Mechanisms of Dopamine Action in Learning: Implications for Addiction

多巴胺在学习中的作用机制：对成瘾的影响

• 批准号: 10089221
• 负责人: Patricia H. Janak
• 金额: $ 47.16万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089221
• 关键词: Addictive Behavior; Anesthesia procedures; Animals; Behavior; Behavior Control; Behavior Disorders; Behavioral; Brain; Conceptions; Corpus striatum structure; Cues; Development; Disease; Dopamine; Dorsal; Electrophysiology (science); Elements; Environment; Evolution; FOS gene; Goals; Hyperphagia; Incentives; Learning; Light; Link; Measures; Mediating; Midbrain structure; Modeling; Movement; Neurons; Neurotransmitters; Nucleus Accumbens; Operant Conditioning; Pathologic; Performance; Pharmaceutical Preparations; Pharmacology; Play; Population; Process; Psychological reinforcement; Publishing; Rattus; Rewards; Role; Stimulus; Substance Use Disorder; Substance abuse problem; Substantia nigra structure; System; Testing; Time; Training; Transgenic Organisms; Ventral Tegmental Area; addiction; approach behavior; base; classical conditioning; conditioning; dopamine system; dopaminergic neuron; drug relapse; drug reward; drug seeking behavior; in vivo; learned behavior; mesolimbic system; nerve supply; neural patterning; neuromechanism; neurotransmission; optogenetics; pars compacta; psychologic; recruit; relating to nervous system; response; transmission process

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.

项目概要 中脑边缘多巴胺及其腹侧纹状体靶标在 巴甫洛夫奖励学习。巴甫洛夫奖励学习过程是许多方面的基础 药物寻求行为的影响并在药物复发中发挥关键作用。器乐学习 过程也构成了药物寻求行为的基本要素，并且可能取决于 对背侧纹状体黑质纹状体多巴胺神经支配的影响。在这里我们试图了解 纹状体目标内的中脑边缘和黑质纹状体多巴胺作用如何介导选择 寻求奖励行为的组成部分，并测试这些行为之间是否存在相互作用 系统有助于正常和病态的寻求奖励行为。我们专注于 多巴胺，因为自然奖励和药物奖励都会激活多巴胺神经元，并且， 我们最近的研究结果证实，当取代时，多巴胺神经元激活 奖励，驱动与成瘾行为有关的特定形式的联想学习。 此处，使用 Th:Cre 转基因大鼠限制视紫红质通道蛋白表达为多巴胺 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、神经活动和整合的影响 腹侧和背侧纹状体系统。我们测试中脑边缘多巴胺神经元是否 奖励相关的激活在特定形式的奖励期间招募更多的背侧纹状体回路 学习。一个突出的假设认为，随着时间的推移，奖励寻求取决于更多 当行为控制成为习惯时，背侧纹状体回路。因此，我们也问 激活中脑边缘多巴胺系统是否可以加速习惯性行为的发展 对自然或药物奖励的反应。此外，我们将确定神经信号 通过中脑边缘多巴胺激活调节行为，以揭示 下游神经元群体的神经变化介导了 这些多巴胺介导的习得行为。这些研究将提供新信息 腹侧和背侧纹状体回路的独立和相互作用的贡献 多巴胺可以引发寻求奖励的行为，并且与我们的行为相关 了解涉及暴饮暴食和物质使用障碍的行为障碍。