Combining mouse and monkey models to understand human risk for psychopathology

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因素之一是极端的行为和社会抑制（BI），这在成年前是明显的。在人类和非人类灵长类动物中的研究表明，患有极端BI的个体通常会增加应激相关系统的反应性，例如下丘脑-垂体-肾上腺轴和杏仁核。虽然在理解BI方面取得了重大进展，但其具体的病理生理机制仍不清楚。使用非人类灵长类动物BI模型的研究是有价值的，因为猴子表现出与人类行为密切相关的气质。然而，由于各种原因，灵长类动物模型并不适合进行深入的机制研究。在这方面，啮齿动物模型是有利的，因为分子和遗传方法可用于建立推定的新机制，其可通过施用选择性药理学试剂操纵特定脑区域来测试。我们的论点是，只有通过使用综合的跨物种方法，结合啮齿动物和非人灵长类动物模型的优势，才能在理解极端BI的分子基础方面取得进一步进展，以确定参与介导焦虑和抑郁发展的早期风险因素的大脑系统和分子机制。我们的实验室在非人灵长类动物和啮齿类动物BI模型方面拥有丰富的经验。在我们的恒河猴模型中，存在BI的生理相关性，如通过脑回路活动的特征样升高模式所证明的，所述脑回路活动包括预测高度焦虑气质的杏仁核。我们的啮齿类动物研究选择了表现出类似特质倾向的大鼠和小鼠，以应对捕食者暴露，为与人类发展焦虑和抑郁风险相关的表型提供了证据。在这个提议中，我们将使用微阵列技术将两个模型物种的结果结合在一起，以识别与恒河猴和小鼠之间共享的极端BI气质相关的基因。这种方法的强大之处在于，它将使我们能够利用使用小鼠识别感兴趣的基因并进行机理研究的相对容易性，同时使用灵长类动物的数据来验证在小鼠中识别的基因与灵长类动物和人类BI相关。重要的是要强调，虽然极端BI是发展与压力相关的精神病理学的风险因素，但只有一部分具有这种气质的人会发展为精神疾病。因此，我们也将使用小鼠来开始了解被鉴定为与极端BI相关的基因如何与极端BI个体在暴露于慢性社会压力时发展精神病理学的脆弱性相关。最终，拟议的研究将提供深入了解的机制，赋予易感性的精神病理学在风险个人。 公共卫生相关性：人类研究已经证明了极端行为抑制作为一种气质的重要性，它是焦虑症和抑郁症发展的早期脆弱性标志。拟议中的实验将通过结合对我们的青春期小鼠和猴子行为抑制模型的分子研究来确定介导这种极端气质的新基因系统。最终，这些研究将为介导焦虑和抑郁症风险的大脑机制提供新的见解。

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.