Mechanisms of Dopamine Action in Learning: Implications for Addiction

项目总结

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.