Ultradian glucocorticoid exposure directs gene-dependent and tissue-specific mRNA expression patterns in vivo

George, Charlotte; Birnie, Matthew T.; Flynn, Benjamin P.; Kershaw, Yvonne M.; Lightman, Stafford L.; Conway-Campbell, Becky

doi:10.1016/j.mce.2016.10.019

Cited by 26 publications

(24 citation statements)

References 65 publications

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“…Endogenous glucocorticoid hormones (cortisol and corticosterone) are synthesized and secreted in response to stressful life experiences as well as released under basal conditions with well-defined basal circadian and ultradian rhythms [1,2]. It is well known that stress-evoked glucocorticoid release yields transcriptional responses [3], but the ultradian rhythm additionally generates a pulsatile transactivation or transrepression of gene targets that maintains basal gene-and cell-type specific transcriptional programs [4][5][6]. This pulsatile gene activation does not occur in response to the commonly used synthetic glucocorticoids, which especially during long term use, are associated with metabolic and neuropsychiatric side-effects [7].…”

Section: Introductionmentioning

confidence: 99%

Beyond the heterodimer model for mineralocorticoid and glucocorticoid receptor interactions in nuclei and at DNA

et al. 2020

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Glucocorticoid (GR) and mineralocorticoid receptors (MR) are believed to classically bind DNA as homodimers or MR-GR heterodimers to influence gene regulation in response to pulsatile basal or stress-evoked glucocorticoid secretion. Pulsed corticosterone presentation reveals MR and GR co-occupy DNA only at the peaks of glucocorticoid oscillations, allowing interaction. GR DNA occupancy was pulsatile, while MR DNA occupancy was prolonged through the inter-pulse interval. In mouse mammary 3617 cells MR-GR interacted in the nucleus and at a chromatin-associated DNA binding site. Interactions occurred irrespective of ligand type and receptors formed complexes of higher order than heterodimers. We also detected MR-GR interactions ex-vivo in rat hippocampus. An expanded range of MR-GR interactions predicts structural allostery allowing a variety of transcriptional outcomes and is applicable to the multiple tissue types that co-express both receptors in the same cells whether activated by the same or different hormones.

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Section: Introductionmentioning

confidence: 99%

Beyond the heterodimer model for mineralocorticoid and glucocorticoid receptor interactions in nuclei and at DNA

et al. 2020

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“…It was shown that ultradian patterns in the circulation, at least in rodents, are maintained in the brain (Qian et al 2012). The existence of ultradian pulses is important to achieve optimal transcriptional activity of neurons in response to corticosteroids (George et al 2017) and modulates the degree to which organisms respond to stress (Sarabdjitsingh et al 2010).…”

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confidence: 99%

Corticosteroids and the brain

Joëls

2018

Journal of Endocrinology

152

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The brain is continuously exposed to varying levels of adrenal corticosteroid hormones such as corticosterone in rodents and cortisol in humans. Natural fluctuations occur due to ultradian and circadian variations or are caused by exposure to stressful situations. Brain cells express two types of corticosteroid receptors, i.e. mineralocorticoid and glucocorticoid receptors, which differ in distribution and affinity. These receptors can mediate both rapid non-genomic and slow gene-mediated neuronal actions. As a consequence of these factors, natural (e.g. stress-induced) shifts in corticosteroid level are associated with a complex mosaic of time- and region-dependent changes in neuronal activity. A series of experiments in humans and rodents have revealed that these time- and region-dependent cellular characteristics are also reflected in distinct cognitive patterns after stress. Thus, directly after a peak of corticosteroids, attention and vigilance are increased, and areas involved in emotional responses and simple behavioral strategies show enhanced activity. In the aftermath of stress, areas involved in higher cognitive functions become activated allowing individuals to link stressful events to the specific context and to store information for future use. Both phases of the brain's response to stress are important to face a continuously changing environment, promoting adaptation at the short as well as long term. We argue that a balanced response during the two phases is essential for resilience. This balance may become compromised after repeated stress exposure, particularly in genetically vulnerable individuals and aggravate disease manifestation. This not only applies to psychiatric disorders but also to neurological diseases such as epilepsy.

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“…Physiological studies have shown that it is the presence of both peaks and troughs of cortisol that is important for optimal regulation of behaviour and of glucocorticoid and mineralocorticoid receptors in animals. 43,44 We are now testing this in new psychological paradigms in man.…”

Section: Subcutaneous Glucocorticoid Infusionsmentioning

confidence: 99%

“…Although we know that stress increases the size of ultradian pulses, there have been no long‐term studies on the modulation of ultradian rhythmicity in normal daily living. Physiological studies have shown that it is the presence of both peaks and troughs of cortisol that is important for optimal regulation of behaviour and of glucocorticoid and mineralocorticoid receptors in animals . We are now testing this in new psychological paradigms in man.…”

Section: Introductionmentioning

confidence: 99%

Improving glucocorticoid replacement profiles in adrenal insufficiency

Choudhury

Lightman

Meeran

2019

Clinical Endocrinology

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There is an increased mortality associated with adrenal insufficiency despite glucocorticoid replacement therapy with a standardized mortality ratio greater than two. The cause of the increased mortality is yet to be definitively elucidated, but may be due to excess steroid exposure, or replacement regimens that are uncoupled from the normal physiological cortisol profile. Cortisol secretion follows an ultradian pattern which is not possible to reproduce using oral replacement. With the advent of new pumps, it is now possible to mimic the pulsatility of the adrenal glands. While the cognitive and emotional benefits of reproducing the ultradian rhythm are known, the presence of long‐term benefits is not yet clear. There is a dearth of evidence and high‐quality studies to underline our current understanding of the pathophysiology of adrenal insufficiency and replacement therapy. There is a particular lack of research comparing objective outcomes between patients receiving hydrocortisone replacement (either standard therapy or new sustained release preparations), prednisolone replacement and ultradian pumps. Direct comparative studies are now warranted to understand the optimal approach.

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Ultradian glucocorticoid exposure directs gene-dependent and tissue-specific mRNA expression patterns in vivo

Cited by 26 publications

References 65 publications

Beyond the heterodimer model for mineralocorticoid and glucocorticoid receptor interactions in nuclei and at DNA

Beyond the heterodimer model for mineralocorticoid and glucocorticoid receptor interactions in nuclei and at DNA

Corticosteroids and the brain

Improving glucocorticoid replacement profiles in adrenal insufficiency

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