Neuroendophenotypes and Risk for Posttraumatic Stress Disorder

描述(申请人提供)：通过研究遗传学和早期生活环境的作用，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，FKBP5基因的多态可能与创伤后应激障碍的易感性有关。值得注意的是，在没有环境应激源的情况下，创伤后应激障碍无法发展；尤其是早期生活创伤似乎会成倍增加创伤后应激障碍发展的风险。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理的方法，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途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相关，是了解创伤后应激障碍风险的有吸引力的内表型候选。当观看情绪显著的线索或从事需要注意的任务时，PTSD患者在与认知控制和情绪调节有关的大脑区域表现出活动的变化，包括内侧前额叶皮质(MPFC)、背外侧前额叶皮质(DlPFC)和杏仁核。在涉及情绪注意的任务中，mPFC、dlPFC和杏仁核等神经反应的变化可能是功能性内表型。连接这些结构的三条白质(WM)束同样是作为候选结构内表型的有价值的探索目标，因为这些路径的完整性对于这些不同皮质区域之间的有效沟通至关重要。弓状束(AF)，扣带束(CB)，胼胝体(CC)，在虐待儿童和患有创伤后应激障碍的混合人群的研究中被强调。总体而言，房颤、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，这项拟议的研究旨在检查PTSD潜在的功能和结构神经内表型。具体地说，我计划在关注创伤相关线索的过程中，检查FKBP5基因状态、童年虐待史和dlPFC、mPFC和杏仁核(使用功能磁共振)中神经反应之间的关系，这些个体具有不同的PTSD症状。我还将研究FKBP5基因状态、儿童期虐待史和患有不同创伤后应激障碍症状的个体的房颤、CB和CC中的WM完整性之间的关系。 公共卫生相关性： 遗传学和早期创伤显然是创伤后应激障碍发展的重要因素，但在创伤后应激障碍的研究中，基因和表型之间的联系并不直接。对中间生物学因素或内表型的探索有助于解释从基因到创伤后应激障碍风险的复杂途径。因此，这项研究旨在调查遗传特征、虐待、神经内表型和创伤后应激障碍症状之间的关系，以扩大目前关于遗传变异如何导致创伤后应激障碍易感性的科学知识。

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.