Brain Mechanisms Mediating Genetic Risk Factors for Anxiety and Depression

介导焦虑和抑郁遗传风险因素的大脑机制

• 批准号: 7688670
• 负责人: Ned H Kalin
• 金额: $ 113.99万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-17 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688670
• 关键词: Accounting; Affective; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Base of the Brain; Behavior; Behavioral; Behavioral inhibition; Brain; Brain region; Candidate Disease Gene; Cerebrospinal Fluid; Child; Childhood; Clinical; Complex; Corticotropin-Releasing Hormone; DNA; Data; Deoxyglucose; Development; Disease; Emotions; Environmental Risk Factor; Functional Imaging; Functional disorder; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Heritability; Human; Human Development; Image; Individual; Individual Differences; Inherited; Lesion; Link; Macaca mulatta; Maps; Measures; Mediating; Mental disorders; Meta-Analysis; Methods; Modeling; Monkeys; Mood Disorders; Neuropeptides; Parents; Pattern; Phenotype; Physiological; Physiology; Play; Population; Prefrontal Cortex; Primates; Process; Psychopathology; Quantitative Trait Loci; Resolution; Risk; Risk Factors; Rodent; Role; Sampling; Scanning; Shyness; Structure of terminal stria nuclei of preoptic region; Study Subject; System; Time; Variant; Work; base; behavior influence; biological adaptation to stress; brain behavior; depression; expectation; genetic linkage analysis; genetic pedigree; genetic risk factor; interest; morphometry; neural circuit; novel; novel strategies; promoter; public health relevance; research study; response; serotonin transporter; stressor; trait

DESCRIPTION (provided by applicant): Anxiety and affective disorders constitute a group of heterogeneous illnesses that are common and show significant heritability. Considerable work has focused on identifying the genes involved in anxiety and affective disorders providing interesting leads, but no definitive answers. One of the most prominent childhood risk factors for the development of these illnesses is behavioral inhibition (BI), a temperamental disposition characterized by extreme shyness and inhibition in response to novel situations or strangers. Using young rhesus monkeys, we have developed a model that is analogous to childhood BI and have demonstrated that individual differences in monkey BI are significantly heritable. In addition, we have used functional imaging to identify the brain regions associated with BI. In this project we will measure BI, associated physiological parameters, and functional brain activity in a large multi-generation pedigree of rhesus monkeys. These phenotypes will be used in whole genome linkage analyses to investigate the genetic basis of brain mechanisms underlying anxiety and depression. By combining proven approaches to the study of the genetics of complex disease with simultaneous analysis of intermediate brain reactivity phenotypes, our novel strategy using young rhesus monkeys will: 1) identify novel genes that influence BI, 2) quantitate the influence of genetic variation on individual differences in reactivity of the neurocircuitry underlying emotion, and 3) determine specific genes that are involved in mediating both individual differences in BI and increased reactivity of emotion-related brain circuits. These studies are not feasible in rodent species or humans. The proposed experiments provide an invaluable opportunity to identify novel genetic factors that play a major role in the development of human anxiety and affective disorders, results that will be immediately relevant to children at risk for the development of psychopathology. PUBLIC HEALTH RELEVANCE Anxiety and affective disorders constitute a group of mental illnesses that can be inherited. Using young rhesus monkeys as subjects, this study will: 1) identify genes that influence behavioral inhibition, 2) quantitate the influence of genetic variation on individual differences in reactivity of emotion-related brain circuits, and 3) determine specific genes that are involved in mediating both individual differences in behavioral inhibition and increased reactivity of emotion-related brain circuits. The proposed experiments provide an invaluable opportunity to identify genetic factors that play a major role in the development of human anxiety and affective disorders, results that will be immediately relevant to children at risk for the development of psychopathology.

描述(由申请人提供)：焦虑和情感障碍构成了一组不同的疾病，这些疾病很常见，并显示出显著的遗传性。相当多的工作集中在确定与焦虑和情感障碍有关的基因上，提供了有趣的线索，但没有确定的答案。导致这些疾病发生的最突出的童年风险因素之一是行为抑制(BI)，这是一种气质倾向，特征是对新情况或陌生人做出极端害羞和抑制的反应。利用年轻的恒河猴，我们开发了一个类似于童年BI的模型，并证明了猴子BI的个体差异是显著可遗传的。此外，我们还使用功能成像来识别与BI相关的大脑区域。在这个项目中，我们将测量一个大型多世代恒河猴家系的BI、相关的生理参数和脑功能活动。这些表型将被用于全基因组连锁分析，以研究焦虑和抑郁背后的大脑机制的遗传基础。通过将成熟的复杂疾病遗传学研究方法与大脑中间反应性表型的同步分析相结合，我们使用年轻恒河猴的新策略将：1)识别影响BI的新基因，2)量化遗传变异对潜在情绪神经回路反应性个体差异的影响，3)确定参与调节BI个体差异和情绪相关大脑回路反应性增加的特定基因。这些研究在啮齿类动物或人类身上是不可行的。拟议的实验提供了一个宝贵的机会来确定在人类焦虑和情感障碍的发展中发挥主要作用的新的遗传因素，这些结果将立即与处于精神病理学发展风险中的儿童相关。与公共健康相关的焦虑和情感障碍构成了一组可遗传的精神疾病。以幼年恒河猴为研究对象，本研究将：1)确定影响行为抑制的基因，2)量化遗传变异对情绪相关脑回路反应性个体差异的影响，3)确定参与调节行为抑制个体差异和情绪相关脑回路反应性增强的特定基因。拟议的实验提供了一个宝贵的机会，以确定在人类焦虑和情感障碍的发展中发挥主要作用的遗传因素，这些结果将立即与处于精神病理学发展风险中的儿童相关。