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.
|State||Published - Apr 2020|
Bibliographical noteFunding 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.
- Rodent behavior
ASJC Scopus subject areas
- Developmental Neuroscience