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HPA Axis‐Rhythms

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Abstract

The hypothalamic‐pituitary‐adrenal (HPA) axis regulates circulating levels of glucocorticoid hormones, and is the major neuroendocrine system in mammals that provides a rapid response and defense against stress. Under basal (i.e., unstressed) conditions, glucocorticoids are released with a pronounced circadian rhythm, characterized by peak levels of glucocorticoids during the active phase, that is daytime in humans and nighttime in nocturnal animals such as mice and rats. When studied in more detail, it becomes clear that the circadian rhythm of the HPA axis is characterized by a pulsatile release of glucocorticoids from the adrenal gland that results in rapid ultradian oscillations of hormone levels both in the blood and within target tissues, including the brain. In this review, we discuss the regulation of these circadian and ultradian HPA rhythms, how these rhythms change in health and disease, and how they affect the physiology and behavior of the organism. © 2014 American Physiological Society. Compr Physiol 4:1273‐1298, 2014.

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Figure 1. Figure 1. The hypothalamic‐pituitary‐adrenal (HPA) axis and glucocorticoid rhythms. (A) The hypothalamic paraventricular nucleus (PVN) receives circadian input from the SCN and stress inputs from the brainstem and from regions of the limbic system such as the hippocampus and amygdala. The PVN projects to the median eminence where it releases corticotrophin‐releasing hormone (CRH) and arginine vasopressin (AVP) into the hypothalamic‐pituitary portal circulation. CRH passes through this vascular route to access corticotroph cells in the anterior pituitary, which respond with the rapid release of adrenocorticotropic hormone (ACTH) from preformed vesicles into the general circulation. In turn, ACTH reaches the adrenal cortex where it activates the synthesis and secretion of glucocorticoid hormones (CORT). Glucocorticoids regulate the activity of the HPA axis, and thus their own production, through feedback mechanisms acting at the level of the pituitary gland where they inhibit ACTH release, and at the level of the PVN where they inhibit the release of CRH and AVP. Reproduced with permission from (116). (B) Under basal (i.e., unstressed) conditions, the dynamics of glucocorticoid secretion is characterized by both a circadian (gray line) and an approximately hourly ultradian rhythm (black line). In the rat, peak levels of corticosterone occur during the active evening phase. Shaded region indicates the dark phase. Reproduced with permission from (201).
Figure 2. Figure 2. Circadian rhythms in the HPA axis. Rat ACTH (A) and corticosterone (B) profiles show a clear circadian variation over the 24‐h period with peak levels during the active phase. Steroidogenic acute regulatory protein (StAR), the rate limiting protein in adrenal glucocorticoid synthesis, is also expressed in the adrenal with a circadian pattern that is similar to that observed for ACTH and corticosterone (C). In contrast, the expression pattern of the specific ACTH receptor melanocortin 2 (MC2R) appears to be in antiphase with both StAR and ACTH (D). Reproduced with permission from (145).
Figure 3. Figure 3. Ultradian corticosterone pulsatility is maintained following lesioning of the SCN. (A) Plasma corticosterone levels in a control (sham lesion) rat. (B) Plasma corticosterone levels in a rat with SCN lesion. Corticosterone was measured in blood samples collected at 10 min intervals from freely behaving male Sprague‐Dawley rats using an automated blood sampling system. Gray curves indicate circadian trend. Shaded regions indicate the dark phase. Reproduced with permission from (201).
Figure 4. Figure 4. An ultradian pattern underlies all the components of the HPA axis. (A) Pulsatile release of CRH in the rat median eminence. CRH was measured in perfusate from push‐pull cannulas implanted in the rat median eminence; samples were collected at 5 min intervals from an unanesthetized male rat under basal conditions. Reproduced with permission from (84). (B) ACTH levels in rat plasma samples collected every 2 min from the jugular vein via an indwelling cannula. Reproduced with permission from (27). (C) Corticosterone levels in rat blood samples collected every 5 min using an automated blood sampling system. Reproduced with permission from (202). Note that in the rat, CRH pulse frequency is higher (∼3 pulses/h) than the near‐hourly oscillation in ACTH and corticosterone.
Figure 5. Figure 5. Human cortisol and ACTH dynamics. Ultradian ACTH and cortisol oscillations in a healthy man are tightly correlated with ACTH leading cortisol. ACTH and cortisol were measured in blood samples collected at 10 min intervals using an automated blood sampling system. Light was off between 2300 and 0700. Adapted and reproduced with permission from (73).
Figure 6. Figure 6. Mathematical modeling predictions of the pituitary‐adrenal response to different levels of constant CRH drive. (A) Computed two‐parameter bifurcation diagram shows that different combinations of constant CRH drive and adrenal delay result in qualitatively different dynamic responses from the pituitary‐adrenal system. On one side of the transition curve, the pituitary‐adrenal system responds with oscillations in ACTH and glucocorticoids (CORT), despite the fact that the CRH drive is constant (point B). On the other side of the transition curve, the pituitary‐adrenal system responds with steady state levels in ACTH and CORT (point C). (B) Model predictions for ACTH (grey) and CORT (black) corresponding to point B in panel (A). (C) Numerical simulations for ACTH (grey) and CORT (black) corresponding to point C in panel (A). Model predictions are shown for a 5‐h period after transient dynamics have decayed. AU, arbitrary units. Reproduced with permission from (203).
Figure 7. Figure 7. Constant infusion of CRH induces pulsatile secretion of ACTH and corticosterone. (A) Individual corticosterone response to constant CRH infusion. In line with the modeling hypothesis, constant infusion of CRH (0.5 μg/h) induces ultradian corticosterone oscillations that persist throughout the infusion period. This oscillatory response is characterized by an initial rapid increase in corticosterone within approximately 15 min following the onset of the CRH infusion, reaching peak levels by approximately 30 min and returning to low levels by approximately 80 min. Following the initial pulse, the amplitude of the oscillation is relatively constant throughout the infusion. Samples were collected every 5 min from a freely behaving male rat using an automated blood sampling system. Grey bar indicates the period of infusion. (B) ACTH and corticosterone responses to constant CRH infusion. Samples were collected manually at 20 min intervals throughout the infusion via an indwelling cannula implanted in the jugular vein. In agreement with the modeling predictions, CRH induces ACTH and corticosterone oscillations that persist throughout the infusion period. (C) Phase‐shifted ACTH and corticosterone response to constant CRH infusion (0.5 μg/h) over the initial activation phase (0‐25 min) of the oscillation. This phase shift between ACTH and corticosterone presumably reflects the time taken for de novo biosynthesis and release of corticosterone in the adrenal cortex. Reproduced with permission from (202).
Figure 8. Figure 8. Effect of pulsatile ACTH administration on plasma corticosterone levels and StAR and MRAP primary transcript levels. (A) Pulsatile corticosterone secretion in rats chronically treated with methylprednisolone (MP) and infused with pulsatile ACTH (4 ng/h, 5 min pulse/h). ACTH infusion started at 10 am and blood samples were collected every 10 min using an automated blood sampling system. Data are the mean of 9 different rats. Data reproduced with permission from (180). (B and C). Administration of a small dose of ACTH (4ng/rat; i.v.) induces a rapid but transient increase in the primary transcript of StAR (B) and MRAP (C), suggesting that pulsatile expression of steroidogenic genes is important for the ultradian rhythm of corticosterone secretion. Transcriptional response of StAR and MRAP was measured by RT‐qPCR using specific primers targeting the gene primary transcript. Data in (B) reproduced with permission from (179). Data in (C) reproduced with permission from (119).
Figure 9. Figure 9. Changes in ultradian glucocorticoid dynamics in different physiological and pathological states. (A and B) Ultradian corticosterone oscillations in a female (A) and male (B) Sprague‐Dawley rat. Reproduced with permission from (169) (C and D). Ultradian corticosterone oscillations in juvenile (C) and adults (D) rats (unpublished observations). (E and F) Ultradian corticosterone oscillations in a control male PVG rat (E) and a male PVG rat with active immune‐mediated adjuvant‐induced arthritis (F). Reproduced with permission from (213). In all experiments, corticosterone was measured in blood samples collected at 10 min intervals from freely behaving rats. Shaded regions indicate the dark phase.
Figure 10. Figure 10. Stress responsiveness is dependent on the phase of the ultradian corticosterone rhythm. Corticosterone response in rats exposed to a noise stress (10 min, 114 dB); blood samples were collected every 10 min using an automated blood sampling system. Rats stressed during the rising phase of an endogenous corticosterone pulse (A) show much greater corticosterone responses than animals stressed during the falling phase (B). Reproduced with permission from (215).
Figure 11. Figure 11. Ultradian rhythm of hippocampal free corticosterone measured by in vivo microdialysis in a freely behaving male Wistar rat. Hippocampal dialysate samples were collected every 10 min between 0800 and 2200 h and every 30 min between 2200 and 0800 h. Male Wistar rats show a clear and distinct circadian and ultradian pattern of corticosterone in the hippocampus with a pulse frequency that is similar to that observed in plasma corticosterone. Reproduced with permission from (53).
Figure 12. Figure 12. Ultradian corticosterone pulses induce pulsatile GR‐GRE interactions and pulsatile gene transcription. (A) Real time single cell imaging of GFP‐labeled GR loading at an engineered array of GREs in the MCF‐7 (3617) mouse cell line. Each pulse of corticosterone causes a “wave” of GR‐GRE binding (fluorescent green points) that is rapidly reversed (GR‐GRE dissociation) following hormone withdrawal (washout). (B) Dependence of transcriptional dynamics on the pattern of hormone stimulation. Ultradian corticosterone treatment results in pulsatile transcription of the Period 1 gene (Per1) (black), whereas constant corticosterone induces sustained transcription (grey). Levels of Per1 primary transcript were measured in the 3134 cell line by real‐time quantitative PCR. Data reproduced with permission from (182).
Figure 13. Figure 13. Corticosterone ultradian rhythm induces pulsatile GR activation and GR‐mediated gene transcription in the rat hippocampus. To determine the effect of pulsatile corticosterone treatment on GR nuclear translocation and transcription of the Period 1 (Per1) gene, multiple corticosterone pulses (100ng/pulse; i.v.) were given at hourly intervals. (A) GR immunofluorescence in the CA1 region of the hippocampus throughout the time course of one corticosterone pulse in adrenalectomized rats. At time 0 min, GR immunoreactivity is predominantly cytoplasmic. A clear transient increase of approximately twofold can be seen in nuclear GR within 15 min of the corticosterone injection, which returns to baseline levels by 60 min. (B) Circulating corticosterone levels induced by four corticosterone pulses in adrenalectomized rats. Corticosterone is maximally increased in plasma at 1 min after each injection and then subsequently cleared according to the characterized half‐life of corticosterone in the blood. (C) Each corticosterone pulse induces a pulse of Per1 gene transcription. Per1 primary transcript levels increase rapidly, reaching a maximum at 30 min after each injection and, consistent with the pattern of GR dissociation from the DNA as corticosterone is cleared from the circulation, return to basal levels at 60 min after each pulse. Reproduced with permission from (41).


Figure 1. The hypothalamic‐pituitary‐adrenal (HPA) axis and glucocorticoid rhythms. (A) The hypothalamic paraventricular nucleus (PVN) receives circadian input from the SCN and stress inputs from the brainstem and from regions of the limbic system such as the hippocampus and amygdala. The PVN projects to the median eminence where it releases corticotrophin‐releasing hormone (CRH) and arginine vasopressin (AVP) into the hypothalamic‐pituitary portal circulation. CRH passes through this vascular route to access corticotroph cells in the anterior pituitary, which respond with the rapid release of adrenocorticotropic hormone (ACTH) from preformed vesicles into the general circulation. In turn, ACTH reaches the adrenal cortex where it activates the synthesis and secretion of glucocorticoid hormones (CORT). Glucocorticoids regulate the activity of the HPA axis, and thus their own production, through feedback mechanisms acting at the level of the pituitary gland where they inhibit ACTH release, and at the level of the PVN where they inhibit the release of CRH and AVP. Reproduced with permission from (116). (B) Under basal (i.e., unstressed) conditions, the dynamics of glucocorticoid secretion is characterized by both a circadian (gray line) and an approximately hourly ultradian rhythm (black line). In the rat, peak levels of corticosterone occur during the active evening phase. Shaded region indicates the dark phase. Reproduced with permission from (201).


Figure 2. Circadian rhythms in the HPA axis. Rat ACTH (A) and corticosterone (B) profiles show a clear circadian variation over the 24‐h period with peak levels during the active phase. Steroidogenic acute regulatory protein (StAR), the rate limiting protein in adrenal glucocorticoid synthesis, is also expressed in the adrenal with a circadian pattern that is similar to that observed for ACTH and corticosterone (C). In contrast, the expression pattern of the specific ACTH receptor melanocortin 2 (MC2R) appears to be in antiphase with both StAR and ACTH (D). Reproduced with permission from (145).


Figure 3. Ultradian corticosterone pulsatility is maintained following lesioning of the SCN. (A) Plasma corticosterone levels in a control (sham lesion) rat. (B) Plasma corticosterone levels in a rat with SCN lesion. Corticosterone was measured in blood samples collected at 10 min intervals from freely behaving male Sprague‐Dawley rats using an automated blood sampling system. Gray curves indicate circadian trend. Shaded regions indicate the dark phase. Reproduced with permission from (201).


Figure 4. An ultradian pattern underlies all the components of the HPA axis. (A) Pulsatile release of CRH in the rat median eminence. CRH was measured in perfusate from push‐pull cannulas implanted in the rat median eminence; samples were collected at 5 min intervals from an unanesthetized male rat under basal conditions. Reproduced with permission from (84). (B) ACTH levels in rat plasma samples collected every 2 min from the jugular vein via an indwelling cannula. Reproduced with permission from (27). (C) Corticosterone levels in rat blood samples collected every 5 min using an automated blood sampling system. Reproduced with permission from (202). Note that in the rat, CRH pulse frequency is higher (∼3 pulses/h) than the near‐hourly oscillation in ACTH and corticosterone.


Figure 5. Human cortisol and ACTH dynamics. Ultradian ACTH and cortisol oscillations in a healthy man are tightly correlated with ACTH leading cortisol. ACTH and cortisol were measured in blood samples collected at 10 min intervals using an automated blood sampling system. Light was off between 2300 and 0700. Adapted and reproduced with permission from (73).


Figure 6. Mathematical modeling predictions of the pituitary‐adrenal response to different levels of constant CRH drive. (A) Computed two‐parameter bifurcation diagram shows that different combinations of constant CRH drive and adrenal delay result in qualitatively different dynamic responses from the pituitary‐adrenal system. On one side of the transition curve, the pituitary‐adrenal system responds with oscillations in ACTH and glucocorticoids (CORT), despite the fact that the CRH drive is constant (point B). On the other side of the transition curve, the pituitary‐adrenal system responds with steady state levels in ACTH and CORT (point C). (B) Model predictions for ACTH (grey) and CORT (black) corresponding to point B in panel (A). (C) Numerical simulations for ACTH (grey) and CORT (black) corresponding to point C in panel (A). Model predictions are shown for a 5‐h period after transient dynamics have decayed. AU, arbitrary units. Reproduced with permission from (203).


Figure 7. Constant infusion of CRH induces pulsatile secretion of ACTH and corticosterone. (A) Individual corticosterone response to constant CRH infusion. In line with the modeling hypothesis, constant infusion of CRH (0.5 μg/h) induces ultradian corticosterone oscillations that persist throughout the infusion period. This oscillatory response is characterized by an initial rapid increase in corticosterone within approximately 15 min following the onset of the CRH infusion, reaching peak levels by approximately 30 min and returning to low levels by approximately 80 min. Following the initial pulse, the amplitude of the oscillation is relatively constant throughout the infusion. Samples were collected every 5 min from a freely behaving male rat using an automated blood sampling system. Grey bar indicates the period of infusion. (B) ACTH and corticosterone responses to constant CRH infusion. Samples were collected manually at 20 min intervals throughout the infusion via an indwelling cannula implanted in the jugular vein. In agreement with the modeling predictions, CRH induces ACTH and corticosterone oscillations that persist throughout the infusion period. (C) Phase‐shifted ACTH and corticosterone response to constant CRH infusion (0.5 μg/h) over the initial activation phase (0‐25 min) of the oscillation. This phase shift between ACTH and corticosterone presumably reflects the time taken for de novo biosynthesis and release of corticosterone in the adrenal cortex. Reproduced with permission from (202).


Figure 8. Effect of pulsatile ACTH administration on plasma corticosterone levels and StAR and MRAP primary transcript levels. (A) Pulsatile corticosterone secretion in rats chronically treated with methylprednisolone (MP) and infused with pulsatile ACTH (4 ng/h, 5 min pulse/h). ACTH infusion started at 10 am and blood samples were collected every 10 min using an automated blood sampling system. Data are the mean of 9 different rats. Data reproduced with permission from (180). (B and C). Administration of a small dose of ACTH (4ng/rat; i.v.) induces a rapid but transient increase in the primary transcript of StAR (B) and MRAP (C), suggesting that pulsatile expression of steroidogenic genes is important for the ultradian rhythm of corticosterone secretion. Transcriptional response of StAR and MRAP was measured by RT‐qPCR using specific primers targeting the gene primary transcript. Data in (B) reproduced with permission from (179). Data in (C) reproduced with permission from (119).


Figure 9. Changes in ultradian glucocorticoid dynamics in different physiological and pathological states. (A and B) Ultradian corticosterone oscillations in a female (A) and male (B) Sprague‐Dawley rat. Reproduced with permission from (169) (C and D). Ultradian corticosterone oscillations in juvenile (C) and adults (D) rats (unpublished observations). (E and F) Ultradian corticosterone oscillations in a control male PVG rat (E) and a male PVG rat with active immune‐mediated adjuvant‐induced arthritis (F). Reproduced with permission from (213). In all experiments, corticosterone was measured in blood samples collected at 10 min intervals from freely behaving rats. Shaded regions indicate the dark phase.


Figure 10. Stress responsiveness is dependent on the phase of the ultradian corticosterone rhythm. Corticosterone response in rats exposed to a noise stress (10 min, 114 dB); blood samples were collected every 10 min using an automated blood sampling system. Rats stressed during the rising phase of an endogenous corticosterone pulse (A) show much greater corticosterone responses than animals stressed during the falling phase (B). Reproduced with permission from (215).


Figure 11. Ultradian rhythm of hippocampal free corticosterone measured by in vivo microdialysis in a freely behaving male Wistar rat. Hippocampal dialysate samples were collected every 10 min between 0800 and 2200 h and every 30 min between 2200 and 0800 h. Male Wistar rats show a clear and distinct circadian and ultradian pattern of corticosterone in the hippocampus with a pulse frequency that is similar to that observed in plasma corticosterone. Reproduced with permission from (53).


Figure 12. Ultradian corticosterone pulses induce pulsatile GR‐GRE interactions and pulsatile gene transcription. (A) Real time single cell imaging of GFP‐labeled GR loading at an engineered array of GREs in the MCF‐7 (3617) mouse cell line. Each pulse of corticosterone causes a “wave” of GR‐GRE binding (fluorescent green points) that is rapidly reversed (GR‐GRE dissociation) following hormone withdrawal (washout). (B) Dependence of transcriptional dynamics on the pattern of hormone stimulation. Ultradian corticosterone treatment results in pulsatile transcription of the Period 1 gene (Per1) (black), whereas constant corticosterone induces sustained transcription (grey). Levels of Per1 primary transcript were measured in the 3134 cell line by real‐time quantitative PCR. Data reproduced with permission from (182).


Figure 13. Corticosterone ultradian rhythm induces pulsatile GR activation and GR‐mediated gene transcription in the rat hippocampus. To determine the effect of pulsatile corticosterone treatment on GR nuclear translocation and transcription of the Period 1 (Per1) gene, multiple corticosterone pulses (100ng/pulse; i.v.) were given at hourly intervals. (A) GR immunofluorescence in the CA1 region of the hippocampus throughout the time course of one corticosterone pulse in adrenalectomized rats. At time 0 min, GR immunoreactivity is predominantly cytoplasmic. A clear transient increase of approximately twofold can be seen in nuclear GR within 15 min of the corticosterone injection, which returns to baseline levels by 60 min. (B) Circulating corticosterone levels induced by four corticosterone pulses in adrenalectomized rats. Corticosterone is maximally increased in plasma at 1 min after each injection and then subsequently cleared according to the characterized half‐life of corticosterone in the blood. (C) Each corticosterone pulse induces a pulse of Per1 gene transcription. Per1 primary transcript levels increase rapidly, reaching a maximum at 30 min after each injection and, consistent with the pattern of GR dissociation from the DNA as corticosterone is cleared from the circulation, return to basal levels at 60 min after each pulse. Reproduced with permission from (41).
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Francesca Spiga, Jamie J. Walker, John R. Terry, Stafford L. Lightman. HPA Axis‐Rhythms. Compr Physiol 2014, 4: 1273-1298. doi: 10.1002/cphy.c140003