Resilience of females to acute blood-brain barrier damage and anxiety behavior following mild blast traumatic brain injury

Abstract Low-level blast exposure can result in neurological impairment for military personnel. Currently, there is a lack of experimental data using sex as a biological variable in neurovascular outcomes following blast exposure. To model mild blast traumatic brain injury (mbTBI), male and female rats were exposed to a single 11psi static peak overpressure blast wave using the McMillan blast device and cohorts were then euthanized at 6h, 24h, 7d, and 14d post-blast followed by isolation of the amygdala. After mbTBI, animals experience immediate bradycardia, although no changes in oxygen saturation levels or acute weight loss. Male mbTBI animals displayed significantly higher levels of anxiety-like behavior (open field and elevated plus maze) compared to male sham groups; however, there was no anxiety phenotype in female mbTBI animals. Blast-induced neurovascular damage was explored by measuring expression of tight junction (TJ) proteins (zonula occludens-1 (ZO-1), occludin and claudin-5), glial fibrillary acidic protein (GFAP) and astrocyte end-feet coverage around the blood-brain barrier (BBB). Western blot analysis demonstrates that TJ protein levels were significantly decreased at 6h and 24h post-mbTBI in male rats, but not in female rats, compared to sham. Female animals have decreased GFAP at 6h post-mbTBI while male animals display decreased GFAP expression at 24h post-mbTBI. By 7d post-mbTBI, there were no significant differences in TJ or GFAP levels between groups in either sex. At 24h post-mbTBI, vascular integrity and astrocytic end-feet coverage around the BBB was significantly decreased in males following mbTBI. These results demonstrate that loss of GFAP expression may be due to astrocytic damage at the BBB. Our findings also demonstrate sex differences in acute vascular and behavioral outcomes after single mbTBI. Female animals display a lack of BBB pathology after mbTBI corresponding to improved acute neuropsychological outcomes as compared to male animals.