GWAS for the attribution of incentive salience in outbred rats

项目总结/摘要 激励显著性是归因于奖励预测刺激的激励价值。只有刺激， 已经获得了激励的显着性变得可取，并能够偏向我们的注意力，并引起对 他们这些激励刺激有能力显著影响我们的日常行为。的情况下 成瘾，获得激励显着性的药物相关刺激（条件刺激，CS）可以触发强大的 渴望并激发寻求/服用药物的行为。作为成瘾治疗的首要问题是， 成瘾者有复吸的倾向，而复吸被认为部分是由药物相关的刺激引发的， 重要的是要了解激励显着性归因的遗传基础。 巴甫洛夫条件反射法（PCA）是一种用于大鼠的行为范式，用于可靠地评估其行为。 巴甫洛夫符号追踪（或自动整形）的倾向。信号跟踪行为包括接近和 与奖励配对的CS（符号）的相互作用，并且只发生作为激励显着性归因于 提示。PCA范式中的表现可以作为一种数量性状进行评分，并已被证明是 在Sprague-Dawley（SD）大鼠中具有高度遗传性和可变性。 我们将在一个样本上对这一性状进行第一次大规模的全基因组关联研究（GWAS 大约3,000只远交SD大鼠，通过PCA进行了标记追踪的表型分析。获得 基因型的3,000只大鼠，我们将利用基因型测序（GBS），减少代表性 测序方法正在Palmer博士（申办方）实验室中针对大鼠进行优化。由于人口众多， 在SD大鼠群体中观察到的结构，将使用具有随机项的混合模型进行分析 包含基于SNP基因型的相关性矩阵。这是一个前所未有的大样本， 例如在大鼠或小鼠中进行遗传研究，因此为我们提供了出色的能力。本研究将提供 我们对激励显著性归因的分子机制有了深入的了解， 对今后的药物滥用研究具有重要意义。

PROJECT SUMMARY/ABSTRACT Incentive salience is the motivational value attributed to a reward-predicting stimulus. Only stimuli that have acquired incentive salience become desirable and able to bias our attention and elicit approach towards them. These incentive stimuli have the ability to significantly influence our daily behavior. In the case of addiction, drug-associated stimuli (conditioned stimuli, CS) that acquire incentive salience can trigger powerful craving and motivate drug-seeking/taking behaviors. As the primary issue in the treatment of addiction is the tendency of addicts to relapse, and relapse is believed to be triggered in part by drug-associated stimuli, it is important to understand the genetic basis underlying the attribution of incentive salience. Pavlovian Conditioned Approach (PCA) is a behavioral paradigm used in rats to reliably assess their propensity towards Pavlovian sign-tracking (or autoshaping). Sign-tracking behaviors consist of approach and interaction with a reward-paired CS (sign) and only occur as a result of the attribution of incentive salience to the cue. Performance in the PCA paradigm can be scored as a quantitative trait and has been shown to be both highly heritable and variable in Sprague-Dawley (SD) rats. We will perform the first large-scale genome-wide association study (GWAS) for this trait on a sample of approximately 3,000 outbred SD rats that have been phenotyped for sign-tracking through PCA. To obtain genotypes for the 3,000 rats, we will utilize genotype-by-sequencing (GBS), a reduced-representation sequencing approach being optimized for rats in Dr. Palmer's (sponsor) lab. Due to the extensive population structure observed in SD rat populations, analysis will be done using a mixed model with a random term containing relatedness matrices based on the SNP genotypes. This is an unprecedentedly large sample for such as genetic study in rats or mice, and therefore provides us with outstanding power. This study will provide us with insights into the molecular mechanisms underlying the attribution of incentive salience and may have important implications for future drug-abuse research.