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

W. Brad Hubbard, Gopal V. Velmurugan, Emily P. Brown, Patrick G. Sullivan

Research output: Contribution to journalArticlepeer-review

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 11 psi static peak overpressure blast wave using the McMillan blast device and cohorts were then euthanized at 6 h, 24 h, 7 d and 14 d post-blast followed by isolation of the amygdala. After mbTBI, animals experience immediate bradycardia, although no changes in oxygen saturation levels or weight loss are observed. 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 6 h and 24 h post-mbTBI in male rats, but not in female rats, compared to sham. Female animals have decreased GFAP at 6 h post-mbTBI while male animals display decreased GFAP expression at 24 h post-mbTBI. By 7 d post-mbTBI, there were no significant differences in TJ or GFAP levels between groups in either sex. At 24 h 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.

Original languageEnglish
Article number93
JournalActa neuropathologica communications
Volume10
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
W.B.H. was supported by BLR&D Career Development Award Number IK2 BX004618 from the Department of Veterans Affairs. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. The studies were also supported by Medical Technology Enterprise Consortium (MTEC) and BrightFocus through project 20–16-mTBI-005 and by University of Kentucky Neuroscience Research Priority Area pilot award NRPA016.

Funding Information:
We would like to thank Malinda Spry and Frances Meredith for their assistance in the experimental studies. Additionally, we offer profound thanks to Richard D. Hisel and Eric Dixon of GLR Enterprises for their assistance in McMillan Blast Device set-up.

Publisher Copyright:
© 2022, The Author(s).

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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