Neural circuit control of mesolimbic dopamine and reward

项目摘要 中脑边缘多巴胺（DA）从腹侧被盖区（VTA）向中脑背核（NAc）的投射 在追求目标的过程中扮演重要角色。因此，这种神经回路是自适应行为的核心（例如，寻找食物），但 也可以促进以过度动机为特征的精神病理学（例如，药物滥用或肥胖）或低- 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。 来自许多脑区的传入投射突触到腹侧被盖区DA神经元上以控制它们的活动。的 目前的建议旨在确定DA神经元的特定输入如何促进其在动机行为中的作用 和疾病状态。这项工作将集中在两个主要机制控制大脑DA功能和奖励- 相关行为。首先，外侧下丘脑（LH）一直是深入研究的主题， 由于它在激励行为、奖励处理和奖励的几乎所有方面都起着基础性作用， 消费第二，内源性大麻素（eCB）系统是一个巨大的信号网络，在整个组织中起作用。 大脑和外周调节许多稳态过程，但在以下方面发挥特别重要的作用： 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LH对DA神经元影响的具体机制，以及这些机制如何影响DA神经元， 对觅食行为的特定组成部分有贡献。然后我们将评估相似性和差异性 通过研究控制食物寻找和药物寻找的神经机制在 自愿服用安非他明，这是全世界滥用最广泛的药物之一。所有这些 实验旨在阐明精确神经回路机制之间的功能重叠和区别， 控制适应性与异常形式的奖励驱动行为，最终目标是从根本上 了解动机行为，并为异常形式的奖励开发安全有效的治疗方法 寻求那些特征，例如，药物滥用或肥胖。

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.