Defining the role of compartment-specific dopamine dynamics in reinforcement learning

项目概要和摘要 物质使用障碍（SUD）是一种使人衰弱的疾病，其社会成本超过7亿美元 每年仅在美国。尽管SUD普遍存在并给全球带来重大财政负担， 该疾病的病理生理学知之甚少，目前的治疗效果有限。为核心 SUD是奖励学习和食欲动机的失调。这些作用是由药物介导的- 引起腹侧被盖区（VTA）多巴胺传递到丘脑腹侧核（NAc）的改变 投射途径，这已被因果联系到这些行为表型。此外， SUD显示VTA对NAc兴奋性和终末多巴胺释放的调节异常，进一步表明 支持该系统在表达失调的药物和非药物相关的 行为。在这个VTA到NAc的通路中，多巴胺从多个细胞区室释放- 包括体树突和终末--它们受不同分子、基于电路和受体的调节-- 基础机制。然而，虽然工作集中在体外测量多巴胺释放， 在终末，对该通路中其他隔室的释放作用知之甚少，例如 腹侧被盖区内的体树突释放以及这与基底动脉中动机性行为的执行的关系 状态这个提议的目的是了解特定于隔室的经验依赖可塑性， 是食欲动机和奖励学习的基础，然后定义其分子机制 可塑性为此，我们将结合使用尖端技术，包括体内纤维测光 在操作行为期间与荧光多巴胺传感器结合，以在脑内成像多巴胺瞬变。 VTA和NAc随时间的纵向变化。然后，我们将使用离体快速扫描循环伏安法结合 体树突和终末隔室中的光遗传学刺激和药理学，以定义受体- 这种多巴胺可塑性发生的机制。通过定义这些分子靶点， 作为奖励和动机的基础，这些实验将有助于确定可能推动学习的目标- mesolimbic pathway内的可塑性机制。因此，这些实验的结果 对识别和理解SUD中多巴胺失调的潜在机制具有广泛的意义 并且可以提供治疗途径以逆转这些过程中的缺陷。

Project Summary and Abstract Substance use disorder (SUD) is a debilitating disorder that has a societal cost of more than 700 million dollars per year in the US alone. Despite the prevalence and significant global financial burden of SUD, the pathophysiology of the disorder is poorly understood, and current treatments have limited efficacy. At the core of SUD is a dysregulation in reward learning and appetitive motivation. These effects are mediated by drug- induced alterations in dopamine transmission in the ventral tegmental area (VTA) to nucleus accumbens (NAc) projection pathway, which has been causally linked to these behavioral phenotypes. Further, animal models of SUD show dysregulation of VTA to NAc excitability and accumbal dopamine release at terminals, further supporting the critical role that this system plays in the expression of dysregulated drug and non-drug associated behaviors. Within this VTA to NAc pathway, dopamine is released from multiple cellular compartments – including somatodendritic and terminals - that are regulated by different molecular, circuit-based, and receptor- based mechanisms. However, while work has focused on ex vivo measurements of dopamine release at terminals, relatively little is known about the roles of release in other compartments within this pathway, such as somatodendritic release within the VTA and how this relates to the execution of motivated behaviors in a basal state. The goal of this proposal is to understand the compartment-specific experience-dependent plasticity that underlies appetitive motivation and reward learning in vivo and then define the molecular mechanisms for this plasticity. To this end, we will use a combination of cutting-edge techniques, including in vivo fiber photometry combined with fluorescent dopamine sensors during operant behavior to image dopamine transients within the VTA and NAc longitudinally over time. We will then use ex vivo fast scan cyclic voltammetry combined with optogenetic stimulation and pharmacology in somatodendritic and terminal compartments to define the receptor- based mechanisms by which this dopaminergic plasticity occurs. By defining these molecular targets that underlie reward and motivation, these experiments will help to identify targets that may be driving learning- dependent plasticity mechanisms within the mesolimbic pathway. As such, the results of these experiments have broad implications for identifying and understanding the potential mechanisms of dopamine dysregulation in SUD and may provide therapeutic avenues in order to reverse deficits in these processes.