Repetitive Blast Promotes Chronic Aversion to Neutral Cues Encountered in the Peri-Blast Environment

Abstract

Repetitive mild traumatic brain injury (mTBI) has been called the "signature injury" of military Servicemembers in the Iraq and Afghanistan wars and is highly comorbid with posttraumatic stress disorder (PTSD). Correct attribution of adverse blast-induced mTBI and/or PTSD remains challenging. Preclinical research using animal models can provide important insight into the mechanisms by which blast produces injury and dysfunction-but only to the degree by which such models reflect the human experience. Avoidance of trauma reminders is a hallmark of

Repetitive blast mild traumatic brain injury increases ethanol sensitivity in male mice and risky drinking behavior in male combat veterans

“…Previous work in animal models supports the notion of brain injury as a risk factor for adverse health risk behaviors, including substance misuse/abuse (Cernak et al, 2001;Lim et al, 2015;Lowing et al, 2014;Muelbl et al, 2018;Nawarawong et al, 2019;Perez-Garcia et al, 2019;Schindler et al, 2017;Schindler et al, 2020;Vonder Haar et al, 2019). Indeed, using our established mouse model of blast exposure (Huber et al, 2013;Logsdon et al, 2020;Meabon et al, 2016;Schindler et al, 2017;Schindler et al, 2020), we previously demonstrated increased novelty-seeking behavior at acute (7 days) and chronic (1 month) time points following injury (Schindler et al, 2017). Likewise, increased risk-like behavior has also been reported following mild impact TBI (Krukowski et al, 2020;Mouzon et al, 2014).…”

“…The blast overpressure (BOP) peak intensity (psi), initial pulse duration (ms), and impulse (psi▪ms) used were in keeping with mild blast TBI (19.9 psi +/− 0.14 psi) [32]. Under these experimental conditions, the overall survival rate exceeded 95%, with blast-exposed mice appearing comparable to sham-exposed mice by inspection 2-4 h postblast exposure as previously reported (Huber et al, 2013;Logsdon et al, 2020;Meabon et al, 2016;Schindler et al, 2017;Schindler et al, 2020).…”

“…All animal experiments were carried out in accordance with Association for Assessment and Accreditation of Laboratory Animal Care guidelines and were approved by the VA Puget Sound Institutional Animal Care and Use Committees. The shock tube (Baker Engineering and Risk Consultants) was designed to generate blast overpressures that mimic open-field high explosive detonations encountered by military service members in combat, and the design and modeling characteristics have been described in detail elsewhere (Huber et al, 2013;Logsdon et al, 2020;Meabon et al, 2016;Schindler et al, 2017;Schindler et al, 2020). Briefly, mice were anesthetized with isoflurane (induced at 5% and maintained at 2-3%), secured against a gurney, and placed into the shock tube oriented perpendicular to the oncoming blast wave (ventral body surface toward blast).…”

“…All behavioral tests were conducted starting at 1 month postsham/ blast exposure, a time point that allows for the development of blastinduced neuropathology (Goldstein et al, 2014;Rubovitch et al, 2011) and that correlates to a time period where enduring functional and behavioral deficits are detected (Schindler et al, 2017;Schindler et al, 2020). Separate groups of mice were used for EtOH locomotor stimulation, EtOH sedation, and voluntary EtOH consumption (see below for specific details of each procedure).…”

“…Using an electronically controlled pneumatic shock tube that models battlefield-relevant open-field blast forces generated by detonation of high explosives (Huber et al, 2013;Logsdon et al, 2020;Meabon et al, 2016;Schindler et al, 2017;Schindler et al, 2020), we found that while both single and repetitive blast exposure increased the sedative properties of high-dose EtOH (with no change in tolerance nor metabolism), only repetitive blast exposure resulted in potentiation of EtOH-induced locomotor stimulation and a shift in EtOH intake patterns (i.e., increased consumption "front-loading" and decreased total daily intake) during intermittent 2-bottle choice (2BC). Next, we examined self-report responses to the Alcohol Use Disorders Identification Test-Consumption Questions (AUDIT-C; a widely used measure to identify risky drinking and potential AUD) (Bush et al, 1998;Crawford et al, 2013;Dawson et al, 2005) in male OEF/OIF/OND Veterans and used a novel unsupervised machine learning approach to investigate whether a history of repetitive blast exposure and mTBI affected drinking behaviors.…”