MYELIN PLASTICITY IN THE PROGRESSION OF WHITE MATTER PATHOLOGY IN TBI

Head impact and/or rapid acceleration-deceleration causes traumatic brain injury (TBI) from forces that damage white matter tracts, particularly the corpus callosum. Beyond the initial injury, a cascade of secondary effects can also produce persistent axon pathology and neuroinflammation in white matter tracts. No treatment is available to prevent axon degeneration or promote axon regeneration in the CNS. Therefore, a high priority is to attenuate causes of axon damage, dysfunction and/or vulnerability to damage, especially in long white matter tracts susceptible to traumatic axonal injury. White matter damage is a common component of TBI, including blast exposures. However, the significance of myelin pathology has been relatively unexplored. When TBI causes axon loss, myelin degrades without intact axons to ensheath. Axons may also remain viable but undergo demyelination, which impairs saltatory conduction and desynchronizes neural circuitry. Therefore, demyelination is a potential factor underlying deficits in information processing speed in TBI patients. Demyelination also leaves viable axons at increased risk of further damage that can progress to disconnection and permanent neurological deficits. In addition, myelin debris stimulates microglial activation, which may contribute to persistent neuroinflammation in white matter tracts. Conversely, myelin plasticity may be a tractable neuroprotective and regenerative response to TBI that could be enhanced to promote recovery. Myelin formation and remodeling is stimulated by electrical activity. Indeed, myelin plasticity is emerging as an important form of adult plasticity and modulator of social behavior and cognitive function. Importantly, remyelination both protects axons from further damage and enables recovery of function. HYPOTHESIS: Myelin-axon interactions influence white matter recovery vs neurodegeneration after TBI. AIM 1: Characterize myelin plasticity after TBI. AIM 2: Differentiate the contribution of myelin remodeling to the progression of pathology after TBI. Significance: The proposed studies will open the window on myelin effects by applying advanced techniques in the context of TBI and focus the field on the full range of potential modifications to optimize myelin plasticity and repair.