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严重抑郁障碍(MDD)的核心症状。然而，标准的抗抑郁药物治疗-主要针对5-羟色胺能系统-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)在激励有机体为追求回报而付出努力方面发挥着至关重要的作用。此外，DAR能功能降低和DA周转减少长期以来一直与重度抑郁症有关，尽管这种DAR能功能改变的具体临床效果尚不清楚。该项目的具体目的是阐明健康受试者和MDD患者在基于努力的决策中的行为缺陷以及伴随而来的DAR能功能和皮质-纹状体回路的变化。为了实现这一点，我们开发了一种新的基于努力的决策行为测试。这项测试改编自一个经过充分验证的动物范式，该范式已被广泛用于表征大脑皮层损伤和DA阻断对大鼠基于努力的决策的影响。使用这一范式，我们收集了初步数据，表明在健康对照组中，努力支出减少与特质快感缺失有关。我们建议对一组健康对照受试者进行这项任务，这些受试者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进行系列PET扫描。此外，我们将在重度抑郁障碍患者和报告有享乐障碍症状的样本中使用这项任务，并在fMRI扫描期间将年龄、性别和惯用左撇子的样本与对照组相匹配。与公共卫生相关：MDD的快感缺乏和动力减弱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。通过提供一个减少努力-支出的特定行为模型，这可能与多巴能传递和皮质-纹状体回路的变化有关，这项研究有可能确定治疗抑郁症快感障碍的新靶点。

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.