A Comprehensive Review of Experimental Rodent Models of Repeated Blast TBI

Abstract

We reviewed the relevant literature delineating advances in the development of the experimental models of repeated blast TBI (rbTBI). It appears this subject is a relatively unexplored area considering the first work published in 2007 and the bulk of peer-reviewed papers was published post-2011. There are merely 34 papers published to date utilizing rodent rbTBI models. We performed an analysis and extracted basic parameters to capture the characteristics of the exposure conditions (the blast intensity, inter-exposure interval and the number of exposures), the age and weight of the animal models most commonly used in the studies, and their endpoints. Our analysis revealed three strains of rodents are predominantly used: Sprague Dawley and Long Evans rats and wild type (C57BL/6J) mice, and young adult animals 8 to 12-week-old are a preferred choice. Typical exposure conditions are the following: (1) peak overpressure in the 27–145 kPa (4–21 psi) range, (2) number of exposures: 2 (13.9%), 3 (63.9%), 5 (16.7%), or 12 (5.6%) with a single exposure used for a baseline comparison in 41.24% of the studies. Two inter-exposure interval durations were used: (1) short (1–30 min.) and (2) extended (24 h) between consecutive shock wave exposures. The experiments included characterization of repeated blast exposure effects on auditory, ocular and neurological function, with a focus on brain etiology in most of the published work. We present an overview of major histopathological findings, which are supplemented by studies implementing MRI (DTI) and behavioral changes after rbTBI in the acute (1–7 days post-injury), subacute (7–14 days), and chronic (>14 days) phases post-injury.

Investigation of the direct and indirect mechanisms of primary blast insult to the brain

“…Third, our findings are based on one histopathological (i.e., silver staining) and three immunohistochemical analyses (i.e., GFAP, Iba-1, and NeuN staining). We selected these analyses because they allowed for the evaluation of different brain cells (i.e., neurons, astrocytes, and microglia) that are known to be affected by blast exposure 26 , 32 , 44 , 45 . Nonetheless, we acknowledge that analyses based on other proteins or techniques may reveal additional contributions to changes in the brain tissues.…”

Sex as a Biological Variable in Preclinical Modeling of Blast-Related Traumatic Brain Injury

“…Previous approaches, which have not to date so much addressed blast research, have shown how complex sex difference studies can be, and-consequently-strong experimental design is critical to what may be small but significant experimental effects. The majority of publications related to neurobiological effects have employed laboratory shock tubes using compressed gases (40,196). This will be the emphasis in the discussion below.…”

“…However, the majority of translational TBI work employing both male and female animals has been performed with more severe and/or surgically invasive TBI models such as controlled cortical impact [CCI; e.g., (30)(31)(32)(33)(34)(35)], fluid percussion injury [FPI; e.g., (36,37)], or repetitive concussive brain injury [CBI; e.g., (38,39)]. Although blast injury models have been studied in male animals of many species (23,40), there is a near absence of female inclusion in blast models of neurotrauma.…”

Low-level blast exposure induces chronic vascular remodeling, perivascular astrocytic degeneration and vascular-associated neuroinflammation

“…Research in rat models of repetitive low level blast exposure has shown that animals exposed to repetitive low-level blast exhibit chronic cognitive impairment and PTSD-related traits that develop over time [ 30 , 33 , 100 , 101 , 123 ]. These traits include anxiety, enhanced acoustic startle, altered fear learning and impaired cognition in tests such as novel object recognition.…”