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

• 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
• 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

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.

摘要 线索驱动行为是由显著的环境刺激激发的行为。适应不良的线索变化- 驱动行为是包括物质使用障碍在内的几种神经精神障碍的基础。 中脑被盖区（VTA）多巴胺（DA）神经元通常被认为是均匀编码的 奖励预测错误。然而，即使是在主要的神经元核（NAc）内， 作为腹侧被盖区DA神经元的投射靶点，DA释放与几种行为功能有关， 包括奖励、厌恶、动机和激励显著性。这种差异可能是，至少部分是， 由于用于记录DA细胞体活性与轴突处DA释放的方法不同 终端水平。此外，最近的研究表明，腹侧被盖区DA神经元可能差异 对奖赏和厌恶的贡献取决于它们在大脑中的投射靶点和内外侧位置。 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描述和定义 中脑DA系统的功能异质性。我们会采取三管齐下的方法， 利用药理学操作，基于纤维光度计的DA细胞体活性记录， DA释放，以及使用Neuropixels和 光遗传学我们的研究将采取精确的神经解剖位置的DA神经元内 VTA及其相应的NAc投影目标。将进行实验 在头部固定的小鼠中，在药理学操作期间或在奖励寻求行为期间，以及在 自由行为的老鼠执行一个双臂强盗任务。这将使我们能够测试DA动力学是否 由不同位置的不同机制介导（即，在细胞体与终端的水平上） 构成了不同的行为功能主要目标是（1）研究不同剂量的 尼古丁调节不同NAc亚区DA释放。此外，我们将提供一个系统的 了解尼古丁乙酰胆碱受体功能如何促进尼古丁诱导的DA释放 在不同的北大西洋公约组织次区域。(2)我们将分别研究DA细胞体活性和DA释放 中脑神经元亚回路有助于奖励学习和动机行为。(3)我们将建立一个 利用神经像素和光遗传学记录腹侧被盖区DA神经元的体内电生理方法 在电路和细胞类型的特定方式在头部固定小鼠执行奖励寻求任务。在一起， 我们预期这些实验将为我们的假设提供进一步的证据，即腹侧被盖区DA神经元 以项目定义的方式为奖励学习和激励做出具体贡献。划定 不同中脑DA神经回路在奖赏学习和动机行为中的精确功能 是提高我们对它们在健康和疾病中的不同作用的理解的重要一步。