Neuroendophenotypes and Risk for Posttraumatic Stress Disorder

描述（由申请人提供）：通过研究遗传学和早期生活环境的作用，对创伤后应激障碍（PTSD）的风险和恢复力的研究得到了极大的加强。我们小组的研究表明，FKBP 5基因的多态性可能与PTSD的易感性有关。值得注意的是，PTSD不能在没有环境应激源的情况下发展;特别是早期生活创伤似乎成倍增加PTSD发展的风险。基因与环境相互作用的研究提供了一个合理的方法来调查这种疾病的脆弱性，但提供了一个不完整的模型来理解这种风险。内表型的探索是了解从基因到疾病发生的复杂路径的一种新颖而实用的方法。神经功能模式的特定改变与虐待和创伤后应激障碍有关，并且是理解创伤后应激障碍风险的有吸引力的内表型候选者。当观察情绪突出的线索或从事需要注意的任务时，患有PTSD的个体已经证明了与认知控制和情绪调节有关的大脑区域的活动改变，包括内侧前额叶皮层（mPFC），背外侧前额叶皮层（dlPFC）和杏仁核。神经反应的改变mPFC，dlPFC和杏仁核在涉及注意情绪的任务可能作为功能性内表型。鉴于这些路径的完整性对于这些不同皮质区域之间的有效通信至关重要，连接这些结构的三个白色物质（WM）束同样是作为候选结构内表型进行探索的有价值目标。弓状束（AF）、扣带束（CB）、胼胝体（CC）在受虐待儿童和混合人群的PTSD成人研究中得到了强调。 总的来说，在理解PTSD的遗传风险方面，AF、CB和CC中WM完整性降低似乎代表了重要的结构内表型。因此，拟议的研究旨在检查PTSD的潜在功能和结构神经内表型。具体来说，我计划研究FKBP 5基因状态，童年虐待史和神经反应的dlPFC，mPFC和杏仁核（使用功能性MRI）之间的关联，在注意创伤相关的线索与变量PTSD症状的个体。我还将研究FKBP 5基因状态，儿童虐待史，WM完整性在AF，CB和CC（使用扩散张量成像）在个体变量PTSD症状之间的关联。 公共卫生相关性： 遗传学和早期生活创伤显然是PTSD发展的重要因素，但在PTSD研究中，基因型和表型之间的联系并不简单。对中间生物学因素或内在表型的探索，可以帮助解释从基因到PTSD风险的复杂路径。因此，这项研究旨在调查遗传特征，虐待，神经内表型和PTSD症状之间的关联，以扩大目前关于遗传变异如何导致PTSD脆弱性的科学知识。

DESCRIPTION (provided by applicant): The study of risk and resilience for posttraumatic stress disorder (PTSD) has been greatly enhanced by examining the role of genetics as well as early life environment. Studies from our group indicate that polymorphisms in the FKBP5 gene may be associated with vulnerability for PTSD. Notably, PTSD cannot develop in the absence of an environmental stressor; early life trauma in particular appears to exponentially increase risk for PTSD development. Gene by environment interaction studies have offered a logical approach to investigating vulnerability to this disorder, but offer an incomplete model for understanding this risk. The exploration of endophenotypes is a novel and pragmatic way to understand the complex path from genes to disease occurrence. Specific alterations in patterns of neural function have been associated with maltreatment and PTSD, and are attractive endophenotypic candidates in understanding PTSD risk. When viewing emotionally-salient cues or engaging in tasks that require attention, individuals with PTSD have demonstrated altered activity in brain regions implicated in cognitive control and emotion regulation, including the medial prefrontal cortex (mPFC), the dorsolateral prefrontal cortex (dlPFC), and the amygdala. Alterations in neural response the mPFC, dlPFC and amygdala in response to tasks involving attention to emotion may serve as functional endophenotypes. Three white matter (WM) tracts that connect these structures are likewise valuable targets for exploration as candidate structural endophenotypes, given that the integrity of these paths is critical for efficient communication among these different cortical regions. The arcuate fasciculus (AF) the cingulum bundle (CB), the corpus callosum (CC), have been highlighted in studies of maltreated children and mixed populations of adults with PTSD. Overall, it appears that decreased WM integrity in the AF, CB, and CC represent important structural endophenotypes in understanding genetic risk for PTSD. Thus, the proposed study is designed to examine potential functional and structural neural endophenotypes for PTSD. Specifically, I plan to examine associations among FKBP5 genetic status, childhood maltreatment history and neural response in the dlPFC, mPFC, and amygdala (using functional MRI), in individuals with variable PTSD symptoms during attention to trauma-related cues. I will also examine of associations among FKBP5 genetic status, childhood maltreatment history, and WM integrity in the AF, CB, and CC (using Diffusion Tensor Imaging) in individuals with variable PTSD symptoms. PUBLIC HEALTH RELEVANCE: Genetics and early-life trauma are clearly important contributors to the development of PTSD, but the link between genotype and phenotype is not straightforward in PTSD research. The exploration of intermediate biological factors, or endophenotypes, can help to explain the complex path from genes to PTSD risk. Thus, this study is designed to investigate associations between genetic profiles, maltreatment, neural endophenotypes, and PTSD symptoms as a way to expand current scientific knowledge of how genetic variants contribute to PTSD vulnerability.