Using sticklebacks as a model for identifying genes related to risk- taking behav

描述（由申请人提供）：尽管对个人和社会有明显的成本，对健康也很重要，但我们对冒险行为的病因学知之甚少。基因组学上易于处理的动物模型的可用性将加速理解影响自残倾向、暴力和寻求感觉行为的遗传和环境因素的进展。我们的长期目标是开发棘鱼（Gasterosteus aculeatus）作为模型系统，以了解基因如何与环境相互作用，影响行为。本申请的总体目标是识别和测试潜在的风险行为自然变异的候选基因和途径。我们的中心假设是，有遗传和环境反应基因影响刺鱼的冒险行为，这些基因与其他动物，包括人类共享。提出的研究的基本原理是，一种无偏见的方法来研究从事冒险行为的倾向的自然变异，这种行为既基于遗传又对环境敏感，很可能会识别出与人类健康相关的候选基因。识别风险行为背后的基因通路将有助于NIH的使命，即通过帮助精神药理学的努力来治疗和诊断人类的外化障碍，从而改善国民的健康。在强有力的初步数据的指导下，这一假设将通过追求三个具体目标进行检验：1）识别与个体和群体之间冒险行为差异相关的基因; 2）识别对不利环境条件做出反应的冒险行为背后的基因; 3）在复制群体中测试与冒险行为相关的候选基因。在目标1下，将使用全基因组表达微阵列比较风险倾向与风险厌恶个体的基因表达谱。在第二个目标下，暴露于压力环境的个体的行为和基因表达将与无压力的同类进行比较。这两个压力源是缺乏父母照顾，这对该物种的冒险行为有重要影响，并在发育过程中暴露于捕食者。在目标3下，将在独立的重复群体中检测目标1和2的良好候选基因。这个及时的项目利用了一种生物体的新基因组信息的可用性，这种生物体具有良好的描述和迷人的行为库，直到最近才免于分子解剖。这项工作的关键创新之处在于，它利用遗传和环境变异来源来识别候选基因，并利用刺鱼独特的进化历史以重复的方式测试生物医学相关的假设。 拟议中的研究使用一种新的动物模型来解决有关对健康产生不良后果的行为起源的基本问题。这些研究对理解人类精神病理学的病因学具有潜在的应用价值。这项拟议中的研究与公共卫生有关，因为它将为人类行为障碍的诊断和治疗提供候选基因和途径。

DESCRIPTION (provided by applicant): Despite the obvious costs to individuals and society and importance for health, we know relatively little about the etiology of risk-taking behaviors. Progress toward understanding the genetic and environmental factors influencing the propensity to engage in self-harm, violence and sensation seeking behaviors will be hastened by the availability of a genomically tractable animal model. Our long term goal is to develop stickleback fish (Gasterosteus aculeatus) as a model system to understand how genes interact with the environment to influence behaviors. The overall objective of this application is to identify and test candidate genes and pathways underlying natural variation in risk-taking behaviors. Our central hypothesis is that there are inherited and environmentally-responsive genes that affect risk-taking behaviors in sticklebacks, and those genes are shared with other animals, including humans. The rationale that underlies the proposed research is that an unbiased approach to studying natural variation in the propensity to engage in risk-taking behaviors which are both genetically based and environmentally-sensitive is likely to identify candidate genes that are relevant to human health. Identification of the genes pathways underlying risk-taking behaviors will contribute to the NIH mission to improve the health of the nation by aiding psychopharmacological efforts for the treatment and diagnosis of externalizing disorders in humans. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Identify genes associated with differences in risk- taking behaviors between individuals and populations; 2) Identify genes underlying risk-taking behaviors that are responsive to adverse environmental conditions; 3) Test candidate genes related to risk-taking behaviors in replicated populations. Under Aim 1, the gene expression profiles of risk-prone versus risk-averse individuals will be compared using whole-genome expression microarrays. Under the second Aim, the behavior and gene expression of individuals that are exposed to stressful environments will be compared against unstressed conspecifics. The two stressors are absence of parental care, which has an important effect on risk-taking behaviors in this species, and exposure to predators during development. Under Aim 3, the genes that are good candidates from Aims 1 and 2 will be tested in independent, replicate populations. This timely project capitalizes on the availability of new genomic information for an organism with a well-described and fascinating behavioral repertoire that until recently has been exempt from molecular dissection. The key innovation of this work is that it takes advantage of genetic and environmental sources of variation to identify candidate genes and uses the unique evolutionary history of sticklebacks to test a biomedically-relevant hypothesis in a replicated manner. The proposed studies use a new animal model to address fundamental questions about the origin of behaviors that have adverse consequences for health. The studies have potential application to understanding the etiology of human psychopathology. The proposed research has relevance to public health, because it will suggest candidate genes and pathways for the diagnosis and treatment of behavioral disorders in humans.