Sex Dependent Effects of Mild Brain Blast Injury on Neuroendocrine Stress Response

Presentation Number: MON 366
Date of Presentation: April 3rd, 2017

Ashley Lynn Russell*1, Elizabeth Shupe2, Robert J Handa3 and T John Wu4
1Uniformed Services University of the Health Sciences, 2Uniformed Services University of the Health Sciences, Bethesda, MD, 3Colorado State University, Fort Collins, CO, 4Uniformed Services University, Bethesda, MD


Approximately 1.5 million civilian and military personnel are diagnosed each year with traumatic brain injury (TBI). 15-30% of soldiers who experience TBI have a comorbid diagnosis of neuropsychiatric disorders such as PTSD. TBI results in peripheral and central nervous system dysregulation. The HPA axis, the major regulator of the neuroendocrine stress response, releases corticotropin releasing factor (CRF) from the paraventricular nucleus of the hypothalamus (PVN) to ultimately result in glucocorticoid (CORT) release from the adrenals. CRF is highly expressed in the PVN and in stress-related limbic structures. These limbic structures, specifically the amygdala, prefrontal cortex and hippocampus, are involved in fear and anxiety regulation. TBI results in alterations in these limbic structures and dysregulation of the HPA stress response. Males are more likely to experience TBI; however, females are more likely to develop neuropsychiatric disorders as a result. In order to assess HPA dysregulation after TBI, male and female C57BL/6J mice were exposed to mild (15 psi) brain blast injury utilizing the ORA Advanced Blast Simulator. Animals that received blast injury had increased restraint-induced serum CORT compared to sham animals one day post injury (p<0.05). Blast injured females had increased restraint-induced CORT compared to blast injured males (p<0.05), showing a heightened dysregulation of the stress response in females as a result of injury. Using the fear conditioning paradigm, a model of PTSD-like symptoms, TBI resulted in altered fear acquisition (p<0.05) and decreased fear extinction (p<0.05). Therefore, TBI animals are quicker to develop the fear response but are less capable of extinguishing the fear behavior. Non-injured male and female CRF:tdTomato mice were utilized to examine restraint-induced neuronal activation in all CRF populations. Restraint increased CRF-cFOS colocalization (neuronal activation) in all animals (p<0.05). Current results show that CRF restraint-induced neuronal activation is heightened in females compared to males (p<0.05) with no difference in regards to female estrous cycle stage. Current studies are underway to examine anatomical changes in injured male and female animals. Overall, we demonstrate that blast-induced TBI results in HPA axis dysregulation with a heightened female response. This may be attributed to underlying anatomical CRH stress reactivity and projection integrity alterations that may result in the detrimental fear- and anxiety-related behavioral phenotypes observed after mTBI. These results allow for the beginning of a targeted approach to treatment that may improve the detrimental anxiety disorders observed after TBI.


Nothing to Disclose: ALR, ES, RJH, TJW