Imaging genetics of extinction of conditioned fear responses in anxiety

描述(申请人提供)：难以下调负面情绪是焦虑症的一个显著特征，而厌恶条件反应的消退是焦虑的一个重要模型，可能是这种形式的焦虑相关情绪失调的潜在机制。另一项独立的研究表明，特定基因既与消亡缺陷有关，也与情绪调节的功能神经解剖学有关。具体地说，5-羟色胺转运体启动子基因(5-HTTLPR)与杏仁核大区和情感刺激时嘴前扣带回激活减少有关，DRD4多巴胺受体基因与消退学习有关。对物种灭绝的成像遗传学研究将有助于理解焦虑情绪调节失调和焦虑风险的潜在机制。具体目标：拟议的研究项目将通过评估5-HTTLPR和DRD4基因如何影响先前涉及情绪调节失调和消亡学习的神经回路，来整合这些领域的研究结果。职业发展计划：应聘者的长期目标是成为一名独立的研究人员，在成像、情绪调节遗传学和情感心理病理学领域。拟议的研究和培训活动将集中在三个领域建立专门知识：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。应聘者将与拥有这三个领域专业知识的导师和顾问团队密切合作。除了建议的研究项目外，候选人还将完成正式的课程和基于实验室的培训，以及每个领域由顾问指导的教学。意义：该项目和候选人的后续工作将利用成像遗传学方法的力量，更精确地说明基因调节情绪失调并赋予焦虑和情感性精神病理风险的机制。 公共卫生相关性：我将研究特定基因如何影响焦虑障碍高危个体在试图下调对先前威胁刺激的反应时激活的大脑区域。这些数据将进一步加深我们对与焦虑易感性相关的神经生物学因素的理解，并为确定适当的临床焦虑预防和干预措施提供重要的一步。

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.