Repeated Exposures to Low-Level Blast Induce Acute Region-Specific Changes in the Brain and Acute Elevation in Plasma Cytokine Levels in a Mouse Model

Highly repetitive exposures to low-level blasts (LLBs) during military training (e.g., breaching and heavy weapons exercises) can cause neurological abnormalities, but the pathological mechanisms are poorly understood. We evaluated the effect of repetitive LLB exposures on cellular responses at specific neuroanatomical and cellular strata and on plasma cytokine levels in a mouse model. Animals were exposed to either 5 ± 0.2 sequential LLB exposures with roughly 3 min intervals or sham exposures consisting of anesthesia only. Overpressure properties were 4.49 ± 0.35 pounds per square inch (psi), 1.04 ± 0.13 msec, and 0.0035 ± 0.004 psi × sec impulse occurring during an average total anesthesia of 14.1 ± 0.02 min. Peak pressure was restricted to ∼20 cumulative psi to ensure animal welfare. Following recovery in their home cage, cardiac blood and whole brains were collected at 4 and 24 h postexposures. We found increased tissue levels of the mitochondrial antioxidant SOD2 in protein extracts of the brainstem. LLB did not increase tau phosphorylation (at Ser396), but the acute drop detected in total tau tissue levels resulted in altered ptau:tau ratios and an increase in brain tissue levels of myelin alarmin protein interleukin-33 (IL-33), indicating myelin injury even in the absence of apparent axonal injury. Mass cytometry images indicated astrogliopathy at the medullary surfaces near the foramen magnum and apical inferior cerebellar lobes consistent with interface astroglial scarring detected at 24 h after LLB. In both the medulla and inferior cerebellum, LLB increased the frequency of association of cluster of differentiation-68+ macrophages with IL-33+ myelin and cerebellar Purkinje cells in regions of astroglial scarring. At 4 h, LLB exposures significantly increased the plasma levels of IL-6, Keratinocyte-derived chemokine/Growth-regulated oncogene alpha (KC/GRO-α), and IL-10 (areas under the receiver operating characteristic curve of 0.8, 0.83, and 0.86, respectively) but not that of Neurofilament light chain (NF-L). Our results indicate that repetitive blast exposures near the 4 psi safety threshold can induce diverse neuropathological changes and systemic inflammatory response consistent with the known acute effects of mild traumatic brain injury despite the classification of these exposures as functionally subconcussive.