Imaging genetics of extinction of conditioned fear responses in anxiety

描述（由申请人提供）：难以下调负面情绪是焦虑障碍的一个显著特征，而长期以来作为焦虑重要模型的负面条件反应的消退受损，可能是这种焦虑相关情绪失调形式的潜在机制。另一项研究表明，特定的基因与消退缺陷和情绪调节的功能神经解剖学有关。具体来说，5-羟色胺转运蛋白启动子基因（5-HTTLPR）与情感挑战期间的大杏仁核和吻侧前扣带激活减少有关，DRD4多巴胺受体基因与灭绝学习有关。对消退的成像遗传学研究将有助于理解焦虑和焦虑风险中影响失调的机制。具体目的：拟议的研究项目将通过评估5-HTTLPR和DRD4基因如何影响神经回路来整合这些领域的发现，这些神经回路先前与焦虑风险人群的情绪失调和消退学习有关。职业发展规划：候选人的长期目标是成为情绪调节和情感精神病理学成像遗传学领域的独立研究者。拟议的研究和培训活动将集中在三个领域建立专业知识：1)作为焦虑模型的条件反射，2)情感相关特征的遗传学和成像遗传学，以及3)进一步发展先前建立的神经成像技能。候选人将与具有这三个领域专业知识的导师和顾问团队密切合作。除了拟议的研究项目外，候选人还将完成正式的课程和实验室培训，以及每个领域的指导教学。意义：本项目和候选人的后续工作将利用成像遗传学方法的力量，更精确地指定基因调节情绪失调的机制，并赋予焦虑和情感性精神病理学的风险。

DESCRIPTION (provided by applicant): Difficulty down-regulating negative affect is a prominent feature of anxiety disorders and impairment in the extinction of an aversively-conditioned response, long an important model of anxiety, is a likely mechanism underlying this form of anxiety-related emotion dysregulation. A separate line of inquiry has indicated that specific genes are associated with both extinction deficits and the functional neuroanatomy of emotion regulation. Specifically the serotonin transporter promoter gene (5-HTTLPR) is associated with greater amygdala and reduced rostral anterior cingulate activation during affective challenge and the DRD4 dopamine receptor gene has been linked with extinction learning. Imaging genetics studies of extinction will be useful for understanding the mechanisms underlying affect dysregulation in anxiety and risk for anxiety. SPECIFIC AIMS: The proposed research project will integrate findings from these domains by assessing how the 5-HTTLPR and DRD4 genes influence neural circuitry previously implicated in emotion dysregulation and extinction learning in a sample of those at risk for anxiety. CAREER DEVELOPMENT PLAN: The candidate's long term goal is to become an independent investigator in the area of imaging genetics of emotion regulation and affective psychopathology. The proposed research and training activities will focus on building expertise in three domains: 1) conditioning as a model for anxiety, 2) genetics and imaging genetics of affect-related traits, and 3) further development of previously established neuroimaging skills. The candidate will work closely with a team of mentors and consultants with expertise spanning these three domains. In addition to the proposed research project, the candidate will complete formal coursework and lab-based training, along with advisor-directed didactics in each area. SIGNIFICANCE: This project and the candidate's subsequent work will utilize the power of the imaging genetics approach to more precisely specify the mechanisms via which genes modulate emotion dysregulation and confer risk for anxiety and affective psychopathology. PUBLIC HEALTH RELEVANCE: I will examine how specific genes influence brain regions activated when attempting to down- regulate responses to previously threatening stimuli among individuals at risk for anxiety disorders. These data will further our understanding of neurobiological factors associated with vulerability to anxiety and provide an important step toward identifying appropriate prevention and intervention measures for clinical anxiety.