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行为和社会抑制（BI），这在成年前很明显。对人类和非人类灵长类动物的研究表明，患有极端BI的个体通常具有压力相关系统（如下丘脑-垂体-肾上腺轴和杏仁核）的反应性增加。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然未知。使用非人类灵长类动物的BI模型进行研究是有价值的，因为猴子表现出的喜怒无常的性格与人类的行为密切相关。然而，由于种种原因，灵长类动物模型并不适合进行深入的机制研究。在这方面，啮齿类动物模型是有利的，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理学药物操纵特定的大脑区域来测试。我们的观点是，要进一步了解极端BI的分子基础，只能通过使用综合的跨物种方法，结合啮齿动物和非人类灵长类动物模型的优势，来确定参与调节焦虑和抑郁发展的早期风险因素的脑系统和分子机制。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，脑回路活动的特征样升高模式（包括杏仁核）证明了BI的生理相关性，这预示着高度焦虑的气质。我们的啮齿动物研究选择了大鼠和小鼠，这些大鼠和小鼠在面对捕食者暴露时表现出类似于极端BI的特征倾向，为一种与人类发展为焦虑和抑郁风险相关的表型提供了证据。在本提案中，我们将使用微阵列技术将两个模型物种的结果结合起来，以鉴定恒河猴和小鼠之间共享的与极端BI气质相关的基因。这种方法的强大之处在于，它将允许我们利用相对容易的方法，使用小鼠来识别感兴趣的基因，并进行机制研究，同时使用灵长类动物的数据来验证小鼠中识别的基因与灵长类动物和人类的BI相关。需要强调的是，虽然极端BI是压力相关精神病理学发展的一个风险因素，但只有一小部分具有这种气质的个体会发展为精神疾病。因此，我们也将使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时产生精神病理的脆弱性相关的。最终提出的研究将提供深入了解的机制，赋予易感性的精神病理在高危个体。

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.