Onset, timing, and exposure therapy of stress disorders: mechanistic insight from a mathematical model of oscillating neuroendocrine dynamics
Tóm tắt
The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates numerous physiological processes. Disruptions in the activity of the HPA axis are correlated with stress-related diseases such as post-traumatic stress disorder (PTSD) and major depressive disorder. In this paper, we characterize “normal” and “diseased” states of the HPA axis as basins of attraction of a dynamical system describing the inhibition of peptide hormones such as corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by circulating glucocorticoids such as cortisol (CORT). In addition to including key physiological features such as ultradian oscillations in cortisol levels and self-upregulation of CRH neuron activity, our model distinguishes the relatively slow process of cortisol-mediated CRH biosynthesis from rapid trans-synaptic effects that regulate the CRH secretion process. We show that the slow component of the negative feedback allows external stress-induced reversible transitions between “normal” and “diseased” states in novel intensity-, duration-, and timing-dependent ways. Our two-step negative feedback model suggests a mechanism whereby exposure therapy of stress disorders such as PTSD may act to normalize downstream dysregulation of the HPA axis. Our analysis provides a causative rationale for improving treatments and guiding the design of new protocols. This article was reviewed by Dr. Daniel Coombs, Dr. Yang Kuang, and Dr. Ha Youn Lee.
Tài liệu tham khảo
Denver R. Structural and functional evolution of vertebrate neuroendocrine stress systems. Ann N Y Acad Sci. 2009; 1163(1):1–16.
Gold P, Chrousos G. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry. 2002; 7(3):254–75.
Juruena M, Cleare A, Pariante C. The hypothalamic pituitary adrenal axis, glucocorticoid receptor function and relevance to depression. Rev Bras Psiquiatr. 2004; 26(3):189–201.
Rohleder N, Joksimovic L, Wolf J, Kirschbaum C. Hypocortisolism and increased glucocorticoid sensitivity of pro-inflammatory cytokine production in bosnian war refugees with posttraumatic stress disorder. Biol Psychiatry. 2004; 55(7):745–51.
Giorgio AD, Hudson M, Jerjes W, Cleare A. 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome. Psychosom Med. 2005; 67(3):433–40.
Jerjesnd W, Peters T, Taylor N, Wood P, Wessely S, Cleare A. Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome. J Psychosom Res. 2006; 60(2):145–53.
Crofford L, Young E, Cary NEK, Korszun A, Brucksch C, McClure L, Brown M, Demitrack M. Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun. 2004; 18(4):314–25.
Yehuda R, Teicher M, Levengood R, Trestman R, Siever L. Circadian regulation of basal cortisol levels in posttraumatic stress disorder. Ann N Y Acad Sci. 1994; 746(1):378–80.
Vinther F, Andersen M, Ottesen JT. The minimal model of the hypothalamic-pituitary-adrenal axis. J Math Biol. 2011; 63:663–90.
Jelic S, Cupic Z, Kolar-Anic L. Mathematical modeling of the hypothalmic-pituitary-adrenal system activity. Math Biosci. 2005; 197:173–87.
Kyrylov V, Severyanova L, Vieira A. Modeling robust oscillatory behavior of the hypothalamic-pituitary-adrenal axis. IEEE Trans Biomed Eng. 2005; 52(12):1977–83.
Savić D, Knežević G, Opačić G. A mathematical model of stress reaction: Individual differences in threshold and duration. Psychobiology. 2000; 28(4):581–92.
Walker JJ, Terry JR, Lightman SL. Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis. Proc R Soc Lond B Biol Sci. 2010; 277(1688):1627–33.
Rankin J, Walker J, Windle R, Lightman S, Terry J. Characterizing dynamic interactions between ultradian glucocorticoid rhythmicity and acute stress using the phase response curve. PloS ONE. 2012; 7(2):30978.
Bairagi N, Chatterjee S, Chattopadhyay J. Variability in the secretion of corticotropin-releasing hormone, adrenocorticotropic hormone and cortisol and understandability of the hypothalamic-pituitary-adrenal axis dynamics — a mathematical study based on clinical evidence. Math Med Biol. 2008; 25:37–63.
Sriram K, Rodriguez-Fernandez M, Doyle III FJ. Modeling cortisol dynamics in the neuro-endocrine axis distinguishes normal, depression, and post-traumatic stress disorder (PTSD) in humans. PLoS Comput Biol. 2012; 8:1002379.
Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability. Theor Biol Med Model. 2007; 4:8.
Windle R, Wood S, Lightman S, Ingram C. The pulsatile characteristics of hypothalamo-pituitary-adrenal activity in female Lewis and Fischer 344 rats and its relationship to differential stress responses. Endocrinology. 1998; 139(10):4044–52.
Chrousos G. Editorial: ultradian, circadian, and stress-related hypothalamic-pituitary-adrenal axis activity — a dynamic digital-to-analog modulation. Endocrinology. 1998; 139(2):437–40.
Conway-Campbell B, Sarabdjitsingh R, McKenna M, Pooley J, Kershaw Y, Meijer O, Kloet ED, Lightman S. Glucocorticoid ultradian rhythmicity directs cyclical gene pulsing of the clock gene period 1 in rat hippocampus. J Neuroendocrinol. 2010; 22(10):1093–100.
Windle R, Wood S, Shanks N, Lightman S, Ingram C. Ultradian rhythm of basal corticosterone release in the female rat: Dynamic interaction with the response to acute stress. Endocrinology. 1998; 139(2):443–50.
Watts A. Glucocorticoid regulation of peptide genes in neuroendocrine CRH neurons: a complexity beyond negative feedback. Front Neuroendocrinol. 2005; 26(3):109–30.
Ono N, Castro JD, McCann S. Ultrashort-loop positive feedback of corticotropin (ACTH)-releasing factor to enhance ACTH release in stress. Proc Natl Acad Sci. 1985; 82(10):3528–31.
FitzHugh R. Mathematical models of threshold phenomena in the nerve membrane. Bull Math Biophys. 1955; 17(4):257–78.
Silva FLD, Blanes W, Kalitzin S, Parra J, Suffczynski P, Velis D. Epilepsies as dynamical diseases of brain systems: basic models of the transition between normal and epileptic activity. Epilepsia. 2003; 44(s12):72–83.
Ben-Zvi A, Vernon SD, Broderick G. Model-based therapeutic correction of hypothalamic-pituitary-adrenal axis dysfunction. PLoS Comput Biol. 2009; 5(1):1000273.
Tsai SY, Carlstedt-Duke J, Weigel NL, Dahlman K, Gustafsson J, Tsai MJ, O’Malley BW. Molecular interactions of steroid hormone receptor with its enhancer element: evidence for receptor dimer formation. Cell. 1988; 55(2):361–9.
Andersen M, Vinther F, Ottesen J. Mathematical modeling of the hypothalamic–pituitary–adrenal gland (HPA) axis, including hippocampal mechanisms. Math Biosci. 2013; 246(1):122–38.
Papaikonomou E. Rat adrenocortical dynamics. J Physiol. 1977; 265(1):119–31.
Engler D, Pham T, Liu J, Fullerton M, Clarke I, Funder J. Studies of the regulation of the hypothalamic-pituitary-adrenal axis in sheep with hypothalamic-pituitary disconnection. II, evidence for in vivo ultradian hypersecretion of proopiomelanocortin peptides by the isolated anterior and intermediate pituitary. Endocrinology. 1990; 127(4):1956–66.
Weiser M, Osterlund C, Spencer R. Inhibitory effects of corticosterone in the hypothalamic paraventricular nucleus (pvn) on stress-induced adrenocorticotrophic hormone secretion and gene expression in the pvn and anterior pituitary. J Neuroendocrinol. 2011; 23(12):1231–40.
Ma X, Aguilera G. Differential regulation of corticotropin-releasing hormone and vasopressin transcription by glucocorticoids. Endocrinology. 1999; 140(12):5642–50.
Watts A, Sanchez-Watts G. Region-specific regulation of neuropeptide mRNAs in rat limbic forebrain neurones by aldosterone and corticosterone. J Physiol. 1995; 484(3):721–36.
Tasker J, Di S, Malcher-Lopes R. Rapid glucocorticoid signaling via membrane-associated receptors. Endocrinology. 2006; 147(12):5549–56.
Kasai M, Yamashita H. Inhibition by cortisol of neurons in the paraventricular nucleus of the hypothalamus in adrenalectomized rats; an in vitro study. Neurosci Lett. 1988; 91(1):59–64.
Kasai M, Yamashita H. Cortisol suppresses noradrenaline-induced excitatory responses of neurons in the paraventricular nucleus; an in vitro study. Neurosci Lett. 1988; 91(1):65–70.
Jones M, Hillhouse E, Burden J. Dynamics and mechanics of corticosteroid feedback at the hypothalamus and anterior pituitary gland. J Endocrinol. 1977; 73(3):405–17.
Ginsberg A, Campeau S, Day H, Spencer R. Acute glucocorticoid pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis hormone secretion and expression of corticotropin-releasing hormone hnRNA but does not affect c-fos mRNA or fos protein expression in the paraventricular nucleus of the hypothalamus. J Neuroendocrinol. 2003; 15(11):1075–83.
Chen Y, Hua S, Wang C, Wu L, Gu Q, Xing B. An electrophysiological study on the membrane receptor-mediated action of glucocorticoids in mammalian neurons. Neuroendocrinology. 1991; 53(Suppl. 1):25–30.
Imaki T, Xiao-Quan W, Shibasaki T, Yamada K, Harada S, Chikada N, Naruse M, Demura H. Stress-induced activation of neuronal activity and corticotropin-releasing factor gene expression in the paraventricular nucleus is modulated by glucocorticoids in rats. J Clin Investig. 1995; 96(1):231.
Papadimitriou A, Priftis K. Regulation of the hypothalamic-pituitary-adrenal axis. Neuroimmunomodulation. 2009; 16(5):265.
Makino S, Hashimoto K, Gold P. Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress. Pharmacol Biochem Behav. 2002; 73(1):147–58.
Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander M, Choi D, Cullinan W. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness. Front Neuroendocrinol. 2003; 24(3):151–80.
McEwen BS, Stellar E. Stress and the individual: mechanisms leading to disease. Arch Intern Med. 1993; 153:2093–101.
McEwen BS. Stress, adaptation, and disease: Allostasis and allostatic load. Ann N Y Acad Sci. 1998; 840(1):33–44.
Dince SM, Rome RD, McEwen BS, Tang AC. Enhancing offspring hypothalamic-pituitary-adrenal (hpa) regulation via systematic novelty exposure: the influence of maternal HPA function. Front Behav Neurosci. 2014; 8:204. doi:10.3389/fnbeh.2014.00204.
Hauger RL, Thrivikraman KV, Plotsky PM. Age-related alterations of hypothalamic-pituitary-adrenal axis function in male Fischer 344 rats. Endocrinology. 1994; 134(3):1528–36.
Averill P, Beck J. Posttraumatic stress disorder in older adults: a conceptual review. J Anxiety Disord. 2000; 14(2):133–56.
Regier D, Boyd J, Burke J, Rae D, Myers J, Kramer M, Robins L, George L, Karno M, Locke B. One-month prevalence of mental disorders in the united states: based on five epidemiologic catchment area sites. Arch Gen Psychiatr. 1988; 45(11):977–86.
Simerly RB, Swanson LW, Chang C, Muramatsu M. Distribution of androgen and estrogen receptor mrna-containing cells in the rat brain: An in situ hybridization study. J Comp Neurol. 1990; 294(1):76–95.
Gréco B, Allegretto E, Tetel M, Blaustein J. Coexpression of ER β with ER α and progestin receptor proteins in the female rat forebrain: effects of estradiol treatment. Endocrinology. 2001; 142(12):5172–81.
Feldman S, Conforti N, Saphier D. The preoptic area and bed nucleus of the stria terminalis are involved in the effects of the amygdala on adrenocortical secretion. Neuroscience. 1990; 37(3):775–9.
Yehuda R, Teicher M, Levengood R, Trestman R, Levengood R, Siever L. Cortisol regulation in posttraumatic stress disorder and major depression: a chronobiological analysis. Biol Psychiatry. 1996; 40(2):79–88.
Yehuda R, LeDoux J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron. 2007; 56:19–32.
Olff M, de Vries G, Güzelcan Y, Assies J, Gersons B. Changes in cortisol and DHEA plasma levels after psychotherapy for PTSD. Psychoneuroendocrinology. 2007; 32(6):619–26.
Foa E, Keane T, Friedman M, Cohen J. Effective treatments for PTSD: practice guidelines from the international society for traumatic stress studies. New York: Guilford Press: 2008.
Rauch S, Eftekhari A, Ruzek J. Review of exposure therapy: a gold standard for PTSD treatment. J Rehabil Res Dev. 2012; 49(5):679–88.
Trouche S, Sasaki J, Tu T, Reijmers L. Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses. Neuron. 2013; 80(4):1054–65.
Lemieux A, Coe C. Abuse-related posttraumatic stress disorder: evidence for chronic neuroendocrine activation in women. Psychosom Med. 1995; 57(2):105–15.
Baum A. Implications of psychological research on stress and technological accidents. Am Psychol. 1993; 48(6):665.
Rosenmund C, Stevens C. Definition of the readily releasable pool of vesicles at hippocampal synapses. Neuron. 1996; 16(6):1197–207.