Spatiotemporal dynamics of striatal dopamine release in reinforcement learning

描述（由申请人提供）：经典条件反射可以说是我们拥有的最基本的工具，用于使我们的行为适应不断变化的环境。食欲经典条件反射可以被认为是在强化和环境中的刺激之间建立一种习得性关联的过程，这种关联表明了它的可用性。这种形式的“强化学习”为生物体提供了一种有效的手段，可以使用预测信息来塑造和指导准备行动，以最大限度地提高回报。在过去的三十年里，我们对强化学习背后的神经生物学机制的理解取得了重大进展。特别是，短的“阶段性”的多巴胺神经元，这被认为是产生快速和短暂的增加细胞外多巴胺浓度在整个纹状体的神经元活动的爆发，已受到相当大的关注，作为一个必要的组成部分，自然和药物奖励的强化过程。儿茶酚胺研究中的中心法则认为，多巴胺的传递是从中脑到前脑所有目标结构的统一广播信号。然而，越来越多的证据表明，在学习过程的不同阶段，纹状体内的不同核团可能会收到不同的信号，以响应初级奖励和条件提示。据推测，这种区域特异性的动态和稳定的多巴胺信号对应于在学习和行为控制，多巴胺可能在这些结构中发挥的作用在很大程度上隔离。本提案将以三个具体目标检验这些假设。目的1将研究学习历史和任务的具体特征对腹侧纹状体中相态多巴胺稳定性的影响。目的2将研究在学习的不同阶段阶段，相位多巴胺对纹状体激活的影响，并评估同时发生的区域行为控制。目的3将检查在强化学习的多个阶段（获得，扩展训练和消退）中腹侧和背侧纹状体中的阶段性多巴胺释放，目的是将特定行为的发展与每个结构中的阶段性信号的轮廓相关联和比较。 公共卫生相关性：虽然在正常情况下是适应性的，但强化学习是许多成瘾模型中与药物相关的刺激对寻求药物和服用药物行为的强大控制的几个因素之一。神经调节剂多巴胺的阶段性激活与强化学习和药物滥用的许多方面有关。本研究的主要目的是研究特定脑区阶段性多巴胺释放对强化和行为控制的作用。

DESCRIPTION (provided by applicant): Classical conditioning is arguably the most fundamental tool we possess for adapting our behavior to a changing environment. Appetitive classical conditioning can be thought of as the process that establishes a learned association between reinforcement and the stimuli in the environment that signal its availability. This form of "reinforcement learning" provides organisms with a potent means to use predictive information to mold and guide preparatory action in an effort to maximize reward. The past three decades have been marked by major advances in our understanding of the neurobiological mechanisms that underlie reinforcement learning. In particular, short "phasic" bursts of neuronal activity in dopamine neurons, which are thought to produce rapid and transient increases in extracellular dopamine concentration throughout the striatum, have received considerable attention as a necessary component of the reinforcement process for both natural and drug reward. The central dogma in catecholamine research has held that dopamine transmission proceeds as a uniform broadcast signal from the midbrain to all target structures in the forebrain. However, there is mounting evidence that separate nuclei within the striatum may receive differential signals in response to primary rewards and conditioned cues at different stages in the learning process. It is hypothesized that this regional specificity in the dynamics and stability of dopamine signaling corresponds to the largely segregated roles in both learning and behavioral control that dopamine may play in these structures. The current proposal will test these hypotheses with three specific aims. Aim 1 will examine the impact of learning history and specific features of the task on the stability of phasic dopamine in the ventral striatum. Aim 2 will examine the influence of phasic dopamine on the activation of the striatum during different stages of learning and assess the coincident regional control of behavior. Aim 3 will examine phasic dopamine release in the ventral and dorsal striatum during multiple stages of reinforcement learning (acquisition, extended training and extinction) with the goal of correlating and comparing the development of specific behaviors to the profile of phasic signaling in each structure. PUBLIC HEALTH RELEVANCE: Although adaptive under normal circumstances, reinforcement learning is one of several contributing factors to the powerful control drug-related stimuli have over drug-seeking and drug-taking behaviors in many models of addiction. The phasic activation of the neuromodulator dopamine is implicated in both reinforcement learning and many aspects of drug abuse. The primary goal of this proposal is to examine the contribution of phasic dopamine release in specific brain regions to reinforcement and behavioral control.