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Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability.

Gupta S, Aslakson E, Gurbaxani BM, Vernon SD - Theor Biol Med Model (2007)

Bottom Line: A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels.Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state.This model can be used to explore mechanisms underlying disorders of the HPA axis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. shaktig@gmail.com

ABSTRACT

Background: The body's primary stress management system is the hypothalamic pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases.

Results: We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of pituitary GR synthesis. The nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary. This homodimerization makes possible two stable steady states (low and high) and one unstable state of cortisol production resulting in bistability of the HPA axis. In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state. A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels. Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state. One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS).

Conclusion: Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism. High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis.

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Transient responses of HPA axis to recursive stresses. Initially HPA axis was at a lower GR steady state and stress was given at T = 0, 8 and 16 for 2 hours. Repeated stresses are shown by shaded areas.
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Figure 5: Transient responses of HPA axis to recursive stresses. Initially HPA axis was at a lower GR steady state and stress was given at T = 0, 8 and 16 for 2 hours. Repeated stresses are shown by shaded areas.

Mentions: The robustness of the system was illustrated by the fact that short stress produced small transients that returned to the original, normal steady state. To simulate adaptation of the HPA axis to repeated stress, recursive stress was applied at T = 0, 8 and 16 hours for 2 hour periods. The simulation results showed the continuous decrease in maximum ACTH and cortisol concentration after every stress (Figure 5a and 5b) while CRH is relatively unaffected (Figure 5c). The decrease in secretion of ACTH and cortisol occurred because of an increase in pituitary GR concentration and the fact that the system was pulsed with the stresses before it had time to fully recover (Figure 5d).


Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability.

Gupta S, Aslakson E, Gurbaxani BM, Vernon SD - Theor Biol Med Model (2007)

Transient responses of HPA axis to recursive stresses. Initially HPA axis was at a lower GR steady state and stress was given at T = 0, 8 and 16 for 2 hours. Repeated stresses are shown by shaded areas.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1804264&req=5

Figure 5: Transient responses of HPA axis to recursive stresses. Initially HPA axis was at a lower GR steady state and stress was given at T = 0, 8 and 16 for 2 hours. Repeated stresses are shown by shaded areas.
Mentions: The robustness of the system was illustrated by the fact that short stress produced small transients that returned to the original, normal steady state. To simulate adaptation of the HPA axis to repeated stress, recursive stress was applied at T = 0, 8 and 16 hours for 2 hour periods. The simulation results showed the continuous decrease in maximum ACTH and cortisol concentration after every stress (Figure 5a and 5b) while CRH is relatively unaffected (Figure 5c). The decrease in secretion of ACTH and cortisol occurred because of an increase in pituitary GR concentration and the fact that the system was pulsed with the stresses before it had time to fully recover (Figure 5d).

Bottom Line: A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels.Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state.This model can be used to explore mechanisms underlying disorders of the HPA axis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. shaktig@gmail.com

ABSTRACT

Background: The body's primary stress management system is the hypothalamic pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases.

Results: We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of pituitary GR synthesis. The nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary. This homodimerization makes possible two stable steady states (low and high) and one unstable state of cortisol production resulting in bistability of the HPA axis. In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state. A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels. Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state. One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS).

Conclusion: Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism. High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis.

Show MeSH
Related in: MedlinePlus