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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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Related in: MedlinePlus

Experimental data demonstrating the ultradian glucocorticoid rhythm underlying the classic circadian profile. Levels of blood corticosterone were recorded over a 24 h period in two individual male Sprague–Dawley rats. Blood samples were collected every 10 min using an automated blood sampling system. Grey bars indicate the dark phase (19.15–05.15 h). Adapted from Spiga et al. (2007).
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RSPB20092148F2: Experimental data demonstrating the ultradian glucocorticoid rhythm underlying the classic circadian profile. Levels of blood corticosterone were recorded over a 24 h period in two individual male Sprague–Dawley rats. Blood samples were collected every 10 min using an automated blood sampling system. Grey bars indicate the dark phase (19.15–05.15 h). Adapted from Spiga et al. (2007).

Mentions: The HPA axis has a unique pattern of activity. Levels are low during the periods of sleep inactivity and increase in anticipation of waking, peaking in the morning in man (Weitzman et al. 1971) and evening in the rodent (Dallman et al. 1978), with the resultant classic circadian rhythm. This rhythm, however, is not made up of a simple smooth change in hormone levels over the 24 hours. The circadian changes of glucocorticoids are a result of changes in the activity of an underlying ultradian rhythm (Veldhuis et al. 1989; Jasper & Engeland 1991; Windle et al. 1998a; Spiga et al. 2007). Glucocorticoids are actually released from the adrenal gland in discrete pulses that result in rapidly changing levels of hormone, both in the blood and within the tissues (figure 2). It is in fact the changes in pulse amplitude, and to a lesser extent frequency, that make up the circadian rhythm (Lui et al. 1987; Iranmanesh et al. 1989; Veldhuis et al. 1989, 1990; Windle et al. 1998b) and the changes of HPA activity that occur in response to altered physiological and pathological conditions. This pulsatility of glucocorticoid secretion is also an important factor in determining the responsivity of the HPA axis to stress (Windle et al. 1998a; Lightman et al. 2008) and the transcriptional responses of glucocorticoid responsive genes (Stavreva et al. 2009).


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

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

Experimental data demonstrating the ultradian glucocorticoid rhythm underlying the classic circadian profile. Levels of blood corticosterone were recorded over a 24 h period in two individual male Sprague–Dawley rats. Blood samples were collected every 10 min using an automated blood sampling system. Grey bars indicate the dark phase (19.15–05.15 h). Adapted from Spiga et al. (2007).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSPB20092148F2: Experimental data demonstrating the ultradian glucocorticoid rhythm underlying the classic circadian profile. Levels of blood corticosterone were recorded over a 24 h period in two individual male Sprague–Dawley rats. Blood samples were collected every 10 min using an automated blood sampling system. Grey bars indicate the dark phase (19.15–05.15 h). Adapted from Spiga et al. (2007).
Mentions: The HPA axis has a unique pattern of activity. Levels are low during the periods of sleep inactivity and increase in anticipation of waking, peaking in the morning in man (Weitzman et al. 1971) and evening in the rodent (Dallman et al. 1978), with the resultant classic circadian rhythm. This rhythm, however, is not made up of a simple smooth change in hormone levels over the 24 hours. The circadian changes of glucocorticoids are a result of changes in the activity of an underlying ultradian rhythm (Veldhuis et al. 1989; Jasper & Engeland 1991; Windle et al. 1998a; Spiga et al. 2007). Glucocorticoids are actually released from the adrenal gland in discrete pulses that result in rapidly changing levels of hormone, both in the blood and within the tissues (figure 2). It is in fact the changes in pulse amplitude, and to a lesser extent frequency, that make up the circadian rhythm (Lui et al. 1987; Iranmanesh et al. 1989; Veldhuis et al. 1989, 1990; Windle et al. 1998b) and the changes of HPA activity that occur in response to altered physiological and pathological conditions. This pulsatility of glucocorticoid secretion is also an important factor in determining the responsivity of the HPA axis to stress (Windle et al. 1998a; Lightman et al. 2008) and the transcriptional responses of glucocorticoid responsive genes (Stavreva et al. 2009).

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