Connectome Analysis of the Nigrostriatal Neuronal Tract after Blast TBI

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Military personnel deployed to the wars in Afghanistan (Operation Enduring Freedom; OEF) and Iraq (Operation Iraqi Freedom; OIF) are at high risk of sustaining a traumatic brain injury (TBI) from exposures to a blast (bTBI) and other types of head injuries. Furthermore, exposure to blast waves from firing shoulder-fired weapons can affect the brain, even during training. TBI of all severities can result in chronic post-deployment disturbances of cognitive, behavioral, emotional, and physical functioning. There is extensive evidence that traumatic brain injury (TBI) produces chronic deficits in the dopaminergic system that may contribute to postinjury cognitive function. The goal of this SPiRE grant is to evaluate the use of diffusion MRI tractography and network analysis to determine the effects of single and repetitive simulated blast (shock tube) exposures on the integrity of nigrostriatal-associated tracts. hTH-GFP reporter rats will be exposed to single or repeated pressure waves at either peak pressure of 30psi or 40psi. These pressures are based on preliminary data demonstrating greater spatial memory deficits in the 40psi vs. 30psi. A battery of behavioral outcome tests to assess motor, cognitive, and stress-related function will be measured. At 4-weeks post-simulated blast, ex-vivo high-definition fiber tracking (HDFT) in conjunction with network topology analysis will be performed to characterize the integrity of substantia nigral and striatal neuronal network pathways. Ventral tegmental area tracts will also be assessed. Preliminary connectome analyses indicate that midbrain and striatal connectivity is impaired after bTBI. Loss of dopaminergic transporter protein was preliminarily observed after 4-week post-bTBI. Preliminary imaging network topological analysis showed that the nigrostriatal pathway underwent larger neuronal network re- organization after bTBI than hippocampal or amygdala regions. Immunohistochemical analyses of dopamine- related proteins will be assessed after imaging. The overall hypothesis is that exposure to varying simulated blast overpressures will result in graded reductions in nigrostriatal integrity, dopaminergic markers, and behavioral function. The application is in line with the SPiRE purpose to support senior investigators seeking to explore new research approaches in areas where they have not previously been funded.