Augmentation of psychiatric symptom onset vulnerability in male mice due to mild traumatic brain injury

Abstract

Mild traumatic brain injury (mTBI) can induce psychiatric symptoms, including anxiety, depression, and diminished interest. These symptoms can manifest shortly after injury or exhibit delayed onset months or years later, often worsening in severity. Therefore, early intervention and effective treatment are crucial. However, mTBI lacks clear diagnostic markers, making the underlying pathophysiological mechanisms elusive. Additionally, there is a dearth of suitable animal models and a limited understanding of the biochemical changes in the brain that contribute to post-mTBI psychological symptoms. In this study, we hypothesized that mTBI can trigger brain vulnerability mechanisms, which eventually lead to symptom manifestation in response to subsequent stressors. Using a mouse model, we induced very mild blast-induced mTBI without overt trauma or behavioral changes and subsequently subjected the mice to psychological stress. We analyzed the behavioral alterations and gene expression changes in the brain, focusing on microglial and astrocytic markers involved in the immune system and immune responses. The mice exposed to both blast and defeat stress exhibited significantly lower preference scores in the social interaction test than the mice subjected to blast exposure alone, defeat stress alone, or the control condition. Gene expression analysis revealed a distinct set of genes associated with blast exposure during the development of psychiatric symptoms and genes associated with social defeat stress. The results revealed that neither blast exposure nor defeat stress alone significantly affected mouse social behavior; however, their combined influence resulted in noticeable aberrations in social interactions and/or interest. The findings of the present study provide critical insights into the complex interplay between mTBI and psychological stress. Additionally, they provide a novel mouse model for future research aimed at elucidating the pathophysiological mechanisms underlying the psychiatric symptoms associated with mTBI. Ultimately, this knowledge may enhance early intervention and therapeutic strategies for individuals with mTBI-related psychiatric disorders.