ReviewFunctional profile of the binary brain corticosteroid receptor system: Mediating, multitasking, coordinating, integrating
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)
- et al.
mTOR signaling in the hippocampus is necessary for memory formation
Neurobiology of Learning and Memory
(2007) - et al.
Cognition and diabetes: a lifespan perspective
Lancet Neurology
(2008) - et al.
Mineralocorticoid receptors in control of emotional arousal and fear memory
Hormones and Behavior
(2009) - et al.
The use of mifepristone in the treatment of neuropsychiatric disorders
Trends in Endocrinology and Metabolism
(2006) - et al.
Feedback action and tonic influence of corticosteroids on brain function: a concept arising from the heterogeneity of brain receptor systems
Psychoneuroendocrinology
(1987) - et al.
Stress and cognition: are corticosteroids good or bad guys?
Trends in Neuroscience
(1999) - et al.
Corticosteroid receptor polymorphisms: determinants of vulnerability and resilience
European Journal of Pharmacology
(2008) - et al.
Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behavior
Psychoneuroendocrinology
(2013) - et al.
Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness
Frontiers in Neuroendocrinology
(2003) - et al.
The role of 11â-hydroxysteroid dehydrogenases in the brain
Molecular Cellular Endocrinolology
(2006)
The corticosteroid receptor hypothesis of depression
Neuropsychopharmacol
The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Corticosteroid effects in the brain: U-shape it
Trends in Pharmacology Science
Control of neuronal excitability by corticosteroid hormones
Trends in Neuroscience
The coming out of the brain mineralocorticoid receptor
Trends in Neuroscience
Chronic stress: implications for neuronal morphology, function and neurogenesis
Frontiers in Neuroendocrinology
Synaptic transmission changes in the pyramidal cells of the hippocampus in streptozotocin-induced diabetes mellitus in rats
Brain Research
Decreased expression of mineralocorticoid receptor mRNA and its splice variants in postmortem brain regions of patients with major depressive disorder
Journal of Psychiatry Research
Stress revisited: a critical evaluation of the stress concept
Neuroscience and Biobehavioral Reviews
The concept of allostasis in biology and biomedicine
Hormones and Behavior
What is in a name? Integrating homeostasis, allostasis and stress
Hormones and Behavior
Molecular genetics approaches to investigate individual variations in behavioral and neuroendocrine stress responses
Psychoneuroendocrinology
The history of pharmacology in The Netherlands
Trends in Pharmacology Science
Brain development under stress: hypotheses of glucocorticoid actions revisited
Neuroscience and Biobehavioral Reviews
Punch sampling biopsy technique
Methods in Enzymology
Neuronal and astroglial alterations in the hippocampus of a mouse model for type 1 diabetes
Brain Research
Effects of chronic stress on contextual fear conditioning and the hippocampal expression of the neural cell adhesion molecule, its polysialylation, and L1
Neuroscience
Subregion-specific differences in translocation patterns of mineralocorticoid and glucocorticoid receptors in rat hippocampus
Brain Research
Modulation of spatial and stimulus-response learning strategies by exogenous cortisol in healthy young women
Psychoneuroendocrinology
Stress impairs spatial but not early stimulus-response learning
Behavioral Brain Research.
The prevalence of comorbid depression in adults with diabetes: a meta-analysis
Diabetes Care
Resetting of circadian time in peripheral tissues by glucocorticoid signaling
Science
Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons
Science
Selective glucocorticoid receptor (type II) antagonist prevents and reverses olanzapine-induced weight gain
Diabetes, Obesity and Metabolism
Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease?
Diabetes
Cerebral function in diabetes mellitus
Diabetologia
Maternal care and cippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning and differential responsiveness to glucocorticoids and stress
Journal of Neuroscience
Expression profiling in laser-microdissected hippocampal subregions in rat brain reveals large subregion-specific differences in expression
European Journal of Neuroscience
Brain corticosteroid receptor balance and homeostatic control
Frontiers in Neuroendocrinology
Stress in the hippocampus
From the stalk to down under about brain glucocorticoid receptors, stress and development
Neurochemical Research
Stress and the brain: from adaptation to disease
Nature Review Neuroscience
Brain corticosteroid receptor balance in health and disease
Endocrine Reviews
Hoofdlijnen van het endocrinologisch onderzoek in Nederland na
Mineralocorticoid receptor gene variants as determinants of HPA axis regulation and behavior
Endocrine Development
A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness
Journal of Clinical Endocrinology and Metabolism
Chronic stress causes frontostriatal reorganzation and affects decision making
Science
The contribution of the adrenal gland to the total amount of progesterone produced in the female rat
Journal of Physiology
Cited by (58)
The unconditioned fear response in vertebrates deficient in dystrophin
2024, Progress in NeurobiologyNo influence of mineralocorticoid and glutamatergic NMDA receptor stimulation on spatial learning and memory in individuals with major depression
2022, Journal of Psychiatric ResearchThe interplay of hypoxic and mental stress: Implications for anxiety and depressive disorders
2022, Neuroscience and Biobehavioral ReviewsCitation 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 TherapeuticsA voxel-level brain-wide association study of cortisol at 8 a.m.: Evidence from Cushing's disease
2021, Neurobiology of Stress