David J. King Hall, #2027
November 15, 2018, 10:30 AM to 12:00 PM
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition caused by repetitive mild traumatic brain injury (TBI) that leads to disordered memory, impaired executive functioning, and personality and emotional disturbances. Currently, the World Health Organization predicts that TBI (and its consequences, such as CTE) will become a leading cause of death and disability by the year 2020, warranting both basic and translational research of potential therapeutic targets. One area of research concerns prophylactic treatment and includes zinc (Zn) supplementation. Brain injury causes an immediate increase in Zn release followed by Zn deficiency in the synapse, worsening secondary injury cascades beyond levels caused by the initial Zn release. Prophylactic dietary Zn supplementation increased neuronal proliferation and improved behavioral outcomes following a single severe TBI in rats; however, Zn supplementation also exacerbated TBI-related neuropathology such as tau aggregation in other TBI models. Given the conflicting evidence, this project sought to explore whether Zn supplementation would be beneficial or detrimental in a mouse model of repetitive mild TBI. One hundred four-week-old male and female C57BL/6J mice consumed either standard lab water or 10 parts per million Zn-supplemented water for eight weeks prior to injury. At 12 weeks of age, mice underwent either five sham procedures or five closed-head injuries spaced apart by 48 hours after which they completed behavioral tests. Repetitive mild TBI impaired righting and normal ambulation recovery, but males on Zn water righted themselves and regained normal ambulatory function as fast as non-injured mice across the five injury days. Injury also caused increased anxiety in the open field test and decreased general spatial memory in the Morris water maze in females, but Zn did not have a therapeutic effect. Zinc did not have a therapeutic effect in nesting or burrowing behaviors. Overall, it appeared that Zn improved acute neurological recovery. Injury reduced fluorescence representing free, ionic Zn in the dentate gyrus and CA3 region of the hippocampus, but injury did not change ionic Zn levels in the overlying cortex. Zinc supplementation partially remediated the reduced Zn fluorescence but not to the values of shams. Injury did not affect white matter and neuronal cell body densities in the hippocampus and areas under the impact site, suggesting that these brain regions had intact neuronal cell bodies that presumably internalized Zn, causing a Zn-deficient state in the external milieu. It is possible that the administered level of Zn supplementation in this study was too mild to significantly influence the main effect of brain injury. These results further demonstrate the need for additional research documenting underlying mechanisms of Zn in TBI-related neuropathology.