Profiling the Heterogeneous Outcomes of Blast Trauma and Substance Use in Translational Mouse Models

Abstract

There is a complicated and bidirectional relationship between stress and substance use. Individuals who are diagnosed with a psychiatric disorder and a substance use disorder (SUD) tend to have a higher number of symptoms, more severe symptoms, decreased quality of life, and less responsiveness to treatment. Traumatic brain injury (TBI) is a unique form of stress in that it has both physical and psychological components. The most common type of TBI is mild TBI (mTBI), representing nearly 75% of all TBI diagnoses. Despite the label of “mild,” mTBI can result in behavioral and physiological symptoms that develop acutely and persist for years after the initial injury. Individuals who have a history of TBI show elevated rates of various substance use disorders, including alcohol, opioids, nicotine, cannabis, and psychostimulants. The Veteran population has a higher risk of psychiatric disorders and hazardous substance use, particularly alcohol, due to the frequency of exposure to traumatic events. Exposure to blast overpressure waves is the primary source of mTBI in military service members, and also commonly results in PTSD and chronic pain. Effective treatments and personalized clinical guidance is critical to improving outcomes for individuals experiencing comorbid stress and substance use disorders. Preclinical animal models are a valuable method for improving our understanding of the relevant mechanisms underlying the pathophysiological progression; however, there is currently a translatability crisis, in which potential treatments that have been effective in animal models are not effective in clinical trials. Therefore, it is critical to utilize translationally-relevant preclinical models and embrace the heterogeneity that they capture. The aim of this dissertation was to understand substance use patterns, stress and anxiety-like behavior, blast trauma, and the relationship between them in translational mouse models. First, I demonstrated the value of our novel Socially Integrated Polysubstance (SIP) system and the insights that it provides into individual intake patterns in group-house male and female mice. Again using the SIP system, I next quantified alcohol and opioid polysubstance use patterns in group-house male and female mice. Based on differences in behavioral phenotypes, I identified three clusters of mice with distinct alcohol and opioid dose preference and polysubstance use patterns. Building upon this, I used the SIP system to investigate how repetitive blast trauma influences various alcohol drinking patterns, as well as the chronic outcomes after blast trauma and alcohol use. This experiment revealed that only certain alcohol drinking patterns are predictive of biological outcomes and there are differential effects of repetitive blast exposure and chronic alcohol intake on glymphatic function and brain glucose metabolism. In the discussion, I consider various experimental parameters that are critical to designing translationally-relevant preclinical animal models. Finally, I cogitate on a number of future experiments that are still needed to help refine treatment options and identify therapeutic or lifestyle interventions at multiple stages of progression for individuals with comorbid stress and hazardous substance use.