The effects of mild closed head injuries on tauopathy and cognitive deficits in rodents: Primary results in wild type and rTg4510 mice, and a systematic review

Adam D. Bachstetter, Josh M. Morganti, Colleen N. Bodnar, Scott J. Webster, Emma K. Higgins, Kelly N. Roberts, Henry Snider, Shelby E. Meier, Grant K. Nation, Danielle S. Goulding, Matthew Hamm, David K. Powell, Moriel Vandsburger, Linda J. Van Eldik, Jose F. Abisambra

Research output: Contribution to journalReview articlepeer-review

10 Scopus citations


In humans, the majority of sustained traumatic brain injuries (TBIs) are classified as ‘mild’ and most often a result of a closed head injury (CHI). The effects of a non-penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction, which could be worsened by repeated head injury. Clinical-neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates (p-tau) could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs. However, the link between p-tau and CHI in rodents remains controversial. To address this question experimentally, we induced a single CHI or two CHIs to WT or rTg4510 mice. We found that 2× CHI increased tau phosphorylation in WT mice and rTg4510 mice. Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2× CHI mice that had partially resolved in the 1× CHI mice. Moreover, using Manganese-Enhanced Magnetic Resonance Imaging with R1 mapping – a novel functional neuroimaging technique – we found greater deficits in the rTg4510 mice following 2× CHI compared to 1× CHI. To integrate our findings with prior work in the field, we conducted a systematic review of rodent mild repetitive CHI studies. Following Prisma guidelines, we identified 25 original peer-reviewed papers. Results from our experiments, as well as our systematic review, provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies; however, changes in p-tau levels are not universally reported. Together, our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI, but the direct link between the worsened outcome and elevated p-tau could not be established.

Original languageEnglish
Article number113180
JournalExperimental Neurology
StatePublished - Apr 2020

Bibliographical note

Funding Information:
Research reported in this publication was supported by National Institutes of Health under award numbers R00 AG044445 (ADB ), P30 GM110787 (JFA & ADB) , R01 NS103785 (ADB) , P30 AG028383 (JFA & ADB) , R01 NS091329 (JFA) , UL1 TR000117 (JFA) , and L32 MD009205 (JFA) , and Department of Defense grant AZ140097 (JFA) , The MRISC is supported by NIH S10 shared instruments grant number S10 RR029541 . The content is solely the responsibility of the authors and does not represent the official views of the funding organizations.

Publisher Copyright:
© 2020


  • CTE
  • Concussion
  • Neurodegeneration
  • Rodent behavior
  • TBI
  • Tau

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience


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