Timing matters: Sex differences in inflammatory and behavioral outcomes following repetitive blast mild traumatic brain injury.

BACKGROUND: Repetitive blast-related mild traumatic brain injury (mTBI) caused by exposure to high explosives is increasingly common among warfighters as well as civilians. While women have been serving in military positions with increased risk of blast exposure since 2016, there are few published reports examining sex as a biological variable in models of blast mTBI, greatly limiting diagnosis and treatment capabilities. As such, here we examined outcomes of repetitive blast trauma in female and male mice in relation to potential behavioral, inflammatory, microbiome, and vascular dysfunction at multiple timepoints. METHODS: In this study we utilized a well-established blast overpressure model to induce repetitive (3x) blast-mTBI in both female and male mice. Acutely following repetitive exposure, we measured serum and brain cytokine levels, blood-brain barrier (BBB) disruption, fecal microbial abundance, and locomotion and anxiety-like behavior in the open field assay. At the one-month timepoint, in female and male mice we assessed behavioral correlates of mTBI and PTSD-related symptoms commonly reported by Veterans with a history of blast-mTBI using the elevated zero maze, acoustic startle, and conditioned odorant aversion paradigms. RESULTS: Repetitive blast exposure resulted in both similar (e.g., increased IL-6), and disparate (e.g., IL-10 increase only in females) patterns of acute serum and brain cytokine as well as gut microbiome changes in female and male mice. Acute BBB disruption following repetitive blast exposure was apparent in both sexes. While female and male blast mice both exhibited acute locomotor and anxiety-like deficits in the open field assay, only male mice exhibited adverse behavioral outcomes that lasted at least one-month. DISCUSSION: Representing a novel survey of potential sex differences following repetitive blast trauma, our results demonstrate unique similar yet divergent patterns of blast-induced dysfunction in female vs. male mice and highlight novel targets for future diagnosis and therapeutic development.

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

BACKGROUND: Mild traumatic brain injury (mTBI) is common in civilians and highly prevalent among military service members. mTBI can increase health risk behaviors (e.g., sensation seeking, impulsivity) and addiction risk (e.g., for alcohol use disorder (AUD)), but how mTBI and substance use might interact to promote addiction risk remains poorly understood. Likewise, potential differences in single vs. repetitive mTBI in relation to alcohol use/abuse have not been previously examined. METHODS: Here, we examined how a history of single (1×) or repetitive (3×) blast exposure (blast-mTBI) affects ethanol (EtOH)-induced behavioral and physiological outcomes using an established mouse model of blast-mTBI. To investigate potential translational relevance, we also examined self-report responses to the Alcohol Use Disorders Identification Test-Consumption questions (AUDIT-C), a widely used measure to identify potential hazardous drinking and AUD, and used a novel unsupervised machine learning approach to investigate whether a history of blast-mTBI affected drinking behaviors in Iraq/Afghanistan Veterans. RESULTS: Both single and repetitive blast-mTBI in mice increased the sedative properties of EtOH (with no change in tolerance or metabolism), but only repetitive blast potentiated EtOH-induced locomotor stimulation and shifted EtOH intake patterns. Specifically, mice exposed to repetitive blasts showed increased consumption "front-loading" (e.g., a higher rate of consumption during an initial 2-h acute phase of a 24-h alcohol access period and decreased total daily intake) during an intermittent 2-bottle choice condition. Examination of AUDIT-C scores in Iraq/Afghanistan Veterans revealed an optimal 3-cluster solution: "low" (low intake and low frequency), "frequent" (low intake and high frequency), and "risky" (high intake and high frequency), where Veterans with a history of blast-mTBI displayed a shift in cluster assignment from "frequent" to "risky," as compared to Veterans who were deployed to Iraq/Afghanistan but had no lifetime history of TBI. CONCLUSIONS: Together, these results offer new insight into how blast-mTBI may give increase AUD risk and highlight the increased potential for adverse health risk behaviors following repetitive blast-mTBI.