Circuit-specific mechanisms of reward and aversion in ventral tegmental area dopamine neurons

腹侧被盖区多巴胺神经元奖励和厌恶的电路特异性机制

基本信息

批准号：
10585085
负责人：
Stephan Lammel
金额：
$ 55.64万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585085
关键词：
Anatomy Attention Aversive Stimulus Award Behavior Behavior Disorders Behavioral Brain Cells Cues Development Disease Dopamine Dose Electrophysiology (science)Fiber Genetic Identity Goals Head Health Heterogeneity Human Image Individual Intravenous infusion procedures Investigation Lateral Learning Location Measurement Measures Medial Mediating Methodology Microdialysis Motivation Mus Neuroanatomy Neurons Nicotine Nicotinic Receptors Nucleus Accumbens Outcome Study Periodicity Photometry Positioning Attribute Prefrontal Cortex Presynaptic Terminals Prosencephalon Rewards Role Scanning Source Stimulus Structure Substance Use Disorder Testing Ventral Tegmental Area Virus cell type dopamine system dopaminergic neuron experimental study improved in vivo incentive salience insight learned behavior motivated behavior neuropsychiatric disorder novel optogenetics pharmacologic receptor function response

项目摘要

ABSTRACT Cue-driven behaviors are actions motivated by salient environmental stimuli. Maladaptive changes in cue- driven behaviors are fundamental to several neuropsychiatric disorders, including substance use disorder. Ventral tegmental area (VTA) dopamine (DA) neurons have often been assumed to homogeneously encode reward prediction errors. However, even within the nucleus accumbens (NAc), which is the major projection target of VTA DA neurons, DA release has been implicated in several behavioral functions, including reward, aversion, motivation, and incentive salience. This discrepancy might be, at least in part, due to the different methodologies used to record DA cell body activity versus DA release at the axon terminal level. Additionally, recent investigations suggest that VTA DA neurons might differentially contribute to reward and aversion dependent on their projection target and mediolateral position within the VTA. Here, we propose to further detail and define, in a circuit- and cell-type specific manner, the functional heterogeneity of the mesoaccumbal DA system. We will employ a three-pronged approach that leverages pharmacological manipulations, fiber photometry-based recordings of DA cell body activity and DA release, as well as in vivo electrophysiological recordings of DA neurons using Neuropixels and optogenetics. Our investigations will that takes the precise neuroanatomical position of DA neurons within the VTA and their corresponding NAc projection target into consideration. Experiments will be performed in head fixed mice during pharmacological manipulation or during reward seeking behavior as well as in freely behaving mice performing a two-armed bandit task. This will allow us to test whether DA dynamics mediated by different mechanisms in different locations (i.e., at the level of cell bodies versus terminals) underlie distinct behavioral functions. The primary goals are to (1) investigate how different doses of nicotine modulate DA release in distinct NAc subregions. Additionally, we will provide a systematic understanding of how nicotinic acetylcholine receptor function contributes to nicotine-induced DA release in different NAc subregions. (2) We will study how DA cell body activity and DA release in separate mesoaccumbal subcircuits contributes to reward learning and motivated behavior. (3) We will establish an in vivo electrophysiological approach that utilizes Neuropixels and optogenetics to record VTA DA neurons in a circuit- and cell-type specific manner in head fixed mice performing a reward seeking task. Together, we anticipate that these experiments will provide further evidence for our hypothesis that VTA DA neurons make specific contributions to reward learning and motivation in a projection-defined manner. Delineating the precise functions of separate mesoaccumbal DA subcircuits for reward learning and motivated behavior is a significant step in improving our understanding of their diverse roles in health and disease.

抽象的线索驱动的行为是由显着的环境刺激激发的行为。提示的适应不良变化驱动行为是多种神经精神疾病的基础，包括物质使用障碍。腹侧被盖区 (VTA) 多巴胺 (DA) 神经元通常被认为均匀编码奖励预测错误。然而，即使在伏隔核（NAc）内，这是主要的 VTA DA 神经元的投射目标，DA 释放与多种行为功能有关，包括奖励、厌恶、动机和激励显着性。这种差异可能是，至少部分是，由于记录 DA 细胞体活性与轴突处 DA 释放的方法不同终端级别。此外，最近的研究表明 VTA DA 神经元可能存在差异奖赏和厌恶的贡献取决于他们的投射目标和中间位置 VTA。在这里，我们建议以电路和单元类型特定的方式进一步详细说明和定义中累积 DA 系统的功能异质性。我们将采取三管齐下的方式利用药理操作、基于纤维光度测定的 DA 细胞体活动记录和 DA 释放，以及使用 Neuropixels 和 DA 神经元的体内电生理记录光遗传学。我们的研究将获取 DA 神经元的精确神经解剖学位置考虑 VTA 及其相应的 NAc 投影目标。将进行实验在药物操作或奖励寻求行为期间以及在头部固定的小鼠中行为自由的小鼠执行双臂强盗任务。这将使我们能够测试 DA 动态是否由不同位置的不同机制介导（即在细胞体与末端水平）是不同行为功能的基础。主要目标是 (1) 研究不同剂量的尼古丁调节不同 NAc 亚区的 DA 释放。此外，我们还将提供系统化的了解烟碱乙酰胆碱受体功能如何促进尼古丁诱导的 DA 释放位于不同的 NAc 次区域。 (2) 我们将研究DA细胞体活性和DA释放如何分开中累积子电路有助于奖励学习和动机行为。 (3) 我们将建立一个利用 Neuropixel 和光遗传学记录 VTA DA 神经元的体内电生理方法以电路和细胞类型特定的方式在头部固定的小鼠中执行奖励寻求任务。一起，我们预计这些实验将为我们的假设提供进一步的证据，即 VTA DA 神经元以预测定义的方式为奖励学习和动机做出具体贡献。描绘奖励学习和动机行为的独立中累积 DA 子电路的精确功能这是提高我们对它们在健康和疾病中不同作用的理解的重要一步。