Research ReportGlucocorticoid signaling and stress-related limbic susceptibility pathway: About receptors, transcription machinery and microRNA
Introduction
Glucocorticoid hormone secretion by the adrenals occurs in hourly pulses, which coordinate and synchronize daily- and sleep-related events (Lightman et al., 2008). This ultradian rhythm in glucocorticoids has the highest amplitude around awakening; it is thought that such large glucocorticoid pulses are needed in anticipation of an energy-consuming day. If an organism becomes ill, old or stressed out the ultradian rhythm becomes disorganized compromising the hormone's ability to adjust the organism to the demands of day and night (Young et al., 2004).
Glucocorticoid secretion can be enhanced any time in response to a stressor. A rapid stress-induced secretion of glucocorticoids is a sign of health and resilience as long as hormone secretion is turned off efficiently. In fact, the glucocorticoid surge after stress promotes behavioral adaptation, but if the hormone response is inadequate, excessive or prolonged, cognition becomes impaired and emotions imbalanced (de Kloet et al., 2005, Joels et al., 2007, McEwen, 2007). Inappropriate glucocorticoid signaling also has unwanted consequences for e.g. immune competence, inflammatory responses, bone and intermediary metabolism and cardiovascular functions (Chrousos and Gold, 1992). Hence, dysregulated glucocorticoid secretion either in basal pulsatility or in the response to stressors has profound consequences for body and brain functions. The principal glucocorticoid hormone of man is cortisol, and of rat corticosterone, collectively indicated here as CORT.
The stress reaction represents a physiological and behavioral adaptation to conditions that threaten the integrity of the organism, either real or imagined. The most severe stress reaction occurs if an individual has no information and no control of upcoming events and an uncertain fearful feeling. Such psychological stressful information is typically processed in limbic circuitry, e.g. in interconnected hippocampal, amygdaloid and cortical circuits where the appraisal of novel situations is intimately linked to emotional responses and cognitive processes (Aggleton and Brown, 2005, LeDoux, 2007, McGaugh, 2004).
Signals from the limbic circuitry reach trans-synaptically afferents to the neurons in the paraventricular nucleus of the hypothalamus, which produce corticotrophin releasing hormone (CRH) and other peptidergic secretagogs such as vasopressin (Herman et al., 2005). Peptidergic efferents from the CRH neuron organize the behavioral, autonomous and neuroendocrine response to the stressor in which CORT plays such an important role (Holsboer and Ising, 2008). The neuroendocrine responses are funneled predominantly through the hypothalamic–pituitary–adrenal (HPA) axis, but also prolactine and growth hormone cascades are profoundly affected by stressors.
CORT, the end product of the HPA axis, feeds back precisely on the pathways that triggered the initial stress reaction, and this feedback occurs in concert with the actions of numerous stress mediators. Feedback on the brain re-establishes stability in these circuits and hence facilitates attenuation of the stress reaction. While exerting this feedback action CORT enhances plasticity and remodeling of nerve cells, a process that forms the basis of the allostasis concept (McEwen and Wingfield, 2003). Hence, the limbic circuit processing the psychological component of a stress reaction is targeted by CORT. The signaling cascade of CORT locally in limbic neurons is considered here a stress-related susceptibility pathway. This pathway is crucial in the search for new targets to treat stress-related brain disorders (de Kloet et al., 2007, Holsboer, 2008, Krishnan and Nestler, 2008).
This contribution to the special issue on Stress, Coping and Disease is about the feedback of CORT to the limbic brain, a process thought fundamental for adaptive plasticity during stress. We will first consider the feedback concept based on CORT activation of its receptors, then follow the executive function of the hormone from adrenocortical secretion to receptor modulation of the genome (Fig. 1), culminating into the latest twist in the story: translational control by microRNAs (Fig. 2). With this new information at hand we turn to the crucial question: how come that CORT, which is essential for adaptation and health, can change from protective to harmful? What is the cause? What are the consequences?
Section snippets
Glucocorticoid and mineralocorticoid receptors
Only 2 years after Selye (1936; Selye, 1998) launched the stress concept, Dwight Ingle (Ingle and Kendall, 1937) demonstrated the negative feedback action of CORT in a classic experiment. First, removal of the pituitary caused atrophy of the adrenals and the same occurred after administration of CORT, which was just discovered by Reichstein and Laqueur (Reichstein et al., 1936). Second, adrenal weight recovered after the administration of pituitary extracts to the hypophysectomized rats, but in
CORT receptor balance hypothesis
Interestingly, many years ago Selye (1952) proposed the pendulum hypothesis, which viewed excess mineralocorticoids as pro-inflammatory and promoting risk of inflammation, while excess glucocorticoids as anti-inflammatory and enhancing the risk of infection. Today, the MR:GR balance hypothesis requires only 1 hormone: the naturally occurring glucocorticoids cortisol or corticosterone and two receptor types: MR and GR.
The balance in MR:GR mediated actions in the limbic brain is thought crucial
Access to the receptors
The adrenocortical response to a stressor and ACTH is acute in corticosterone secretion and with a slow onset in adrenal growth. The biosynthetic pathway leading to CORT synthesis involves cytochrome P-450 enzymes. The rate-limiting step is the conversion of cholesterol to pregnenolone which occurs upon the transportation of cholesterol to mitochondria by steroidogenic acute regulatory protein (StAR), a process which is stimulated by ACTH via melanocortin 2 (MC-2) receptors (Stocco, 2001). In
Receptor translocation
CORT-mediated effects are exerted through different genomic and non-genomic mechanisms. These mechanisms differ in their intracellular location and timeframe. Genomic mechanisms are slower, require modulation of gene expression and take place in the nuclear compartment, while non-genomic mechanisms are faster and take place at the membrane level (Fig. 1) (Stahn et al., 2007). Non-genomic effects contribute to fast behavioral effects, while genomic effects facilitate suppression of temporarily
Transcription factors and co-regulators
MR and GR both bind to GREs, but GR is much better capable to interact with transcription factors such as activating protein (AP-1) and nuclear factor kappa B (NFkB) (Pearce and Yamamoto, 1993). This finding provided a firm mechanistic underpinning to the concept advanced by Munck (Munck et al., 1984, Sapolsky et al., 2000) that glucocorticoids actually block primary stress reactions. It is now known that they achieve this blockade through the interaction of the GR monomers with transcription
Regulation of genes involved in CORT signaling
Large-scale expression profiling studies in animal models exposed to acute or chronic stressors, or to pharmacological manipulation of CORT levels, have provided insight into the functional gene classes regulated by CORT in the brain. From these studies it has become very clear that the pleiotropic action of CORT is reflected at the molecular level by the many classes of transcripts that are subject to CORT regulation (Datson et al., 2008). One particular group of transcripts that stands out is
Regulation of MR and GR protein levels: a potential role for microRNAs
Absolute GR and MR protein levels are an important determinant for the magnitude of glucocorticoid-responsiveness in a particular cell (Bamberger et al., 1996). In that respect, it is important to note that by recent progress in gene expression profiling techniques (see e.g. t Hoen et al., 2008) a novel class of small non-coding RNAs have been discovered. These non-coding transcripts of approximately 21 nucleotides are called microRNAs that downregulate protein levels in a cell by translational
Perspectives
This contribution to the Special volume of Stress, Coping and Disease highlights a specific susceptibility pathway in the pathogenesis stress-related psychopathology: the feedback loop of CORT in the limbic circuitry. We focus on limbic CORT action because any stressor has a psychological component and involves the limbic circuitry, where cognitive processes and emotions are fundamental in processing of stressful information. Above all limbic structures are important targets for the action of
Acknowledgments
Supported by Royal Netherlands Academy of Arts and Science, the Netherlands Science Foundation, TopInstitute Pharma and EU-Lifespan. Dr. SA Fratantoni is acknowledged for editorial assistance.
References (137)
- et al.
Subcellular distribution of the glucocorticoid receptor and evidence for its association with microtubules
J. Steroid Biochem. Mol. Biol.
(1995) A hierarchy of regulatory genes controls a larva-to-adult developmental switch in C. elegans
Cell
(1989)- et al.
Neuronal microtubules: when the MAP is the roadblock
Trends Cell Biol.
(2005) MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
(2004)Glucocorticoid feedback increases the sensitivity of the limbic system to stress
Physiol. Behav.
(2002)- et al.
Regulation of ACTH secretion: variations on a theme of B
Recent Prog. Horm. Res.
(1987) - et al.
Central corticosteroid actions: Search for gene targets
Eur. J. Pharmacol.
(2008) - et al.
Stress and cognition: are corticosteroids good or bad guys?
Trends Neurosci.
(1999) - et al.
Corticosteroid hormones in the central stress response: quick-and-slow
Front Neuroendocrinol.
(2008) - et al.
Mineralocorticoid receptor polymorphisms
Corticosteroid receptor polymorphisms: determinants of vulnerability and resilience
Eur. J. Pharmacol.
Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification
J. Steroid Biochem. Mol. Biol.
The genomic structure of the human glucocorticoid receptor
J. Biol. Chem.
Multi-modulation of nuclear receptor coactivators through posttranslational modifications
Trends Endocrinol. Metab
Evidence for glucocorticoid receptor transport on microtubules by dynein
J. Biol. Chem.
Limbic system mechanisms of stress regulation: hypothalamo–pituitary–adrenocortical axis
Prog. Neuropsychopharmacol. Biol. Psychiatry
The role of 11beta-hydroxysteroid dehydrogenases in the brain
Mol. Cell. Endocrinol.
The corticosteroid receptor hypothesis of depression
Neuropsychopharmacology
Central CRH system in depression and anxiety-evidence from clinical studies with CRH1 receptor antagonists
Eur. J. Pharmacol.
Corticosteroid effects in the brain: U-shape it
Trends Pharmacol. Sci.
Learning under stress: how does it work?
Trends Cogn. Sci.
Chronic stress: implications for neuronal morphology, function and neurogenesis
Front Neuroendocrinol.
The coming out of the brain mineralocorticoid receptor
Trends Neurosci.
Localization of glucocorticoid receptors at postsynaptic membranes in the lateral amygdala
Neuroscience
Corticosteroid-binding globulin, a structural basis for steroid transport and proteinase-triggered release
J. Biol. Chem.
A mammalian microRNA expression atlas based on small RNA library sequencing
Cell
The amygdala
Curr. Biol.
The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14
Cell
Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets
Cell
The significance of glucocorticoid pulsatility
Eur. J. Pharmacol.
Glucocorticoid receptor isoforms generate transcription specificity
Trends Cell Biol.
The concept of allostasis in biology and biomedicine
Horm. Behav.
Epigenetic mechanisms of perinatal programming of hypothalamic–pituitary–adrenal function and health
Trends Mol. Med.
The problem of neuronal cell types: a physiological genomics approach
Trends Neurosci.
Chaperoning steroid hormone action
Trends. Endocrinol. Metab.
Role of hsp90 and the hsp90-binding immunophilins in signalling protein movement
Cell Signal.
Contrasting hippocampal and perirhinal cortex function using immediate early gene imaging
Q. J. Exp. Psychol. B
Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor
Science
Corticosteroids mediate fast feedback of the rat hypothalamic–pituitary–adrenal axis via the mineralocorticoid receptor
Am. J. Physiol. Endocrinol Metab.
Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids
Endocr. Rev.
Maternal care and hippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress
J. Neurosci.
The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis
JAMA
Intracellular glucocorticoid signaling: a formerly simple system turns stochastic
Sci. STKE
A novel antiinflammatory maintains glucocorticoid efficacy with reduced side effects
Mol. Endocrinol.
Reciprocal actions of REST and a microRNA promote neuronal identity
Proc. Natl. Acad. Sci. U. S. A.
Pharmacological evidence that the inhibition of diurnal adrenocorticotropin secretion by corticosteroids is mediated via type I corticosterone-preferring receptors
Endocrinology
Starvation: early signals, sensors, and sequelae
Endocrinology
Identification of corticosteroid-responsive genes in rat hippocampus using serial analysis of gene expression
Eur. J. Neurosci.
The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression
Endocr. Rev.
Differences in corticosterone and dexamethasone binding to rat brain and pituitary
Endocrinology
Cited by (109)
Heterogeneity in major depressive disorder: The need for biomarker-based personalized treatments
2023, Advances in Clinical ChemistryTargeting epigenetics as future treatments of trauma- and stress-or-related disorders. Epidrugs and epinutraceuticals
2022, Epigenetics of Stress and Stress DisordersStress & executive functioning: A review considering moderating factors
2020, Neurobiology of Learning and MemoryMicroRNAs and the Response to Stress
2020, Stress: Genetics, Epigenetics and Genomics Volume 4: Handbook of Stress