Abstract
Repeated mild blast-induced traumatic brain injury (rmbTBI), caused by recurrent exposure to low levels of explosive blast, is a significant concern for military health systems. However, the pathobiology of rmbTBI is currently poorly understood. Animal models are important tools to identify the molecular changes of rmbTBI, but comparisons across different models can present their own challenges. In this study, we compared two well-established rodent models of mbTBI, the “KI model” and the “USU/WRAIR model.” These two models create different pulse forms, in terms of peak pressure and duration. Following single and double exposures to mild levels of blast, we used in situ hybridization (ISH) to assess changes in mRNA levels of tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH2), and galanin in the locus coeruleus (LC) and dorsal raphe nucleus (DRN). These systems and their transmitters are known to mediate responses to stress and anxiety. We found increased mRNA levels of TH, TPH2 and galanin in the LC and DRN of single-exposed rats relative to sham rats in the KI but not the USU/WRAIR model. Sham mRNA values measured in the USU/WRAIR model were substantially higher than their KI counterparts. Double exposure caused similarly significant increases in mRNA values in the KI model but not the USU/WRAIR model, except TPH2 and galanin levels in the DRN. We detected no cumulative effect of injury in either model at the used inter-injury interval (30 min), and there were no detectable neuropathological changes in any experimental group at 1 day post-injury. The apparent lack of early response to injury as compared to sham in the USU/WRAIR model is likely caused by stressors (e.g., transportation and noise), associated with the experimental execution, that were absent in the KI model. This study is the first to directly compare two established rodent models of rmbTBI, and to highlight the challenges of comparing findings from different animal models. Additional studies are needed to understand the role of stress, dissect the effects of psychological and physical injuries and to identify the window of increased cerebral vulnerability, i.e., the inter-injury interval that results in a cumulative effect following repeated blast exposure.
Highlights
Exposure to explosive blast causes a specific form of traumatic brain injury (TBI), termed blast-induced TBI or blast-induced traumatic brain injury (bTBI) [1]
We found that repeated exposure to mild blast overpressure has a cumulative effect on the brain as indicated by both proteomics and diffusion tensor imaging (DTI) [22]
In the dorsal raphe nucleus (DRN) of rats processed for the KI model, an increase in the transcript levels of tryptophan hydroxylase 2 (TPH2) and galanin was observed in the mid/caudal part of the DRN at 1 d post-exposure (Figure 3)
Summary
Exposure to explosive blast causes a specific form of traumatic brain injury (TBI), termed blast-induced TBI or bTBI [1]. PCS can include cognitive impairments, such as problems with memory or concentration, visual disturbances, tinnitus and headaches, as well as mood disorders, such as anxiety or depression, increased irritability or rage [8, 9]. Some of these symptoms are observed in post-traumatic stress disorder (PTSD) that can be caused by exposure(s) to psychological stress without evidence of physical injury [9]. The exact pathobiology of PTSD is currently poorly understood, but alterations in the catecholamine, serotonin, and galanin systems have been implicated in the neurobehavioral abnormalities [10]
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