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）：Anhedonia和减少奖励动机是重度抑郁症（MDD）的核心症状。但是，已经发现标准抗抑郁药（主要针对血清素能系统）在解决这些症状方面不太成功。临床前研究的大量证据表明，神经递质多巴胺（DA）在激励有机体以追求奖励方面的努力方面起着至关重要的作用。此外，尽管这种改变的DAergic功能的特定临床效应尚不清楚，但长期以来，DAERGIC功能和DA周转率降低一直与重度抑郁症相关。该项目的具体目的是阐明基于努力的决策做出的行为缺陷，以及在健康受试者和患有MDD的个人中的DAERGIC功能和皮质 - 纹状体电路的变化。为了实现这一目标，我们已经开发了基于努力的决策的新型行为测试。该测试改编自验证良好的动物范式，该范式已广泛用于表征皮质病变和DA阻断对大鼠基于努力的决策的影响。使用此范式，我们收集了初步数据，这表明减少的努力支出与健康对照中的特征 - anhedonia有关。我们建议通过一组健康的对照对象进行此任务，他们将在基线时间点和苯丙胺挑战期间使用D2/D3受体配体[18F] Fallypride进行连环PET扫描。此外，我们将在患有严重抑郁症的个体样本中使用此任务，并报告了在fIMRI扫描期间的厌氧症状以及年龄，性别和握手的样本。公共卫生相关性：Anhedonia的症状和MDD动机减少是该疾病的重要组成部分，但缺乏针对这些症状的具体治疗方法。通过提供减少努力支出的特定行为模型，这可能与DAERGIC传播和皮质 - 纹状体电路的变化有关，这项研究有可能识别抑郁症Anhedonia的新目标。