Combining mouse and monkey models to understand human risk for psychopathology

结合小鼠和猴子模型来了解人类的精神病理学风险

• 批准号: 8047063
• 负责人: Ned H Kalin
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047063
• 关键词: Adolescence; Adolescent; Adult; Affect; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Behavior; Behavioral; Behavioral inhibition; Brain; Brain region; Chronic; Chronic stress; Data; Depressive disorder; Development; Ensure; Gene Chips; Genes; Genetic; Genome; Goals; Human; Human Development; Individual; Laboratories; Macaca mulatta; Maps; Mediating; Mental Depression; Methods; Microarray Analysis; Modeling; Molecular; Molecular Genetics; Monkeys; Mus; Pattern; Phenotype; Physiological; Population; Positron-Emission Tomography; Predisposition; Primates; Principal Investigator; Psychopathology; Publishing; RNA; Rattus; Relative (related person); Risk; Risk Factors; Rodent; Rodent Model; Role; Staging; Stress; System; Temperament; Testing; Tissue Extracts; Tissues; base; brain tissue; cohort; experience; high risk; hypothalamic-pituitary-adrenal axis; in vivo; insight; interest; mouse model; neural circuit; nonhuman primate; novel; programs; research study; resilience; response; social; social stress; time use; trait

DESCRIPTION (provided by applicant): One of the most promising predictors of the development of human anxiety disorders and depression is extreme behavioral and social inhibition (BI) which is evident prior to adulthood. Studies in human and nonhuman primates demonstrate that individuals with extreme BI commonly have increased reactivity of stress-related systems such as the hypothalamic-pituitary-adrenal axis and the amygdala. While significant advances have been made in understanding BI, its specific pathophysiological mechanisms remain unknown. Studies using non-human primate models of BI are valuable because monkeys display a temperamental disposition that closely maps onto human behavior. However, for various reasons, primate models are not ideal for performing in-depth mechanistic studies. In this regard, rodent models are advantageous as molecular and genetic approaches can be used to establish putative novel mechanisms which can be tested by manipulating specific brain regions with the administration of selective pharmacological agents. It is our contention that further progress in understanding the molecular basis of extreme BI can only be achieved by using an integrative, cross species approach that combines the advantages of both the rodent and non-human primate models to identify brain systems and molecular mechanisms involved in mediating this early risk factor for the development of anxiety and depression. Our laboratory has extensive experience with both non-human primate and rodent models of BI. In our rhesus monkey model there is a physiological correlate of BI as evidenced by a trait-like elevated pattern of brain circuit activity that includes the amygdala that is predictive of a highly anxious temperament. Our rodent studies selecting rats and mice that display a trait-like disposition to engage in extreme BI in response to predator exposure, provide evidence for a phenotype that is analogous to that associated with the human risk to develop anxiety and depression. In this proposal, we will bring together results from both model species using microarray technology to identify genes that are associated with the extreme BI temperament that are shared between rhesus monkeys and mice. The power of this approach is that it will allow us to exploit the relative ease of using mice to identify genes of interest and to perform mechanistic studies while at the same time using data from primates to verify that the genes identified in mice are relevant to primate and human BI. It is important to underscore that while extreme BI is a risk factor for the development of stress-associated psychopathology, only a subset of individuals with this temperament will develop psychiatric illnesses. Therefore, we will also use mice to begin to understand how the genes identified as being associated with extreme BI are related to the vulnerability of extreme BI individuals to develop psychopathology when exposed to chronic social stress. Ultimately the proposed studies will provide insight into the mechanisms that confer susceptibility to psychopathology in at-risk individuals. PUBLIC HEALTH RELEVANCE: Human studies have demonstrated the importance of extreme behavioral inhibition as a temperamental disposition that serves as an early vulnerability marker for the development of anxiety disorders and depression. The proposed experiments will identify novel genes systems that mediate this extreme temperament by combining molecular studies on our adolescent mouse and monkey models of behavioral inhibition. Ultimately, these studies will provide new insights into brain mechanisms mediating the risk to develop anxiety and depressive disorders.

描述（由申请人提供）：人类焦虑症和抑郁症发展的最有希望的预测指标之一是极端的行为和社会抑制（BI），这是在成年之前明显的。对人类和非人类灵长类动物的研究表明，具有极端BI的个体通常具有与压力相关系统（如下丘脑 - 垂体 - 肾上腺轴和杏仁核）的反应性增加。尽管在理解BI方面已经取得了重大进展，但其特定的病理生理机制仍然未知。使用非人类BI的非人类灵长类动物模型的研究很有价值，因为猴子表现出一种密切映射到人类行为的气质性格。但是，由于各种原因，灵长类动物模型并不是进行深入机理研究的理想选择。在这方面，啮齿动物模型是有利的，因为可以使用分子和遗传方法来建立假定的新型机制，可以通过使用选择性药理剂来操纵特定的大脑区域来测试这些机制。我们的论点是，只有使用综合性的跨物种方法，才能实现进一步的进步，以结合啮齿动物和非人类灵长类动物模型的优势来识别脑系统和介导这种早期危险因素的焦虑和抑郁症的危险因素，从而实现了极端BI的分子基础。我们的实验室在BI的非人类灵长类动物和啮齿动物模型中都有丰富的经验。在我们的恒河猴模型中，BI存在生理相关性，这是由特征样的脑电路活动模式提高的，其中包括杏仁核，可预测高度焦虑的气质。我们的啮齿动物研究选择大鼠和小鼠，这些大鼠和小鼠表现出类似性状的性格，以响应捕食者暴露，从而提供了与与人类发展焦虑和抑郁症相关的表型的证据。在此提案中，我们将使用微阵列技术从两种模型物种中汇总出与恒河猴和小鼠之间共享的极端性气质相关的基因。这种方法的力量是，它将使我们能够利用使用小鼠来识别感兴趣的基因并进行机械研究的相对容易，同时使用灵长类动物的数据来验证小鼠中鉴定出的基因是否与灵长类动物和人类BI相关。重要的是要强调，尽管极限BI是发展与压力相关的心理病理学发展的危险因素，但只有这种气质患者的一部分才会发展出精神病。因此，我们还将使用小鼠开始了解与极端BI相关的基因如何与极端BI个人在暴露于慢性社会压力时发展心理病理学的脆弱性有关。最终，拟议的研究将提供对赋予高危个体心理病理易感性的机制的见解。 公共卫生相关性：人类研究表明，极端行为抑制作用是一种气质倾向的重要性，它是焦虑症和抑郁症发展的早期脆弱性标记。提出的实验将通过在行为抑制的青少年小鼠和猴子模型上结合分子研究来识别介导这种极端气质的新型基因系统。最终，这些研究将提供有关介导焦虑和抑郁症风险的大脑机制的新见解。