Imaging genetics of extinction of conditioned fear responses in anxiety

焦虑中条件性恐惧反应消失的影像遗传学

• 批准号: 7893407
• 负责人: Christine L Larson
• 金额: $ 16.52万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893407
• 关键词: Affect; Affective; Alleles; Amygdaloid structure; Anterior; Anxiety; Anxiety Disorders; Area; Brain; Brain region; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Conditioned Stimulus; Cues; DRD4 gene; Data; Development; Development Plans; Dopamine Receptor; Down-Regulation; Emotions; Extinction (Psychology); Functional Magnetic Resonance Imaging; Genes; Genetic; Genotype; Goals; Image; Impairment; Individual; Link; Measures; Mentors; Modeling; Neuroanatomy; Neurobiology; Participant; Patients; Pattern; Prefrontal Cortex; Preventive Intervention; Process; Psychopathology; Receptor Gene; Regulation; Research; Research Personnel; Research Project Grants; Research Training; Risk; Sampling; Specific qualifier value; Stimulus; Training; Training Activity; Variant; Work; base; career development; clinical anxiety; conditioned fear; conditioning; emotion regulation; emotional stimulus; learning extinction; meetings; neural circuit; neuroimaging; neuromechanism; promoter; public health relevance; relating to nervous system; response; serotonin transporter; skills; trait; valylvaline

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.

描述（由申请人提供）：难以下调负面情绪是焦虑症的一个显着特征，并且厌恶条件反应的消退受到损害，长期以来一直是焦虑的重要模型，是这种形式的焦虑相关的可能机制。情绪失调。另一项研究表明，特定基因与消退缺陷和情绪调节的功能神经解剖学相关。具体而言，血清素转运蛋白启动子基因 (5-HTTLPR) 与大杏仁核和情感挑战期间头侧前扣带回激活减少有关，而 DRD4 多巴胺受体基因与消退学习有关。灭绝的影像遗传学研究将有助于理解焦虑影响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 基因如何影响先前与焦虑风险样本中的情绪失调和消退学习有关的神经回路，来整合这些领域的发现。职业发展计划：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侧重于建立三个领域的专业知识：1）作为焦虑模型的调节，2）情感相关特征的遗传学和影像遗传学，以及3）进一步发展先前建立的神经影像技能。候选人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。除了拟议的研究项目之外，候选人还将完成正式的课程作业和基于实验室的培训，以及每个领域的顾问指导的教学。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，更精确地确定基因调节情绪失调并赋予焦虑和情感精神病理学风险的机制。 公共健康相关性：我将研究当试图下调有焦虑症风险的个体对先前威胁性刺激的反应时，特定基因如何影响激活的大脑区域。这些数据将进一步加深我们对与焦虑脆弱性相关的神经生物学因素的理解，并为确定临床焦虑的适当预防和干预措施提供重要一步。