In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.
This review summarizes the evidence that chronic or repeated stressors can cause neuronal disturbances that resemble the changes that are observed in the brain during depression. We focus on the stress hormones that are secreted by the adrenal gland (that is, primarily, cortisol in humans and corticosterone in rodents), which are secreted after stimulation by peptides that are released from the brain (corticotropin-releasing hormone or CRH) and pituitary gland (corticotropin or ACTH). The corticosteroids act together with the neuropeptides to facilitate adaptation to stress, but if dysregulated, they fail to do so during depression. The goal of the review is to identify mechanisms that are driven by the hormones that might explain why maladaptive changes produce stress-related disorders, such as depression, in some individuals, whereas others remain in excellent health under similar adverse conditions.
In the first part of the review, we highlight the adaptive stress-related processes in the limbic brain, which is an area that is involved in the appraisal of new experiences, learning and memory processes. The corticosteroid actions are mediated by nuclear receptors, which are abundantly expressed in these limbic neurons. Two receptor types have been identified: one receptor system (mineralocorticoid receptors or MRs) has a role in the appraisal process and, therefore, in the onset of the stress response; the other system (glucocorticoid receptors or GRs) facilitates recovery from stress. We postulate that MRs and GRs function in a binary fashion.
In the second part of the review, we discuss how an inappropriate stress response might lead to a vulnerable phenotype. One model of such an inappropriate response is the chronically stressed animal that shows structural and functional changes in the limbic brain. These changes include aspects of neurogenesis, structural remodelling and synaptic plasticity that might be related to behavioural impairments. Other animal models focus on the role of genetic background and early experience in shaping stress reactivity. Conditions are discussed that programme adaptation to stress depending on mother–infant interactions.
In the third and final part of the review, we address how, in genetically predisposed humans, stressful situations might precipitate hypercortisolaemia, as seen in depression, or hypocortisolaemia, as found in post-traumatic stress disorder (PTSD). In the most extreme cases of hypercortisolaemia, psychotic symptoms occur (steroid psychosis). This research has proceeded to the point that genetic factors can be identified in, for example, MR- and GR-related genes, which render individuals either resilient or vulnerable to developing affective disorders.
The review concludes with the statement that, together with other stress-system mediators, a binary response system that is operated by corticosteroids preserves health and homeostasis. Their proper function determines the capacity of the organism to contain stress reactions in the acute phase and in the management of the late recovery phase. Imbalance might cause a vulnerable phenotype for mental illness to evolve.
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The authors gratefully acknowledge support by the Netherlands Organization for Scientific Research (NWO) and the Royal Netherlands Academy for Arts and Sciences.
E.R.d.K. and F.H. are on the scientific advisory board of Corcept Therapeutics Inc., and F.H. is on the board of directors of Affectis Pharmaceuticals AG.
Excess levels of circulating cortisol.
- POST-TRAUMATIC STRESS DISORDER
(PTSD). The symptoms of PTSD consist of re-experiencing an extreme stressor or traumatic event, avoidance of reminders of the event and hyperarousal.
- HYPOTHALAMIC–PITUITARY–ADRENAL AXIS
(HPA axis). The HPA axis is the endocrine core of the stress system, which involves hypothalamic corticotropin-releasing hormone, pituitary corticotropin and adrenal cortisol.
- ULTRADIAN RHYTHM
The regular recurrence of cycles of less than 24 h from one stated point to another.
- AMINERGIC PATHWAYS
Systems that involve serotonin or catecholamines.
- SERIAL ANALYSIS OF GENE EXPRESSION
(SAGE). This method allows the analysis of overall gene-expression patterns. SAGE does not require a pre-existing clone, so it can be used to identify and quantify new as well as known genes.
- DNA MICROARRAY
Technology that can simultaneously measure the expression patterns of thousands of genes on a single chip.
- LONG-TERM POTENTIATION
The prolonged strengthening of synaptic communication, which is induced by patterned input and is thought to be involved in learning and memory formation.
- CUSHING DISEASE
A hormonal disorder that is caused by prolonged exposure of the body tissues to high levels of cortisol, owing to a tumour in the adrenal or anterior pituitary.
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