Brain Mechanisms Mediating Genetic Risk Factors for Anxiety and Depression

描述（由申请人提供）：焦虑和情感障碍构成了一组常见的异质性疾病，并显示出显着的遗传性。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，但没有明确的答案。这些疾病发展的最突出的儿童风险因素之一是行为抑制（BI），这是一种以极端害羞和抑制为特征的气质，以应对新的情况或陌生人。使用年轻的恒河猴，我们已经开发了一个模型，这是类似于儿童BI，并已证明，猴子BI的个体差异是显着遗传。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BI，相关的生理参数和功能性脑活动在一个大的多代恒河猴谱系。这些表型将被用于全基因组连锁分析，以研究焦虑和抑郁的大脑机制的遗传基础。通过将复杂疾病遗传学研究的成熟方法与中间脑反应性表型的同时分析相结合，我们使用年轻恒河猴的新策略将：1）鉴定影响BI的新基因，2）定量遗传变异对情绪神经回路反应性个体差异的影响，和3）确定参与介导BI个体差异和情绪相关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中不可行。拟议的实验提供了一个宝贵的机会，以确定新的遗传因素，在人类焦虑和情感障碍的发展中发挥重要作用，结果将立即相关的儿童在精神病理学的发展风险。焦虑和情感障碍是一组可以遗传的精神疾病。以年轻的恒河猴为研究对象，本研究将：1）识别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）确定参与介导行为抑制个体差异和情绪相关脑回路反应性增加的特定基因。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重要作用的遗传因素，结果将立即相关的儿童在精神病理学的发展风险。

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.