Traumatic brain injury (TBI) presents a major healthcare problem for millions of Americans. Studies of TBI have revealed that axons are among the most vulnerable, and the most commonly injured, cellular components in the nervous system. Evidence shows that traumatic axonal injury (TAI) is a multiphasic pathology, with initial failures of ionic homeostasis evolving to a protracted secondary phase involving aberrant biochemical cascades. However, important questions remain concerning whether all axons respond to TAI in the same way. This project directly addresses the issue of differential vulnerability among populations of axons. This investigation focuses on the role of unmyelinated axons in TAI pathology, assessing how this population of axons undergoes a distinctive response to injury and shows a functional recovery which differs from that of myelinated axons. Existing theories of TAI pathology are based almost exclusively on the readily observable large myelinated axons, while the histologically inconspicuous unmyelinated axons have eluded examination. Yet recent stereological axon counts have revealed that the unmyelinated axons comprise a numerical majority among fibers in subcortical white matter. The preliminary studies which support this proposal revealed that, following central fluid percussion injury in adult rats, unmyelinated axons in the corpus callosum exhibited more severe and prolonged electrophysiological abnormalities than were observed in myelinated axons. The research plan of this investigation will apply quantitative electrophysiological, ultrastructural, and molecular measures to evaluate the progress and extent of injury in unmyelinated callosal fibers, and to contrast this pathology with that in myelinated axons. We will test the hypothesis that specific molecular domains, localized to the axolemma of unmyelinated axons, are targets in the early phases of TBI and are the basis for the differential vulnerability of fiber subtypes. In addition, we will test a pharmacological treatment, based on calcineurin inhibition, which has proved neuroprotective in experimental TAI, and evaluate the efficacy of this therapy to improve the postinjury status of unmyelinated axons. Collectively these studies will lead to a greater understanding of the role of unmyelinated axons in TAI, and will form the basis for developing new therapeutic strategies for the treatment of brain injury. This project investigates distinctive pathology affecting unmyelinated axons in a rat model of experimental brain injury. Electrophysiological, ultrastructural, and molecular methods are used to characterize the axonal pathology, and determine the severity and duration of the deficits. Neuroprotective drugs are also used to alter the course of the functional and structural effects of injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Hicks, Ramona R
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Virginia Commonwealth University
Anatomy/Cell Biology
Schools of Medicine
United States
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Schurman, Lesley D; Smith, Terry L; Morales, Anthony J et al. (2017) Investigation of left and right lateral fluid percussion injury in C57BL6/J mice: In vivo functional consequences. Neurosci Lett 653:31-38
Reeves, Thomas M; Trimmer, Patricia A; Colley, Beverly S et al. (2016) Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury. Exp Neurol 283:188-203
Sato, Masatoshi; Sagawa, Yohei; Hirai, Nobuhide et al. (2014) Noninvasive detection of sleep/wake changes and cataplexy-like behaviors in orexin/ataxin-3 transgenic narcoleptic mice across the disease onset. Exp Neurol 261:744-51
Phillips, Linda L; Chan, Julie L; Doperalski, Adele E et al. (2014) Time dependent integration of matrix metalloproteinases and their targeted substrates directs axonal sprouting and synaptogenesis following central nervous system injury. Neural Regen Res 9:362-76
Chan, Julie L; Reeves, Thomas M; Phillips, Linda L (2014) Osteopontin expression in acute immune response mediates hippocampal synaptogenesis and adaptive outcome following cortical brain injury. Exp Neurol 261:757-71
Hait, Nitai C; Wise, Laura E; Allegood, Jeremy C et al. (2014) Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat Neurosci 17:971-80
Reeves, Thomas M; Smith, Terry L; Williamson, Judy C et al. (2012) Unmyelinated axons show selective rostrocaudal pathology in the corpus callosum after traumatic brain injury. J Neuropathol Exp Neurol 71:198-210
Warren, Kelly M; Reeves, Thomas M; Phillips, Linda L (2012) MT5-MMP, ADAM-10, and N-cadherin act in concert to facilitate synapse reorganization after traumatic brain injury. J Neurotrauma 29:1922-40
Harris, Janna L; Reeves, Thomas M; Phillips, Linda L (2011) Phosphacan and receptor protein tyrosine phosphatase ýý expression mediates deafferentation-induced synaptogenesis. Hippocampus 21:81-92
Reeves, Thomas M; Greer, John E; Vanderveer, Andrew S et al. (2010) Proteolysis of submembrane cytoskeletal proteins ankyrin-G and ?II-spectrin following diffuse brain injury: a role in white matter vulnerability at Nodes of Ranvier. Brain Pathol 20:1055-68

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