Neurobiological Correlates of Fear in Veterans with Military Sexual Trauma

退伍军人恐惧与军事性创伤的神经生物学相关性

• 批准号: 10097951
• 负责人: LORI L. DAVIS
• 金额: --
• 依托单位: TUSCALOOSA VETERANS AFFAIRS MEDICAL CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10097951
• 关键词: Acoustics; Adult; Afghanistan; Alleles; Amygdaloid structure; Anxiety; Anxiety Disorders; Base of the Brain; Biological; Biological Markers; Candidate Disease Gene; Caring; Childhood; Clinical; Code; Complex; DNA Methylation; Development; Diagnosis; Disease; Endocrine; Epigenetic Process; Estrogens; Exposure to; Extinction (Psychology); Female; Fright; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Risk; Genomics; Genotype; Goals; Health behavior; Hippocampus (Brain); Hormonal; Hormones; Impairment; Individual; Individual Differences; Intervention; Iraq; Knowledge; Laboratories; Lead; Limbic System; Measures; Mediating; Medical; Mental Depression; Mental Health; Mental disorders; Methylation; Military Personnel; Mission; Molecular Genetics; Nature; Neurobiology; Neurosciences Research; Neurosecretory Systems; Patients; Phenotype; Physiological; Population; Post-Traumatic Stress Disorders; Prediction of Response to Therapy; Psychopathology; Psychophysiology; Recording of previous events; Regulation; Research; Research Personnel; Risk; Risk Factors; Severities; Sex Differences; Sleep disturbances; Startle Reaction; Substance abuse problem; Symptoms; Trauma; Trauma recovery; Treatment outcome; Variant; Veterans; Woman; Work; base; chronic pain; combat; comorbid depression; comorbidity; conditioned fear; disorder risk; experience; genetic approach; health administration; improved; indexing; individual patient; individual variation; insight; mRNA Expression; novel; operation; outcome prediction; personalized approach; personalized medicine; physical conditioning; physical symptom; pituitary adenylate cyclase activating polypeptide; prognostic; programs; public health relevance; receptor; resilience; response; sexual assault; sexual trauma; study population; symptom cluster; symptomatology; tool; traumatic event

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.

描述（由申请人提供）： 暴露于引起极端恐惧，恐怖或无助的创伤事件会导致焦虑症，例如创伤后应激障碍（PTSD），通常可以与抑郁症共处。经历了军事性创伤（MST）的女性退伍军人尤其面临各种相关的与精神和身体健康问题的风险，包括PTSD，抑郁症，焦虑，慢性疼痛，睡眠障碍，滥用药物，身体症状广泛，身体症状广泛和负面健康行为。个别患者可以随着不同症状簇的呈现程度而变化，因此“一种适合所有尺寸”的治疗通常不足。该个体变异可能与增加疾病脆弱性或阻碍治疗的生物危险因素有关。尽管神经生物学因素（例如，激素，基因组学）相互作用以增加个人患PTSD的风险，但尚不清楚这些因素如何塑造基本神经生物学，从而导致观察到的失调。 PTSD的标志是边缘系统的皮质控制受损，特别是杏仁核和海马。恐惧调节方法为PTSD风险提供了强大的基于大脑的表型，无论创伤类型如何，在平民和战斗PTSD种群中都可以观察到。拟议的研究将利用MST的女性可观察到的标记和个人变异性，以研究PTSD的神经生物学基础以及该表型的实用性以预测治疗反应。使用最先进的分子遗传学方法和对恐惧回路的机械理解将提供对风险和对创伤的韧性的个体差异的深刻见解。恐惧反应将使用经过验证的恐惧感激发范式观察到，该范式允许调查人员评估条件恐惧反应的获取，灭绝和返回。通过测量将包括在本研究中的女性退伍军人人群中的雌激素变异来研究荷尔蒙对加剧恐惧反应的贡献。 ADCYAP1R1基因编码为1型受体（PAC1）的垂体腺苷酸环化酶激活多肽（PACAP）是与创伤女性中与PTSD相关的主要候选基因之一。使用假说中性基因组收敛方法鉴定出这种遗传多态性，但此后在几个不同的PTSD研究人群中得到了复制。拟议的项目将包括对PTSD症状表达的PAC1基因型，甲基化状态，mRNA表达和雌激素变化的检查，以及在女性退伍军人研究不足的人群中的恐惧和焦虑量。最后，我们将评估神经生物学指数的预测性质 拟议的工作与亚特兰大VAMC的创伤恢复计划中的PTSD治疗结果有关。