Previous exposure to traumatic brain injury alters acute stress responses in mice

Acute stress (AS) exposure and traumatic brain injury (TBI) have a high prevalence and result in emotional and behavioral impairments. In fact, TBI is a leading cause of mortality in young adults and survivors cope with neuropsychological sequelae including memory decline, addiction, anxiety and compromised stress responses. So far, the interaction of psychological stress with previous TBI is poorly understood. Herein, the impact of a previous TBI on AS responsiveness was investigated. For this, a model of mild TBI and restraint AS was employed and mice were grouped into sham, TBI alone, AS alone and TBI + AS cohorts. The impact of an initial TBI on subsequent AS was analyzed by immediate early gene (IEG) and neuroinflammatory gene expression as well as proteomics. In addition, behavioral consequences were monitored by open field, ladder walk and the Catwalk gait analysis. Finally, since both TBI and AS impinge on hypothalamus-pituitary-adrenal (HPA) axis regulation, CORT and ACTH levels were measured. We observed that some AS associated responses such as gene induction in the brain and HPA axis were largely unaffected by TBI occurring one day before AS exposure. In contrast, on the behavioral level, several AS associated locomotor alterations were modulated post-TBI. Hormone levels of the HPA axis were likewise modulated by the TBI and AS interaction. Finally, blood-derived proteomics identified proteins regulated by individual exposures as well as by the TBI and AS interaction. In summary, we demonstrate that previous TBI affects responsiveness to AS exposure on behavioral level and HPA axis regulation.