Neural Systems of Learning and Memory in Addiction

描述（由申请人提供）：习惯是驱动行为的强大力量。在药物滥用中，反复使用药物的快乐体验所形成的习惯比明确了解药物的有害影响更为强大。最近关于学习和记忆的认知神经科学研究极大地推进了我们对这两种学习形式的理解，表明它们依赖于不同的神经系统。然而，在将这一研究领域扩展到成瘾研究方面，进展甚微。在这里，我们建议弥合这一差距，以了解促进不同形式的学习和动机的神经机制，以及它们在成瘾中的破坏。研究表明，习惯学习依赖于纹状体及其多巴胺能输入，而对事实和事件的外显记忆，通常被称为陈述性记忆，则依赖于内侧颞叶（MTL；海马体及其周围皮层）。最近的证据表明，在某些情况下，这些系统可能会相互竞争。这一提议的核心假设是，药物滥用可能与这两个学习系统之间的平衡被破坏以及它们各自指导行为的程度有关。这项拟议中的研究将使用功能成像（fMRI）和行为分析来研究不同形式的学习如何指导决策和行动。中心目标是了解如何在神经和行为层面调节这两种学习系统对选择行为的贡献。在第一项研究中，我们将研究纹状体对学习和选择的调节作用。为此，我们将操纵强化，并将确定对驱动后续选择行为的认知和神经系统的影响（见第1章）。在第二项研究中，我们将研究调节MTL对学习和选择的影响。为此，我们将操纵刺激和联想新颖性，并将确定对驱动后续选择行为的认知和神经系统的影响（见图2）。确定调节学习和选择依赖于一个系统或另一个系统的程度的因素将为未来潜在治疗干预的翻译工作奠定基础，这些治疗干预可以减少对纹状体习惯系统的行为依赖，而有利于MTL声明系统。公共卫生相关性：药物滥用是一个严重的公共卫生问题。对大脑和认知机制的破坏是药物滥用和成瘾病理的核心。在药物滥用中，个体的行为是由习惯驱动的，这些习惯是由于反复体验药物的享乐和强化效应而习得的。这些习得的习惯超越了任何其他形式的学习，比如对药物有害影响的明确认识或经验。本研究旨在了解习惯学习和外显学习之间平衡的神经和认知机制，以及如何改变这种平衡。由此产生的知识将为未来潜在的认知和药物治疗策略提供信息，这些策略可以减少行为对习惯的依赖，从而支持明确的、目标导向的机制。

DESCRIPTION (provided by applicant): Habits are powerful in driving actions. In substance abuse, habits formed by repeated hedonic experience with a drug are more powerful than explicit knowledge of the drug's detrimental effects. Recent research in the cognitive neuroscience of learning and memory has greatly advanced our understanding of these two forms of learning, suggesting they depend on distinct neural systems. Yet there has been remarkably little progress in extending this line of research to the study of addiction. Here, we propose to bridge this gap to understand the neural mechanisms contributing to different forms of learning and motivation, and their disruption in addiction. Research demonstrates that habit learning depends on the striatum and its dopaminergic inputs, while explicit memory for facts and events, often referred to as declarative memory, depends on the medial temporal lobe (MTL; hippocampus and surrounding cortices). Recent evidence suggests these systems may interact competitively under some circumstances. The core hypothesis motivating this proposal is that substance abuse may be related to a disrupted balance between these two learning systems and the extent to which each of them guides behavior. The proposed research will use functional imaging (fMRI) and behavioral analyses to investigate how different forms of learning guide decisions and actions. The central aim is to understand how to modulate the contribution of these two learning systems to choice behavior, at both the neural and behavioral levels. In the first study, we will examine the effects of modulating striatal contributions to learning and choice. To that end, we will manipulate reinforcement, and will determine the effects on the cognitive and neural systems driving subsequent choice behavior (Expt 1). In the second study, we will examine the effects of modulating MTL contributions to learning and choice. To that end, we will manipulate stimulus and associative novelty, and will determine the effects on the cognitive and neural systems driving subsequent choice behavior (Expt 2). Determining factors that modulate the extent to which learning and choice depend on one system or the other will lay the foundation for future translational work on potential treatment interventions that can reduce the dependence of behavior on the striatal habit system in favor of the MTL declarative system. PUBLIC HEALTH RELEVANCE: Substance abuse is a serious problem of public health. Disruption to the brain and cognitive mechanisms underlying learning are central to the pathology of substance abuse and addiction. In substance abuse, individuals' behavior is driven by habits that are learned as a result of repeated experiences with the drug's hedonic, reinforcing effects. These learned habits override any other forms of learning, such as explicit knowledge or experiences of the drugs' detrimental effects. The proposed studies aim to understand the neural and cognitive mechanisms underlying the balance between habitual and explicit forms of learning, and how this balance can be modified. The resulting knowledge will inform future work on potential cognitive and pharmacological treatment strategies that can reduce the dependence of behavior on habits in favor of explicit, goal-directed mechanisms.