Wild-derived zebrafish as models for anxiety and stress responsiveness

描述(申请人提供)：焦虑症是美国疾病的主要原因之一，但其起源以及个体的基因与环境相互作用影响疾病的方式仍鲜为人知。这些研究的长期目标是更好地了解焦虑和压力反应变异的遗传和神经生物学基础。这项工作将采用斑马鱼模型，但创新的重点是最近从野生种群中提取的鱼类。这些野生来源的个体的价值在于，相对于已建立的实验室种群，它们表现出的与焦虑相关的行为水平更高，变化更大。这个探索性项目的具体目标是首先比较两个野生斑马鱼品系大脑中的基因表达谱，这些斑马鱼品系在表现焦虑相关行为方面存在差异(分别为高和低)和两个已建立的也显示行为变异的实验室品系。野生的斑马鱼品系在其他模型系统中表现出被称为“主动性”和“反应性”的应对方式，而且雌性斑马鱼表现出更高水平的焦虑相关行为，也存在明显的性别差异。这些研究的第二个目标是比较这两个不同的野生来源系在从早期发育到成熟后的时间点大脑中的基因表达谱，此时焦虑相关行为的性别差异已经出现。第二个目标是开始探索成人应对方式差异的发展根源。该项目的好处应该包括斑马鱼模型系统的行为和神经基因组特征，这将导致斑马鱼的机械学研究，并可能在人类关联研究中研究已确定的候选基因。斑马鱼模型系统也特别适合于研究焦虑相关行为的基因组和发育基础，以及这些机制受到生物体环境影响的方式。 公共卫生相关性： 这个项目以斑马鱼为模型系统，研究焦虑相关行为的遗传和发育起源。焦虑症很普遍，因此是一个重大的公共卫生问题，给美国人民带来了严重的疾病和经济负担。

DESCRIPTION (provided by applicant): Anxiety disorders are among the leading causes of illness in the U.S., yet their origins and the way in which an individual's genotype interacts with the environment to influence disease remain poorly understood. The long-term goal of these studies is to better understand the genetic and neurobiological underpinnings of variation in anxiety and stress-responsiveness. This work will employ the zebrafish model, but with an innovative focus on fish recently derived from wild stocks. The value of these wild-derived individuals is in the heightened levels and greater variation in anxiety-related behaviors they display relative to an established laboratory stocks. The specific goals of this exploratory project are first to compare gene expression profiles in the brains of two wild-derived zebrafish lines divergent in the display of anxiety-related behavior (high and low respectively) to two established laboratory lines that also show behavioral variation. The wild-derived zebrafish lines exhibit what have been termed 'proactive' and 'reactive' coping styles in other model systems and also pronounced sex differences with females exhibiting higher levels of anxiety-related behavior. The second goal of these studies is to compare gene expression profiles in the brain between the two divergent wild-derived lines at time points ranging from early development until after maturation when sex differences in anxiety-related behaviors have emerged. The goal of this second aim is to begin exploring the developmental origins of coping style differences in adulthood. The benefits of this project should include behavioral and neurogenomic characterization of a zebrafish model system that will lead to mechanistic studies in zebrafish and potentially studies of identified candidate genes in human association studies. The zebrafish model system is also particularly well suited to studying the genomic and developmental underpinnings of anxiety-related behaviors and the ways in which these mechanisms are influenced by an organism's environment. PUBLIC HEALTH RELEVANCE: This project addresses the genetic and developmental origins of anxiety-related behaviors using the zebrafish as a model system. Anxiety disorders are prevalent and therefore represent a significant public health issue imposing significant illness and economic burdens on the U.S. population.