Repetitive mild traumatic brain injury with impact acceleration in the mouse: Multifocal axonopathy, neuroinflammation, and neurodegeneration in the visual system
Introduction
There are at least 2–3 million new cases of civilian TBI in the US every year, most of them from motor vehicle accidents (MVA) or falls. A recent trend that has attracted much attention is an increasing number of cases of progressive tauopathy in professional and amateur athletes with careers in collision sports such as football (Omalu et al., 2005, Omalu et al., 2006, McKee et al., 2009, Goldstein et al., 2012). These cases have been linked to repetitive concussions and appear to be identical to cases of dementia pugilistica (Martland, 1928, Millspaugh, 1937, Corsellis et al., 1973), with which they are classified under the rubric of chronic traumatic encephalopathy (CTE) (Goldstein et al., 2012). Repetitive mild blast TBI from exposure to explosive munitions is the signature injury in the Iraq and Afghanistan war theaters (Warden, 2006) and the Defense and Veterans Brain Injury Center has recently developed return-to-duty guidelines to prevent further TBI incidents in soldiers with concussive histories (Barth, 2011). The public concern over repeat concussions is growing not only because of the risk among NFL professionals and active-duty soldiers or veterans, but also because of the exposure of millions of non-professional athletes playing football, soccer and other contact sports (Langlois et al., 2006).
The development of animal models that approximate human concussion scenarios can provide a much-needed proof of concept by linking repetitive injury to adverse long-term effects, including neurodegeneration. Furthermore, animal models of repetitive TBI can be applied to transgenic rodents to work out molecular mechanisms that may help identify subjects with genetic predispositions to traumatic tauopathy. Such genetic backgrounds may include pathogenic tau mutations (Ballatore et al., 2007) or H1 tau haplotypes (Ferrari et al., 2011, Vandrovcova et al., 2010). In addition, animal models can serve as vehicles for therapeutic targeting and experimental therapeutics.
In this paper, we modified a well-characterized rat model of closed, non-contusive head injury, i.e. the impact acceleration (IA) model (Marmarou et al., 1994, Beaumont et al., 1999), for repetitive use in mice at a mild impact level. Although the IA model can produce a graded, widespread injury involving neurons, astrocytes, axons, and the microvasculature, it does not cause focal damage regardless of injury severity. We believe that the mild, repetitive, non-contusive IA injury by this IA mouse model that approximates conditions encountered in repetitive concussion in contact sports, is instructive for repetitive blast TBI occurring in combat, and may provide general insights for situations featured by repetitive TBI such as epilepsy, self-injurious behaviors, and child and domestic abuse. Our findings are consistent with the view that repetitive TBI causes cumulative axonopathy that can lead to degeneration of axotomized CNS neurons.
Section snippets
Experimental animals and surgical procedures
The subjects of these experiments were 5–6 weeks old C57BL6/J mice (male, n = 117; Charles River Laboratories, Wilmington, MA). The animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals, 8th Ed. (National Academy Press, Washington, DC, 2011) and all animal care, surgical and post-operative procedures were approved by the Animal Care and Use Committee of The Johns Hopkins Medical Institutions. The animals were housed in the vivarium with 12 h light/12 h
General characterization of mouse IA model with single and repetitive mild impacts
As laid out in Materials and methods, the weight drop height was set at 1 m. Weight of impactor was tested starting at 10 g and further loaded at 10 g increments. There was no fatality until weight reached 50 g. With the 50 g− 1 m impact, mortality was 18.2% and with the 60 g− 1 m impact, mortality was increased up to 40%. Based on these initial mortality data, the 40 g− 1 m impact was used in all subsequent repetitive injury paradigms.
Change of body weight was used as an index to determine the optimal
General
Our findings indicate that our mild repetitive TBI mouse model, a modification of the rat IA paradigm, does not cause either focal contusive or anoxic–ischemic injury in the mouse brain. Rather, our model produces selective TAI in certain white matter tracts; this effect is coupled with local neuroinflammatory responses and is positively associated with TBI severity. A remarkable finding is the consistent involvement of the visual system, with degeneration of axons in both ON and optic tract
Conflict of interest
No competing financial interests exist.
Acknowledgment
This work was supported by Maryland Technology Development Corporation funds to VEK.
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2023, Experimental NeurologyCitation Excerpt :Traumatic (diffuse) axonal injury and the associated axonopathy is a common neuropathology in various types of TBI across the severity spectrum (Strich, 1956; Adams et al., 1984; Blumbergs et al., 1989; Blumbergs et al., 1994; Mittl et al., 1994; Koliatsos et al., 2011). The study of white matter integrity in various models of TBI including impact acceleration (Foda and Marmarou, 1994; Povlishock et al., 1997; Xu et al., 2016; Ziogas and Koliatsos, 2018; Welsbie et al., 2019) closed head impact (Marion et al., 2018; Marion et al., 2019; Maynard et al., 2020), fluid percussion injury (Lifshitz et al., 2007; Wang et al., 2011; Eakin et al., 2015), optic nerve stretch (Maxwell et al., 1991; Maxwell and Graham, 1997; Maxwell et al., 2015) and blast injury (Koliatsos et al., 2011) has been the focus of several investigations. Previous studies employing electron microscopy in some of these models have revealed some key features of axoplasmic and myelin pathology (Maxwell and Graham, 1997; Povlishock et al., 1997; Wang et al., 2011; Maxwell et al., 2015; Mierzwa et al., 2015; Marion et al., 2018) and, in the present study, we have confirmed and extended several of these observations.
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