Recovery from Disrupted Ultradian Glucocorticoid Rhythmicity Reveals a Dissociation Between Hormonal and Behavioural Stress Responsiveness

Ultradian release of glucocorticoids is thought to be essential for homeostasis and health. Furthermore, deviation from this pulsatile release pattern is considered to compromise resilience to stress‐related disease, even after hormone levels have normalised. In the present study, we investigate how constant exposure to different concentrations of corticosterone affects diurnal and ultradian pulsatility. The rate of recovery in pulsatile hypothalamic‐pituitary‐adrenal (HPA) activity after withdrawal of exogenous corticosterone is also examined. Finally, the behavioural and neuroendocrine responsiveness to an audiogenic stressor is studied. Adrenally intact male rats were subcutaneously implanted with vehicle, 40% or 100% corticosterone pellets for 7 days. The continuous release of corticosterone from these implants abolished diurnal and ultradian corticosterone variation, as measured with high‐frequency automated blood sampling. Pellet removal on post‐surgery day 8 allowed rapid recovery of endogenous rhythms in animals previously exposed to daily average concentrations (40%) but not after exposure to high concentrations (100%) of corticosterone. Behavioural and neuroendocrine responsiveness to stress was distinctly different between the treatment groups. Audiogenic stimulation 1 day after pellet removal resulted in a similar corticosterone response in animals previously exposed to 40% corticosterone or vehicle. The 40% pellet group, however, showed less and shorter behavioural activity (i.e. locomotion, risk assessment) to noise stress compared to 100% corticosterone and vehicle‐treated animals. In conclusion, unlike the animals impanted with 100% corticosterone, we find that basal HPA axis activity in the 40% group, which had mean daily levels of circulating corticosterone in the physiological range, rapidly reverts to the characteristic pulsatile pattern of corticosterone secretion. Upon reinstatement of the ultradian rhythm, and despite the fact that these animals did not differ from controls in their response to noise stress, they did show substantial changes in their behavioural response to stress.

[1]  Lars Schwabe,et al.  Corticosteroids Operate as a Switch between Memory Systems , 2010, Journal of Cognitive Neuroscience.

[2]  J. Romijn,et al.  Subtle cognitive impairments in patients with long-term cure of Cushing's disease. , 2010, The Journal of clinical endocrinology and metabolism.

[3]  N. Datson,et al.  Disrupted corticosterone pulsatile patterns attenuate responsiveness to glucocorticoid signaling in rat brain. , 2010, Endocrinology.

[4]  John R. Terry,et al.  Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis , 2010, Proceedings of the Royal Society B: Biological Sciences.

[5]  Ty C. Voss,et al.  Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription , 2009, Nature Cell Biology.

[6]  L. Schwabe,et al.  Chronic stress modulates the use of spatial and stimulus-response learning strategies in mice and man , 2008, Neurobiology of Learning and Memory.

[7]  E. D. de Kloet,et al.  Everything has rhythm: focus on glucocorticoid pulsatility. , 2008, Endocrinology.

[8]  S. Lightman,et al.  Corticosteroids mediate fast feedback of the rat hypothalamic-pituitary-adrenal axis via the mineralocorticoid receptor. , 2008, American journal of physiology. Endocrinology and metabolism.

[9]  Francesca Spiga,et al.  The significance of glucocorticoid pulsatility. , 2008, European journal of pharmacology.

[10]  S. Lightman,et al.  Effect of the glucocorticoid receptor antagonist Org 34850 on fast and delayed feedback of corticosterone release. , 2008, The Journal of endocrinology.

[11]  Marian Joëls,et al.  The coming out of the brain mineralocorticoid receptor , 2008, Trends in Neurosciences.

[12]  S. Lightman,et al.  Proteasome-dependent down-regulation of activated nuclear hippocampal glucocorticoid receptors determines dynamic responses to corticosterone. , 2007, Endocrinology.

[13]  F. Thomson,et al.  Effect of the Glucocorticoid Receptor Antagonist Org 34850 on Basal and Stress‐Induced Corticosterone Secretion , 2007, Journal of neuroendocrinology.

[14]  M. Joëls,et al.  Chronic stress: Implications for neuronal morphology, function and neurogenesis , 2007, Frontiers in Neuroendocrinology.

[15]  B. Czéh,et al.  Remodeling of neuronal networks by stress. , 2006, Frontiers in bioscience : a journal and virtual library.

[16]  S. Lightman,et al.  Diurnal Variation in the Responsiveness of the Hypothalamic‐Pituitary‐Adrenal Axis of the Male Rat to Noise Stress , 2006, Journal of neuroendocrinology.

[17]  Marian Joëls,et al.  Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Y. Lacasse,et al.  From the authors , 2005, European Respiratory Journal.

[19]  D. Torpy,et al.  Plasma free cortisol fraction reflects levels of functioning corticosteroid-binding globulin. , 2005, Clinica chimica acta; international journal of clinical chemistry.

[20]  F. Holsboer,et al.  Stress and the brain: from adaptation to disease , 2005, Nature Reviews Neuroscience.

[21]  E. Young,et al.  Cortisol pulsatility and its role in stress regulation and health , 2004, Frontiers in Neuroendocrinology.

[22]  J. Haller,et al.  Genomic and non-genomic effects of glucocorticoids on aggressive behavior in male rats , 2004, Psychoneuroendocrinology.

[23]  J. Haller,et al.  Chronic Glucocorticoid Deficiency‐Induced Abnormal Aggression, Autonomic Hypoarousal, and Social Deficit in Rats , 2004, Journal of neuroendocrinology.

[24]  S. L. la Fleur,et al.  Chronic Stress‐Induced Effects of Corticosterone on Brain: Direct and Indirect , 2004, Annals of the New York Academy of Sciences.

[25]  S. Di,et al.  Nongenomic Glucocorticoid Inhibition via Endocannabinoid Release in the Hypothalamus: A Fast Feedback Mechanism , 2003, The Journal of Neuroscience.

[26]  D. Middlemiss,et al.  Implantation of a Slow Release Corticosterone Pellet Induces Long‐Term Alterations in Serotonergic Neurochemistry in the Rat Brain , 2003, Journal of neuroendocrinology.

[27]  A. Kalsbeek,et al.  Output pathways of the mammalian suprachiasmatic nucleus: coding circadian time by transmitter selection and specific targeting , 2002, Cell and Tissue Research.

[28]  S L Lightman,et al.  Increased Corticosterone Pulse Frequency During Adjuvant‐Induced Arthritis and its Relationship to Alterations in Stress Responsiveness , 2001, Journal of neuroendocrinology.

[29]  Florian Holsboer,et al.  The Corticosteroid Receptor Hypothesis of Depression , 2000, Neuropsychopharmacology.

[30]  R. Sapolsky,et al.  How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. , 2000, Endocrine reviews.

[31]  M. Joëls,et al.  Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Joëls,et al.  Brain corticosteroid receptor balance in health and disease. , 1998, Endocrine reviews.

[33]  S. Watson.  Neuroendocrine and Behavioral Responses and Brain Pattern of c‐fos Induction Associated with Audiogenic Stress , 1997, Journal of neuroendocrinology.

[34]  E. R. Kloet,et al.  Elevated basal trough levels of corticosterone suppress hippocampal 5-hydroxytryptamine1A receptor expression in adrenally intact rats: implication for the pathogenesis of depression , 1997, Neuroscience.

[35]  I. Heuser,et al.  Twenty-Four Hour Cortisol Release Profiles in Patients With Alzheimer’s and Parkinson’s Disease Compared to Normal Controls: Ultradian Secretory Pulsatility and Diurnal Variation , 1997, Neurobiology of Aging.

[36]  M. Oitzl,et al.  Chronic brain glucocorticoid receptor blockade enhances the rise in circadian and stress-induced pituitary-adrenal activity. , 1996, Endocrinology.

[37]  C. Sandi,et al.  Novelty‐related Rapid Locomotor Effects of Corticosterone in Rats , 1996, The European journal of neuroscience.

[38]  M. Meaney,et al.  Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[39]  W. Paré,et al.  Effect of repeated novel stressors on depressive behavior and brain norepinephrine receptor system in Sprague-Dawley and Wistar Kyoto (WKY) rats , 1994, Brain Research.

[40]  M. Dallman,et al.  Feedback sensitivity of the rat hypothalamo-pituitary-adrenal axis and its capacity to adjust to exogenous corticosterone. , 1992, Endocrinology.

[41]  W. Engeland,et al.  Synchronous ultradian rhythms in adrenocortical secretion detected by microdialysis in awake rats. , 1991, The American journal of physiology.

[42]  A. Ratka,et al.  On the role of brain mineralocorticoid (type I) and glucocorticoid (type II) receptors in neuroendocrine regulation. , 1989, Neuroendocrinology.

[43]  A. Ratka,et al.  Long-lasting glucocorticoid suppression of opioid-induced antinociception. , 1988, Neuroendocrinology.

[44]  M. Dallman,et al.  Constant corticosterone replacement normalizes basal adrenocorticotropin (ACTH) but permits sustained ACTH hypersecretion after stress in adrenalectomized rats. , 1988, Endocrinology.

[45]  M. Dallman,et al.  Circadian variations in plasma corticosterone permit normal termination of adrenocorticotropin responses to stress. , 1988, Endocrinology.

[46]  M. Dallman,et al.  Corticosterone: narrow range required for normal body and thymus weight and ACTH. , 1985, The American journal of physiology.

[47]  K. Wachter,et al.  Algorithms for the study of episodic hormone secretion. , 1982, The American journal of physiology.

[48]  T. Dickmeis.  Glucocorticoids and the circadian clock. , 2009, The Journal of endocrinology.

[49]  A. Young,et al.  Flattening the Corticosterone Rhythm Attenuates 5-HT1A Autoreceptor Function in the Rat: Relevance for Depression , 2003, Neuropsychopharmacology.

[50]  S. Lightman,et al.  Significance of pulsatility in the HPA axis. , 2000, Novartis Foundation symposium.

[51]  M. Joëls,et al.  Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA 1 neurons , 1999 .

[52]  I. Heuser,et al.  Diurnal activity and pulsatility of the hypothalamus-pituitary-adrenal system in male depressed patients and healthy controls. , 1997, The Journal of clinical endocrinology and metabolism.

[53]  S. Lightman,et al.  Printed in U.S.A. Copyright © 1998 by The Endocrine Society Ultradian Rhythm of Basal Corticosterone Release in the Female Rat: Dynamic Interaction with the Response to Acute Stress* , 2022 .

[54]  Printed in U.S.A. Copyright © 1998 by The Endocrine Society The Pulsatile Characteristics of Hypothalamo-Pituitary- Adrenal Activity in Female Lewis and Fischer 344 Rats and Its Relationship to Differential Stress Responses* , 2022 .