Blocking the Mineralocorticoid Receptor in Humans Prevents the Stress-Induced Enhancement of Centromedial Amygdala Connectivity with the Dorsal Striatum

Abstract

Two research lines argue for rapid stress-induced reallocations of neural network activity involving the amygdala. One focuses on the role of norepinephrine (NE) in mediating a shift towards the salience network and improving vigilance processing, whereas the other focuses on the role of cortisol in enhancing automatic, habitual responses. It has been suggested that the mineralocorticoid receptor (MR) is critical in shifting towards habitual responses, which are supported by the dorsal striatum. However, until now it remained unclear whether these two reallocations of neural recourses might be part of the same phenomenon and develop immediately after stress onset. We combined methods used in both approaches and hypothesized specifically that stress would lead to rapidly enhanced involvement of the striatum as assessed by amygala-striatal connectivity. Furthermore, we tested the hypothesis that this shift depends on cortisol interacting with the MR, by using a randomized, placebo-controlled, full-factorial, between-subjects design with the factors stress and MRblockade (spironolactone). We investigated 101 young, healthy men using functional magnetic resonance imaging after stress induction, which led to increased negative mood, heart rate, and cortisol levels. We confirmed our hypothesis by revealing a stress-by-MR-blockade interaction on the functional connectivity between the centromedial amygdala (CMA) and the dorsal striatum. Stress rapidly enhanced CMA-striatal connectivity and this effect was correlated with the stress-induced cortisol response, but required MR availability. This finding might suggest that the stress-induced shift described by distinct research lines might capture different aspects of the same phenomenon, ie, a reallocation of neural resources coordinated by both NE and cortisol. Neuropsychopharmacology (2015) 40, 947-956;

Stress Induces a Shift Towards Striatum-Dependent Stimulus-Response Learning via the Mineralocorticoid Receptor

“…The current study was part of a large-scale study investigating stress-effects depending on MR-availability. Two other data sets acquired in the same participants using independent tasks investigated the role of the MR in emotional face processing (Vogel et al, 2015b) and fear learning (Vogel et al, 2015a). Thus, the overall study set-up was described elsewhere and is only briefly summarized here, focusing on the spatial memory experiment.…”

“…Three participants were excluded due to either panic attacks, motion sickness, or the discovery of concurrent participation in another drug study. This resulted in a final number of 98 participants (mean age 21.9 years (SD = 2.9)) not differing in age, body-mass-index, or trait anxiety (Vogel et al, 2015a(Vogel et al, , 2015b.…”

“…Inside the MRI room, participants underwent a stress induction or a non-stressful control procedure (described below). A short emotional face processing task followed (Vogel et al, 2015b). Approximately 17 (±4) min after stress induction, participants started with the spatial memory task.…”

“…After pill ingestion and habituation to the laboratory environment, participants were brought to the MRI room and underwent either the socially evaluated cold pressure test (S1) or a non-stressful control procedure. After another task probing emotional face processing (Vogel et al, 2015b), participants performed the spatial memory task. Stress-related increases in negative mood, cortisol, and, at trend level, heart rate displayed successful stress induction in both drug groups.…”

“…Other studies in rodents suggested that this shift depends on corticosteroids binding to the mineralocorticoid receptor (MR) (Schwabe et al, 2010) which can rapidly activate the amygdala in-vitro (Karst et al, 2010). In humans, MR-activation under stress was associated with increased functional connectivity between amygdala and striatum in tasks probing emotional face processing and classification learning, possibly contributing to the stress-induced shift (Schwabe et al, 2013a;Vogel et al, 2015b).…”