Real-time neurochemical encoding of reward- and punishment-prediction errors and associated subjective experiences in humans

人类奖励和惩罚预测错误及相关主观体验的实时神经化学编码

• 批准号: 10614972
• 负责人: Kenneth Tucker Kishida
• 金额: $ 34.51万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614972
• 关键词: Affect; Amygdaloid structure; Association Learning; Behavior; Behavior Control; Behavioral; Brain; Brain region; Chemicals; Cocaine; Conscious; Corpus striatum structure; Data; Decision Making; Decision Theory; Desire for food; Development; Dopamine; Exposure to; Feedback; Feeling; Foundations; Functional Magnetic Resonance Imaging; Future; Gambling; Goals; Grant; Human; Individual; Intractable Epilepsy; Knowledge; Learning; Maps; Mathematics; Measurement; Measures; Neurobiology; Nicotine; Nucleus Accumbens; Operant Conditioning; Opioid; Outcome; Participant; Patient Self-Report; Peer Review; Persons; Play; Prefrontal Cortex; Procedures; Process; Psychological reinforcement; Publishing; Punishment; Reporting; Research; Rewards; Role; Serotonergic System; Serotonin; Signal Transduction; Specificity; Substance Use Disorder; Substance of Abuse; System; Technology; Temporal Lobe; Testing; Time; Work; conditioning; design; dopamine system; drug of abuse; emotional experience; experience; experimental study; extracellular; financial incentive; human subject; insight; model organism; neurochemistry; novel; putamen; reward anticipation; reward processing; temporal measurement; theories

SUMMARY: Drugs of abuse (like opiates, cocaine, and nicotine) are initially taken because people want to alter how they subjectively feel, but these substances have potentially longer lasting negative consequences on the human brain, because of neurobiological effects that can lead to substance use disorder. The dopamine and serotonin systems have been strongly implicated in these processes, but these systems have not been investigated in humans with the temporal resolution required to connect (1) how these rapid signals alter our behavior as human navigate the world, nor (2) how these neurochemical signals alter how we feel subjectively. Progress has been hindered by lack of technology that permits simultaneous, real-time, measurements of dopamine and serotonin release during conscious decision-making and experience in humans (and for the fact that non-human model organisms cannot report ‘how they feel’). This proposal capitalizes on recent advances in mathematized human decision theory and our group’s first-of- its-kind technological approach, which now allows simultaneous, col-localized, measurements of dopamine and serotonin release in the human brain with sub-second temporal resolution during conscious decision- making and experience. Here, we pursue two specific goals, which uniquely combines our validated, peer- reviewed, and published approach with probabilistic learning tasks that have been specifically designed to probe the interplay between opponent reward and punishment behavioral signals, rapid changes in dopamine and serotonin release, and moment-to-moment changes in how participants feel during sequences of experience. First (aim 1), we will test the hypothesis that sub-second changes in extracellular dopamine and serotonin encode monetary reward/appetitive prediction errors and monetary punishment/aversive prediction errors, respectively, as opponent signals in the human striatum during an instrumental learning task and a passive Pavlovian conditioning task. Second (aim 2), we will test the hypothesis that sub-second changes in extracellular dopamine and serotonin, together, direct moment-to-moment changes in how people feel. The experiments proposed will for the first time directly test the controversial “opponent hypothesis” for serotonin/dopamine function in learning and decision-making in humans; and, we will for the first time begin to expose what role rapid microfluctuations in dopamine and serotonin play in encoding positive and negative subjective feelings in humans. We expect that these first-of-their-kind data will provide new insight into how drugs of abuse may alter how people feel, the impact drugs of abuse may have on critical neurochemical learning systems in the human brain, and may lay a foundation for future work aimed at understanding how these neurochemical systems affect other human brain regions (including nucleus accumbens, prefrontal cortex, amygdala, and the temporal lobes) where access maybe afforded by new DBS procedures or intracranial mapping for refractory epilepsy.

总结：滥用药物（如阿片类药物，可卡因和尼古丁）最初是因为人们想改变他们的主观感受，但这些物质对人类大脑的负面影响可能会持续更长时间，因为神经生物学效应可能导致物质使用障碍。多巴胺和5-羟色胺系统与这些过程密切相关，但这些系统尚未在人类中进行研究，其时间分辨率需要连接（1）这些快速信号如何改变我们在世界上的行为，也没有（2）这些神经化学信号如何改变我们的主观感受。由于缺乏能够同时、实时测量人类在有意识的决策和体验过程中多巴胺和血清素释放的技术（以及非人类模式生物无法报告“他们的感受”），进展受到了阻碍。 这项提议利用了数学化人类决策理论的最新进展和我们小组的第一种技术方法，该方法现在允许在有意识的决策和经验期间以亚秒级的时间分辨率同时，共定位测量人脑中多巴胺和5-羟色胺的释放。在这里，我们追求两个特定的目标，它独特地结合了我们的验证，同行评审，并公布的方法与概率学习任务，这些任务专门设计用于探测对手奖励和惩罚行为信号之间的相互作用，多巴胺和血清素释放的快速变化，以及参与者在体验序列中感受的时刻变化。首先（目的1），我们将测试的假设，即细胞外多巴胺和5-羟色胺的亚秒级变化编码货币奖励/食欲预测错误和货币惩罚/厌恶的预测错误，分别作为对手的信号在人类纹状体的工具学习任务和被动巴甫洛夫条件反射任务。第二（目标2），我们将检验一个假设，即细胞外多巴胺和5-羟色胺的亚秒级变化，共同指导人们感受的瞬间变化。这些实验将首次直接检验血清素/多巴胺在人类学习和决策过程中的功能这一有争议的“对手假说”;而且，我们将首次开始揭示多巴胺和血清素的快速微波动在编码人类积极和消极主观感受中所起的作用。我们希望这些首次获得的数据将为药物滥用如何改变人们的感受提供新的见解，药物滥用可能对人类大脑中关键的神经化学学习系统产生的影响，并可能为未来的工作奠定基础旨在了解这些神经化学系统如何影响人类大脑的其他区域。（包括脑桥核、前额叶皮质、杏仁核和颞叶），新的DBS手术或难治性癫痫的颅内标测可以提供这些通路。