Neurochemical bases for changes in decision-making across the lifespan

描述（由申请人提供）：决定从事一项行动，导致有益的结果是由几个因素，可能会随着年龄的变化。其中最重要的是在决策时对奖励的价值，这是根据之前对奖励的情感体验不断更新的。与奖励经验相关的线索也通过巴甫洛夫激励动机过程影响决策。内源性阿片类物质发挥了重要作用，通过行动在丘脑核/腹侧苍白球调解情绪反应可口的食物奖励，并独立地促进工具性激励学习通过μ阿片受体在基底外侧杏仁核。多巴胺在丘脑核的传递对于奖赏相关线索的激励作用是必不可少的。这项建议的目标是研究是否在这些大脑区域的内源性阿片类药物和多巴胺传输的发展转变表现为转变的方式，在青少年，中年和老年啮齿类动物的经验奖励值和环境线索预测奖励的变化作出反应。我们将使用舔架构在消费的甜的解决方案，以评估如何奖励的情感体验（适口性）的变化在整个生命周期和一个工具性的激励学习任务，以解析老化的影响如何奖励的情感影响被转化为目标值在决策过程中使用。巴甫洛夫到工具转移测试将评估奖励配对线索启动和激励奖励寻求行动的能力，以及这个过程在生命周期中如何变化。阿片类药物和多巴胺传递的发展变化在这些因素的影响在不同年龄的变化的作用将确定使用中枢药理学操作，病毒介导的基因转移，脑啡肽和多巴胺释放的体内措施，和小鼠有针对性的条件操纵脑啡肽原表达。了解衰老如何影响线索诱发的激励动机、奖励适口性和激励学习，可以为开发针对年龄依赖性决策障碍和行为控制障碍的靶向认知行为和药物治疗提供信息。

DESCRIPTION (provided by applicant): The decision to engage in an action leading to a rewarding outcome is governed by several factors that may vary with age. Primary among these is the value placed on the reward at the time of the decision, which is continually updated on the basis of previous emotional experience with the reward. Cues associated with reward experience also impact decision-making through a Pavlovian incentive motivation process. Endogenous opioids play a major role in mediating emotional responsiveness to palatable food rewards through actions in the nucleus accumbens/ventral pallidum, and independently facilitate instrumental incentive learning via mu opioid receptors in the basolateral amygdala. Dopamine transmission in the nucleus accumbens is essential for the invigorating effects of reward-associated cues. The goal of this proposal is to examine whether developmental transitions in endogenous opioid and dopamine transmission in these brain regions manifest as shifts in the manner in which adolescent, middle-aged, and aged rodents react to changes in experienced reward value and to environmental cues predictive of reward. We will use licking architecture during consumption of sweet solutions to assess how emotional experience of reward (palatability) changes over the lifespan and an instrumental incentive learning task to parse the effects of aging on how the emotional impact of a reward is translated into a goal value used in the decision-making process. The Pavlovian-to- instrumental transfer test will assess the ability of reward-paired cues to initiate and invigorate reward-seeking actions and how this process changes over the lifespan. The role of developmental shifts in opioid and dopamine transmission in the shifting influence of these factors across ages will be determined using central pharmacological manipulations, viral-mediated gene transfer, in vivo measures of enkephalin and dopamine release, and mice with targeted conditional manipulation of pro-enkephalin expression. Understanding how aging impacts cue-evoked incentive motivation, reward palatability, and incentive learning may inform development of targeted cognitive-behavioral and pharmacological therapies for age-dependent decision- making impairments and behavioral control disorders.