Combining mouse and monkey models to understand human risk for psychopathology

描述(由申请人提供)：极端的行为和社会抑制(BI)是人类焦虑症和抑郁症发展的最有希望的预测指标之一，这在成年前就很明显了。对人类和非人类灵长类动物的研究表明，患有极端BI的个体通常会增加与压力相关的系统的反应性，如下丘脑-垂体-肾上腺轴和杏仁核。虽然对BI的认识已经取得了重大进展，但其具体的病理生理机制仍不清楚。使用BI的非人类灵长类动物模型进行的研究是有价值的，因为猴子表现出与人类行为密切相关的气质倾向。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以用来建立假定的新机制，这些机制可以通过使用选择性药物来操纵特定的大脑区域来测试。我们认为，只有结合啮齿动物和非人类灵长类动物模型的优点，才能在理解极端BI的分子基础上取得进一步的进展，以确定参与调节这一早期焦虑和抑郁危险因素的大脑系统和分子机制。我们的实验室在非人类灵长类动物和啮齿动物BI模型方面都有丰富的经验。在我们的恒河猴模型中，存在BI的生理相关性，大脑回路活动的特征样升高模式证明了这一点，包括杏仁核，这预示着高度焦虑的气质。我们的啮齿动物研究选择了表现出类似特质的倾向的大鼠和小鼠，以应对捕食者的暴露，从而为这种表型提供了证据，这种表型与人类发展焦虑和抑郁的风险相似。在这项提案中，我们将使用微阵列技术将两个模式物种的结果结合在一起，以确定与恒河猴和小鼠共有的极端BI气质相关的基因。这种方法的强大之处在于，它将允许我们利用使用老鼠识别感兴趣的基因和执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在老鼠身上识别的基因与灵长类和人类BI相关。需要强调的是，虽然极端BI是与压力相关的精神病理学发展的风险因素，但只有这种气质的一小部分人会发展成精神疾病。因此，我们还将利用小鼠来开始了解与极端BI相关的基因是如何与极端BI个体在暴露于慢性社会压力下时发展精神病理的脆弱性相关的。最终，拟议的研究将提供对高危个体精神病理易感性的机制的洞察。 与公共健康相关：人类研究已经证明，极端行为抑制作为一种气质倾向的重要性，是焦虑症和抑郁症发展的早期脆弱标志。拟议中的实验将结合对行为抑制的青春期小鼠和猴子模型的分子研究，确定调节这种极端气质的新基因系统。最终，这些研究将为调节患焦虑和抑郁障碍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.