Research ArticleTraumatic Brain Injury

Repetitive blast exposure in mice and combat veterans causes persistent cerebellar dysfunction

Science Translational Medicine  13 Jan 2016:
Vol. 8, Issue 321, pp. 321ra6
DOI: 10.1126/scitranslmed.aaa9585

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The cerebellum is vulnerable to blast injury in mice and combat veterans

Mild traumatic brain injury (TBI) is often referred to as the “signature injury” of the wars in Iraq and Afghanistan. Most of these TBIs are blast-related. Currently, there is limited understanding of how mild blast causes persistent brain injuries. There is also limited insight into how blast-induced brain injuries in animal models correspond to humans with mild TBI. Meabon et al. report that the cerebellum, a brain structure important for integrating sensory information and movement, is injured by blast exposure in mice in specific areas that correspond to abnormal brain imaging findings obtained in similar cerebellar regions in blast-exposed combat veterans.

Abstract

Blast exposure can cause mild traumatic brain injury (TBI) in mice and other mammals. However, there are important gaps in our understanding of the neuropathology underlying repetitive blast exposure in animal models compared to the neuroimaging abnormalities observed in blast-exposed veterans. Moreover, how an increase in the number of blast exposures affects neuroimaging endpoints in blast-exposed humans is not well understood. We asked whether there is a dose-response relationship between the number of blast-related mild TBIs and uptake of 18F-fluorodeoxyglucose (FDG), a commonly used indicator of neuronal activity, in the brains of blast-exposed veterans with mild TBI. We found that the number of blast exposures correlated with FDG uptake in the cerebellum of veterans. In mice, blast exposure produced microlesions in the blood-brain barrier (BBB) predominantly in the ventral cerebellum. Purkinje cells associated with these BBB microlesions displayed plasma membrane disruptions and aberrant expression of phosphorylated tau protein. Purkinje cell loss was most pronounced in the ventral cerebellar lobules, suggesting that early-stage breakdown of BBB integrity may be an important factor driving long-term brain changes. Blast exposure caused reactive gliosis in mouse cerebellum, particularly in the deep cerebellar nuclei. Diffusion tensor imaging tractography of the cerebellum of blast-exposed veterans revealed that mean diffusivity correlated negatively with the number of blast-related mild TBIs. Together, these results argue that the cerebellum is vulnerable to repetitive mild TBI in both mice and humans.

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