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

描述（由申请人提供）：虽然先前的工作表明，血清素参与调节对厌恶事件的耐受性，但对血清素与认知之间的关系知之甚少。推进我们对神经和遗传机制的理解，通过这些机制，5-羟色胺影响个体在学习应对厌恶事件方面的差异，是深入理解抑郁症、焦虑症和应激障碍等心理健康障碍的脆弱性的必要的第一步。为此，该项目的主要目的是研究两种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与学习避免惩罚的偏见，以及认知方式中的这些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在健康个体中也表现出自然发生的变异，因此了解这些基因的功能是理解学习和记忆个体差异以及遗传变异如何导致精神障碍风险的关键组成部分。 该提案代表了两位知名认知神经科学家（PI，Mark Gluck和Co-I，Catherine Myers）和两位遗传学家Emilia Vitale和Annette Lee之间新的跨学科合作，他们是该基金的顾问。使用的主要认知测量将是PI，Co-PI及其同事开发的一种新的概率分类任务，其中受试者被训练将四种刺激分为两类。由于两个刺激是通过积极的奖励反馈来训练正确的答案，两个刺激是通过消极的惩罚反馈来训练不正确的答案，该任务允许分析学习过程中对积极反馈和消极反馈的敏感性的个体差异。这项任务，沿着测量寻求新奇和避免伤害的人格评估工具，提供了一种方法来测试假设，即具有大脑中血清素水平降低的遗传倾向的个体在这样的学习任务中会偏向于以牺牲积极反馈为代价来处理消极反馈。待评价的特定基因型为：（1）5-羟色胺2a受体基因（5-HT 2AR）中的单核苷酸多态性His 452 Tyr和（2）5-羟色胺转运蛋白基因（5 HTTLPR）启动子区中的44个核苷酸插入/缺失。预测具有这些不太常见的多态性中的一种或两种的个体在学习中表现出最高水平的对惩罚的敏感性和最高水平的伤害回避人格。 公共卫生相关性：基于先前的工作表明血清素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，这可能会导致更深入地了解个体差异对精神健康障碍的脆弱性，如抑郁症，焦虑症，应激障碍和饮食失调。更好地了解健康个体中5-羟色胺功能的功能也可以深入了解为什么这些疾病的药物疗效可能会因个体而异。

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.