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

描述（由申请人提供）：尽管冒险行为对个人和社会的成本以及对健康的重要性显而易见，但我们对冒险行为的病因知之甚少。在了解影响自残、暴力和寻求感觉行为倾向的遗传和环境因素方面的进展，将会因一种基因上可处理的动物模型的可用性而加速。我们的长期目标是发展棘鱼（Gasterosteus aculeatus）作为一个模型系统，以了解基因如何与环境相互作用以影响行为。该应用程序的总体目标是识别和测试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，这些基因与包括人类在内的其他动物共享。所提议的研究的基本原理是，以一种无偏见的方法来研究从事冒险行为倾向的自然变异，这种行为既基于基因，又对环境敏感，有可能确定与人类健康有关的候选基因。确定冒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研究来治疗和诊断人类外部性疾病，从而改善国民健康。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来验证：1)确定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作出反应的冒险行为背后的基因；3)在复制人群中测试与冒险行为相关的候选基因。在目标1中，风险倾向个体和风险厌恶个体的基因表达谱将使用全基因组表达微阵列进行比较。在第二个目标下，暴露于压力环境中的个体的行为和基因表达将与未受到压力的同种个体进行比较。这两种压力源分别是缺乏对该物种冒险行为有重要影响的亲代关爱和在发育过程中暴露于捕食者。在目标3中，目标1和目标2中的候选基因将在独立的、复制的种群中进行测试。这个及时的项目利用了新的基因组信息的可用性，这种生物具有良好的描述和迷人的行为曲目，直到最近才被免除分子解剖。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，并利用棘鱼独特的进化史，以复制的方式测试生物医学相关的假设。拟议的研究使用一种新的动物模型来解决有关对健康产生不利影响的行为起源的基本问题。这些研究对理解人类精神病理的病因有潜在的应用价值。拟议的研究与公共卫生有关，因为它将为诊断和治疗人类行为障碍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.