Brain mineralocorticoid receptors (MR) mediate effects of glucocorticoid hormones in stress adaptation, as well as the effects of aldosterone itself in relation to salt homeostasis. Brain stem MRs ...respond to aldosterone, whereas forebrain MRs mediate rapid and delayed glucocorticoid effects in conjunction with the glucocorticoid receptor (GR). MR‐mediated effects depend on age, gender, genetic variations, and environmental influences. Disturbed MR activity through chronic stress, certain (endocrine) diseases or during glucocorticoid therapy can cause deleterious effects on affective state, cognitive and behavioural function in susceptible individuals. Considering the important role MR plays in cognition and emotional function in health and disease, MR modulation by pharmacological intervention could relieve stress‐ and endocrine‐related symptoms. Here, we discuss recent pharmacological interventions in the clinic and genetic developments in the molecular underpinnings of MR signalling. Further understanding of MR‐dependent pathways may help to improve psychiatric symptoms in a diversity of settings.
LINKED ARTICLES
This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone‐Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc
Glucocorticoids are steroid hormones that are of pivotal importance in human physiology. Glucocorticoid signaling is complex in nature and dependent on many interacting factors. As glucocorticoids ...exhibit sexually dimorphic effects on several key processes including in metabolism, crosstalk with the sex steroid hormones (androgens and estrogens) is relevant. In this review, we highlight the state-of-the-art knowledge on glucocorticoid sexual dimorphism and sex hormone crosstalk. We include current insight in the molecular mechanisms that underlie nuclear steroid receptor crosstalk, and sex hormone effects on glucocorticoid metabolism. Finally, we show how these findings translate to humans exposed to excess glucocorticoid signaling, and we propose future avenues in the emerging field of steroid hormone crosstalk.
Preclinical evidence shows that glucocorticoids have sexually dimorphic effects on metabolism in mice.Glucocorticoid-induced metabolic adverse effects like hyperinsulinemia and insulin resistance in mice are lost upon androgen deficiency.Receptors for androgens and estrogens can modulate transcriptional regulation by glucocorticoid receptors.Androgens and estrogens influence enzymatic regeneration of glucocorticoids by regulating 11β-HSD1 activity.Sexual dimorphism exists in the symptoms that patients with Cushing’s disease develop as a consequence of their hypercortisolism.
The pachychoroid disease spectrum (PDS) includes several chorioretinal diseases that share specific choroidal abnormalities. Although their pathophysiological basis is poorly understood, diseases ...that are part of the PDS have been hypothesized to be the result of venous congestion. Within the PDS, central serous chorioretinopathy is the most common condition associated with vision loss, due to an accumulation of subretinal fluid in the macula. Central serous chorioretinopathy is characterized by distinct risk factors, most notably a high prevalence in males and exposure to corticosteroids. Interestingly, sex differences and corticosteroids are also strongly associated with specific types of arteriovenous anastomoses in the human body, including dural arteriovenous fistula and surgically created arteriovenous shunts. In this manuscript, we assess the potential of such arteriovenous anastomoses in the choroid as a causal mechanism of the PDS. We propose how this may provide a novel unifying concept on the pathophysiological basis of the PDS, and present cases in which this mechanism may play a role.
Rationale
While human depressive illness is indeed uniquely human, many of its symptoms may be modeled in rodents. Based on human etiology, the assumption has been made that depression-like behavior ...in rats and mice can be modulated by some of the powerful early life programming effects that are known to occur after manipulations in the first weeks of life.
Objective
Here we review the evidence that is available in literature for early life manipulation as risk factors for the development of depression-like symptoms such as anhedonia, passive coping strategies, and neuroendocrine changes. Early life paradigms that were evaluated include early handling, separation, and deprivation protocols, as well as enriched and impoverished environments. We have also included a small number of stress-related pharmacological models.
Results
We find that for most early life paradigms per se, the actual validity for depression is limited. A number of models have not been tested with respect to classical depression-like behaviors, while in many cases, the outcome of such experiments is variable and depends on strain and additional factors.
Conclusion
Because programming effects confer vulnerability rather than disease, a number of paradigms hold promise for usefulness in depression research, in combination with the proper genetic background and adult life challenges.
Glucocorticoid hormones are essential for health, but overexposure may lead to many detrimental effects, including metabolic, psychiatric, and bone disease. These effects may not only be due to ...increased overall exposure to glucocorticoids, but also to elevated hormone levels at the time of the physiological circadian trough of glucocorticoid levels. The late Mary Dallman developed a model that allows the differentiation between the effects of overall 24-hour glucocorticoid overexposure and the effects of a lack of circadian rhythmicity. For this, she continuously treated rats with a low dose of corticosterone (or "B"), which leads to a constant hormone level, without 24-hour overexposure using subcutaneously implanted pellets. The data from this "B-flat" model suggest that even modest elevations of glucocorticoid signaling during the time of the normal circadian trough of hormone secretion are a substantial contributor to the negative effects of glucocorticoids on health.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Neuroimaging studies suggest that intranasal oxytocin (IN‐OXT) may modulate emotional and social processes by altering neural activity patterns. The extent of brain penetration after IN‐OXT is ...unclear, and it is currently unknown whether IN‐OXT can directly bind central oxytocin receptors (OXTRs). We investigated oxytocin pathway gene expression in regions affected by IN‐OXT on task‐based fMRI. We found that OXTR is more highly expressed in affected than unaffected subcortical regions; this effect did not vary by task type or sex. Cortical results revealed higher OXTR expression in regions affected by IN‐OXT in emotional processing tasks and in male‐only data. No significant differences were found in expression of the closely related vasopressin receptors. Our findings suggest that the mechanism by which IN‐OXT may alter brain functionality involves direct activation of central OXTRs.
This work combines brain imaging data with brain transcriptomic atlas data. This work suggests that intranasal oxytocin (IN‐OXT) exerts its effects on affected brain areas by directly binding locally expressed OXTR in human. The local expression of OXTR in subcortical brain areas affected (on fMRI) by intranasal oxytocin (IN‐OXT) is significantly higher than in unaffected regions, independent of task type or gender.
•Adolescence is a stress-sensitive window.•Stress in adolescence affects the response to a second stressor in adulthood.•Combination of adolescent and adult stressors induces sex-dependent effects.
...The two-hit stress model predicts that exposure to stress at two different time-points in life may increase or decrease the risk of developing stress-related disorders later in life. Most studies based on the two-hit stress model have investigated early postnatal stress as the first hit with adult stress as the second hit. Adolescence, however, represents another highly sensitive developmental window during which exposure to stressful events may affect programming outcomes following exposure to stress in adulthood. Here, we discuss the programming effects of different types of stressors (social and nonsocial) occurring during adolescence (first hit) and how such stressors affect the responsiveness toward an additional stressor occurring during adulthood (second hit) in rodents. We then provide a comprehensive overview of the potential mechanisms underlying interindividual and sex differences in the resilience/susceptibility to developing stress-related disorders later in life when stress is experienced in two different life stages.
Glucocorticoid stress hormones are powerful modulators of brain function and can affect mood and cognitive processes. The hippocampus is a prominent glucocorticoid target and expresses both the ...glucocorticoid receptor (GR: Nr3c1) and the mineralocorticoid receptor (MR: Nr3c2). These nuclear steroid receptors act as ligand‐dependent transcription factors. Transcriptional effects of glucocorticoids have often been deduced from bulk mRNA measurements or spatially informed individual gene expression. However, only sparse data exists allowing insights on glucocorticoid‐driven gene transcription at the cell type level. Here, we used publicly available single‐cell RNA sequencing data to assess the cell‐type specificity of GR and MR signaling in the adult mouse hippocampus. The data confirmed that Nr3c1 and Nr3c2 expression differs across neuronal and non‐neuronal cell populations. We analyzed co‐expression with sex hormones receptors, transcriptional coregulators, and receptors for neurotransmitters and neuropeptides. Our results provide insights in the cellular basis of previous bulk mRNA results and allow the formulation of more defined hypotheses on the effects of glucocorticoids on hippocampal function.
Highlights • We review direct and indirect effects of stress and glucocorticoids on neural stem/progenitor cell proliferation and adult hippocampal neurogenesis. • Glucocorticoids are released in a ...circadian as well as pulsatile manner which bear considerable biological significance. • We propose that glucocorticoid oscillations are crucial for regulation of neural stem/progenitor cell proliferation. • We discuss implications of changes in glucocorticoid oscillations for pathophysiology.
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