Mild traumatic brain injury (mTBI) has been a major cause of morbidity in the wars in Iraq and Afghanistan. In both theatres of operation, blast exposure has been the most common cause of TBI. One striking feature of the clinical presentations of OIF/OEF veterans with mTBI is the prominence of post-traumatic stress disorder (PTSD). Indeed the high prevalence of PTSD and depression in returning OIF/OEF veterans with mTBI is well documented and distinction between the two disorders has proven clinically challenging. The association between PTSD and mTBI might be explained by co-incident exposures to TBI events and PTSD stressors. However, an alternative hypothesis that we have been exploring is that blast-related mTBI damages brain structures that are important in mediating responses to psychological stressors and thus enhances the likelihood of developing PTSD. In collaboration with a Department of Defense investigator, Dr. Stephen Ahlers, we have been studying a rat model of blast injury that mimics mTBI. We have found that animals tested several months post-exposure exhibit PTSD-related traits including increased acoustic startle, increased anxiety, an altered response to a predator scent challenge and an increased cued response in a fear conditioning paradigm. These observations suggest that blast exposure in the absence of any psychological trauma induces PTSD related traits that are chronic and persistent. Dr. Ahlers has found that plasma corticosterone levels become elevated after blast exposure and that these levels remain high for at least one month. PTSD is commonly thought to result from an abnormal and prolonged stress response with abundant evidence suggesting that abnormalities in the hypothalamic/pituitary/adrenal axis are chronically present. These observations have lead us to postulate that blast injury to the brain induces a chronic state of stress that even in the absence of any psychological trauma produces PTSD-related traits and exaggerated responses to subsequent PTSD-related stressors. Here we will examine whether stress responses in the brain are chronically altered by exposure to blast injury and determine whether treatment with a glucocorticoid receptor antagonist is able to block the development of or reverse PTSD-related behavioral traits. We will also examine whether blast injury induces structural effects in the medial prefrontal cortex, amygdala and hippocampus, the principal anatomic substrates that are thought to underlie the neurobiological basis of PTSD. These studies will further understanding of the relationship of blast injury to PTSD related traits and will have implications for designing treatment strategies for veterans who have suffered blast induced mTBIs.

Public Health Relevance

Mild traumatic brain injury (mTBI) has been common in the wars in Iraq and Afghanistan. In both theatres of operation, blast exposure has been the most common cause of TBI. The high prevalence of post-traumatic stress disorder (PTSD) in returning OIF/OEF veterans with mTBI is well documented and the distinction between the two disorders has proven clinically challenging. Here we will determine whether blast injury creates chronic stress-related changes in the neuroendocrine axis and explore the molecular and anatomic basis for PTSD related traits seen in a rat model of blast-induced mTBI. These studies will further understanding of the relationship of blast injury to PTSD related traits and will have implications for designing treatment strategies for veterans who have suffered blast induced mTBIs.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01RX000996-05
Application #
9643881
Study Section
Brain Health & Injury (RRD1)
Project Start
2014-02-01
Project End
2018-09-30
Budget Start
2018-02-01
Budget End
2018-09-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
James J Peters VA Medical Center
Department
Type
DUNS #
040077133
City
Bronx
State
NY
Country
United States
Zip Code
10468
Perez-Garcia, Georgina; Gama Sosa, Miguel A; De Gasperi, Rita et al. (2018) Chronic post-traumatic stress disorder-related traits in a rat model of low-level blast exposure. Behav Brain Res 340:117-125
Perez-Garcia, Georgina; De Gasperi, Rita; Gama Sosa, Miguel A et al. (2018) PTSD-Related Behavioral Traits in a Rat Model of Blast-Induced mTBI Are Reversed by the mGluR2/3 Receptor Antagonist BCI-838. eNeuro 5:
Agoston, Denes; Arun, Peethambaran; Bellgowan, Patrick et al. (2017) Military Blast Injury and Chronic Neurodegeneration: Research Presentations from the 2015 International State-of-the-Science Meeting. J Neurotrauma 34:S6-S17
Gama Sosa, Miguel A; De Gasperi, Rita; Perez Garcia, Georgina S et al. (2017) Lack of chronic neuroinflammation in the absence of focal hemorrhage in a rat model of low-energy blast-induced TBI. Acta Neuropathol Commun 5:80
Cernak, Ibolja; Stein, Donald G; Elder, Gregory A et al. (2017) Preclinical modelling of militarily relevant traumatic brain injuries: Challenges and recommendations for future directions. Brain Inj 31:1168-1176
Zhao, Wei; Ho, Lap; Wang, Jun et al. (2016) In Silico Modeling of Novel Drug Ligands for Treatment of Concussion Associated Tauopathy. J Cell Biochem 117:2241-8
Gama Sosa, Miguel A; De Gasperi, Rita; Hof, Patrick R et al. (2016) Fibroblast growth factor rescues brain endothelial cells lacking presenilin 1 from apoptotic cell death following serum starvation. Sci Rep 6:30267
Perez-Garcia, Georgina; Gama Sosa, Miguel A; De Gasperi, Rita et al. (2016) Exposure to a Predator Scent Induces Chronic Behavioral Changes in Rats Previously Exposed to Low-level Blast: Implications for the Relationship of Blast-Related TBI to PTSD. Front Neurol 7:176
Haghighi, Fatemeh; Ge, Yongchao; Chen, Sean et al. (2015) Neuronal DNA Methylation Profiling of Blast-Related Traumatic Brain Injury. J Neurotrauma 32:1200-9
Elder, Gregory A (2015) Update on TBI and Cognitive Impairment in Military Veterans. Curr Neurol Neurosci Rep 15:68

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