Acute stress modulates the outcome of traumatic brain injury-associated gene expression and behavioral responses

Psychological stress and traumatic brain injury (TBI) result in long-lasting emotional and behavioral impairments in patients. So far, the interaction of psychological stress with TBI not only in the brain but also in peripheral organs is poorly understood. Herein, the impact of acute stress (AS) occurring immediately before TBI is investigated. For this, a mouse model of restraint stress and TBI was employed, and their influence on behavior and gene expression in brain regions, the hypothalamic-pituitary-adrenal (HPA) axis, and peripheral organs was analyzed. Results demonstrate that, compared to single AS or TBI exposure, mice treated with AS prior to TBI showed sex-specific alterations in body weight, memory function, and locomotion. The induction of immediate early genes (IEGs, e.g., c-Fos) by TBI was modulated by previous AS in several brain regions. Furthermore, IEG upregulation along the HPA axis (e.g., pituitary, adrenal glands) and other peripheral organs (e.g., heart) was modulated by AS-TBI interaction. Proteomics of plasma samples revealed proteins potentially mediating this interaction. Finally, the deletion of Atf3 diminished the TBI-induced induction of IEGs in peripheral organs but left them largely unaltered in the brain. In summary, AS immediately before brain injury affects the brain and, to a strong degree, also responses in peripheral organs. Exposure to traumatic brain injury (TBI) results in hematoma formation and immediate early gene (IEG) expression in the brain and peripheral organs. IEG induction and hematoma formation are significantly reduced by pre-exposure to acute restraint stress (AS). This AS-induced reduction of hematoma formation and TBI-induced IEG expression in the periphery are in part dependent on the transcription factor Atf3 (activating transcription factor 3). Additionally, mice demonstrated behavioral alterations following TBI, which were modulated by AS pre-exposure and the Atf3 mutation.image