Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability
Tóm tắt
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.
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).
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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Munck A, Guyre PM, Holbrook NJ: Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev. 1984, 5: 25-44.
Tuckermann JP, Kleiman A, McPherson KG, Reichardt HM: Molecular mechanisms of glucocorticoids in the control of inflammation and lymphocyte apoptosis. Crit Rev Clin Lab Sci. 2005, 42: 71-104. 10.1080/10408360590888983.
Juruena MF, Cleare AJ, Pariante CM: The hypothalamic pituitary adrenal axis, glucocorticoid receptor function and relevance to depression. Rev Bras Psiquiatr. 2004, 26: 189-201. 10.1590/S1516-44462004000300009.
Gold PW, Chrousos GP: Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry. 2002, 7: 254-75. 10.1038/sj.mp.4001032.
Rohleder N, Joksimovic L, Wolf JM, Kirschbaum C: Hypocortisolism and increased glucocorticoid sensitivity of pro-inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder. Biol Psychiatry. 2004, 55: 745-751. 10.1016/j.biopsych.2003.11.018.
Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ: Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991, 73: 1224-1234.
Di GA, Hudson M, Jerjes W, Cleare AJ: 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome. Psychosom Med. 2005, 67: 433-440. 10.1097/01.psy.0000161206.55324.8a.
Jerjes WK, Peters TJ, Taylor NF, Wood PJ, Wessely S, Cleare AJ: Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome. J Psychosom Res. 2006, 60: 145-153. 10.1016/j.jpsychores.2005.07.008.
Crofford LJ, Young EA, Engleberg NC, Korszun A, Brucksch CB, McClure LA, Brown MB, Demitrack MA: Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun. 2004, 18: 314-25. 10.1016/j.bbi.2003.12.011.
National Scientific Council on the Developing Child, Early Exposure to Toxic Substances Damages Brain Architecture. Working Paper No. 4. 2006, Retrieved July 14, 006,http://www.developingchild.net/reports.shtml
Turner-Cobb JM: Psychological and stress hormone correlates in early life: a key to HPA-axis dysregulation and normalisation. Stress. 2005, 8: 47-57.
Jacobson L: Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am. 2005, 34: 271-92. 10.1016/j.ecl.2005.01.003.
Gonzalez-Heydrich J, Steingard RJ, Kohane I: A computer simulation of the hypothalamic-pituitary-adrenal axis. Proc Annu Symp Comput Appl Med Care. 1994, 1010-
Dempsher DP, Gann DS, Phair RD: A mechanistic model of ACTH-stimulated cortisol secretion. Am J Physiol. 1984, 246: R587-R596.
Sharma DC, Gabrilove JL: A study of the adrenocortical disorders related to the biosynthesis and regulation of steroid hormones and their computer simulation. Mt Sinai J Med. 1975, 42: S2-S39.
Savic D: A mathematical model of the hypothalamo-pituitary-adrenocortical system and its stability analysis. Chaos, solitons, and fractals. 2005, 26: 427-436. 10.1016/j.chaos.2005.01.013.
Lenbury Y, Pornsawad P: A delay-differential equation model of the feedback-controlled hypothalamus-pituitary-adrenal axis in humans. Math Med Biol. 2005, 22: 15-33. 10.1093/imammb/dqh020.
Drouin J, Sun YL, Tremblay S, Lavender P, Schmidt TJ, de LA: Homodimer formation is rate-limiting for high affinity DNA binding by glucocorticoid receptor. Mol Endocrinol. 1992, 6: 1299-1309. 10.1210/me.6.8.1299.
Tsai SY, Carlstedt-Duke J, Weigel NL, Dahlman K, Gustafsson JA, Tsai MJ: Molecular interactions of steroid hormone receptor with its enhancer element: evidence for receptor dimer formation. Cell. 1988, 55: 361-369. 10.1016/0092-8674(88)90059-1.
Makino S, Smith MA, Gold PW: Increased expression of corticotropin-releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: association with reduction in glucocorticoid receptor mRNA levels. Endocrinology. 1995, 136: 3299-3309. 10.1210/en.136.8.3299.
Nishimura K, Makino S, Tanaka Y, Kaneda T, Hashimoto K: Altered expression of p53 mRNA in the brain and pituitary during repeated immobilization stress: negative correlation with glucocorticoid receptor mRNA levels. J Neuroendocrinol. 2004, 16: 84-91. 10.1111/j.1365-2826.2004.01131.x.
Hugin-Flores ME, Steimer T, Aubert ML, Schulz P: Mineralo- and glucocorticoid receptor mRNAs are differently regulated by corticosterone in the rat hippocampus and anterior pituitary. Neuroendocrinology. 2004, 79: 174-184. 10.1159/000078099.
Dayanithi G, Antoni FA: Rapid as well as delayed inhibitory effects of glucocorticoid hormones on pituitary adrenocorticotropic hormone release are mediated by type II glucocorticoid receptors and require newly synthesized messenger ribonucleic acid as well as protein. Endocrinology. 1989, 125: 308-31.