Traumatic brain injury (TBI) remains a national health care problem, impacting upon both our civilian and military populations. With severe TBI, focal and diffuse changes are seen in the brain while mild to moderate TBI is typically associated with scattered changes, with diffuse axonal injury (DAI) being a major determinant of the subsequent morbidity and recovery. Because of the importance of DAI, our lab and many others have focused on achieving a better understanding of its pathogenesis and its potential therapeutic management. Despite progress in this area, there has been virtually no consideration of DAI's downstream/deafferentation- mediated morphological, physiological, and functional consequences or the brain's ability to adapt to DAI. The failure of the basic scientific community to address this issue is related to the complexity of DAI and the difficulties in following diffusely/scattered damaged axons and their terminal projections in a diffusely injured brain. Recently, we have explored mild TBI in multiple strains of YFP-expressing mice. Using the YFP-16 variant expressing YFP throughout the visual axis, we recognized DAI scattered throughout the prechiasmatic segment of the optic nerve and the subcortical white matter within the visual cortex, allowing us to follow, for the first time, the consequences of DAI for its downstream sites in the lateral geniculate body and the associated primary visual cortex. Using advanced bioimaging and electrophysiological studies conducted in vivo and in vitro, we now seek to determine if DAI translates into diffuse deafferentation within the lateral geniculate nucleus and visual cortex, while also assessing its implications for long-term synaptic function and rearrangement. These studies will be interfaced with a critical evaluation of the natural history o recovery of visual function post DAI while also seeking to determine if DAI compromises visual cortical plasticity, reflected in the ability of the visual axis to respond to manipulations in visal experience. Lastly, with this information in hand, we will utilize multiple therapeutic approaches previously reported by our lab to exert axonal protection to determine if significant reductions in the burden of axonal damage within the visual axis translate into either temporally altered or significantly improved visual function and plasticity. We believe these studies are important in that they represent a comprehensive attempt to understand the consequences of DAI for its downstream target sites. Moreover, in that the organization of the mouse visual system has many structural and functional homologies with the visual system of higher order animals and provides an excellent model system for understanding basic cortical synaptic plasticity and regenerative failure, we believe the proposed studies take on even more importance. Lastly, because disturbances of visual function have been reported in a large cohort of brain-injured soldiers returning from Iraq and Afghanistan, the importance of these studies is further highlighted.

Public Health Relevance

These studies will provide valuable information about how trauma-induced diffuse axonal injury and its scattered deafferentation, a hallmark of human traumatic brain as well as blast injury, affects the structure and function of the visual system. B better understanding the acute and chronic traumatic consequences of diffuse axonal injury while also exploring the efficacy of various therapeutic strategies the proposed work will most likely change key concepts and approaches in the field of traumatic brain injury, providing a unique platform for the continued assessment of the sequelae and treatment of this major component of traumatic brain injury.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD055813-29A1
Application #
8631960
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Nitkin, Ralph M
Project Start
1983-12-01
Project End
2018-12-31
Budget Start
2014-01-10
Budget End
2014-12-31
Support Year
29
Fiscal Year
2014
Total Cost
$554,702
Indirect Cost
$161,732
Name
Virginia Commonwealth University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Wang, Jiaqiong; Fox, Michael A; Povlishock, John T (2013) Diffuse traumatic axonal injury in the optic nerve does not elicit retinal ganglion cell loss. J Neuropathol Exp Neurol 72:768-81
Fujita, Motoki; Wei, Enoch P; Povlishock, John T (2012) Effects of hypothermia on cerebral autoregulatory vascular responses in two rodent models of traumatic brain injury. J Neurotrauma 29:1491-8
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Greer, John E; McGinn, Melissa J; Povlishock, John T (2011) Diffuse traumatic axonal injury in the mouse induces atrophy, c-Jun activation, and axonal outgrowth in the axotomized neuronal population. J Neurosci 31:5089-105
Wang, Jiaqiong; Hamm, Robert J; Povlishock, John T (2011) Traumatic axonal injury in the optic nerve: evidence for axonal swelling, disconnection, dieback, and reorganization. J Neurotrauma 28:1185-98
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Povlishock, John T; Wei, Enoch P (2009) Posthypothermic rewarming considerations following traumatic brain injury. J Neurotrauma 26:333-40
McGinn, Melissa J; Kelley, Brian J; Akinyi, Linnet et al. (2009) Biochemical, structural, and biomarker evidence for calpain-mediated cytoskeletal change after diffuse brain injury uncomplicated by contusion. J Neuropathol Exp Neurol 68:241-9
Baranova, Anna I; Wei, Enoch P; Ueda, Yuji et al. (2008) Cerebral vascular responsiveness after experimental traumatic brain injury: the beneficial effects of delayed hypothermia combined with superoxide dismutase administration. J Neurosurg 109:502-9

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