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Nature Reviews Neuroscience
6, 463-475 (2005); doi:10.1038/nrn1683
STRESS AND THE BRAIN: FROM ADAPTATION TO
DISEASE
E. Ron de Kloet,
Marian Joëls & Florian Holsboer
about the authors
Abstract
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.
Summary
- 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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