MR/GR Signaling in the Brain during the Stress Response

Abstract

This contribution is about mineralocorticoid receptors (MRs) in their capacity as mediators of glucocorticoid action in the brain. This paradox has evolved because MRs are promiscuous and bind with high-affinity cortisol and corticosterone as well as aldosterone, deoxycorticosterone, and progesterone. The MRs "see," however, predominantly glucocorticoids, because of their 100-1000-fold excess over aldosterone; bioavailability is further enhanced because of local regeneration of glucocorticoids by 11βOH-steroid dehydrogenase (HSD-1). In contrast to these glucocorticoid-preferring MR, the evolutionary later appearance of aldosterone-selective MR in epithelial cells depends on co-localization with the oxidase 11β-hydroxysteroid-dehydrogenase type 2 (HSD-2) in a few hundred neurons in the nucleus tractus solitarii (NTS), which innervate frontal brain regions to regulate cognitive, emotional, and motivational aspects of salt appetite. The glucocorticoid-MRs and classical glucocorticoid receptors (GRs) mediate in a complementary manner the glucocorticoid coordination of circadian events and mediate the regulation of stress coping and adaptation. If an individual is exposed to a threat, MRs are crucial for the selection of a particular coping style, which is via GR activation subsequently stored in the memory for future use. Our contribution is concluded with the notion that an imbalance in MR-and GR-mediated actions increases susceptibility to stress-related disorders.

Excitation-Inhibition Imbalance Leads to Alteration of Neuronal Coherence and Neurovascular Coupling under Acute Stress

“…Acute stress increases the level of corticosterone and subsequently activates two adrenal steroid receptors, namely, GRs and MRs, both of which induce the alteration of synaptic transmission via nongenomic and genomic pathways ( de Kloet and Meijer, 2019 ). In this study, we found that acute stress decreased the ratio of sEPSCs to sIPSCs with an increasing trend in the sIPSC amplitude and a decreasing trend in the sEPSC amplitude ( Fig.…”

Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders

“…Thus, MRs and GRs form a tightly co-regulated network that coordinates stress response and this observation led to the genesis of MR/GR balance hypothesis [ 30 ]. According to this hypothesis, an imbalance between the effects of GRs and MRs during the stress response may lead to dysregulation of the HPA axis and an inability to adapt to stressors and restore homeostasis, thereby conferring an increased vulnerability to a number of stress-related disorders [ 45 ].…”

Unexpected Consequences of Noise-Induced Hearing Loss: Impaired Hippocampal Neurogenesis, Memory, and Stress

“…Under normal conditions, low-levels of CORT mainly binds to and activates MRs (see Ogita et al, 2012 ; Mifsud and Reul, 2018 ), but during periods of stress, CORT increases to high enough levels that it activates GRs. GRs are expressed on cells throughout the brain, but are heavily expressed on cells in the hippocampus (de Kloet et al, 1993 ; de Kloet and Meijer, 2019 ). The hippocampus is believed to be especially vulnerable to stress because it contains one of the highest densities of GRs in the brain (Joels et al, 2018 ).…”