Nature Communications volume 12, Article number: 3166 (2021 ) Cite this article
Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear. Preclinically, adaptive and maladaptive stress-induced changes in glutamatergic function have been observed in the medial prefrontal cortex (mPFC). Here, we examine stress-induced changes in human mPFC glutamate using magnetic resonance spectroscopy (MRS) in two healthy control samples and a third sample of unmedicated participants with MDD who completed the Maastricht acute stress task, and one sample of healthy control participants who completed a no-stress control manipulation. In healthy controls, we find that the magnitude of mPFC glutamate response to the acute stressor decreases as individual levels of perceived stress increase. This adaptative glutamate response is absent in individuals with MDD and is associated with pessimistic expectations during a 1-month follow-up period. Together, this work shows evidence for glutamatergic adaptation to stress that is significantly disrupted in MDD.
Stress is a major risk factor for physical and psychological health problems1 and has been strongly linked to the onset of major depressive disorder (MDD)1,2. Although ‘stress’ is often broadly defined, prior research has divided this construct into ‘good stress’, ‘tolerable stress’, and ‘toxic stress’, with the latter being associated with significant risk for physiological damage and mental illness3. Toxic stressors are frequently characterized by a lack of predictability and controllability4 and are often related to social threat, such as isolation, rejection, and exclusion5,6. One of the most widely replicated consequences of toxic stressors is stress-induced anhedonia, resulting in behavioral inhibition and a failure to pursue rewards7,8,9. Stress reduces acquisition of reward-related information8,10 and blunts activity in corticostriatal regions involved in reward processing, including the medial prefrontal cortex (mPFC), dorsal striatum, and orbitofrontal cortex11,12. Importantly, responses to stress are sensitive to individual differences, with diminished reward sensitivity only being observed in stress-reactive individuals13. Additionally, elevated perceptions of stress have been found to confer particular risk for blunted reward processing4,8,14, with self-reported levels of perceived stress predicting blunted neural responses to monetary reward in the mPFC14. To date, however, the neural mechanisms of stress-induced anhedonia and interactive effects of acute and perceived stress remain unclear.