Central and Peripheral Nervous System Sequelae Following Blast Exposures: A Multi-Organ System Analysis of a Complex Full-Body Injury

Abstract

Many injuries have the capacity to impact the entire body, even if the inciting incident was something seemingly localized to one body part, like a concussion, it can affect the whole-body. Injuries sustained following exposure to blast overpressure (such as in the case of exposure to improvised explosive devices (IED), industrial explosions, etc.) are unique due to their mechanism of action in that they do not just start in one location and spread to the rest of the body but occur as the result of the overpressure wave hitting the entire body at approximately the same time. Thus, the focus of my dissertation was to examine the impact of blast injuries on the entire body. I accomplished this by 1) using our mouse model of blast injuries to gain further insight into a clinical disorder seen in a large portion of Veterans with a history of symptomatic blast exposure 2) analyze higher level cognitive functioning following blast exposure at a chronic time point and 3) analyzing a broad range of central and peripheral biological markers and behavioral changes in both male and female mice at multiple timepoints following blast exposures. Taken together, these experiments detail a full-body sequelae that often co-occurs with blast-induced mild traumatic brain injuries (mTBI) A common theme of the study results presented in this dissertation is the finding that traumatic brain injury (TBI) resulting from exposure to blast overpressure waves can occur without any additional physical impact to the skull and can be particularly detrimental to functioning. In the studies done in male mice only, blast mice expressed increased motivation for food reward, cognitive inflexibility, and increased alcohol intake patterns related to risky alcohol consumption, the latter of which mimicked risky drinking behaviors in male Veterans with a history of blast mTBI diagnosis. When analyzing both sexes, both males and females exhibited changes in pro- and anti-inflammatory cytokine expression and gut microbiome flora (some changes were similar and others dissimilar) with specific bacteria tracking with increased blood-brain barrier permeability and adverse behavioral outcomes following repetitive blast, suggesting potential targets for downstream diagnosis and therapeutic development. Chronic deficits in PTSD-related phenotypes occurred only in males at the chronic timepoint examined and in a separate set of experiments Therefore, this dissertation demonstrates that the impact of a blast exposure can be seen across a broad range of behaviors and blast injuries can have a negative impact on multiple different systems in the body, from the brain, to vasculature structure, circulating chemokines, to the gut microbiome.