A novel closed-body model of spinal cord injury caused by high-pressure air blasts produces extensive axonal injury and motor impairments

Abstract

Diffuse axonal injury is thought to be the basis of the functional impairments stemming from mild traumatic brain injury. To examine how axons are damaged by traumatic events, such as motor vehicle accidents, falls, sports activities, or explosive blasts, we have taken advantage of the spinal cord with its extensive white matter tracts. We developed a closed-body model of spinal cord injury in mice whereby high-pressure air blasts targeted to lower thoracic vertebral levels produce tensile, compressive, and shear forces within the parenchyma of the spinal cord and thereby cause extensive axonal injury. Markers of cytoskeletal integrity showed that spinal cord axons exhibited three distinct pathologies: microtubule breakage, neurofilament compaction, and calpain-mediated spectrin breakdown. The dorsally situated axons of the corticospinal tract primarily exhibited microtubule breakage, whereas all three pathologies were common in the lateral and ventral white matter. Individual axons typically demonstrated only one of the three pathologies during the first 24 h after blast injury, suggesting that the different perturbations are initiated independently of one another. For the first few days after blast, neurofilament compaction was frequently accompanied by autophagy, and subsequent to that, by the fragmentation of degenerating axons. TuJ1 immunolabeling and mice with YFP-reporter labeling each revealed more extensive microtubule breakage than did βAPP immunolabeling, raising doubts about the sensitivity of this standard approach for assessing axonal injury. Although motor deficits were mild and largely transient, some aspects of motor function gradually worsened over several weeks, suggesting that a low level of axonal degeneration continued past the initial wave. Our model can help provide further insight into how to intervene in the processes by which initial axonal damage culminates in axonal degeneration, to improve outcomes after traumatic injury. Importantly, our findings of extensive axonal injury also caution that repeated trauma is likely to have cumulative adverse consequences for both brain and spinal cord.

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

“…This approach is different from past work that often focused on one type of behavioral deficit, whether it was related to anxiety (Patel et al, 2014a; Xie et al, 2013; Yin et al, 2014), memory (Ning et al, 2013; Rubovitch et al, 2011), or motor impairment (del Mar et al, 2015). With our interest in primary blast loading, we focused on understanding a deficit in spatial object recognition that remained even when the head was restrained during blast exposure.…”

Mild Traumatic Brain Injury with Associated Visual System Dysfunction: Investigating Histopathology, Functional Correlates, and a Novel Therapeutic Immune Modulator

“…Axon bulbs were quantified and found to peak at 3 days, then decrease by nearly half at 7 days, before returning to control levels two weeks out from blast. This time course is similar to that described in the literature for axon damage and subsequent axonal degeneration by autophagy 184,185 .…”

Serum SNTF, a Surrogate Marker of Axonal Injury, Is Prognostic for Lasting Brain Dysfunction in Mild TBI Treated in the Emergency Department

“…Sequencing of the BDPs and development of cleavage site-specific antibodies identified the preferred calpain cleavage sites in the subunit (19, 49, 50), thereby defining the amino acid sequences of each fragment. Subsequent publications referred to the two major carboxyterminal α II -spectrin fragments as SBDP150 and 145, and did not distinguish SNTF from these SBDPs (53)(54)(55)(56). Whereas the SBDP carboxy-terminal fragments have also been studied as candidate cerebrospinal fluid and blood biomarkers for acute brain injuries, neither has shown promise as a blood diagnostic or prognostic for mTBI.…”