Serotonin Genes & Individual Differences in Reward vs. Punishment-Based Learning

描述(申请人提供)：虽然先前的工作表明5-羟色胺参与调节对厌恶事件的耐受性，但对5-羟色胺和认知之间的关系知之甚少。提高我们对5-羟色胺影响个体差异应对厌恶事件的神经和遗传机制的理解，是深入理解抑郁、焦虑和应激障碍等心理健康障碍易感性的必要的第一步。为此，该项目的主要目标是研究两个血清素基因中自然发生的变异，它们如何不同地影响人们学习获得奖励和学习逃避惩罚的偏见，以及这些认知风格的遗传变异如何与个性和性别相互作用。由于许多与精神障碍有关的基因也显示出健康个体中自然发生的变异，因此了解这些基因的功能是理解学习和记忆方面的个体差异以及基因变异如何导致精神障碍风险的关键组成部分。该提案代表了两位著名的认知神经学家(PI，Mark Gluck和Co-I，Catherine Myers)与这笔赠款的顾问埃米莉亚·维塔尔和Annette Lee之间的一项新的跨学科合作。使用的主要认知测量将是由Pi、Co-Pi和同事开发的一种新的概率分类任务，在该任务中，受试者被训练将四种刺激分类为两类。由于其中两个刺激物是通过正面奖励反馈训练成正确答案，而两个刺激物是通过负面惩罚性反馈训练成错误答案，因此该任务允许分析学习过程中个体对正反馈和负反馈的敏感度差异。这项任务与衡量寻求新奇和避免伤害的个性评估工具一起，提供了一种方法来检验这样一种假设，即大脑中5-羟色胺水平降低的遗传倾向的人在此类学习任务中会偏向于以牺牲正反馈为代价来处理负面反馈。要评估的特殊基因类型是：(1)5-羟色胺2a受体基因(5-HT2AR)中的单核苷酸多态His452Tyr；(2)5-羟色胺转运体基因启动子区的44个核苷酸插入/缺失(5HTTLPR)。这些不太常见的多态中的一个或两个的个体被预测在学习中表现出对惩罚的最高水平的敏感性和最高水平的伤害避免个性。 与公共健康相关：这项研究基于先前的工作，表明5-羟色胺参与调节对厌恶事件的耐受性，这项研究将扩大我们对学习预测和应对厌恶事件的个体差异的神经和遗传基础的理解。反过来，这可能会导致对抑郁、焦虑、压力障碍和饮食障碍等精神健康障碍易感性的个体差异有更深的理解。更好地了解5-羟色胺在健康个体中的功能也可能有助于深入了解为什么对其中一些疾病的药物疗效可能因个体而异。

DESCRIPTION (provided by applicant): While prior work has suggested that serotonin is involved in modulating tolerance to aversive events, far too little is known about the relationship between serotonin and cognition. Advancing our understanding of the neural and genetic mechanisms through which serotonin influences individual differences in learning to respond to aversive events is a necessary first step towards a deeper understanding of vulnerabilities to mental health disorders such as depression, anxiety, and stress disorders. Toward that end, the primary aim of this project is to study naturally occurring variations in two serotonin genes, how they differentially affect peoples' biases for learning to obtain reward versus learning to avoid punishment, and how these genetic variations in cognitive styles interact with personality and gender. Because many genes that are implicated in mental disorders also show naturally occurring variations in healthy individuals, understanding the function of these genes is a key component of understanding both individual differences in learning and memory, and how genetic variation can contribute to risk for mental disorders. The proposal represents a new cross-disciplinary collaboration between two established cognitive neuroscientists (the PI, Mark Gluck and the Co-I, Catherine Myers) and two geneticists, Emilia Vitale and Annette Lee, consultants to this grant. The primary cognitive measure used will be a novel probabilistic categorization task developed by the PI, Co-PI and colleagues in which subjects are trained to classify four stimuli into two categories. Because two of the stimuli are trained via positive-rewarding feedback to correct answers and two of the stimuli are trained via negative-punishing feedback to incorrect answers, the task allows for analysis of individual differences in sensitivity to positive versus negative feedback during learning. This task, along with personality assessment tools that measure novelty seeking and harm avoidance, provide a means to test the hypothesis that individuals with a genetic predisposition for reduced levels of serotonin in the brain will be biased to process negative feedback at the expense of positive feedback during such learning tasks. The particular genotypes to be evaluated are: (1) a single nucleotide polymorphism, His452Tyr, in the serotonin 2a receptor gene (5-HT2AR) and (2) a 44-nucleotide insertion/deletion in the promoter region of the serotonin transporter gene (5HTTLPR). Individuals with one or both of these less common polymorphisms are predicted to show the highest levels of sensitivity to punishment in learning and highest levels of harm avoidance personality. PUBLIC HEALTH RELEVANCE: Building on prior work suggesting that serotonin is involved in modulating tolerance to aversive events, this research will expand our understanding of the neural and genetic bases of individual differences in learning to predict and respond to aversive events. This, in turn, may lead to a deeper understanding of individual differences in vulnerability to mental health disorders such as depression, anxiety, stress disorders, and eating disorders. Better understanding of the function of serotonin function in healthy individuals may also provide insights into why drug efficacy for some of these disorders may vary across individuals.