Abstract
Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation.
Highlights
The Department of Defense reported that mild traumatic brain injuries comprise 82.3% of TBIs in all military branches from 2000-2021 [1], owing in large part to improvements in battlefield medicine [2, 3]
Our present review focuses on the effects of low-intensity blast (LIB) (< 100 kPa) exposure in preclinical open-field blast studies aiming to identify research gaps and guide future research
In our initial study using a LIB model (46.7 kPa), we identified characteristic spatial learning and memory deficits using the Barnes maze [41]
Summary
Preclinical models should be well-aligned with clinical findings to provide valuable information on blast-induced acute and chronic pathological changes and guide the development of novel diagnostics and treatment. LIB-exposed mice (46.7 kPa) showed anxietylike behavior in open field assessment at 3- and 6-days post injury and when tested using the light-dark box test at 5 days postinjury [41]. Another study on unanesthetized rats exposed to a 95 kPa blast resulted in anxiety-like behavior assessed by elevated plus maze and acoustic startle response tests at 38- and 62 days post injury [60].
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