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

描述（由申请人提供）：5-羟色胺（5-HT）是中枢神经系统中的关键调节性神经递质。5-HT系统的早期扰动可能具有广泛和持久的行为影响。5-HT体内平衡的破坏与精神疾病如抑郁症、焦虑症、药物成瘾和自闭症的发展有关。尽管成功表征了与成人5-羟色胺转运体（5-HTT）基因（SLC 6A 4）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，本研究的主要目的是探索儿童和青少年5-HTT基因启动子区（5-HTTLPR）基因多态性相关的脑结构和功能特征。考虑到这些多态性和随后的疾病之间的关系，第二个目标是研究生物应激反应（由皮质醇对应激的反应指数）基因型之间的可能关系，以及大脑结构和功能的测量。拟议的研究将结合联合收割机自我报告的措施，神经影像学评估，HPA轴功能和反应性的指标，基因分型，以检查儿童和青少年的情绪调节和反应的负面和/或威胁性刺激。提出了三个具体目标：1）检查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）检查基因型是否调节儿童和青少年参与情绪材料处理的大脑区域内的神经激活模式;以及3）检查具有不同5-羟色胺转运体基因变体的儿童和青少年的应激反应。拟议项目的参与者将包括30名9至11岁发育正常的儿童和30名14至16岁的青少年。该项目对公共卫生具有重要意义。5-HTT基因中的遗传多态性与成人大脑中的形态和功能变化有关，这些变化与已发现与各种形式的精神病理学相关的变化相似（例如，抑郁症、焦虑症、创伤后应激障碍）。通过增加我们对这些异常发展的了解，并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心理，生物和遗传方面的精神病理学发展提供更强有力的科学基础。

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.