Neural circuit control of mesolimbic dopamine and reward

中脑边缘多巴胺和奖励的神经回路控制

• 批准号: 10242228
• 负责人: Daniel Patrick Covey
• 金额: $ 24.9万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242228
• 关键词: Adaptive Behaviors; Amphetamines; Behavior; Behavioral; Brain; Brain region; CNR1 gene; Calcium; Cells; Consumption; Cues; Desire for food; Disease; Dopamine; Drug Addiction; Drug abuse; Electron Microscopy; Elements; Fiber; Food; Functional disorder; Glutamates; Goals; Hyperphagia; Hypothalamic structure; Image; Immunohistochemistry; In Situ Hybridization; Individual; Institution; Intake; Lateral; Learning; Measures; Mediating; Mental Depression; Mentors; Morale; Motivation; National Institute of Drug Abuse; Neurons; Nucleus Accumbens; Obesity; Optics; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Photometry; Population; Presynaptic Terminals; Process; Psychopathology; Research; Research Proposals; Rewards; Role; Self Administration; Shapes; Signal Transduction; Sucrose; Synapses; Techniques; Training; Ventral Tegmental Area; Viral; Work; cell type; cellular targeting; clinically relevant; dopaminergic neuron; drug of abuse; drug reinforcement; drug reward; effective therapy; endocannabinoid signaling; endogenous cannabinoid system; experience; experimental study; gamma-Aminobutyric Acid; genetic approach; health economics; knock-down; motivated behavior; neural circuit; neuromechanism; novel; optogenetics; psychostimulant; relating to nervous system; response; reward processing; skills; therapy development; virtual; virus genetics

Project Summary Mesolimbic dopamine (DA) projections from the ventral tegmental area (VTA) to nucleus accumbens (NAc) serve a fundamental role in goal-seeking. This neural circuit is thus central to adaptive behavior (e.g., finding food), but can also promote psychopathologies characterized by hyper-motivation (e.g., drug abuse or obesity) or hypo- motivation (e.g., apathy or depression), all of which exact an enormous toll on individual an economic health. Afferent projections from numerous brain regions synapse onto VTA DA neurons to control their activity. The current proposal aims to identify how specific inputs to DA neurons contribute to their role in motivated behaviors and disease states. This work will focus on two primary mechanisms controlling brain DA function and reward- related behavior. First, the lateral hypothalamus (LH) has been the subject of intense research for well over 50 years due to its fundamental role in virtually all aspects of motivated behaviors, reward processing, and reward consumption. Second, the endocannabinoid (eCB) system is a vast signaling network that acts throughout the brain and periphery to regulate numerous homoeostatic processes, but serves a particularly important role in modulating brain DA function. We will use state-of-the art techniques to identify cell type- and neural circuit- specific mechanisms by which eCB signaling controls LH influence on DA neurons and how these mechanisms contribute to specific components of food-seeking behaviors. We will then assess similarities and differences between the neuronal mechanisms that control food seeking versus drug-seeking by investigating their role in the voluntary intake of amphetamine, one of the most widely abused drugs worldwide. Together, these experiments aim to elucidate the functional overlap and distinctions between precise neural circuit mechanisms that control adaptive versus aberrant forms of reward-driven behavior, with the ultimate goal of fundamentally understanding motivated actions and developing safe and effective treatments for aberrant forms of reward seeking that characterize, for example, drug abuse or obesity.

项目摘要 腹侧被盖区(VTA)至伏核(NAC)的中脑边缘多巴胺投射 在寻找目标的过程中起着重要的作用。因此，这种神经回路是适应行为(例如，寻找食物)的中心，但是 还可以促进以过度动机(例如，药物滥用或肥胖)或缺乏动力为特征的精神病理。 动机(例如，冷漠或抑郁)，所有这些都对个人的经济健康造成了巨大的损失。 来自许多大脑区域的传入投射突触到VTA DA神经元，以控制它们的活动。这个 目前的提案旨在确定DA神经元的特定输入如何有助于它们在动机行为中的作用 和疾病状态。这项工作将集中在控制大脑DA功能和奖赏的两个主要机制上。 相关行为。首先，50多年来，外侧下丘脑一直是密集研究的对象。 多年来，由于它在激励行为、奖励处理和奖励的几乎所有方面都发挥了基础作用 消费。其次，内源性大麻素(ECB)系统是一个庞大的信号网络，它作用于整个 大脑和外周调节许多稳态过程，但在以下方面起着特别重要的作用 调节大脑DA功能。我们将使用最先进的技术来识别细胞类型和神经回路- ECB信号控制促黄体生成素对DA神经元影响的具体机制及其机制 对食物寻觅行为的特定组成部分有贡献。然后，我们将评估相似和不同之处 通过研究神经机制在控制食物寻找和药物寻找中的作用 自愿服用苯丙胺，这是世界上被滥用最广泛的药物之一。加在一起，这些 实验旨在阐明精确的神经回路机制之间的功能重叠和区别 控制奖励驱动行为的适应性和反常形式，其最终目标是从根本上 了解动机行为并开发安全有效的奖励形式异常治疗方法 例如，寻求这一特征的药物滥用或肥胖。