Neural Mechanisms of Effort-Based Reward in Humans

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，标准的抗抑郁治疗——主要针对血清素能系统——已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）在激励生物体付出努力追求奖励方面起着至关重要的作用。此外，DA能功能降低和DA转换减少长期以来与重度抑郁症有关，尽管这种改变的DA能功能的具体临床效果尚不清楚。本项目的具体目的是阐明健康受试者和重度抑郁症患者在努力决策中的行为缺陷，以及伴随的能功能和皮质纹状体回路的改变。为了达到这个目的，我们开发了一种新的基于努力的决策行为测试。该测试改编自一个经过充分验证的动物模型，该模型已被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。使用这种模式，我们收集到的初步数据表明，在健康对照中，努力支出的减少与特质快感缺乏症有关。我们建议在一组健康的对照受试者中进行这项任务，他们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，我们将在患有重度抑郁症和报告的快感缺乏症状的个体样本中使用该任务，并在fMRI扫描中使用年龄，性别和利手性匹配的对照样本。公共卫生相关性：重度抑郁症中快感缺乏和动机降低的症状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。通过提供一种可能与能量传递和皮质纹状体回路改变有关的减少努力-消耗的特定行为模型，该研究有可能确定治疗抑郁症快感缺乏的新靶点。

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.