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

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 18 F-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 blastexposed 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.

Behavioral and inflammatory response in animals exposed to a low-pressure blast wave and supplemented with β-alanine

“…The resiliency seen for mTBI in animals supplemented with β-alanine was noted despite elevations in tau protein expression, suggests that elevations in tau protein from a single blast may not lead directly to impaired spatial memory. Recent evidence indicates that a greater degree of neuropathology is observed from multiple blast exposures rather than a single blast exposure (Meabon et al 2016). Thus, elevations in brain carnosine may provide resiliency to an isolated or single exposure to a low-pressure blast wave, despite elevations observed in tau protein expression.…”

A Network-Based Neurobiological Model of PTSD: Evidence From Structural and Functional Neuroimaging Studies

“…For example, one structure that did not received much attention in PTSD but has been repeatedly implicated by model-free whole-brain meta-analyses, is the cerebellum [4, 7, 5]. Although there has been a recent increased interest in this structure [82, 83], the specific role of the cerebellum in stress-related psychopathology is yet to be fully elucidated.…”

Considerations for Experimental Animal Models of Concussion, Traumatic Brain Injury, and Chronic Traumatic Encephalopathy—These Matters Matter

“…For this purpose, other animal models designed with a frame of reference that targets injury consequences (“output”; Figure 4) would be more informative. Justification of “output” models relies on concordance with brain pathology, neuroimaging, and behavioral deficits in humans (112, 120, 134). Stated differently, validity and utility of these models are based on the degree to which the model recapitulates clinical features and pathophysiological mechanisms of the human disease being modeled (3).…”

“…Exposure to explosive blast is known to induce TBI and CTE brain pathology in humans (103, 112, 134, 173). Goldstein et al developed a mouse model of blast-related neurotrauma that reliably induces CTE-linked phosphorylated tau proteinopathy, neuroinflammation, diffuse astrocytosis, TMI, myelinated axonopathy, neurophysiological abnormalities, and learning-memory deficits that strikingly recapitulate acute and chronic effects of blast-related TBI and CTE in humans (112, 120).…”