Genetics of Anxious and Depressive Behaviors

焦虑和抑郁行为的遗传学

• 批准号: 6690703
• 负责人: JUDY L CAMERON
• 金额: $ 55.15万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-16 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690703
• 关键词: Macaca mulatta; amines; anxiety disorders; behavior test; behavioral /social science research tag; behavioral genetics; cerebrospinal fluid; comorbidity; cortisol; depression; genetic polymorphism; genetic screening; genetic susceptibility; genotype; hypothalamic pituitary adrenal axis; linkage mapping; neurogenetics; neuropsychology; phenotype; quantitative trait loci

DESCRIPTION (provided by applicant): The overall goal of this grant, which has been revised for a second time, is to take a novel approach, using a nonhuman primate model, to identify genes that may underlie the development of two common psychiatric illnesses, anxiety and depression. These disorders are common psychiatric illnesses of both childhood and adulthood, that are highly comorbid and strongly aggregate within families, with the same genes affecting liability to both kinds of disorders. The commonness and complex nature of these disorders, however, argue it will be difficult to determine their genetic underpinnings. Special study designs may be required to make serious headway. One such design, proposed here, examines the neurobehavioral genetics of young rhesus monkeys. Specifically, we plan to study the genetic underpinnings of behaviors in rhesus monkeys that parallel several interrelated behavioral and temperamental traits linked to anxiety disorders and depression in humans, including fearfulness, behavioral inhibition, propensity towards distress, and reactivity. In addition, we will evaluate the genetic basis of a physiological attributes associated with anxiety and depression, specifically blunted growth hormone (GH) responsiveness to pharmacological stimulation, activity of the HPA axis, and CSF neurotransmitter levels. This proposal is particularly timely in that increased evidence supporting these behavioral and physiological measures as markers of an underlying predisposition to develop anxiety and depression in humans has recently been published, and we have recently found that in young infant rhesus monkeys there is a strong correlation between low GH responsiveness and behavioral inhibition, and that these measures show a high degree of heritability. The specific aims of the grant include (1) phenotyping a large kindred of rhesus monkeys using four standardized human tests of anxious, fearful and inhibited behaviors, and a clinical protocol for testing GH and CRH responsiveness to stimulation, and measuring CSF monoamine metabolite levels, (2) a genome-wide scan using 300 QTLs, (3) identification of candidate linkage regions, and (4) screening candidate genes. This project has been developed as a collaborative effort between investigators at three institutions, in order to bring together a team with expertise in assessment of nonhuman primate behavior and physiological measurements, QTL analysis in nonhuman primates, and large scale genomics research.

描述（由申请人提供）：该拨款的总体目标已第二次修订，是采用一种新颖的方法，使用非人类灵长类动物模型，来识别可能导致两种常见精神疾病发展的基因，焦虑和抑郁。这些疾病是儿童期和成年期常见的精神疾病，具有高度共病性并且在家庭内强烈聚集，具有影响这两种疾病的易感性的相同基因。然而，这些疾病的普遍性和复杂性表明很难确定其遗传基础。可能需要特殊的研究设计才能取得重大进展。这里提出的一种这样的设计检查了年轻恒河猴的神经行为遗传学。具体来说，我们计划研究恒河猴行为的遗传基础，这些行为与人类焦虑症和抑郁症相关的几种相互关联的行为和气质特征相似，包括恐惧、行为抑制、痛苦倾向和反应性。此外，我们将评估与焦虑和抑郁相关的生理属性的遗传基础，特别是生长激素 (GH) 对药理刺激的反应迟钝、HPA 轴的活动和脑脊液神经递质水平。这项提议特别及时，因为最近发表了越来越多的证据支持这些行为和生理测量作为人类潜在的焦虑和抑郁倾向的标志，而且我们最近发现，在年幼的恒河猴中，两者之间存在很强的相关性。低 GH 反应性和行为抑制，并且这些措施显示出高度的遗传力。该拨款的具体目标包括（1）使用四项针对焦虑、恐惧和抑制行为的标准化人体测试，以及用于测试 GH 和 CRH 对刺激的反应性以及测量 CSF 单胺代谢物水平的临床方案，对一大群恒河猴进行表型分析， (2) 使用 300 个 QTL 进行全基因组扫描，(3) 识别候选连锁区域，以及 (4) 筛选候选基因。该项目是三个机构的研究人员共同努力开发的，目的是汇集在非人类灵长类动物行为和生理测量评估、非人类灵长类动物 QTL 分析和大规模基因组学研究方面具有专业知识的团队。