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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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Regulation of HPA axis activity. The hypothalamic PVN receives circadian inputs from the SCN and homeostatic/stress inputs from the brain stem and limbic areas. The PVN projects to the median eminence where it releases CRH into the portal circulation. This passes to corticotrophs in the anterior pituitary which release ACTH from pre-formed granules into the venous circulation. This ACTH reaches the adrenal cortex where it activates the synthesis and secretion of CORTisol (in man) or CORTicosterone (in the rodent). CORT in turn feeds back to inhibit the release of ACTH from the anterior pituitary, and to a lesser extent, CRH from the hypothalamus.
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RSPB20092148F1: Regulation of HPA axis activity. The hypothalamic PVN receives circadian inputs from the SCN and homeostatic/stress inputs from the brain stem and limbic areas. The PVN projects to the median eminence where it releases CRH into the portal circulation. This passes to corticotrophs in the anterior pituitary which release ACTH from pre-formed granules into the venous circulation. This ACTH reaches the adrenal cortex where it activates the synthesis and secretion of CORTisol (in man) or CORTicosterone (in the rodent). CORT in turn feeds back to inhibit the release of ACTH from the anterior pituitary, and to a lesser extent, CRH from the hypothalamus.

Mentions: Another system that is characterized by an ultradian rhythm is the hypothalamic–pituitary–adrenal (HPA) axis (figure 1). This stress-responsive neuroendocrine system is extremely well adapted to respond to homeostatic challenge. The HPA axis governs the circulating levels of vital glucocorticoid hormones (CORT), which in turn have major regulatory effects on the cardiovascular, metabolic, cognitive and immunological state of the animal (Chrousos 1995; de Kloet et al. 2005; McEwen 2007). The central regulator of this axis—the paraventricular nucleus (PVN) of the hypothalamus—is a major relay for afferent information from limbic areas of the central nervous system that can detect cognitive or emotional stressors, and also from brain stem structures that detect more physical stressors such as inflammation or hypotension (Ulrich-Lai & Herman 2009). The PVN also receives a major input from the hypothalamic suprachiasmatic nucleus (SCN) that coordinates the body's circadian rhythms (Reppert & Weaver 2002). The corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) containing parvocellular neurons in the PVN project to the median eminence of the hypothalamus from where they release CRH and AVP into the hypothalamic–pituitary portal circulation (Engler et al. 1989; Ixart et al. 1991). The CRH and AVP pass along this vascular route to access their receptors on corticotroph cells in the anterior pituitary. These cells in turn are activated by occupation of their CRH and AVP receptors to release corticotrophin (ACTH) into the general circulation through which it accesses the glucocorticoid-secreting cells in the cortex of the adrenal gland. It is these cells that synthesize and release the final product of HPA activation—the glucocorticoid hormones. The final link in this circuit is that physiological levels of glucocorticoid hormones themselves feedback in a negative manner predominantly on the pituitary gland—but also at the level of the PVN and hippocampus—to inhibit further release of ACTH (Jones et al. 1977; Dallman et al. 1987).


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

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

Regulation of HPA axis activity. The hypothalamic PVN receives circadian inputs from the SCN and homeostatic/stress inputs from the brain stem and limbic areas. The PVN projects to the median eminence where it releases CRH into the portal circulation. This passes to corticotrophs in the anterior pituitary which release ACTH from pre-formed granules into the venous circulation. This ACTH reaches the adrenal cortex where it activates the synthesis and secretion of CORTisol (in man) or CORTicosterone (in the rodent). CORT in turn feeds back to inhibit the release of ACTH from the anterior pituitary, and to a lesser extent, CRH from the hypothalamus.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSPB20092148F1: Regulation of HPA axis activity. The hypothalamic PVN receives circadian inputs from the SCN and homeostatic/stress inputs from the brain stem and limbic areas. The PVN projects to the median eminence where it releases CRH into the portal circulation. This passes to corticotrophs in the anterior pituitary which release ACTH from pre-formed granules into the venous circulation. This ACTH reaches the adrenal cortex where it activates the synthesis and secretion of CORTisol (in man) or CORTicosterone (in the rodent). CORT in turn feeds back to inhibit the release of ACTH from the anterior pituitary, and to a lesser extent, CRH from the hypothalamus.
Mentions: Another system that is characterized by an ultradian rhythm is the hypothalamic–pituitary–adrenal (HPA) axis (figure 1). This stress-responsive neuroendocrine system is extremely well adapted to respond to homeostatic challenge. The HPA axis governs the circulating levels of vital glucocorticoid hormones (CORT), which in turn have major regulatory effects on the cardiovascular, metabolic, cognitive and immunological state of the animal (Chrousos 1995; de Kloet et al. 2005; McEwen 2007). The central regulator of this axis—the paraventricular nucleus (PVN) of the hypothalamus—is a major relay for afferent information from limbic areas of the central nervous system that can detect cognitive or emotional stressors, and also from brain stem structures that detect more physical stressors such as inflammation or hypotension (Ulrich-Lai & Herman 2009). The PVN also receives a major input from the hypothalamic suprachiasmatic nucleus (SCN) that coordinates the body's circadian rhythms (Reppert & Weaver 2002). The corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) containing parvocellular neurons in the PVN project to the median eminence of the hypothalamus from where they release CRH and AVP into the hypothalamic–pituitary portal circulation (Engler et al. 1989; Ixart et al. 1991). The CRH and AVP pass along this vascular route to access their receptors on corticotroph cells in the anterior pituitary. These cells in turn are activated by occupation of their CRH and AVP receptors to release corticotrophin (ACTH) into the general circulation through which it accesses the glucocorticoid-secreting cells in the cortex of the adrenal gland. It is these cells that synthesize and release the final product of HPA activation—the glucocorticoid hormones. The final link in this circuit is that physiological levels of glucocorticoid hormones themselves feedback in a negative manner predominantly on the pituitary gland—but also at the level of the PVN and hippocampus—to inhibit further release of ACTH (Jones et al. 1977; Dallman et al. 1987).

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