Ultrastructural brain abnormalities and associated behavioral changes in mice after low-intensity blast exposure

Abstract

Explosive blast-induced mild traumatic brain injury (mTBI), a "signature wound" of recent military conflicts, commonly affects service members. While past blast injury studies have provided insights into TBI with moderate- to high-intensity explosions, the impact of primary low-intensity blast (LIB)-mediated pathobiology on neurological deficits requires further investigation. Our prior considerations of blast physics predicted ultrastructural injuries at nanoscale levels. Here, we provide quantitative data using a primary LIB injury murine model exposed to open field detonation of 350 g of high-energy explosive C4. We quantified ultrastructural and behavioral changes up to 30 days post blast injury (DPI). The use of an open-field experimental blast generated a primary blast wave with a peak overpressure of 6.76 PSI (46.6 kPa) at a 3-m distance from the center of the explosion, a positive phase duration of approximate 3.0 milliseconds (ms), a maximal impulse of 8.7 PSI × ms and a sharp rising time of 9 × 10 ms, with no apparent impact/acceleration in exposed animals. Neuropathologically, myelinated axonal damage was observed in blast-exposed groups at 7 DPI. Using transmission electron microscopy, we observed and quantified myelin sheath defects and mitochondrial abnormalities at 7 and 30 DPI. Inverse correlations between blast intensities and neurobehavioral outcomes including motor activities, anxiety levels, nesting behavior, spatial learning and memory occurred. These observations uncover unique ultrastructural brain abnormalities and associated behavioral changes due to primary blast injury and provide key insights into its pathogenesis and potential treatment.

Effect of mild blast-induced TBI on dendritic architecture of the cortex and hippocampus in the mouse

“…In another recent blast TBI mouse model, Konan et al observed decreased synapse density within the cortex, which mirror our results indicating a reduction in the dendritic arbor within the cortex 41 . In a previous study using the same blast TBI mouse model, myelinated axonal damage and mitochondrial abnormalities were also observed 42 . These morphological changes were also accompanied by deficits in neurobehavioral outcomes.…”

Brain-related proteins as serum biomarkers of acute, subconcussive blast overpressure exposure: A cohort study of military personnel

“…In the context of low level exposure without a direct impact to the head, this study indicated that median levels of serum Nf-L and tau were elevated (although tau did not meet statistical thresholds). Exposure is reported to impact brain tissues in a way that may mirror a sub-concussive event [24,25], causing cytoskeletal abnormalities and demyelination in rodent models [26][27][28]. In animal models, serum tau is elevated within 6h-1d of and the heavy chain isoform of neurofilament is increased within 2h after mild exposure [29].…”

Blast-Exposed Veterans With Mild Traumatic Brain Injury Show Greater Frontal Cortical Thinning and Poorer Executive Functioning

“…Nevertheless, experimental manipulation of peak pressure in mice and rats has revealed that even low levels induce neuronal loss, white matter alterations, cell signaling disruptions, and behavioral changes ( 18 – 20 ). Moreover, ultrastructural brain changes, poorer motor and memory performance, as well as increased anxiety levels, have been observed in mice exposed to primary low-intensity blast in the absence of head motion ( 21 ).…”