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A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks

2020; Springer Nature; Volume: 16; Issue: 7 Linguagem: Inglês

10.15252/msb.20209510

1744-4292

Omer Karin, Moriya Raz, Avichai Tendler, A. Bar, Yael Korem Kohanim, Tomer Milo, Uri Alon,

Menstrual Health and Disorders

Article16 July 2020Open Access Transparent process A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks Omer Karin Omer Karin orcid.org/0000-0002-9426-5362 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Moriya Raz Moriya Raz Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Avichai Tendler Avichai Tendler Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Alon Bar Alon Bar Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Yael Korem Kohanim Yael Korem Kohanim Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Tomer Milo Tomer Milo Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Uri Alon Corresponding Author Uri Alon [email protected] orcid.org/0000-0003-1121-5907 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Omer Karin Omer Karin orcid.org/0000-0002-9426-5362 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Moriya Raz Moriya Raz Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Avichai Tendler Avichai Tendler Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Alon Bar Alon Bar Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Yael Korem Kohanim Yael Korem Kohanim Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Tomer Milo Tomer Milo Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Uri Alon Corresponding Author Uri Alon [email protected] orcid.org/0000-0003-1121-5907 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Search for more papers by this author Author Information Omer Karin1, Moriya Raz1, Avichai Tendler1, Alon Bar1, Yael Korem Kohanim1, Tomer Milo1 and Uri Alon *,1 1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel *Corresponding author. Tel: +972-8-934-4448; E-mail: [email protected] Molecular Systems Biology (2020)16:e9510https://doi.org/10.15252/msb.20209510 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Stress activates a complex network of hormones known as the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone-secreting glands. The mass changes are caused by HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia, and postpartum. Dysregulation occurs for a wide range of parameters and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland-mass dynamics may play an important role in the pathophysiology of stress-related disorders. Synopsis Prolonged activation of the HPA axis leads to dysregulation and has clinical consequences. This study presents a mechanism for HPA dysregulation based on the effect of HPA hormones acting as growth factors for their downstream glands. A mathematical model that includes gland functional mass dynamics introduces a new slow timescale of weeks to the HPA axis. The gland masses grow during prolonged activation, providing dynamical compensation, and recover with overshoots over weeks after withdrawal of activation. These overshoots explain the observed HPA dysregulation in pathological conditions, and clarify the role of glucocorticoid receptors in resilience to prolonged stress. Introduction A major hormone system that responds to stress is the HPA axis (Tsigos & Chrousos, 2002; Hosseinichimeh et al, 2015; Melmed et al, 2015; Zavala et al, 2019). Activation of the HPA axis results in the secretion of cortisol, which has receptors in almost all cell types, and exerts widespread effects on metabolism, immunity, and behavior, to help the organism cope with stress. The HPA axis is organized in a cascade of hormones (Fig 1A): physiological and psychological stresses cause secretion of CRH from the hypothalamus (H in Fig 1A). CRH causes the pituitary corticotroph cells to secrete ACTH, which in turn causes the adrenal cortex to secrete cortisol. Cortisol negatively feeds back on the secretion of the two upstream hormones. Figure 1. After prolonged stress, ACTH response is blunted for weeks after cortisol response normalizes Schema of the classic HPA axis. CRH causes the secretion of ACTH and cortisol. In the CRH test, the secretion of these hormones is measured after CRH administration. Patients suffering from major depressive disorder (MDD) show a blunted ACTH response to CRH (black line, N = 10), compared with controls (gray line, N = 10)—data from (von Bardeleben et al, 1988), shown are mean ± SEM. Patients suffering from anorexia and admitted to treatment show a blunted ACTH response and hypercortisolemia, which resolves within 6–24 months after weight normalization—data from Gold et al (1986a). However, 3–4 weeks after weight normalization, cortisol dynamics are normal whereas ACTH dynamics are blunted. Pregnancy is associated with elevated cortisol levels due to CRH secretion by the placenta. 3 weeks after delivery, cortisol levels and dynamics return to normal, whereas ACTH dynamics are blunted—data from Magiakou et al (1996). After 12 weeks, ACTH dynamics normalize as well. Individuals recovering from alcohol abuse show hypercortisolemia and blunted ACTH response after admission—data from von Bardeleben et al (1989). After 2–6 weeks, these individuals show normal cortisol dynamics, but blunted ACTH responses persist. In all panels, control patient data are denoted by thin gray line (Anorexia: N = 13. Pregnancy: N was unspecified. Alcohol abuse disorder: N = 11), and case data by a thicker black line (Anorexia: left panel, N = 9, center panel, N = 5, right panel, N = 6. Pregnancy: N = 17. Alcohol abuse disorder: N = 20). Shown are mean ± SEM for all panels. Download figure Download PowerPoint The HPA axis is dysregulated in a wide range of physiological and pathological conditions. HPA dysregulation is measured by an assay of HPA function called the CRH test. In the CRH test, CRH is administered and cortisol and ACTH dynamics are measured for a few hours (Fig 1B). Major depression is associated with a blunted (reduced) ACTH response (Holsboer et al, 1984; Gold et al, 1986b; von Bardeleben & Holsboer, 1989) in the CRH test (Fig 1C), as well as with elevated baseline cortisol (Murphy, 1991). Elevated cortisol and blunted ACTH responses are also observed in other conditions that involve prolonged HPA axis activation (Fig 1D), including anorexia nervosa (Gold et al, 1986a), alcohol abuse disorder (von Bardeleben et al, 1989), and pregnancy (Magiakou et al, 1996). In these conditions, one can see three stages of HPA axis dysregulation after HPA over-activation stops (e.g., by weight normalization after anorexia, cessation of alcohol consumption, and childbirth, respectively). The stages are defined in Fig 1D. The first stage occurs right after the over-activation stops. In this early withdrawal stage, ACTH is blunted and cortisol is high. In the second stage of intermediate withdrawal, which occurs 2–6 weeks after resolution of HPA over-activation, cortisol returns to baseline levels but ACTH remains blunted. This ACTH blunting may be causal for some of the clinical aspects of these conditions, since ACTH is co-regulated with beta-endorphin that modulates pain and mood (Guillemin et al, 1977; Vale et al, 1981; Marrazzi & Luby, 1986; Adinoff et al, 2005; Racz et al, 2008; Peciña et al, 2019). In the third stage, months after withdrawal, both ACTH and cortisol normalize (for alcohol abuse disorder this time-point was not measured in von Bardeleben et al, 1989; Fig 1D). The dysregulation of the HPA axis is not explained by the existing mechanistic models of the HPA axis. The models cannot show the middle withdrawal phase with persistent blunting of ACTH responses despite the resolution of hypercortisolemia. This is because in current models, the dynamics of ACTH are strongly associated with the dynamics of cortisol, and so once cortisol normalizes, so should ACTH, within minutes to hours. Likewise, current models cannot explain how a deficient ACTH response produces a normal cortisol response, given that ACTH is the main regulator of cortisol secretion. Explaining this dysregulation requires a process on the scale of weeks that decouples the dynamics of ACTH and cortisol. This timescale cannot be readily explained by existing models of the HPA axis, where the relevant timescale is the lifetime of hormones, which is minutes to hours (Bingzheng et al, 1990). One important process with potentially a timescale of weeks is epigenetic regulation of the sensitivity of the cortisol receptor GR (glucocorticoid receptor) (Schaaf & Cidlowski, 2002; McGowan et al, 2009; Turner et al, 2010; Anacker et al, 2011; Cohen et al, 2012, 20; Watkeys et al, 2018). This process, however, cannot explain, on its own, the observed dysregulation. The reason is that GR resistance does not break the association between ACTH and cortisol: GR resistance should cause both ACTH and cortisol levels to increase, in contrast to the observed ACTH blunting. Here, we provide a mechanism for HPA axis dysregulation, and more generally for HPA dynamics on the time-scale of weeks. To do so, we add to the classic model two additional interactions which are experimentally characterized but have not been considered on the systems level. These are the interactions in which the HPA hormones act as the primary growth factors for the cells in their downstream glands. This causes the functional mass of the HPA glands to change over time, where by "functional mass of a gland" we mean the total capacity of the cells for the secretion of a hormone. A large body of research, beginning with Hans Selye in the 1930s, showed that the mass and number of adrenal cortisol-secreting cells increases under stress. Subsequent studies established the role of ACTH as the principle regulator of the functional mass of the adrenal cortex (Swann, 1940; Lotfi & de Mendonca, 2016). Imaging and postmortem studies also showed that adrenal mass increases in humans suffering from major depression (Amsterdam et al, 1987; Dorovini-Zis & Zis, 1987; Nemeroff et al, 1992; Szigethy et al, 1994; Rubin et al, 1996; Dumser et al, 1998; Ludescher et al, 2008) and returns to its original size after remission (Rubin et al, 1995). Similarly, CRH causes the growth of pituitary corticotrophs that secrete ACTH. Prolonged administration of CRH, or a CRH-secreting tumor, leads to increases in corticotroph cell mass (Carey et al, 1984; Westlund et al, 1985; Schteingart et al, 1986; Gertz et al, 1987; Horvath, 1988; Asa et al, 1992; O'Brien et al, 1992) as well as ACTH output (Bruhn et al, 1984; Young & Akil, 1985). Adrenalectomy, which removes the negative feedback inhibition from the HPA axis, shows similar effects in rodents (Bruhn et al, 1984; Westlund et al, 1985; McNicol et al, 1988; Gulyas et al, 1991) and leads to increased proliferation of corticotrophs (Gulyas et al, 1991), which is potentiated by CRH treatment. Changes in functional masses can occur by hypertrophy (enlarged cells) and/or hyperplasia (more cells); the exact mechanism does not matter for the present analysis. The changes in functional mass take weeks, due to the slow turnover time of cell mass. Such changes in functional mass have been shown in other hormonal axes (the insulin–glucose system) to provide important functions, including dynamical compensation, in which gland-mass changes buffer variations in physiological parameters (Topp et al, 2000; Ha et al, 2016; Karin et al, 2016). We therefore asked whether the interplay of interactions between hormones and gland mass in the HPA axis can explain the observed dysregulation of the HPA axis on the timescale of weeks in the pathological and physiological situations mentioned above. We also tested other putative slow processes such as epigenetic regulation of GR (and more generally, GR resistance), slow changes in the input signal, or changes in the removal rate of cortisol. Our model incorporates both the hormonal interactions and the gland-mass dynamics in the HPA axis. The model includes cortisol feedback through the high-affinity cortisol receptor MR (mineralocorticoid receptor) and the low-affinity receptor GR. We find that prolonged HPA activation enlarges the functional masses of the pituitary corticotrophs and adrenal cortex and that the recovery of these functional masses takes weeks after stress is removed. The dynamics of this recovery explains the observed HPA dysregulation: ACTH responses remain blunted for weeks after cortisol has normalized. Other putative slow processes that we tested cannot explain this dysregulation because they do not break the strong association between ACTH and cortisol. We further show that the GR protects the HPA axis against this dysregulation after high levels of stress, providing an explanation for the association between deficient GR feedback and depression. Finally, we demonstrate the physiological advantages conferred by the control of functional mass. Thus, functional mass changes provide an integrated explanation of HPA dysregulation and dynamics on the scale of weeks to months. Results A model for HPA axis dynamics that includes functional mass changes We begin by showing that the classic HPA model cannot produce the observed dysregulation. We then add new equations for the gland masses and show that they are sufficient to explain the dysregulation. The classical understanding of the HPA model is described by several minimal models (Gupta et al, 2007; Sriram et al, 2012; Andersen et al, 2013; Bangsgaard & Ottesen, 2017). These models are designed to address the timescale of hours to days and capture HPA dynamics on this timescale including circadian and ultradian rhythms. The input to these HPA models is the combined effects of physical and psychological stresses, including low blood glucose, low blood pressure, inflammation signals, psychological stressors, or effects of drugs such as alcohol. All inputs acting at a given time-point are considered as a combined input signal which we denote as u. The concentration of the three hormones CRH, ACTH, and cortisol are x1, x2, x3. The three-hormone cascade, with feedback by x3, is described by (1) (2) (3)where the hormone secretion parameters are k1, k2, k3, and hormone removal rates are w1, w2, w3. Hormone half-lives, given by log 2/wi, are 4 minutes for x1, 20 minutes for x2, and 80 min for x3 (Bingzheng et al, 1990; Table 1). The feedback functions g1(x3) and g2(x3) are Hill functions which describe the negative effect of cortisol on secretion of x1 and x2 (see Materials and Methods). Table 1. Parameter values Parameter Value w 1 0.17/min (Andersen et al, 2013) w 2 0.035/min (Andersen et al, 2013) w 3 0.0086/min (Andersen et al, 2013) w C 0.099/day w A 0.049/day K GR 4 0.016/min (Saphier et al, 1992) W 30 min D 20 0.023/day λ 1 w R 0.023/day n 3 (Andersen et al, 2013) These equations have a single stable steady-state solution (Andersen et al, 2013). Their response to prolonged stress, namely a pulse of input u(t) that lasts for a few weeks, shows elevated hormones during the stress, and a return to baseline within hours after the stress is over. Figure 2A shows a simulated CRH test, in which external CRH is added at a given time-point. ACTH shows no blunted ACTH responses in either early, intermediate, or late withdrawal phases (Fig 2A). This behavior can also be shown analytically (Materials and Methods). Figure 2. Model with functional mass dynamics shows ACTH blunting for weeks even after cortisol normalizes The classic model of HPA axis dynamics without gland-mass dynamics produces elevated levels of stress hormones during prolonged stress. However, it does not produce blunted ACTH responses in the CRH test, and, after cessation of the stressor, all hormones return to baseline within hours. To account for the control of pituitary corticotroph growth by CRH and adrenal cortex growth by ACTH, we added to classic HPA model two equations that represent the dynamics of the functional mass of corticotrophs (C) and the adrenal cortex (A). (Inset) Such dynamics explain, for example, the enlarged adrenals of stressed rats (inset, right) compared with control (inset, left), adapted from Selye (1952). The model shows the three distinct phases of HPA axis dysregulation observed in experiments. At the end of a prolonged stress period, the adrenal mass is enlarged and the corticotroph mass is slightly enlarged, which results in hypercortisolemia and blunted ACTH responses in the CRH test. After a few weeks, corticotroph mass drops below baseline, while adrenal mass is slightly enlarged, causing normal cortisol dynamics with blunted ACTH responses to the CRH test. Finally, after a few months both tissue masses return to normal, leading to normalization of both cortisol and ACTH dynamics. Data information: In all panels, simulations are of a CRH test (Materials and Methods), where "case" (black) is after stress and "control" (gray) is after basal HPA axis activation, as described in Fig 3. Download figure Download PowerPoint To describe HPA dynamics over weeks, we add to the classic model two interactions between the hormones and the total functional mass of the cells that secrete these hormones. We introduce two new variables, the functional mass of the corticotrophs, C(t), and the functional mass of the adrenal cells that secrete cortisol, A(t). To focus on the role of the mass, we separate the secretion parameters into a product of secretion per cell times the total cell mass. The secretion parameter of ACTH is thus k2 = b2C, where C is the corticotroph mass and b2 is the rate of ACTH secretion per unit corticotroph mass. The parameter b2 includes the metabolic capacity of the corticotrophs, the number of CRH receptors and the total blood volume which dilutes out ACTH. A similar equation describes the secretion parameter of cortisol, k3 = b3A. To isolate the effects of mass changes, we assume for simplicity that the per-unit-biomass secretion rates b2 and b3 are constant, whereas A(t) and C(t) can vary with time. This introduces two new equations for the functional masses, which have a slow timescale of weeks. Corticotrophs proliferate under control of x1, and adrenal cortex cells under control of x2, and thus (4) (5)where the cell-mass production rates are kCx1 and kAx2, and the cell-mass removal rates are wC and wA. The removal rates are taken from experimental data that indicate cell half-lives of days–weeks (Swann, 1940; Westlund et al, 1985; Gulyas et al, 1991). We use half-life of 6 days for C and 12 days for A (parameters given in Table 1), but the results do not depend sensitively on these parameters, as shown below. The new model thus has five equations, three on the fast timescale of hours and two on the slow timescale of weeks. One can prove that they have a single stable steady state. We non-dimensionalized the equations to provide hormone and cell-mass steady-state levels of 1 (Materials and Methods; equations 6-2). Model shows HPA axis dysregulation after prolonged activation The HPA model with gland-mass changes captures the experimentally observed dysregulation (Fig 2A and B). In response to a prolonged stress input u of a few weeks or longer, the adrenal gland-mass A and corticotroph mass C both grow. When the prolonged stress input is over, the glands are large (Fig 2B—early withdrawal). They gradually return to baseline, but the corticotroph mass returns with an undershoot, dropping below baseline mass and then returning over several weeks (Fig 2B). These qualitative properties of the dynamics can be shown analytically (Materials and Methods) and do not depend on model parameters. These transients of gland masses are at the core of the hormone dysregulation. The changed masses of the glands affect the response of the hormones to a CRH test. In early withdrawal, cortisol is high and ACTH responses are blunted (Fig 2B). Then, for a period of several weeks in intermediate withdrawal, cortisol has returned to its original baseline but ACTH remains blunted. Finally, after several months, both cortisol and ACTH return to their original baselines. Thus, the model recapitulates the experimentally observed dynamics of Fig 1. To understand these dynamics in detail, we plot in Fig 3 the full behavior of the functional masses and hormones during and after the prolonged pulse of input (Fig 3A). Importantly, the qualitative conclusions are insensitive to the precise values of the model parameters. Figure 3 shows the dynamics of corticotroph and adrenal masses (Fig 3B), as well as the hormone levels (Fig 3C). To compare to CRH tests, we also simulated a CRH test at each time-point (Fig 3D). To visualize the result of the CRH tests, we plot the ratio of the peak hormone level after CRH administration relative to a control CRH test without the prolonged stress input (Fig 3E). Blunted responses correspond to values less than 1. Figure 3. Model dynamics of HPA axis after prolonged stress A–C. Numerical solution of the HPA model after a prolonged pulse of input (u = 4) lasting 3 months, followed by return to baseline input u = 1 (A). During the pulse, gland masses (B) increase over weeks, leading to exact adaptation of ACTH and CRH levels after a few weeks (C) despite the increased input level. After stress ends, gland masses adjust back over weeks. During this adjustment period, the HPA axis is dysregulated. D. To model a CRH test, we add exogenous CRH to the simulation and follow the hormones over several hours. The response is defined as the maximum response to a CRH test (case) relative to the maximum response to a CRH test in steady state with basal input conditions (control). E. The response to a CRH test given at time t is shown as a function of t. Thus, this is the predicted response to CRH tests done at different days during and after the stressor. The model (black lines) shows blunted (reduced) responses to CRH tests after the stress similar to those observed in Fig 1, as well as a mismatch between cortisol and ACTH dynamics that develops a few weeks after cessation of stress. EW is early withdrawal, IW is intermediate withdrawal and LW is late withdrawal. Download figure Download PowerPoint One can see two phases during the stress pulse. The initial phase occurs after the onset of the stressor and before adaptation to the stressor (Marked ONSET in Fig 3). It lasts several weeks. In this phase, the increase in input u causes elevated levels and responses of CRH, ACTH, and cortisol (Fig 3C). However, over weeks of stress input, the corticotroph and adrenal masses grow (Fig 3B). These gland masses thus effectively adjust to the stressor, as example of the more general phenomenon of dynamical compensation in physiological systems (Karin et al, 2016). The mass growth causes a return to baseline of hypothalamic CRH and ACTH, due to negative feedback by cortisol. More precisely, a larger adrenal functional mass means that less ACTH is needed to produce a concentration of cortisol that drives ACTH down to baseline. Such a return to baseline is called exact adaptation. Exact adaptation is a robust feature of this circuit due to a mathematical principle in the functional mass equations, equations (4 and 5), called integral feedback (Karin et al, 2016; Materials and Methods): The only steady-state solution of equations (4 and 5) is that the hormones x1 and x2 balance proliferation and growth parameters. Exact adaptation does not occur in models without the effects of functional mass changes—the hormones do not adapt to the stressor (Appendix Fig S1, Appendix Section 1). The enlarged functional masses result in elevated cortisol levels during the stress period, but in adapted (that is, baseline) levels of CRH, ACTH, and blunted responses of CRH and ACTH to inputs (Fig 3E). During prolonged stress, there is thus a transition from an elevated to a blunted response of ACTH that occurs due to changes in functional masses, and results from cortisol negative feedback. At the end of the prolonged stress pulse, the early withdrawal (or EW) phase, the functional masses are abnormal and take weeks to months to recover. This fundamental process is the reason for the hormonal dysregulation that is the subject of this study. In the first weeks after the stressor is removed, the adrenal and corticotroph functional masses shrink, accompanied by dropping cortisol levels. ACTH responses are blunted, and blunting may even worsen over time. Then, cortisol and CRH levels and responses simultaneously normalize. This marks the beginning of the next phase, intermediate withdrawal (IW, Fig 3). In this phase, ACTH responses remain blunted, despite the fact that cortisol is back to baseline, because adrenal functional mass is enlarged, and corticotroph functional mass is deficient. Finally, over time, the entire dynamics of the HPA axis normalize (Late Withdrawal, LW in Fig 3), and the system has fully recovered. These recovery phases are robust features of the HPA model with mass dynamics. After withdrawal of the stressor, cortisol and CRH levels and dynamics recover together, before the recovery of ACTH. This order occurs regardless of parameter values such as turnover times of the tissues (proof in Materials and Methods). The intuitive reason for this is that before CRH returns to baseline, the growth rate of the pituitary corticotrophs is negative, preventing ACTH from returning to baseline. We conclude that the gland-mass model is sufficient to explain the dynamics of recovery from chronic HPA activation in the conditions mentioned in the introduction—anorexia, alcohol addiction, and pregnancy (Fig 3). In order to explain the timescales of recovery, the only model parameters that matter are the tissue turnover times. Good agreement is found with turnover times on the scale of 1–3 weeks for the corticotrophs and adrenal cortex cells (see Appendix Fig S2 for comparison of different turnover times, Appendix Section 2). The model therefore explains how ACTH responses remain blunted despite normalization of cortisol baseline and dynamics. We also tested several alternative mechanisms with a slow timescale of weeks. We tested models with constant gland masses and the following processes to which we assigned time constants on the order of 1 month: GR resistance following HPA activation (Appendix Fig S1, purple lines), slow changes in input signal (Appendix Fig S1, blue lines), and slow changes in cortisol removal rate (Appendix Fig S1, gray lines). None of these putative models show the dysregulation that we consider. The reason is that these slow processes do not cause a mismatch between ACTH and cortisol needed to capture the blunting of ACTH despite normal cortisol responses during intermediate withdrawal. Deficient GR feedback exacerbates HPA dysregulation following prolonged stress We next considered the role of glucocorticoid receptor (GR) in recovery from prolonged HPA activation. GR mediates the negative feedback of cortisol on CRH and ACTH secretion. Impaired feedback by GR is observed in many cases of depression. For example, administration of dexamethasone, which binds the GR in the pituitary, fails to suppress cortisol secretion in the majority of individuals suffering from depression (Coppen et al, 1983). Reduced expression of GR and impaired GR function in people with depression was also demonstrated in post mortem brains (López et al, 1998; Webster et al, 2002; McGowan et al, 2009; Pandey et al, 2013) and in peripheral tissues (Pariante, 2004). The feedback strength of the GR is regulated epigenetically and is affected by early-life adversity (Weaver et al, 2004; McGowan et al, 2009). The relation between depression and impaired GR function seems paradoxical, since GR signaling mediates many of the detrimental effects associated with high cortisol levels such as hippocampal atrophy (Sapolsky et al, 1985). One explanation for the association between impaired GR feedback and depres