Top‐down and bottom‐up control of stress‐coping

Abstract

In this 30th anniversary issue review, we focus on the glucocorticoid modulation of limbic‐prefrontocortical circuitry during stress‐coping. This action of the stress hormone is mediated by mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) that are co‐expressed abundantly in these higher brain regions. Via both receptor types, the glucocorticoids demonstrate, in various contexts, rapid nongenomic and slower genomic actions that coordinate consecutive stages of information processing. MR‐mediated action optimises stress‐coping, whereas, in a complementary fashion, the memory storage of the selected coping strategy is promoted via GR. We highlight the involvement of adipose tissue in the allocation of energy resources to central regulation of stress reactions, point to still poorly understood neuronal ensembles in the prefrontal cortex that underlie cognitive flexibility critical for effective coping, and evaluate the role of cortisol as a pleiotropic regulator in vulnerability to, and treatment of, trauma‐related psychiatric disorders.

Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression

“…NMDA receptor stimulation did not affect hormone secretion, but the MR agonist fludrocortisone inhibited cortisol (but not aldosterone or DHEA-S) across groups. It is well known that MR stimulation inhibits HPA activity 51,52 . In accordance with our previous findings, the cortisol responses to fludrocortisone did not differ between young, unmedicated depressed patients and healthy individuals in the current study 53 .…”

MR/GR Signaling in the Brain during the Stress Response

“…Via GR, the experience is contextualized in the hippocampus and rationalized in the prefrontal cortex, with more "altruistic" solutions that increase motivation to assign a valence to social solutions and rewards. Phase 4: "Priming" refers to memory storage of the experience for future use (adapted from [27,28,64,65] is maintained. Finally, via MRs the context of the experience and the selected coping style are encoded for learning [71][72][73].…”

“…The coping circuit and its modulating inputs are all targets of the glucocorticoids that convey environmental and physiological information. This bottom-up control exerted by the glucocorticoids is mediated by the MR and GR in a complementary manner along the four different phases of stress coping and adaptation [64] (see Figure 1). The action of the glucocorticoid during stress coping and adaptation has led to the formulation of the MR/GR balance hypothesis, which states that "upon imbalance of the MR-and GR-mediated actions, the initiation and/or management of the stress response becomes compromised.…”

Brain preparedness: The proactive role of the cortisol awakening response

“…It is released mainly by the zona fasciculata of the adrenal cortex in the adrenal gland (14) and can cross the blood-brain barrier to affect the neuronal excitability and functional organization of brain networks, thereby fostering behavioral adaptation to cognitive and environmental challenges (15). The conventional neurobiological models posit that glucocorticoids exert both rapid nongenomic and slower genomic actions on the limbic-frontal networks especially the hippocampus and prefrontal cortex (PFC), via high-affinity mineralocorticoid receptors (MRs) and low-affinity glucocorticoid receptors (GRs) that are co-expressed abundantly in these brain regions (16,17). Specifically, the MR initiates rapid changes in the assembly of specific neural circuits allowing a quick and adequate response to the ongoing stressful event (18).…”

“…Research in animal models and humans has shown that the GR-mediated slow genomic effect on neuronal activity is not expected to start earlier than approximately 90 min after cortisol administration, and often lasts for hours (19,20). This process can promote contextualization, rationalization and memory storage of experiences, thereby priming brain circuits to be prepared for upcoming challenges in similar contexts (17,21). Thus, it is conceivable that the CAR, with a burst of the cortisol concentration in response to awakening in the morning, may proactively affect the brain and cognition via a similar MR/GR-mediated actions of cortisol.…”