Project Summary/Abstract Anhedonia in patients with major depressive disorder (MDD) frequently fails to respond to available psychosocial and pharmacological treatments and has been robustly linked to marked disability as well as suicidal risk. A well-validated model of anhedonia suggests that anhedonia may result from prolonged exposure to stress (i.e. “stress-induced anhedonia”) as manifested by chronic behavioral inhibition and a failure to pursue rewards. One proposed mechanism of stress-induced anhedonia is alteration of glutamate function in medial prefrontal cortex (mPFC). To investigate this hypothesis in humans, we recently conducted a series of studies using single-voxel MR spectroscopy measures of glutamate in mPFC before and after an acute stress challenge. We found that mPFC glutamate increased in healthy controls with low levels of stress, but decreased glutamate responses in controls with high levels of stress. Interestingly, in unmedicated MDD patients, we found no change or an increase in mPFC glutamate following stress. This altered mPFC glutamate response to stress in MDD patients was in turn correlated with negative expectations of future events and thus may be a mechanism by which chronic stress is translated into impaired reward valuation and reduced motivation. Consistent with this notion, the NMDA receptor antagonist ketamine has been shown to improve anhedonic symptoms in both pre-clinical and clinical studies. Nevertheless, the role of mPFC and other regions in this altered glutamate stress response in MDD or its association with RDoC positive valence constructs that underlie anhedonia has yet to be fully established. Moreover, whether reversal of this altered glutamate response in MDD underlies the effects of ketamine on anhedonia is unknown. Thus, the current proposal seeks to use whole-brain multi-modal 3D ultrahigh resolution spectroscopic MRI (SMRI) and fMRI assessments of RDoC constructs related to reward valuation and motivation to examine glutamate responses to stress and its relationship with symptoms and neurocognitive correlates of anhedonia before and after a ketamine challenge in MDD patients. We will use a novel SMRI sequence to measure glutamate before and after an acute stressor and a no-stress control in 60 healthy controls and 80 MDD patients. After baseline scanning, MDD patients will be randomized to receive a single dose of intravenous ketamine or placebo, and complete follow-up scans at 24-hours and 2 weeks. By establishing an altered glutamate response to stress as a mechanism for anhedonic effects of chronic stress and its reversal by ketamine, these data will be able to serve as a drug discovery platform for other pharmacologic agents targeting the glutamate system to treat stress-induced anhedonia.