Exposure to a traumatic event that causes extreme fear, horror or helplessness can lead to anxiety disorders, such as posttraumatic stress disorder (PTSD), which can often be co-morbid with depression. Female Veterans who experienced Military Sexual Trauma (MST) are particularly at risk for a wide range of trauma- related mental and physical health problems including PTSD, depression, anxiety, chronic pain, sleep disturbances, substance abuse, wide-ranging physical symptoms, and negative health behaviors. Individual patients can vary in the degree to which they present with the different symptom clusters, such that a one size fits all treatment is often inadequate. This individual variation may be associated with biological risk factors that increase vulnerability to the disorder or impede treatment. While neurobiological factors (e.g., hormones, genomics) interact to increase an individual's risk of developing PTSD, it is unclear how the underlying neurobiology is shaped by these factors to result in the observed dysregulations. PTSD is marked by impaired cortical control of the limbic system, specifically the amygdala and hippocampus. Fear conditioning approaches have provided robust brain-based phenotypes of PTSD risk regardless of trauma type, as it is observed in both civilian and combat PTSD populations. The proposed study will capitalize on this observable marker and individual variability among women with MST to investigate the neurobiological underpinnings of PTSD as well as the utility of this phenotype to predict treatment response. Using state-of-the art molecular-genetic approaches with a mechanistic understanding of fear circuitry will offer tremendous insight into individual differences in risk and resilience to traum. Fear responses will be observed using a validated fear-potentiated startle paradigm that allows investigators to assess the acquisition, extinction, and return of conditioned fear responses. Hormonal contributions to heightened fear responding will be investigated by measuring estrogen variation in the female Veteran population to be included in this study. The ADCYAP1R1 gene, which codes for the type 1 receptor (PAC1) for pituitary adenylate cyclase activating polypeptide (PACAP) is one of the leading candidate genes related to PTSD in traumatized women. This genetic polymorphism was identified using a hypothesis neutral genomic convergence approach, but has since been replicated in several different PTSD study populations. The proposed project will include the examination of PAC1 genotype, methylation status, mRNA expression, and estrogen variation on PTSD symptom expression as well as laboratory measures of fear and anxiety in an understudied population of female Veterans. Lastly, we will evaluate the predictive nature of the neurobiological indices to be included in the proposed work as they relate to PTSD treatment outcome within the Trauma Recovery Program at the Atlanta VAMC.

Public Health Relevance

Exposure to traumatic events can result in posttraumatic stress disorder (PTSD), a highly debilitating and complex disorder frequently co-morbid with many medical and psychiatric illnesses. Understanding the biological mechanisms underlying this disorder will provide improved tools for targeting symptoms that are specific to PTSD and predicting positive treatment outcomes. The goal of this proposal is to combine clinical psychopathology research and basic neuroscience research to inform the development of novel and effective approaches for personalized treatment of PTSD. PTSD symptom severity in female Veterans is often exacerbated by a history of interpersonal trauma in childhood and as adults, yet this population is largely understudied. The increasing numbers of female Veterans means that advancing our knowledge of the potential neuroendocrine and genetic factors influencing PTSD risk versus resilience is essential to the mission of the VHA.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Mental Health and Behavioral Science A (MHBA)
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Veterans Health Administration
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Michopoulos, Vasiliki; Norrholm, Seth Davin; Jovanovic, Tanja (2015) Diagnostic Biomarkers for Posttraumatic Stress Disorder: Promising Horizons from Translational Neuroscience Research. Biol Psychiatry 78:344-53
Glover, Ebony M; Jovanovic, Tanja; Norrholm, Seth Davin (2015) Estrogen and extinction of fear memories: implications for posttraumatic stress disorder treatment. Biol Psychiatry 78:178-85