Elsevier

Brain Research

Volume 1293, 1 October 2009, Pages 129-141
Brain Research

Research Report
Glucocorticoid signaling and stress-related limbic susceptibility pathway: About receptors, transcription machinery and microRNA

https://doi.org/10.1016/j.brainres.2009.03.039Get rights and content

Abstract

Background. Stress is essential for health, but if coping with stress fails, the action of the stress hormones cortisol and corticosterone (CORT) becomes dysregulated, precipitating a condition favorable for increased susceptibility to psychopathology. We focus on the question how the action of CORT can change from protective to harmful. Approach. CORT targets the limbic brain, where it affects cognitive processes and emotional arousal. The magnitude and duration of the CORT feedback signal depends on bio-availability of the hormone, the activity of the CORT receptor machinery and the stress-induced drive. If CORT action becomes dysregulated, we postulate that this is linked to compromised receptor regulation in the limbic brain's susceptibility pathway. Results. CORT action on gene transcription is mediated by high affinity mineralocorticoid (MR) and 10 fold lower affinity glucocorticoid (GR) receptors that also can mediate fast non-genomic actions. MR and GR operate a feedback loop that involves access and binding to the receptors, activation and shuttling of the CORT receptor complexes, which require interaction with coregulators and transcription factors for transcriptional outcome. CORT modulates the expression of gene transcripts encoding specific chaperones, motor proteins and transcription factors as well as its own receptors. The emerging evidence of microRNAs operating translational control points to further fine-tuning in receptor signaling. Conclusion. Imbalance in MR:GR-mediated actions caused by receptor variants and epigenetic modulations have been proposed as risk factor in stress-related disease. We here provide key regulatory steps in the activation, transport and regulation of CORT receptors that may sensitize susceptibility pathways underlying psychopathology.

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.

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