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

定义隔室特异性多巴胺动力学在强化学习中的作用

• 批准号: 10458064
• 负责人: Suzanne Olivia Nolan
• 金额: $ 0.56万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458064
• 关键词: Affect; Animal Model; Animals; Area; Automobile Driving; Autoreceptors; Bathing; Behavior; Binding; Biological Models; Brain; Cells; Complex; Cues; Data; Desire for food; Disease; Dopamine; Dopamine Receptor; Exposure to; Feedback; Fiber; Financial Hardship; Foundations; Functional disorder; Goals; Image; Impairment; Individual; Injections; Knowledge; Learning; Link; Measurement; Measures; Mediating; Molecular; Molecular Target; Motivation; Nerve; Neurons; Neurophysiology - biologic function; Nose; Nucleus Accumbens; Pathway interactions; Pattern; Periodicity; Pharmaceutical Preparations; Pharmacology; Photometry; Play; Prevalence; Process; Proteins; Psychological reinforcement; Rewards; Role; Scanning; Signal Transduction; Site; Slice; Stimulus; Substance Use Disorder; Sucrose; Synapses; System; Techniques; Therapeutic; Time; Training; Ventral Tegmental Area; Work; awake; base; behavioral phenotyping; brain behavior; classical conditioning; conditioning; dopamine system; drug of abuse; effective therapy; experience; experimental study; in vivo; in vivo imaging; mRNA Differential Displays; mesolimbic system; motivated behavior; non-drug; optogenetics; receptor; response; selective expression; sensor; societal costs; targeted treatment; transmission process

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.

项目摘要和摘要 药物使用障碍（SUD）是一种使人衰弱的疾病，其社会成本超过7亿美元 仅在美国，每年。尽管SUD的普遍性和全球财务燃烧，但 该疾病的病理生理学知之甚少，目前的治疗效率有限。在核心 SUD是奖励学习和开胃动力的失调。这些作用是由药物介导的 腹侧换段区域（VTA）向伏隔核（NAC）的多巴胺传播的诱导变化 投影途径，偶尔与这些行为表型有关。此外，动物模型 SUD显示VTA对NAC兴奋性的失调和端子上的伏苯胺多巴胺释放，进一步 支持该系统在药物失调和非药物相关的表达中所起的关键作用 行为。在此VTA到NAC途径中，多巴胺从多个细胞室释放 - 包括分子，基于电路和接收器的体系中的体育和末端 - 基于机制。但是，尽管工作重点是在体内测量多巴胺释放的测量 终端对在此途径中其他隔室中释放的作用相对较少，例如 VTA中的somatdendritic释放，以及这与基本中成熟行为的执行之间的关系 状态。该提议的目的是了解特定于隔间的经验依赖性可塑性 在体内开胃动力和奖励学习的基础，然后为此定义分子机制 可塑性。为此，我们将使用尖端技术的组合，包括体内纤维光度法 在操作行为期间，与荧光多巴胺传感器结合图像多巴​​胺瞬变 VTA和NAC随着时间的流逝。然后，我们将使用离体快速扫描循环伏安法与 在体内和末端室中的光遗传学模拟和药理学，以定义接收器 这种多巴胺能可塑性的基于基于机制。通过定义这些分子靶标的 这些实验将有助于确定可能推动学习的目标 - 中边途径内的依赖性可塑性机制。因此，这些实验的结果具有 识别和理解SUD中多巴胺失调的潜在机制的广泛含义 并可能提供热途径以逆转这些过程。