisher Supplied
Year: 2022

description: Myelin is a crucial structural and functional component of white matter in the central nervous system. Myelin is necessary for fast action potential propagation, which is required for proper communication within neural circuits. Thus, appropriate myelin formation and maintenance are importance for overall function of the nervous system. White matter damage and loss are common occurrences after traumatic brain injury (TBI). In human TBI, severe injuries result in oligodendrocytes apoptosis and white matter necrosis. Similar observations have been made in various animal models of TBI. Somewhat understandably, the effects of TBI on oligodendrocytes and myelin have been understudied, as myelin loss has long been attributed to loss of axons. Mild TBI (mTBI) is by far the most prevalent type of head injury, comprising 75-80% of all human TBIs. White matter damage is detectable through diagnostic imaging in human mTBI patients, and the effects of even a single mTBI on white matter and myelin are chronic. Studies using animal models have shown that while secondary demyelination accompanying axonal loss does occur following mTBI, there is a significant amount of primary demyelination on intact axons, and most notably in the absence of oligodendrocyte death. This suggests that there is an intrinsic change that occurs in myelin or in the myelinating oligodendrocyte that triggers myelin breakdown. The molecular mechanisms associated with primary myelin loss following mTBI have not been elucidated fully. While the fluid percussion injury (FPI) model has been used extensively in studies of experimental TBI, it has been used infrequently to model mild injury in mice, and even less so to examine the effects of mild FPI (mFPI) on oligodendrocytes and myelin in white matter. In chapter one, the effects of mFPI on two discrete regions of the corpus callosum are compared: the one immediately inferior to the site of impact at the level of the cortex (focal), and the portion of the corpus callosum anterior to the craniectomy and site of impact (distal). This type of injury is reproducible without causing cavitation or hemorrhage. Extensive βAPP is detectable in the focal but not distal corpus callosum, and injury induced astrogliosis occurs globally.In the current study, I show that mFPI does not alter the total number of oligodendrocytes in either region of the corpus callosum at early post-injury timepoints (one and three days post injury). It does not result in apoptosis in either the cortex or corpus callosum in either region or trigger proliferation of OPCs. The effect of mFPI is specific to mature oligodendrocytes and myelin. The GST-π+ oligodendrocyte population is not affected by mFPI. In the focal but not distal corpus callosum, there is a decrease in the number of CC1+ mature oligodendrocytes at one day post injury that continues to decline through three days post injury. The population of BCAS1+ myelinating oligodendrocytes also decreases only in the focal corpus callosum at three days post injury. Although myelin protein expression does not appear to be altered through immunohistochemical or biochemical assays, the total myelin lipid component as detected by Fluoromyelin is also decreased in the focal corpus callosum at three days post injury. Nodal abnormalities, including increased nodal asymmetry, a decrease in the number of complete triplets and an increase in the number of heminodes, have been reported after mild closed head injury in mice. In this study, a significant decrease in the total number of Nav1.6+ nodes of Ranvier was observed in both the distal and focal corpus callosum at three days post mFPI, as well as a decrease in the percentage of complete triplets and an increase in the percentage of heminodes. While other injury induced white matter damage is isolated to the focal corpus callosum in this study, the nodes and paranodes seem particularly vulnerable to mFPI in the distal corpus callosum. In our previous study, we identified the Erk1/2 pathway as an important negative regulator of oligodendrocyte myelin after in vitro stretch injury. After mFPI, oligodendrocytes in both the distal and focal corpus callosum experience a robust activation of Erk1/2. In Chapter two, I describe the outcome of oligodendrocyte specific Erk1/2 ablation after injury. In both Erk1 sKO and Erk1/2 dKO mice, the population of both CC1+ mature oligodendrocytes and BCAS1+ myelinating oligodendrocytes is retained in the focal corpus callosum after injury, in contrast to injured wild type animals. Additionally, the total number of Nav1.6+ nodes of Ranvier is unaltered after mFPI in both the distal and focal corpus callosum of Erk1 sKO and Erk1/2 dKO mice compared to wild type, and there is no reduction in the myelin lipid component. Taken together, this study demonstrates the use of the mFPI model for investigating the effects of mild type injury on oligodendrocytes and myelin and establishes the role of the Erk1/2 pathway as a primary contributor in mature oligodendrocyte and myelin damage after mild traumatic brain injury.