Interactions of the circadian CLOCK system and the HPA axis

Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Trends in Endocrinology and Metabolism (Impact Factor: 9.39). 05/2010; 21(5):277-86. DOI: 10.1016/j.tem.2009.12.011
Source: PubMed


Organisms have developed concurrent behavioral and physiological adaptations to the strong influence of day/night cycles, as well as to unforeseen, random stress stimuli. These circadian and stress-related responses are achieved by two highly conserved and interrelated regulatory networks, the circadian CLOCK and stress systems, which respectively consist of oscillating molecular pacemakers, the Clock/Bmal1 transcription factors, and the hypothalamic-pituitary-adrenal (HPA) axis and its end-effector, the glucocorticoid receptor. These systems communicate with one another at different signaling levels and dysregulation of either system can lead to development of pathologic conditions. In this review, we summarize the mutual physiologic interactions between the circadian CLOCK system and the HPA axis, and discuss their clinical implications.

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Available from: George Chrousos
    • "d Earlier wake-up yielded higher awakening responses. autonomous endogenous clock mechanism in the suprachiasmatic nucleus (SCN) to the input signals from outside world, mainly light, food intake and activity (Kalsbeek et al., 2011;Nader et al., 2010). We assume that potential compensatory mechanisms of the HPAaxis break down at the acute stress challenge in children with internalizing or externalizing disorders. "
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    ABSTRACT: Background: Stress biomarkers of the autonomic nervous system and hypothalamic-pituitary-adrenal axis (HPA-axis) can be measured via alpha-amylase (AA) and cortisol and cortisone in saliva. Objectives were to determine 1) the response patterns of cortisol, cortisone, and AA under both circadian conditions and the Trier Social Stress Test for Children (TSST-C), 2) which reactivity index is most suitable to differentiate internalizing or externalizing disorders from controls, and to explore 3) the interaction between AA and cortisol in the presence of internalizing or externalizing disorders. Methods: Saliva samples (n = 2893) from children with internalizing (n = 55) or externalizing disorders (n = 33) and healthy children (n = 81) were analyzed for cortisol, cortisone, and AA under circadian conditions and TSST-C. Results: Circadian rhythm of three biomarkers did not differ between diagnostic groups. Age and gender were significant predictors for cortisol and awakening time influenced all three biomarkers significantly. TSST-C responses appeared sequentially in the order of AA, cortisol, and cortisone. Trajectories of cortisol and cortisone responses, not in AA, were significantly lower in children with internalizing or externalizing disorders than in healthy children. Cortisol percentage increase appeared to be the most suitable reactivity index to detect the difference between the diagnostic groups. Internalizing disorders had a negative association between AA decrease and cortisol increase (β = -.199, p < .05, R(2) = .304). Externalizing disorders had a positive association between AA baseline and cortisol increase (β = .229, p < .05, R(2) = .304). Conclusion: An altered HPA-axis response during stress might result from chronic allostatic load in internalizing disorders and underaroused stress response system in externalizing disorders.
    No preview · Article · Oct 2015 · Journal of Psychiatric Research
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    • "Hypothalamic PVN receives many axons from various areas of the brains, such as hippocampus, amygdala, prefrontal cortex, and locus ceruleus of the brainstem, and integrates stressful information obtained from peripheral sensory organs and nerves and then assembled in these brain regions (Gold and Chrousos, 2002). In a basal state, the HPA axis demonstrates circadian activity under the control of the circadian rhythm center suprachiasmatic nucleus (SCN) of the hypothalamus, and creates a typical diurnal fluctuation in serum cortisol concentrations, which reaches the zenith in early morning and the nadir at midnight (Nader et al., 2010; Kino, 2012; Nicolaides et al., 2014). When exposed to stressors, the HPA axis escapes from this regular circadian control and secretes massive amounts of glucocorticoids (cortisol in humans and corticosterone in rodents) to adjust the body's functions (Kino, 2012). "
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    ABSTRACT: The hypothalamic-pituitary-adrenal (HPA) axis and its end-effectors glucocorticoid hormones play central roles in the adaptive response to numerous stressors that can be either internal or external. Thus, this system has a strong impact on the brain hippocampus and its major functions, such as cognition, memory as well as behavior, and mood. The hippocampal area of the adult brain contains neural stem cells or more committed neural progenitor cells, which retain throughout the human life the ability of self-renewal and to differentiate into multiple neural cell lineages, such as neurons, astrocytes, and oligodendrocytes. Importantly, these characteristic cells contribute significantly to the above-indicated functions of the hippocampus, while various stressors and glucocorticoids influence proliferation, differentiation, and fate of these cells. This review offers an overview of the current understanding on the interactions between the HPA axis/glucocorticoid stress-responsive system and hippocampal neural progenitor cells by focusing on the actions of glucocorticoids. Also addressed is a further discussion on the implications of such interactions to the pathophysiology of mood disorders.
    Full-text · Article · Sep 2015 · Frontiers in Physiology
    • "Cortisol affects the peripheral clocks in almost all tissues and organs, adjusting the phase of the cycle under stress situations. As cortisol does not reach the SCN, this keeps its intrinsic circadian rhythm regardless of the changes in the rest of the body, so that once the stress situation has been resolved, the SCN resynchronizes the peripheral clocks (Nader et al., 2010). It is contemplated that other hormones such as aldosterone, testosterone, luteinizing hormone, growth hormone, thyroid stimulating hormone (TSH), and follicle stimulating hormone also exhibit periodic variations throughout the day under the control of the SCN (Nakagawa and Okumura, 2010). "
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    ABSTRACT: Bipolar Disorder is characterized by episodes running the full mood spectrum, from mania to depression. Between mood episodes, residual symptoms remain, as sleep alterations, circadian cycle disturbances, emotional deregulation, cognitive impairment and increased risk for comorbidities. The present review intends to reflect about the most recent and relevant information concerning the biunivocal relation between bipolar disorder and circadian cycles. It was conducted a literature search on PubMed database using the search terms "bipolar", "circadian", "melatonin", "cortisol", "body temperature", "Clock gene", "Bmal1 gene", "Per gene", "Cry gene", "GSK3β", "chronotype", "light therapy", "dark therapy", "sleep deprivation", "lithum" and "agomelatine". Search results were manually reviewed, and pertinent studies were selected for inclusion as appropriate. Several studies support the relationship between bipolar disorder and circadian cycles, discussing alterations in melatonin, body temperature and cortisol rhythms; disruption of sleep/wake cycle; variations of clock genes; and chronotype. Some therapeutics for bipolar disorder directed to the circadian cycles disturbances are also discussed, including lithium carbonate, agomelatine, light therapy, dark therapy, sleep deprivation and interpersonal and social rhythm therapy. This review provides a summary of an extensive research for the relevant literature on this theme, not a patient-wise meta-analysis. In the future, it is essential to achieve a better understanding of the relation between bipolar disorder and the circadian system. It is required to establish new treatment protocols, combining psychotherapy, therapies targeting the circadian rhythms and the latest drugs, in order to reduce the risk of relapse and improve affective behaviour. Copyright © 2015 Elsevier B.V. All rights reserved.
    No preview · Article · Jul 2015 · Journal of Affective Disorders
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