Neuroendophenotypes and Risk for Posttraumatic Stress Disorder

描述（申请人提供）：通过研究遗传和早期生活环境的作用，创伤后应激障碍（PTSD）的风险和恢复能力的研究得到了极大的加强。我们小组的研究表明，FKBP5基因的多态性可能与PTSD易感性有关。值得注意的是，创伤后应激障碍不能在没有环境压力源的情况下发展；尤其是生命早期的创伤似乎会成倍地增加PTSD发展的风险。基因与环境相互作用的研究为研究这种疾病的易感性提供了一种合乎逻辑的方法，但为理解这种风险提供了一个不完整的模型。内表型的探索是理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，并且是了解创伤后应激障碍风险的有吸引力的内表型候选者。当看到情绪显著的线索或参与需要注意力的任务时，PTSD患者在涉及认知控制和情绪调节的大脑区域表现出活动的改变，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和杏仁核对涉及注意情绪的任务的反应可能是功能性内表型。连接这些结构的三个白质束（WM）作为候选结构内表型同样是有价值的探索目标，因为这些路径的完整性对于这些不同皮层区域之间的有效通信至关重要。弓形束（AF）、扣带束（CB）、胼胝体（CC）在受虐待儿童和患有PTSD的成人混合人群的研究中被强调。总之，AF、CB和CC中WM完整性的降低似乎代表了理解PTSD遗传风险的重要结构内表型。因此，本研究旨在研究创伤后应激障碍的潜在功能和结构神经内表型。具体来说，我计划研究FKBP5基因状态、童年虐待史和dlPFC、mPFC和杏仁核的神经反应之间的关系（使用功能性MRI），在注意创伤相关线索时具有不同PTSD症状的个体中。我还将研究FKBP5基因状态、儿童虐待史和AF、CB和CC中WM完整性（使用弥散张量成像）与不同PTSD症状个体之间的关系。

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.