Mechanisms of Dopamine Action in Learning: Implications for Addiction

项目总结 中脑边缘多巴胺及其腹侧纹状体靶点在 巴甫洛夫式的奖励学习。巴甫洛夫式的奖励学习过程是许多方面的基础 并在毒品复发中起着关键作用。工具性学习 过程也构成了寻求毒品行为的基本要素，并可能取决于 黑质纹状体背侧多巴胺神经支配的研究。在这里，我们试图理解 纹状体靶区内中脑边缘和黑质纹状体的多巴胺作用如何介导选择 寻找奖励行为的组成部分，并测试这些行为之间的交互作用 制度导致了正常和病态的奖赏行为。我们专注于 多巴胺是因为自然奖励和药物奖励都能激活多巴胺神经元，而且，作为 我们最近的发现证实，当多巴胺神经元被取代时， 奖励，驱动与成瘾行为有关的特定形式的联想学习。 在这里，使用Th：Cre转基因大鼠将视紫红质的通道表达限制为多巴胺 神经元，我们利用选择性激活中脑边缘多巴胺的能力 神经元，以更好地了解它们对行为、神经活动和 腹侧和背侧纹状体系统。我们测试了中脑边缘多巴胺神经元 奖赏相关激活招募更多背侧纹状体环路在特定形式的 学习。一个重要的假说认为，随着时间的推移，寻求奖励取决于更多 作为行为控制的背侧纹状体回路变得习惯性。因此，我们还要求 激活中脑边缘多巴胺系统能否加速习惯性发育 对自然的或毒品的奖励做出反应。此外，我们还将确定神经信号 调节中脑边缘多巴胺激活的行为以揭示 下游神经元群中的神经变化介导了 这些由多巴胺介导的后天习得行为。这些研究将提供新的信息 腹侧纹状体环路和背侧纹状体环路的分离和交互作用 寻求奖励的行为可以由多巴胺启动，并与我们的 了解包括暴饮暴食和物质使用障碍在内的行为障碍。

Project summary Mesolimbic dopamine, along with its ventral striatal targets, plays a major role in Pavlovian reward learning. Pavlovian reward learning processes underlie many aspects of drug seeking behavior and play a critical role in drug relapse. Instrumental learning processes also form a fundamental element of drug seeking behavior, and may depend on nigrostriatal dopamine innervation of dorsal striatum. Here we seek to understand how mesolimbic and nigrostriatal dopamine action within striatal targets mediates select components of reward-seeking behavior, and to test whether interactions between these systems contribute to normal and pathological reward-seeking behavior. We focus on dopamine because both natural and drug rewards activate dopamine neurons, and, as confirmed in our recent findings, dopamine neuron activation, when substituted for reward, drives specific forms of associative learning implicated in addictive behavior. Here, using the Th:Cre transgenic rat to limit channelrhodopsin expression to dopamine neurons, we take advantage of the ability to selectively activate mesolimbic dopamine neurons to better understand their impact on behavior, neural activity, and integration of ventral and dorsal striatal systems. We test whether mesolimbic dopamine neuron reward-related activation recruits more dorsal striatal circuits during specific forms of learning. A prominent hypothesis posits that reward seeking depends over time on more dorsal striatal circuits as behavioral control becomes habitual. Thus, we also ask whether activating mesolimbic dopamine systems can hasten development of habitual responding for natural or drug reward. In addition, we will determine neural signals mediating behaviors conditioned by mesolimbic dopamine activation in order to reveal neural changes in downstream neuronal populations that mediate the performance of these dopamine-mediated learned behaviors. These studies will provide new information on the separate and interactive contributions of ventral and dorsal striatal circuits to reward seeking behavior that can be initiated by dopamine, and are relevant for our understanding of behavioral disorders involving overeating and substance use disorders.