The Effect of Chronic Variable Stress on Repetitive Mild Traumatic Brain Injury with Intranasal Zinc Treatment

William R. Kochen

Advisor: Jane M Flinn, PhD, Department of Psychology

Committee Members: Martin Wiener, Erin Murdoch, Robert Lipsky

David J. King Hall, #2027
November 28, 2018, 09:00 AM to 10:30 AM


Traumatic Brain Injuries (TBI) are a leading cause of morbidity and mortality across ages. Most TBIs are mild TBIs (mTBI) which are identified by minor loss of consciousness (if any) and no fracturing of the skull. Accumulating evidence indicates that the effects of stress alter the pathology seen following TBI. This is especially relevant in military populations, where post-traumatic stress disorder (PTSD) and chronic stress are hallmark problems seen in soldiers returning from combat. Zinc (Zn) supplementation prior to TBI has been shown to mitigate the damage seen following injury. This experiment examined the efficacy of acute intranasal Zn therapy following repetitive mild TBI in both stressed and unstressed mice. Mice received chronic variable stress for one week which was followed by behavioral testing (nesting, burrowing, elevated zero, and forced swim). Immediately following behavioral testing, mice endured a second week of stress during which four mild TBIs were administered with a 48-hour inter-injury interval. Following each injury, mice received either intranasal Zn or vehicle. The same behavioral tests were then conducted following the final day of injury. Western Blots were performed for proBDNF, mature BDNF, doublecortin, TrkB, and phosphoTrkB. Results following the first week of stress show stressed mice spent significantly more time in the open areas of the elevated zero maze as well as spent more time helpless in forced swim.  For non-stressed mice, Traumatic Brain Injury alone did not significantly alter number of head dips or time spent in the open quadrant; however, zinc treatment caused significant increases is the amount of time spent in the open quadrant but only for non-stressed mice. There were no clinically significant effects in burrowing or nesting. ZinPyr Staining indicated that mice who received intranasal Zinc treatment had significantly more free Zinc in their hippocampus then mice who received vehicle treatment. Stress and Zinc Treatment significantly altered protein expression as evidenced through Western Blots. Overall this study shows that the efficacy of treatment in TBI is modulated by pre-injury stress. Future studies testing new therapeutic for TBI in soldiers should involve pre-injury stress to better translate human injuries.