Investigating Neuroinflammation and Behavioral Deficits in a Mouse Model of Blast Traumatic Brain Injury

With the escalation of regional conflicts, mild blast traumatic brain injury (bTBI) becomes an increasingly frequent type of injury linked to the development of neuropsychiatric disorders, including anxiety and memory dysfunctions. However, the mechanisms underlying bTBI-induced cognitive impairments remain poorly understood. A growing body of evidence suggests that persistent oxidative stress and chronic neuroinflammation from mild bTBI, even without detectable hemorrhage or tissue loss, may be the key triggers of long-term neurological dysfunction after injury. To fully elucidate these mechanisms, an experimental platform is needed to allow controlled, reproducible investigations into the effects of blast exposure on brain alterations and behavior changes.

This dissertation presents the development of a mouse shock-tube model of mild, repeated bTBI optimized to incorporate the acceleration-deceleration component, and thereby closely mimic real-world injuries experienced by blast injury patients. The model was validated through assessments of animal mortality, coma duration, and neurological severity scores, as well as physical properties including blast wave pressure measurement and 3-D head acceleration. After model establishment, I then employed it to study early oxidative stress and neuroinflammatory responses at acute and subacute stages post-injury in mice. Notably, I identified sex-specific differences in fear-related memory retrieval, neuroinflammation, and blood-brain barrier (BBB) disruption in brain regions susceptible to oxidative damage, suggesting differential biological and behavioral responses to bTBI between males and females. To further study the comorbidity effects of bTBI and chronic alcohol consumption on cognitive outcomes, I combined a voluntary alcohol drinking protocol with bTBI, revealing that alcohol intake following bTBI significantly exacerbates oxidative damage and impairs long-term object recognition memory, likely through neuronal dysfunction.

In summary, this work establishes and applies a clinically relevant mouse bTBI model to link early pathophysiological changes following blast exposure to behavioral and cognitive dysfunction post-bTBI. The mechanistic insight gained by this platform extends our understanding of blast injury etiology and can help identify novel means of mitigating behavioral and cognitive disorders after bTBI.