Abstract:
Mild traumatic brain injury (mTBI) has become the “signature wound” of the military
population in recent combat operations. Repeated mTBI (rmTBI) produces long-term
cognitive and behavioral deficits, including irregular circadian rhythm (CR). This can be
exacerbated by the high-stress environment experienced by service members. This study
employed a mouse model to examine the behavioral effects of rmTBI with chronic
variable stress (CVS) on daily circadian activity. In addition, we tested the hypothesis
that rmTBI + CVS effects would be ameliorated by supplemental zinc, a biometal that is
known to be reduced in the brain following head trauma. Six-week old mice received two
varied stressors (e.g., food deprivation, physical restraint, ice bath, predator urine) each
day for 14 days. Four closed-head mild TBIs were concurrently administered, with each
injury immediately followed by either intranasal zinc treatment or a vehicle control
(saline solution). Mice underwent behavioral testing that assessed daily activity via 24-
hour wheel-running activity for seven days, and by consecutive Morris water maze
(MWM) testing for indices of spatial learning and anxiety. A significant interaction was
found between stress and zinc in daily activity (F(1.42, 56.82) = 3.610, p = .048).
Stressed mice given vehicle treatment showed a significant deficit in wheel-running
activity at the beginning of the dark cycle, but when zinc was administered, the deficit
was corrected and activity for stressed mice nearly doubled. For non-stressed mice, zinc
resulted in decreased wheel-running activity. MWM performance yielded consistent
results, as the stressed-zinc group had the greatest number of platform crossings (F(1,39)
= 4.207, p = .047) and reduced thigmotaxis (F(1,39) = 3.222, p = .034) compared to all
other groups. Together, these findings suggest that zinc reduced behavioral deficits
depending on the level of stress experienced with rmTBI, and that zinc may be
efficacious under conditions of chronic stress. Additionally, zinc treatment increased
TrkB receptor phosphorylation in the hippocampus in rmTBI animals, suggesting a TrkBmediated
neuroprotective mechanism for zinc’s effect in stressed mice.
