Reduced adaptation of glutamatergic stress response is associated with pessimistic expectations in depression

Jessica A Cooper,Makiah R Nuutinen,Emma C Hahn,Elyssa M Barrick,J Eric Jensen,George M Slavich,Fei Du,Daniel J Cole,Diego A Pizzagalli,Shabnam Hossein,Brittany A M Devries,Chelsea V Leonard,Victoria M Lawlor,Andrew P Teer,Michael T Treadway,Grant S Shields,Dost Ongur

doi:10.1038/s41467-021-23284-9

Abstract

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.

Highlights

Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear
We examine changes in glutamate following an acute stressor and how these changes relate to perceived stress using magnetic resonance spectroscopy (MRS), a method that has been widely used to examine in vivo changes in glutamatergic metabolites[29,30,31]
We found that healthy individuals exhibited a clear reduction of medial prefrontal cortex (mPFC) glutamate response to a new stressor (%ΔGlu) as their levels of recent perceived stress increased

Summary

Introduction

Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear. 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. Animal studies have strongly implicated this region in both risk and resilience for learned helplessness behavior, where individuals form expectations that their actions are incapable of impacting future outcomes[28] Taken together, this literature suggests that repeated stress exposure may significantly alter mPFC glutamate function, which in turn may contribute to depressive phenotypes. Consistent with our hypotheses, we find that in healthy control participants, but not participants with depression, the magnitude of mPFC glutamate response to the acute stress task decreases as individual levels of perceived stress increase. This work shows evidence for glutamatergic adaptation to stress that is significantly disrupted in MDD

Methods

Results

Conclusion