Neural Mechanisms of Effort-Based Reward in Humans

人类基于努力的奖励的神经机制

• 批准号: 7886565
• 负责人: Michael Tilghman Treadway
• 金额: $ 2.25万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886565
• 关键词: Address; Age; Amphetamines; Anhedonia; Animal Model; Animals; Anterior; Antidepressive Agents; Behavioral; Behavioral Model; Biological Neural Networks; Corpus striatum structure; Data; Decision Making; Diagnosis; Disease; Dopamine; Event; Exhibits; Expenditure; Functional Magnetic Resonance Imaging; Gender; Goals; Handedness; Human; Image; Individual; Individual Differences; Lesion; Ligands; Link; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Mental Depression; Mental disorders; Motivation; Neurobiology; Neurotransmitters; Organism; Patient Self-Report; Performance; Play; Positron-Emission Tomography; Prevalence; Process; Productivity; Psychopathology; Rattus; Reporting; Research; Rewards; Role; Running; Sampling; Severities; Symptoms; System; Techniques; Testing; Training; United States; Ventral Striatum; base; behavior measurement; behavior test; clinical effect; cost; dopamine system; human subject; insight; instrument; neuromechanism; novel; preclinical study; preference; public health relevance; receptor; receptor binding; relating to nervous system; sex; theories; trait; transmission process; willingness

DESCRIPTION (provided by applicant): Anhedonia and reduced motivation for reward are core symptoms of major depressive disorder (MDD). However, standard antidepressant treatments - which primarily target the serotonergic system - have been found to be less successful at addressing these symptoms. A significant body of evidence from preclinical studies suggests that the neurotransmitter dopamine (DA) plays a crucial role in motivating an organism to expend effort in pursuit of reward. Furthermore, reduced DAergic function and decreased DA turnover have long been associated with major depression, though the specific clinical effects of this altered DAergic function remain unclear. The specific aims of this project are to elucidate behavioral deficits in effort-based decision making and accompanying alterations in DAergic function and cortico-striatal circuitry in healthy subjects and individuals with MDD. To achieve this, we have developed a novel behavioral test of effort-based decision making. This test was adapted from a well-validated animal paradigm that has been used extensively to characterize the impact of cortical lesions and DA blockade on effort-based decision making in rats. Using this paradigm, we have collected preliminary data suggesting that reduced effort-expenditure is associated with trait-anhedonia in healthy controls. We propose to run this task with a group of healthy control subjects who will undergo serial PET scans using the D2/D3 receptor ligand [18F] Fallypride during both a baseline timepoint and during an amphetamine challenge. In addition, we will use this task in a sample of individuals with Major Depressive Disorder and reported anhedonic symptoms and a sample of age, gender and handedness matched controls during an fMRI scan. PUBLIC HEALTH RELEVANCE: Symptoms of anhedonia and reduced motivation in MDD are a significant component of the disorder, but specific treatments for these symptoms are lacking. By providing a specific behavioral model of reduced effort-expenditure that may be linked to alterations in DAergic transmission and cortico-striatal circuitry, this research has the potential to identify novel targets for the treatment of anhedonia in depression.

描述（由申请人提供）：快感缺乏和奖励动机降低是重度抑郁症（MDD）的核心症状。然而，主要针对血清素能系统的标准抗抑郁治疗被发现在解决这些症状方面不太成功。来自临床前研究的大量证据表明，神经递质多巴胺 (DA) 在激励有机体努力追求奖励方面发挥着至关重要的作用。此外，DAergic 功能的降低和 DA 周转率的降低长期以来一直与重度抑郁症相关，尽管这种 DAergic 功能改变的具体临床效果仍不清楚。该项目的具体目标是阐明健康受试者和重度抑郁症患者基于努力的决策中的行为缺陷以及伴随的 DAergic 功能和皮质纹状体回路的改变。为了实现这一目标，我们开发了一种新颖的基于努力的决策行为测试。该测试改编自经过充分验证的动物范例，该范例已被广泛用于表征皮质损伤和 DA 阻断对大鼠基于努力的决策的影响。使用这种范式，我们收集了初步数据，表明健康对照中努力支出的减少与特质快感缺失有关。我们建议与一组健康对照受试者一起运行此任务，这些受试者将在基线时间点和安非他明挑战期间使用 D2/D3 受体配体 [18F] Fallypride 进行连续 PET 扫描。此外，我们将在功能磁共振成像扫描期间对患有重度抑郁症并报告快感缺乏症状的个体样本以及年龄、性别和用手习惯匹配的对照样本中使用此任务。公共卫生相关性：MDD 的快感缺乏和动机降低的症状是该疾病的一个重要组成部分，但缺乏针对这些症状的具体治疗方法。通过提供一种减少努力消耗的特定行为模型（可能与 DAergic 传输和皮质纹状体回路的改变有关），这项研究有可能确定治疗抑郁症快感缺乏的新靶标。