Effect of genetics on reward learning and generalization of associations in aging

描述（由申请人提供）：这项拟议的研究将研究衰老对基于奖励的联想学习和概括的影响，以及这些关系如何因常见的遗传多态性而变化。获得新技能并应用这些经验来预测新情况下的积极结果的能力在所有年龄段都是必不可少的，使人们能够做出关键的经济决策或社会判断。例如，人们经常根据市场上的输赢来选择股票，而将这些强化结果与多种经验相结合，可以帮助人们进行新的投资，比如退休计划。类似地，该提议侧重于基于额纹状体的学习（即，获取新的关联 来自反馈）和基于海马的泛化（即，上下文相关传输）。这些过程在认知老化中仍然相对缺乏研究，这是令人惊讶的，因为它们与所有年龄段的成年人都相关。我们对学习和概括之间的分离的关注与老年人特别相关，因为这些过程需要不同的大脑区域，这些区域受到健康老龄化的不同影响。在这里，175名年轻人和175名老年人将完成各种学习和概括任务，这些任务已被验证用于评估额纹状体和海马功能。据预测，老年人在学习方面表现出更大的年龄相关缺陷，而不是泛化，增加了健康老龄化对纹状体系统的影响大于海马体的数据（目标1）。与健康老龄化中认知功能异质性的证据相一致，我们还将表明，一些老年人在学习和/或概括方面比其他人做得更好。由于遗传多态性可以揭示认知功能的重要个体差异，因此本研究还将研究可能支持学习和概括的个体差异的遗传成分;特别是多巴胺转运基因（DAT 1），其在纹状体中最丰富，以及编码脑源性神经营养因子（BDNF）的基因，其在海马中表达最高。预计DAT 1的功能多态性将预测额纹状体学习的个体差异，而BDNF的功能多态性将预测海马泛化的个体差异（目的2.1）。最后，本研究将通过测试最近的一个假设，即衰老放大了遗传变异对认知的功能意义，来研究健康的衰老是否会调节这些遗传对认知功能的影响（目标2.2）。据预测，老年人在认知方面的基因型差异将大于年轻人。认知相关基因的识别，以及其中与年龄相关的差异，为完善认知的神经生物学机制带来了希望，并可能有助于解释老年认知功能的异质性。了解认知能力下降的个体差异的潜在机制，反过来，可以为旨在最大限度地提高老年认知功能的认知训练和药物治疗计划提供信息。随着世界人口中老年人的人数稳步上升，这些目标越来越重要。

DESCRIPTION (provided by applicant): This proposed study will examine the effects of aging on reward-based associative learning and generalization and how these relationships vary by common genetic polymorphisms. The ability to acquire new skills and apply those experiences to predict positive outcomes in novel situations is essential at all ages, enabling people to make critical economic decisions or social judgments. For example, people often select stocks based on wins and losses in the market, and the integration of these reinforcement outcomes over multiple experiences can help when navigating new investments, such as retirement planning. Similarly, this proposal focuses on frontostriatal-based learning (i.e., acquiring new associations from feedback) and hippocampal- based generalization (i.e., context-dependent transfer). These processes remain relatively understudied in cognitive aging, which is surprising given their relevance to adults of all ages. Our focus on the dissociation between learning and generalization is particularly relevant to older adults because these processes call on different brain regions that are differentially affected by healthy aging. Here, 175 younger and 175 older adults will complete a variety of learning and generalization tasks that have been validated to assess frontostriatal and hippocampal function. Older adults are predicted to show greater age-related deficits on learning than generalization, adding to data that healthy aging affects the striatal system more than the hippocampus (Aim 1). Consistent with evidence of heterogeneity of cognitive function in healthy aging, we will also show that some seniors do better than others during learning and/or generalization. Because genetic polymorphisms can reveal important individual differences in cognitive function, this study will also examine genetic components that may support individual differences in learning and generalization; notably, the dopamine transport gene (DAT1), which is most abundant in the striatum, and the gene coding for Brain-Derived Neurotrophic Factor (BDNF) that has highest expression in the hippocampus. It is expected that a functional polymorphism in DAT1 will predict individual differences in frontostriatal learning, whereas a functional polymorphism in BDNF will predict individual differences in hippocampal generalization (Aim 2.1). Finally, this study will examine whether healthy aging modulates these genetic effects on cognitive function, by testing a recent hypothesis that aging magnifies the functional significance of genetic variants on cognition (Aim 2.2). It is predicted that genotypic differences on cognition will be larger in older than younger adults. The identification of cognitively relevant genes, and age-related differences therein, brings promise to refine knowledge about neurobiological mechanisms of cognition and may help to explain heterogeneity of cognitive function in old age. Understanding the mechanisms underlying individual differences in vulnerability to cognitive decline may, in turn, inform cognitive training and pharmacological treatment programs aimed at maximizing cognitive functioning in old age. These goals are increasingly important as the number of older adults in the world population steadily rises.