Developmental effects of 5-HTT genotype on stress reactivity and brain function

5-HTT 基因型对应激反应和脑功能的发育影响

• 批准号: 7799722
• 负责人: Moriah E Thomason
• 金额: $ 4.85万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-03 至 2011-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799722
• 关键词: 11 year old; 16 year old; Adolescent; Adrenal Glands; Adult; Affect; Alleles; Anxiety Disorders; Area; Autistic Disorder; Behavioral; Biological; Biological Markers; Brain; Brain imaging; Brain region; Cerebrum; Characteristics; Child; Data; Development; Diffusion Magnetic Resonance Imaging; Disease; Drug Addiction; Emotional; Emotions; Event; Exhibits; Face; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Homeostasis; Hydrocortisone; Hypothalamic structure; Knowledge; Life; Link; Measures; Mental Depression; Mental disorders; Neuraxis; Neurons; Neurophysiology - biologic function; Neurotransmitters; Participant; Patient Self-Report; Perfusion; Phenotype; Pituitary Gland; Post-Traumatic Stress Disorders; Process; Promoter Regions; Psychopathology; Public Health; Recovery; Research; Rest; Serotonin; Stimulus; Stress; Structure; System; Variant; age group; aging gene; base; biological adaptation to stress; emotion regulation; emotional stimulus; gray matter; hypothalamic-pituitary-adrenal axis; indexing; morphometry; neural patterning; neuroimaging; psychologic; relating to nervous system; response; serotonin transporter; theories; white matter

DESCRIPTION (provided by applicant): Serotonin (5-HT) is a key modulatory neurotransmitter in the central nervous system. Early perturbations in the 5-HT system can have widespread and long-lasting behavioral effects. Disrupted 5-HT homeostasis has been implicated in the development of psychiatric disorders such as depression, anxiety disorders, drug addiction, and autism. Despite the successful characterization of the brain phenotype associated with the allele structure of the serotonin transporter (5-HTT) gene (SLC6A4) in adults, little is known about the developmental emergence of these phenotypes or about how these features interact with HPA function. The primary goal of the proposed study, therefore, is to explore characteristics of brain structure and function that are associated with genetic polymorphisms in a promoter region (5-HTTLPR) of the 5-HTT gene in children and adolescents. Given the relation between these polymorphisms and subsequent disorder, a secondary goal is to examine the possible relations among biological stress reactivity (indexed by cortisol response to stress) genotype, and measures of brain structure and function. The proposed research will combine self-report measures, neuroimaging assessments, indicators of HPA-axis functioning and reactivity, and genotyping to examine children's and adolescents' emotion regulation and reactivity to negative and/or threatening stimuli. Three specific aims are proposed: 1) to examine whether genetic variation in the serotonin transporter gene is associated with developmental changes in brain structure; 2) to examine whether genotype moderates patterns of neural activation within brain regions that are involved in the processing of emotional material in children and adolescents; and 3) to examine stress reactivity in children and adolescents with different variants of the serotonin transporter gene. Participants in the proposed project will be 30 normally developing children between 9 and 11 years of age and 30 adolescents between 14 and 16 years of age. This project has significant relevance to public health. Genetic polymorphisms in the 5-HTT gene have been linked to morphological and functional changes in the adult brain that are similar to those that have been found to be associated with various forms of psychopathology (e.g., depression, anxiety disorder, post-traumatic stress disorder). By increasing our knowledge of the development of these anomalies, and by also integrating neural and cortisol measures with behavioral data, the proposed studies will provide a stronger scientific basis for understanding and integrating psychological, biological, and genetic aspects of the development of psychopathology.

5-羟色胺（5-HT）是中枢神经系统中一种重要的调节神经递质。5-羟色胺系统的早期扰动可以产生广泛和持久的行为影响。5-羟色胺稳态的破坏与精神疾病的发展有关，如抑郁症、焦虑症、药物成瘾和自闭症。尽管成功表征了成人5-羟色胺转运体（5-HTT）基因（SLC6A4）等位基因结构相关的脑表型，但对这些表型的发育出现或这些特征如何与HPA功能相互作用知之甚少。因此，本研究的主要目标是探索儿童和青少年中与5-HTT基因启动子区域（5-HTTLPR）遗传多态性相关的大脑结构和功能特征。考虑到这些多态性与随后的疾病之间的关系，第二个目标是检查生物应激反应（由皮质醇对应激的反应索引）基因型与大脑结构和功能测量之间的可能关系。该研究将结合自我报告测量、神经影像学评估、hpa轴功能和反应性指标以及基因分型来检查儿童和青少年的情绪调节和对消极和/或威胁刺激的反应。提出了三个具体目标：1)研究5 -羟色胺转运体基因的遗传变异是否与大脑结构的发育变化有关；2)研究基因型是否会调节儿童和青少年参与情绪材料加工的大脑区域内的神经激活模式；3)检测血清素转运体基因不同变异的儿童和青少年的应激反应。计划的参加者为30名9至11岁的正常发育儿童和30名14至16岁的青少年。这一项目对公共卫生具有重大意义。5-HTT基因的遗传多态性与成人大脑的形态和功能变化有关，这些变化与已发现的各种形式的精神病理（如抑郁症、焦虑症、创伤后应激障碍）有关。通过增加我们对这些异常发展的认识，并通过将神经和皮质醇测量与行为数据相结合，拟议的研究将为理解和整合精神病理学发展的心理、生物学和遗传学方面提供更强大的科学基础。

项目成果

Neural and behavioral responses to threatening emotion faces in children as a function of the short allele of the serotonin transporter gene.

• DOI: 10.1016/j.biopsycho.2010.04.009
• 发表时间: 2010-09
• 期刊: BIOLOGICAL PSYCHOLOGY
• 影响因子: 2.6
• 作者: Thomason, Moriah E.;Henry, Melissa L.;Hamilton, J. Paul;Joormann, Jutta;Pine, Daniel S.;Ernst, Monique;Goldman, David;Mogg, Karin;Bradley, Brendan P.;Britton, Jennifer C.;Lindstrom, Kara M.;Monk, Christopher S.;Sankin, Lindsey S.;Louro, Hugo M. C.;Gotlib, Ian H.
• 通讯作者: Gotlib, Ian H.