Sex-Dependent Effects of Mild Blast-induced Traumatic Brain Injury on Corticotropin-releasing Factor Receptor Gene Expression: Potential Link to Anxiety-like Behaviors

Traumatic brain injury (TBI) affects 1.7 million people in the United States every year, resulting in increased risk of death and disabilities. A significant portion of TBIs experienced by military personnel are induced by explosive blast devices. Active duty military personnel are especially vulnerable to mild blast-induced (mb)TBI and the associated long-term effects, such as anxiety disorders. Additionally, females are at an increased risk of being diagnosed with anxiety-related disorders. The mechanism by which mbTBI results in anxiety disorders in males and females is unknown. The sexually dimorphic corticotropin-releasing factor (CRF) is a brain signaling system linked to anxiety. CRF and its family of related peptides modulate anxiety-related behaviors by binding to CRF receptor subtypes 1 and 2 (CRFR1, CRFR2, respectively). These receptors are distributed throughout limbic structures that control behaviors related to emotion, memory, and arousal. Therefore, the aim of this study was to understand the link between mbTBI and anxiety by examining the impact of mbTBI on the CRFR system in male and female mice. mbTBI increased anxiety-like behaviors in both males and females (p < 0.05). In the present study, mbTBI did not alter CRFR1 gene expression in males or females. However, mbTBI disrupted CRFR2 gene expression in different limbic structures in males and females. In males, mbTBI increased baseline CRFR2 gene expression in the ventral hippocampus (p < 0.05) and decreased restraint-induced expression in the anterior bed nucleus of the stria terminalis (aBNST) and amygdala (p < 0.05). In females, mbTBI decreased restraint-induced CRFR2 gene expression in the dorsal hippocampus (p < 0.05). The inherent sex differences and the mbTBI-induced decrease in restraint-induced CRFR2 gene expression may contribute to anxiety-like behaviors. The results of the present study show that the response to mbTBI within the limbic structures modulates anxiety in a sex-dependent manner. The studies further suggest that CRFR2 may serve as a potential target to mitigate mbTBI effects.