Traumatic brain injury (TBI) is a significant U.S. health concern, with over 1.7 million new cases each year. Loss of brain circuitry underlies persistent cognitive deficits suffered by its victims, with axonal damage as a major contributor. Using the injured corpus callosum (CC) as a model, we have shown that postinjury change in matrix metalloproteinases (MMPs) is correlated with distinct myelinated and unmyelinated fiber pathology. MMPs are critical modulators of brain extracellular matrix (ECM) which affect axonal integrity. We found that CC gelatinases MMP2 and 9 peak in activity at different postinjury intervals which are marked by reactive glial response. We also observed that this MMP activity was temporally correlated with unmyelinated axon pathology. Treatment with neuroprotective compounds FK-506 and minocycline resulted in selective, time- dependent reduction of this gelatinase activity and reduced deficits in CC compound action potentials(CAPs). Pilot microarray studies revealed that osteopontin (OPN), a cytokine secreted into the ECM and reciprocally linked to MMP function, was significantly upregulated in injured CC. From these data we hypothesize that gelatinase response to traumatic axonal injury is mediated through acute activation of OPN within reactive glia. We also posit that the time course and glial role in this pathway will differ between unmyelinated and myelinated fibers. To test these hypotheses, the following aims will be explored in the fluid percussion model of TBI : 1) to document OPN/MMP2,9 during axonal injury within fiber environments enriched in unmyelinated (ON, olfactory nerve) and myelinated fibers (IC, internal capsule), and determine if OPN KO and MMP9KO alters these changes, 2) to dissect cell specific OPN/MMP2,9 interaction in vitro using primary CC and ON glial cultures, and 3) to test whether OPNKO or MMPKO alters efficacy of axonal neuroprotective drugs FK-506 and minocycline, then determine if combining optimal drug and OPN/MMP9 manipulation alters functional or structural outcome in the rat model of FPTBI. These studies are likely to identify novel options for regional and fiber targeted therapy in patients suffering from axonal damage after TBI.

Public Health Relevance

Traumatic brain injury (TBI) produces significant axonal damage, which disrupts brain connections and causes persistent loss of function. This project will use rodent TBI models to better understand how molecules in the brain environment surrounding damaged axons influence their injury, and how these molecules can be manipulated to foster axonal repair. This approach will identify new strategies to treat human TBI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Bellgowan, Patrick S F
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Virginia Commonwealth University
Anatomy/Cell Biology
Schools of Medicine
United States
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Hyer, Molly M; Phillips, Linda L; Neigh, Gretchen N (2018) Sex Differences in Synaptic Plasticity: Hormones and Beyond. Front Mol Neurosci 11:266
Powell, Melissa A; Black, Raiford T; Smith, Terry L et al. (2018) Mild Fluid Percussion Injury Induces Diffuse Axonal Damage and Reactive Synaptic Plasticity in the Mouse Olfactory Bulb. Neuroscience 371:106-118
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
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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
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

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