Review
Functional profile of the binary brain corticosteroid receptor system: Mediating, multitasking, coordinating, integrating

https://doi.org/10.1016/j.ejphar.2013.04.053Get rights and content

Abstract

This contribution is focused on the action of the naturally occurring corticosteroids, cortisol and corticosterone, which are secreted from the adrenals in hourly pulses and after stress with the goal to maintain resilience and health. To achieve this goal the action of the corticosteroids displays an impressive diversity, because it is cell-specific and context-dependent in coordinating the individual's response to changing environments. These diverse actions of corticosterone are mediated by mineralocorticoid- and glucocorticoid-receptors that operate as a binary system in concert with neurotransmitter and neuropeptide signals to activate and inhibit stress reactions, respectively. Classically MR and GR are gene transcription factors, but recently these receptors appear to mediate also rapid non-genomic actions on excitatory neurotransmission suggesting that they integrate functions over time. Hence the balance of receptor-mediated actions is crucial for homeostasis. This balanced function of mineralo- and glucocorticoid-receptors can be altered epigenetically by a history of traumatic (early) life events and the experience of repeated stressors as well as by predisposing genetic variants in signaling pathways of these receptors. One of these variants, mineralocorticoid receptor haplotype 2, is associated with dispositional optimism in appraisal of environmental challenges. Imbalance in receptor-mediated corticosterone actions was found to leave a genomic signature highlighting the role of master switches such as cAMP response element-binding protein and mammalian target of rapamycin to compromise health, and to promote vulnerability to disease. Diabetic encephalopathy is a pathology of imbalanced corticosterone action, which can be corrected in its pre-stage by a brief treatment with the antiglucocorticoid mifepristone.

Introduction

My first encounter with Willem Hendrik Gispen was in the spring of 1970. Willem Hendrik (WH), already at young age a distinguished member of David de Wied's dreamteam, welcomed me at the doorstep of the Rudolf Magnus Institute with the words: “Doctor, may I carry your tool bag?”. The reference was to a bag that contained a designer etui with the inscription ‘brain dissection instruments’ containing two pairs of tweezers, one pair of scissors, a razor blade and a small Perspex® surface. These precious instruments allowed an, at the time, innovative dissection of the rat brain on ice into sixteen neuro-anatomically defined areas, which was achieved by gently pulling the tissues apart along natural boundaries. The use of this methodology led to the 7th paper published by Gispen et al. (1972) highlighting the relevance of disturbed RNA metabolism in the brain stem for fear avoidance of the hypophysectomized animals. For me, it was the very first paper in the journal Neuroendocrinology; this first paper bought me right away the status of last and senior author.

Dissection methods have become ever more refined over the years. For instance the ‘Palkovits punch’, which implied the punching of tissue from frozen rat brain sections occurred with hollow stainless steel needles of 200 μm up to 1000 μm in diameter to remove neuro-anatomically defined nuclei (Palkovits, 1983). The data production line was quite rewarding: cutting brain sections, punching, sampling punches, homogenizing, extracting, measuring, collecting data, typing and then the manuscript was accepted right away by a friendly editor in a journal of unknown impact. Today, on screen laser microdissection and subsequent pressure catapulting of the dissected areas from 8 μm frozen brain sections is in vogue. RNA in extracts of such laser-dissected tissue or, alternatively of electrophysiologically identified individual cells (Nair et al., 2004), is amplified and hybridized to GeneChips. Gene profiling combined with refined dissection approaches revealed abundant expression of gene networks involved in cell metabolism and cell adhesion in the hippocampal CA3 pyramidal cell field, while in the hippocampal dentate gyrus gene clusters involved in neurogenesis, cell differentiation and protein biosynthesis prevailed (Datson et al., 2004).

The enormous diversity in actions of the corticosteroid stress hormones corticosterone (rodent) and cortisol (human), as revealed in genomic analysis in microdissected brain areas (Datson et al., 2004) and validated by in situ histochemical approaches is the theme of my contribution. These diverse actions exerted by corticosterone and cortisol are mediated by glucocorticoid- and mineralocorticoid-receptors that display an uneven cellular expression in the brain and operate as a binary system in a complementary, sometimes opposite, fashion (Joëls, 2006). The signaling diversity allows these steroids to coordinate the various brain and body functions required to facilitate behavioral and physiological adaptation of the whole individual to change.

In this essay I will review the evidence that the signaling pathways activated by both receptor types, need to operate in balance in maintenance of homeostasis, resilience and health. Imbalance in these receptor mediated actions as caused by stress, aberrant corticosterone exposure or genetic receptor variations appears to compromise health and to enhance vulnerability to disease (De Kloet, 1991, De Kloet and Reul, 1987, De Kloet et al., 1998, De Kloet et al., 2005). I will conclude, in WH's honor, with a study on the outcome of an imbalanced action of the corticosteroids in an altered insulin milieu: diabetic encephalopathy.

Section snippets

Some facts about corticosteroids

The first adrenal glucocorticoid hormone, corticosterone, was identified in 1936 with support of the Dutch pharmaceutical company ‘Organon’ by Tadeus Reichstein together with Ernst Laqueur (1880–1947). Laqueur may be considered the father of the famous Netherlands School in Neuro-endocrine Pharmacology that nurtured eminent scientists like Marius Tausk and David de Wied, and also my one time predecessor in Leiden, Samuel de Jongh (Noach, 1990, De Knecht-van Eekelen, 19931947, 〈//www.leidenuniv.medicalpharmacology.nl

Stress

What is stress? This simple question has kept numerous investigators entertained ever since Selye coined the term in 1935 (Selye and McKeown, 1935, Selye, 1936) by stating: “stress is a state of non-specific tension in living matter, which manifests itself by tangible morphologic changes in various organs and particularly in the endocrine glands which are under anterior pituitary control”. Another definition states that “stress may be defined as a real or interpreted threat to the physiological

Mineralocorticoid and glucocorticoid receptors

The effects of both naturally occurring corticosteroids in the brain are mediated by two types of nuclear receptors: mineralocorticoid and glucocorticoid receptors, which act in the cell nucleus as gene transcription factors Reul and De Kloet (1985). The mineralocorticoid receptors (MR) are abundantly expressed in limbic structures such as the hippocampus, amygdala, septum and pre-frontal cortical regions. The glucocorticoid receptors (GR) are ubiquitous in neurons and glial cells with highest

Permissive and regulatory corticosterone actions

A favorite approach to study the role of these receptors has been to adrenalectomize rodents and then replace the adrenally-deficient animals with physiological amounts of corticosterone to reveal its permissive function in normalizing energy metabolism, neurogenesis and plasticity in response to challenges. Such effects exerted by low doses of corticosterone are relatively more MR- than GR-mediated. Yet, from clinical studies it is obvious that the efficacy of steroid replacement is more than

The MR:GR balance hypothesis

MR and GR operate in complementary fashion as master switch in control of plasticity, resilience and adaptation to stress. Thus, MR modulates appraisal processes involved in the onset of psychological stress reactions, while GR is more involved in management of later adaptations. The MR:GR balance hypothesis predicts that, upon imbalance in MR:GR signaling pathways, the response to challenge is less well communicated. At a certain threshold, this may lead to a condition of HPA axis

Cognitive flexibility: focus on MR

More than two decades of behavioral studies by Melly S. Oitzl and colleagues have revealed that MR- and GR-mediated effects of corticosterone modulate the integration of emotional expression and cognitive performance (Oitzl and De Kloet, 1992, Oitzl et al., 1994, Oitzl et al., 2010). Hence, MR- and GR-mediated actions interact, proceed in a coordinated manner, and are linked in time to particular stages of information processing. It is important to realize that corticosterone acts conditional.

MR haplotypes and optimism

Individual variation in HPA axis reactivity to stressors has many causes including genetics of the different components including corticosteroid receptors Mormède et al., (2002). MR and GR show genetic variation and protein isoforms (Revollo and Cidlowski, 2009). Moreover, receptor function is influenced by at least 50 proteins such as heatshock proteins, co-regulators and transcription factors, that as well can occur as genetic variants providing all together an impressive signaling diversity.

Chronic stress

Selye (1952) distinguished three phases in the “general adaptation syndrome” that develop in the organism after chronification of stressors: a brief alarm phase, then a resistance phase for several weeks and at last an exhaustion phase when adaptive mechanisms break down. The resistance phase is characterized by increased adrenal weight, an enhanced and prolonged corticosterone response and reduced thymus weight. In brain, hippocampal pyramidal layers and prefrontal targets of corticosterone

Diabetes

Diabetes displays neuropathy which becomes manifest as a moderate slowing of mental speed and diminished mental flexibility (Biessels et al., 2008) and elevated corticosterone, that accompanies diabetes, may contribute to these cognitive impairments (Sandeep et al., 2004). A meta-analysis revealed co-morbidity of diabetes with depression (Anderson et al., 2001). In our studies, Yanina Revsin in collaboration with Alex De Nicola and colleagues, used the streptozotocin-treated mouse as a model to

Concluding remark

Every force requires a counter force for balance ” was a quote from Aristoteles' wisdom in one of WH's wonderful reflections on today's world, entitled: “Because even donkey’s have extremely complex brains (translated in English)” (Gispen, 2008b). The present essay focused on one of the most important hormones controling homeostatic mechanisms: corticosterone. This single hormone is capable to modulate the onset and the termination of the stress response via MR- and GR-mediated signaling

Acknowledgment

The support by the Royal Netherlands Academy of Sciences, Top Institute Pharma #5-209, ESF-Eurostress, EU Lifespan & HFSP is gratefully acknowledged. I also would like to express my gratitude to the colleagues of the Department of Medical Pharmacology, Leiden University, to Professor Marian Joëls and her research group at Utrecht Medical Center, and my dear colleagues in The Netherlands and abroad for sharing experimental data and stimulating discussions. For further information //www.rondekloet.nl

References (124)

  • F. Holsboer

    The corticosteroid receptor hypothesis of depression

    Neuropsychopharmacol

    (2000)
  • C.S. Jernigan et al.

    The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder

    Progress in Neuro-Psychopharmacology and Biological Psychiatry

    (2011)
  • M. Joëls

    Corticosteroid effects in the brain: U-shape it

    Trends in Pharmacology Science

    (2006)
  • M. Joëls et al.

    Control of neuronal excitability by corticosteroid hormones

    Trends in Neuroscience

    (1992)
  • M. Joëls et al.

    The coming out of the brain mineralocorticoid receptor

    Trends in Neuroscience

    (2008)
  • M. Joëls et al.

    Chronic stress: implications for neuronal morphology, function and neurogenesis

    Frontiers in Neuroendocrinology

    (2007)
  • A. Kamal et al.

    Synaptic transmission changes in the pyramidal cells of the hippocampus in streptozotocin-induced diabetes mellitus in rats

    Brain Research

    (2006)
  • M.D. Klok et al.

    Decreased expression of mineralocorticoid receptor mRNA and its splice variants in postmortem brain regions of patients with major depressive disorder

    Journal of Psychiatry Research

    (2011)
  • J.M. Koolhaas et al.

    Stress revisited: a critical evaluation of the stress concept

    Neuroscience and Biobehavioral Reviews

    (2011)
  • B.S. McEwen et al.

    The concept of allostasis in biology and biomedicine

    Hormones and Behavior

    (2003)
  • B.S. McEwen et al.

    What is in a name? Integrating homeostasis, allostasis and stress

    Hormones and Behavior

    (2010)
  • P. Mormède et al.

    Molecular genetics approaches to investigate individual variations in behavioral and neuroendocrine stress responses

    Psychoneuroendocrinology

    (2002)
  • E.L. Noach

    The history of pharmacology in The Netherlands

    Trends in Pharmacology Science

    (1990)
  • M.S. Oitzl et al.

    Brain development under stress: hypotheses of glucocorticoid actions revisited

    Neuroscience and Biobehavioral Reviews

    (2010)
  • M. Palkovits

    Punch sampling biopsy technique

    Methods in Enzymology

    (1983)
  • Y. Revsin et al.

    Neuronal and astroglial alterations in the hippocampus of a mouse model for type 1 diabetes

    Brain Research

    (2005)
  • C. Sandi et al.

    Effects of chronic stress on contextual fear conditioning and the hippocampal expression of the neural cell adhesion molecule, its polysialylation, and L1

    Neuroscience

    (2001)
  • R.A. Sarabdjitsingh et al.

    Subregion-specific differences in translocation patterns of mineralocorticoid and glucocorticoid receptors in rat hippocampus

    Brain Research

    (2009)
  • L. Schwabe et al.

    Modulation of spatial and stimulus-response learning strategies by exogenous cortisol in healthy young women

    Psychoneuroendocrinology

    (2009)
  • L. Schwabe et al.

    Stress impairs spatial but not early stimulus-response learning

    Behavioral Brain Research.

    (2010)
  • R.J. Anderson et al.

    The prevalence of comorbid depression in adults with diabetes: a meta-analysis

    Diabetes Care

    (2001)
  • A. Balsalobre et al.

    Resetting of circadian time in peripheral tissues by glucocorticoid signaling

    Science

    (2000)
  • J. Barik et al.

    Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons

    Science

    (2013)
  • J.K. Belanoff et al.

    Selective glucocorticoid receptor (type II) antagonist prevents and reverses olanzapine-induced weight gain

    Diabetes, Obesity and Metabolism

    (2010)
  • S.B. Bender et al.

    Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease?

    Diabetes

    (2013)
  • G.J. Biessels et al.

    Cerebral function in diabetes mellitus

    Diabetologia

    (1994)
  • D.L. Champagne et al.

    Maternal care and cippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning and differential responsiveness to glucocorticoids and stress

    Journal of Neuroscience

    (2008)
  • Daskalakis, N.P., Bagot, R.C., Parker, K.J., Vinkers, C.H., de Kloet, E.R., 2013. The three-hit concept of...
  • N.A. Datson et al.

    Expression profiling in laser-microdissected hippocampal subregions in rat brain reveals large subregion-specific differences in expression

    European Journal of Neuroscience

    (2004)
  • E.R. De Kloet

    Brain corticosteroid receptor balance and homeostatic control

    Frontiers in Neuroendocrinology

    (1991)
  • E.R. De Kloet

    Stress in the hippocampus

  • E.R. de Kloet et al.

    From the stalk to down under about brain glucocorticoid receptors, stress and development

    Neurochemical Research

    (2008)
  • E.R. De Kloet et al.

    Stress and the brain: from adaptation to disease

    Nature Review Neuroscience

    (2005)
  • De Kloet, E.R., Joëls M., 2013. Stress research: past, presence and future. In: Pfaff, D.Z. (Ed.), Neuroscience in the...
  • E.R. De Kloet et al.

    Brain corticosteroid receptor balance in health and disease

    Endocrine Reviews

    (1998)
  • A. De Knecht-van Eekelen

    Hoofdlijnen van het endocrinologisch onderzoek in Nederland na

    (1993)
    (1947)
  • R.H. DeRijk et al.

    Mineralocorticoid receptor gene variants as determinants of HPA axis regulation and behavior

    Endocrine Development

    (2011)
  • R.H. DeRijk et al.

    A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness

    Journal of Clinical Endocrinology and Metabolism

    (2006)
  • E. Dias-Ferreira et al.

    Chronic stress causes frontostriatal reorganzation and affects decision making

    Science

    (2009)
  • A.B. Fajer et al.

    The contribution of the adrenal gland to the total amount of progesterone produced in the female rat

    Journal of Physiology

    (1971)
  • Cited by (58)

    • The interplay of hypoxic and mental stress: Implications for anxiety and depressive disorders

      2022, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Stressors induce the release of oxytocin, vasopressin, and corticotropin-releasing factor (CRF). The latter stimulates the anterior pituitary to produce adrenocorticotropic hormone (ACTH) (Vale et al., 1981), which – delivered by the blood stream to the adrenal gland – leads to the release of glucocorticoids, the most prominent being cortisol (corticosterone in rodents) (De Kloet, 2013). Cortisol enables the organism to deal more efficiently with stressful situations (e.g., by increasing glucose concentration in the blood), but at the same time exerts a negative feedback loop effect on both the hypothalamus and pituitary to avoid over-production of corticotropin-releasing and adrenocorticotropic hormone.

    • Drugs under investigation for treatment-resistant depression

      2022, Managing Treatment-Resistant Depression: Road to Novel Therapeutics
    View all citing articles on Scopus
    View full text