Neurobiological Correlates of Fear in Veterans with Military Sexual Trauma

描述（由申请人提供）： 暴露于导致极度恐惧，恐怖或无助的创伤事件可能导致焦虑症，如创伤后应激障碍（PTSD），通常与抑郁症并存。经历过军事性创伤（MST）的女性退伍军人特别容易出现各种创伤相关的心理和身体健康问题，包括创伤后应激障碍，抑郁，焦虑，慢性疼痛，睡眠障碍，药物滥用，广泛的身体症状和负面健康行为。个体患者表现出不同症状群的程度可能不同，因此“一刀切”的治疗往往是不够的。这种个体差异可能与增加对疾病的脆弱性或阻碍治疗的生物风险因素有关。虽然神经生物学因素（例如，激素，基因组学）相互作用，以增加个人的风险发展创伤后应激障碍，目前还不清楚如何潜在的神经生物学是由这些因素形成，导致观察到的失调。创伤后应激障碍的特征是边缘系统的皮质控制受损，特别是杏仁核和海马体。无论创伤类型如何，恐惧条件反射方法都提供了强大的基于大脑的PTSD风险表型，因为它在平民和战斗PTSD人群中都有观察到。拟议的研究将利用这一可观察到的标志物和MST女性的个体差异来研究PTSD的神经生物学基础以及这种表型预测治疗反应的实用性。使用最先进的分子遗传学方法，结合对恐惧回路的机械理解，将为个体在创伤风险和恢复力方面的差异提供巨大的洞察力。将使用经验证的恐惧增强惊吓范式观察恐惧反应，该范式允许研究者评估条件性恐惧反应的获得、消退和恢复。将通过测量纳入本研究的女性退伍军人人群中的雌激素变化来研究激素对恐惧反应增强的贡献。ADCYAP1R1基因编码垂体腺苷酸环化酶激活多肽（PACAP）的1型受体（PAC1），是创伤后妇女PTSD相关的主要候选基因之一。这种遗传多态性是使用假设中性的基因组收敛方法确定的，但此后在几个不同的PTSD研究人群中被复制。拟议的项目将包括检查PAC1基因型，甲基化状态，mRNA表达和雌激素变化对PTSD症状表达的影响，以及在未充分研究的女性退伍军人人群中进行恐惧和焦虑的实验室测量。最后，我们将评估神经生物学指标的预测性质，包括在 建议的工作，因为他们涉及创伤后应激障碍的治疗结果在创伤恢复计划在亚特兰大VAMC。

DESCRIPTION (provided by applicant): 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.