The interplay of acute and chronic stress on medial prefrontal glutamate and reinforcement learning in major depression

Stress is a critical risk factor for the development of depressive symptoms, particularly those related to impaired reinforcement learning and decision-making. While numerous studies have implicated medial prefrontal cortex (mPFC) as a critical locus for the deleterious effects of stress, the specific mechanisms that mediate these effects are unknown. One candidate mechanism is alterations in medial prefrontal glutamate (Glu) and GABA neurotransmitters, which animal studies have found to be highly sensitive to stress exposure. To date however, no study has provided an in vivo assessment of Glu and GABA function in response to social stress in humans. Here, we present multimodal neuroimaging data (MR Spectroscopy and fMRI) recruited across three samples. In the first sample, we compared changes in mPFC Glu following an acute stressor in healthy controls (n=42). We observed a significant interaction between %change in mPFC Glu following stress and reported level of recent perceived stress (r = -0.444, p = 0.003). Additionally, we observed an association between %change in mPFC Glu and expected value encoding in the same region of mPFC during a reinforcement learning task. To ensure that these effects were driven by the acute stress manipulation, we also recruited an additional group of healthy controls who completed a non-stressful counting task. Consistent with expectations, there was no association between PSS scores and %change in mPFC for this non-stress control group, and linear regression analysis revealed a significant stress condition X PSS interaction (b = -0.632, p = 0.037). In the third sample, we examined this same acute stress X perceived stress interaction in a group of depressed patients (n = 29). We observed an “inverted U” pattern across the entire sample of patients and control such that as perceived stress scores increased to the maximum level, higher perceived stress was associated with greater %change in Glu following acute stress (quadratic model, p = 0.033). These changes were also associated with alterations in expected value encoding in mPFC during the same reinforcement learning task. Taken together, these data suggest that levels of chronic stress may interact with exposure to an acute stress to alter value encoding, and that dysregulation of glutamate may play a critical role in this process.