Neurochemical bases for changes in decision-making across the lifespan

描述（由申请人提供）：决定从事一项导致有益结果的行动是由几个因素决定的，这些因素可能随着年龄的变化而变化。其中最主要的是在做出决定时给予奖励的价值，这是基于之前对奖励的情感体验而不断更新的。与奖励经验相关的线索也通过巴甫洛夫激励过程影响决策。内源性阿片类物质通过伏隔核/腹侧白质的行为介导对美味食物奖励的情绪反应，并通过杏仁核基底外侧的mu阿片类受体独立促进工具性激励学习。多巴胺在伏隔核的传递对于奖励相关线索的激活作用至关重要。本研究的目的是研究这些脑区内源性阿片样物质和多巴胺传递的发育转变是否表现为青春期、中年和老年啮齿动物对经验奖励值变化和预测奖励的环境线索的反应方式的转变。我们将在食用甜食时使用舔结构来评估奖励的情感体验（适口性）在生命周期中的变化，并通过工具激励学习任务来分析年龄对奖励的情感影响如何转化为决策过程中使用的目标价值的影响。巴甫洛夫-工具转移测试将评估奖励配对线索启动和激发奖励寻求行为的能力，以及这一过程在一生中如何变化。阿片类药物和多巴胺传递的发育变化在这些因素在不同年龄间的变化影响中所起的作用将通过中央药理学操作、病毒介导的基因转移、脑啡肽和多巴胺释放的体内测量以及靶向条件操作前脑啡肽表达的小鼠来确定。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有针对性的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.