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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    • "Besides reactivity to acute stressors, changes to the circadian regulation of cortisol secretion are considered important in this context (Kondratova and Kondratov, 2012; Menet and Rosbash, 2011; Nader et al., 2010). An aspect of cortisol regulation that is of special interest to psychoneuroendocrinological (PNE) inquiry is the cortisol awakening response (CAR), which describes the marked increase in cortisol levels across the first 30–45 min following morning awakening (Clow et al., 2004, 2010; Elder et al., 2014; Kudielka and Wüst, 2010). "
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    ABSTRACT: The cortisol awakening response (CAR), the marked increase in cortisol secretion over the first 30–45 min after morning awakening, has been related to a wide range of psychosocial, physical and mental health parameters, making it a key variable for psychoneuroendocrinological research. The CAR is typically assessed from self-collection of saliva samples within the domestic setting. While this confers ecological validity, it lacks direct researcher oversight which can be problematic as the validity of CAR measurement critically relies on participants closely following a timed sampling schedule, beginning with the moment of awakening. Researchers assessing the CAR thus need to take important steps to maximize and monitor saliva sampling accuracy as well as consider a range of other relevant methodological factors. To promote best practice of future research in this field, the International Society of Psychoneuroendocrinology initiated an expert panel charged with (i) summarizing relevant evidence and collective experience on methodological factors affecting CAR assessment and (ii) formulating clear consensus guidelines for future research. The present report summarizes the results of this undertaking. Consensus guidelines are presented on central aspects of CAR assessment, including objective control of sampling accuracy/adherence, participant instructions, covariate accounting, sampling protocols, quantification strategies as well as reporting and interpreting of CAR data. Meeting these methodological standards in future research will create more powerful research designs, thus yielding more reliable and reproducible results and helping to further advance understanding in this evolving field of research.
    Psychoneuroendocrinology 10/2015; DOI:10.1016/j.psyneuen.2015.10.010 · 4.94 Impact Factor
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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.
    Frontiers in Physiology 09/2015; 6:230. DOI:10.3389/fphys.2015.00230 · 3.53 Impact Factor
    • "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.
    Journal of Affective Disorders 07/2015; 185:219-229. DOI:10.1016/j.jad.2015.07.017 · 3.38 Impact Factor
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