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Origin of ultradian pulsatility in the hypothalamic-pituitary-adrenal axis.

Walker JJ, Terry JR, Lightman SL - Proc. Biol. Sci. (2010)

Bottom Line: Theoretical modelling has enabled us to identify and explore potential mechanisms underlying the ultradian activity in this axis, which to date have not been identified successfully.We demonstrate that the combination of delay with feed-forward and feedback loops in the pituitary-adrenal system is sufficient to give rise to ultradian pulsatility in the absence of an ultradian source from a supra-pituitary site.Moreover, our model enables us to predict the different patterns of glucocorticoid release mediated by changes in hypophysial-portal corticotrophin-releasing hormone levels, with results that parallel our experimental in vivo data.

View Article: PubMed Central - PubMed

Affiliation: Department of Engineering Mathematics, University of Bristol, Bristol, UK. jamie.walker@bristol.ac.uk

ABSTRACT
The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates the circulating levels of vital glucocorticoid hormones. The activity of the HPA axis is characterized not only by a classic circadian rhythm, but also by an ultradian pattern of discrete pulsatile release of glucocorticoids. A number of psychiatric and metabolic diseases are associated with changes in glucocorticoid pulsatility, and it is now clear that glucocorticoid responsive genes respond to these rapid fluctuations in a biologically meaningful way. Theoretical modelling has enabled us to identify and explore potential mechanisms underlying the ultradian activity in this axis, which to date have not been identified successfully. We demonstrate that the combination of delay with feed-forward and feedback loops in the pituitary-adrenal system is sufficient to give rise to ultradian pulsatility in the absence of an ultradian source from a supra-pituitary site. Moreover, our model enables us to predict the different patterns of glucocorticoid release mediated by changes in hypophysial-portal corticotrophin-releasing hormone levels, with results that parallel our experimental in vivo data.

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Effect of subchronic treatment with a GR antagonist on the 24 h corticosterone profile. (a) Data points represent mean levels of blood corticosterone measured from individual male Sprague–Dawley rats injected twice a day for 5 days with either the GR antagonist Org 34850 (10 mg kg−1, subcut., n = 7, grey dots) or VEH (5% mulgofen in 0.9% saline, 1 ml kg−1, subcut., n = 7, black dots). Blood samples were recorded over a 24 h period and collected every 10 min using an automated blood sampling system. Also shown are curves numerically fitted to the two datasets, demonstrating an increase in amplitude during the circadian peak under the influence of Org 34850. Grey bar represents the dark phase (19.15–05.15 h). Adapted from Spiga et al. (2007). (b) Model simulations show the response of the system to circadian CRH both with (grey) and without (black) a GR antagonist. Infusion of a GR antagonist increases the amplitude of the ultradian glucocorticoid rhythm during the peak of the circadian CRH drive together with a minor increase in ultradian frequency (grey). Computed with a delay of 15 min.
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RSPB20092148F6: Effect of subchronic treatment with a GR antagonist on the 24 h corticosterone profile. (a) Data points represent mean levels of blood corticosterone measured from individual male Sprague–Dawley rats injected twice a day for 5 days with either the GR antagonist Org 34850 (10 mg kg−1, subcut., n = 7, grey dots) or VEH (5% mulgofen in 0.9% saline, 1 ml kg−1, subcut., n = 7, black dots). Blood samples were recorded over a 24 h period and collected every 10 min using an automated blood sampling system. Also shown are curves numerically fitted to the two datasets, demonstrating an increase in amplitude during the circadian peak under the influence of Org 34850. Grey bar represents the dark phase (19.15–05.15 h). Adapted from Spiga et al. (2007). (b) Model simulations show the response of the system to circadian CRH both with (grey) and without (black) a GR antagonist. Infusion of a GR antagonist increases the amplitude of the ultradian glucocorticoid rhythm during the peak of the circadian CRH drive together with a minor increase in ultradian frequency (grey). Computed with a delay of 15 min.

Mentions: The model we employ here is the first to incorporate the dynamics of the GR in the anterior pituitary (Gupta et al. 2007), and therefore provides an ideal platform to investigate the effects that GR antagonists/agonists have on the dynamics of endogenous glucocorticoid secretion. Model results demonstrate that infusion of a GR antagonist (such as Org 34850) increases the amplitude of the ultradian glucocorticoid rhythm during the peak of the circadian CRH drive (figure 6b). Furthermore there is a minor increase in ultradian frequency under the influence of a GR antagonist. These theoretical observations are consistent with experimental studies on the rat (Spiga et al. 2007), where following 5 days of treatment with the GR antagonist Org 34850, mean corticosterone levels were elevated over the 24 hour cycle (figure 6a). Furthermore, this general elevation was the result of an underlying increase in both the amplitude and frequency of the ultradian pulses. In the same study, analysis of the corticosterone rhythm revealed that Org 34850 had its greatest effect during the peak of the circadian rhythm.


Origin of ultradian pulsatility in the hypothalamic-pituitary-adrenal axis.

Walker JJ, Terry JR, Lightman SL - Proc. Biol. Sci. (2010)

Effect of subchronic treatment with a GR antagonist on the 24 h corticosterone profile. (a) Data points represent mean levels of blood corticosterone measured from individual male Sprague–Dawley rats injected twice a day for 5 days with either the GR antagonist Org 34850 (10 mg kg−1, subcut., n = 7, grey dots) or VEH (5% mulgofen in 0.9% saline, 1 ml kg−1, subcut., n = 7, black dots). Blood samples were recorded over a 24 h period and collected every 10 min using an automated blood sampling system. Also shown are curves numerically fitted to the two datasets, demonstrating an increase in amplitude during the circadian peak under the influence of Org 34850. Grey bar represents the dark phase (19.15–05.15 h). Adapted from Spiga et al. (2007). (b) Model simulations show the response of the system to circadian CRH both with (grey) and without (black) a GR antagonist. Infusion of a GR antagonist increases the amplitude of the ultradian glucocorticoid rhythm during the peak of the circadian CRH drive together with a minor increase in ultradian frequency (grey). Computed with a delay of 15 min.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2871854&req=5

RSPB20092148F6: Effect of subchronic treatment with a GR antagonist on the 24 h corticosterone profile. (a) Data points represent mean levels of blood corticosterone measured from individual male Sprague–Dawley rats injected twice a day for 5 days with either the GR antagonist Org 34850 (10 mg kg−1, subcut., n = 7, grey dots) or VEH (5% mulgofen in 0.9% saline, 1 ml kg−1, subcut., n = 7, black dots). Blood samples were recorded over a 24 h period and collected every 10 min using an automated blood sampling system. Also shown are curves numerically fitted to the two datasets, demonstrating an increase in amplitude during the circadian peak under the influence of Org 34850. Grey bar represents the dark phase (19.15–05.15 h). Adapted from Spiga et al. (2007). (b) Model simulations show the response of the system to circadian CRH both with (grey) and without (black) a GR antagonist. Infusion of a GR antagonist increases the amplitude of the ultradian glucocorticoid rhythm during the peak of the circadian CRH drive together with a minor increase in ultradian frequency (grey). Computed with a delay of 15 min.
Mentions: The model we employ here is the first to incorporate the dynamics of the GR in the anterior pituitary (Gupta et al. 2007), and therefore provides an ideal platform to investigate the effects that GR antagonists/agonists have on the dynamics of endogenous glucocorticoid secretion. Model results demonstrate that infusion of a GR antagonist (such as Org 34850) increases the amplitude of the ultradian glucocorticoid rhythm during the peak of the circadian CRH drive (figure 6b). Furthermore there is a minor increase in ultradian frequency under the influence of a GR antagonist. These theoretical observations are consistent with experimental studies on the rat (Spiga et al. 2007), where following 5 days of treatment with the GR antagonist Org 34850, mean corticosterone levels were elevated over the 24 hour cycle (figure 6a). Furthermore, this general elevation was the result of an underlying increase in both the amplitude and frequency of the ultradian pulses. In the same study, analysis of the corticosterone rhythm revealed that Org 34850 had its greatest effect during the peak of the circadian rhythm.

Bottom Line: Theoretical modelling has enabled us to identify and explore potential mechanisms underlying the ultradian activity in this axis, which to date have not been identified successfully.We demonstrate that the combination of delay with feed-forward and feedback loops in the pituitary-adrenal system is sufficient to give rise to ultradian pulsatility in the absence of an ultradian source from a supra-pituitary site.Moreover, our model enables us to predict the different patterns of glucocorticoid release mediated by changes in hypophysial-portal corticotrophin-releasing hormone levels, with results that parallel our experimental in vivo data.

View Article: PubMed Central - PubMed

Affiliation: Department of Engineering Mathematics, University of Bristol, Bristol, UK. jamie.walker@bristol.ac.uk

ABSTRACT
The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates the circulating levels of vital glucocorticoid hormones. The activity of the HPA axis is characterized not only by a classic circadian rhythm, but also by an ultradian pattern of discrete pulsatile release of glucocorticoids. A number of psychiatric and metabolic diseases are associated with changes in glucocorticoid pulsatility, and it is now clear that glucocorticoid responsive genes respond to these rapid fluctuations in a biologically meaningful way. Theoretical modelling has enabled us to identify and explore potential mechanisms underlying the ultradian activity in this axis, which to date have not been identified successfully. We demonstrate that the combination of delay with feed-forward and feedback loops in the pituitary-adrenal system is sufficient to give rise to ultradian pulsatility in the absence of an ultradian source from a supra-pituitary site. Moreover, our model enables us to predict the different patterns of glucocorticoid release mediated by changes in hypophysial-portal corticotrophin-releasing hormone levels, with results that parallel our experimental in vivo data.

Show MeSH
Related in: MedlinePlus