Neural Mechanisms of Effort-Based Reward in Humans

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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.