Jamie J Walker

University of Bristol, Bristol, ENG, United Kingdom

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Publications (6)29.7 Total impact

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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.
    Comprehensive Physiology. 07/2014; 4(3):1273-98.
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    ABSTRACT: The circadian rhythm of corticosterone (CORT) secretion from the adrenal cortex is regulated by the suprachiasmatic nucleus (SCN), which is entrained to the light-dark cycle. Since the circadian CORT rhythm is associated with circadian expression of the steroidogenic acute regulatory (StAR) protein, we investigated the 24 h pattern of hormonal secretion (ACTH and CORT), steroidogenic gene expression (StAR, SF-1, DAX1 and Nurr77) and the expression of genes involved in ACTH signalling (MC2R and MRAP) in rats entrained to a normal light-dark cycle. We found that circadian changes in ACTH and CORT were associated with the circadian expression of all gene targets; with SF-1, Nurr77 and MRAP peaking in the evening, and DAX1 and MC2R peaking in the morning. Since disruption of normal SCN activity by exposure to constant light abolishes the circadian rhythm of CORT in the rat, we also investigated whether the AM-PM variation of our target genes was also disrupted in rats exposed to constant light conditions for 5 weeks. We found that the disruption of the AM-PM variation of ACTH and CORT secretion in rats exposed to constant light was accompanied by a loss of AM-PM variation in StAR, SF-1 and DAX1, and a reversed AM-PM variation in Nurr77, MC2R and MRAP. Our data suggest that circadian expression of StAR is regulated by the circadian expression of nuclear receptors and proteins involved in both ACTH signalling and StAR transcription. We propose that ACTH regulates the secretion of CORT via the circadian control of steroidogenic gene pathways that become dysregulated under the influence of constant light.
    Molecular and Cellular Endocrinology 11/2012; · 4.04 Impact Factor
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    ABSTRACT: Plasma levels of corticosterone exhibit both circadian and ultradian rhythms. The circadian component of these rhythms is regulated by the suprachiasmatic nucleus (SCN). Our studies investigate the importance of the SCN in regulating ultradian rhythmicity. Two approaches were used to dissociate the hypothalamic-pituitary-adrenal (HPA) axis from normal circadian input in rats: (i) exposure to a constant light (LL) environment and (ii) electrolytic lesioning of the SCN. Blood was sampled using an automated sampling system. As expected, both treatments resulted in a loss of the circadian pattern of corticosterone secretion. Ultradian pulsatile secretion of corticosterone however, was maintained across the 24 h in all animals. Furthermore, the loss of SCN input revealed an underlying relationship between locomotor and HPA activity. In control (LD) rats there was no clear correlation between ultradian locomotor activity and hormone secretion, whereas, in LL rats, episodes of ultradian activity were consistently followed by periods of increased pulsatile hormone secretion. These data clearly demonstrate that the ultradian rhythm of corticosterone secretion is generated through a mechanism independent of the SCN input, supporting recent evidence for a sub-hypothalamic pulse generator.
    European Journal of Neuroscience 07/2012; 36(8):3142-50. · 3.75 Impact Factor
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    ABSTRACT: Oscillating levels of adrenal glucocorticoid hormones are essential for optimal gene expression, and for maintaining physiological and behavioural responsiveness to stress. The biological basis for these oscillations is not known, but a neuronal "pulse generator" within the hypothalamus has remained a popular hypothesis. We demonstrate that pulsatile hypothalamic activity is not required for generating ultradian glucocorticoid oscillations. We show that a constant level of corticotrophin-releasing hormone (CRH) can activate a dynamic pituitary-adrenal peripheral network to produce ultradian adrenocorticotrophic hormone and glucocorticoid oscillations with a physiological frequency. This oscillatory response to CRH is dose dependent and becomes disrupted for higher levels of CRH. These data suggest that glucocorticoid oscillations result from a sub-hypothalamic pituitary-adrenal system, which functions as a deterministic peripheral hormone oscillator with a characteristic ultradian frequency. This constitutes a novel mechanism by which the level, rather than the pattern, of CRH determines the dynamics of glucocorticoid hormone secretion.
    PLoS Biology 06/2012; 10(6):e1001341. · 12.69 Impact Factor
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    ABSTRACT: The hypothalamic-pituitary-adrenal (HPA) axis is a dynamic oscillatory hormone signalling system that regulates the pulsatile secretion of glucocorticoids from the adrenal glands. In addition to regulation of basal levels of glucocorticoids, the HPA axis provides a rapid hormonal response to stress that is vitally important for homeostasis. Recently it has become clear that glucocorticoid pulses encode an important biological signal that regulates receptor signalling both in the central nervous system and in peripheral tissues. It is therefore important to understand how stressful stimuli disrupt the pulsatile dynamics of this system. Using a computational model that incorporates the crucial feed-forward and feedback components of the axis, we provide novel insight into experimental observations that the size of the stress-induced hormonal response is critically dependent on the timing of the stress. Further, we employ the theory of Phase Response Curves to show that an acute stressor acts as a phase-resetting mechanism for the ultradian rhythm of glucocorticoid secretion. Using our model, we demonstrate that the magnitude of an acute stress is a critical factor in determining whether the system resets via a Type 1 or Type 0 mechanism. By fitting our model to our in vivo stress-response data, we show that the glucocorticoid response to an acute noise stress in rats is governed by a Type 0 phase-resetting curve. Our results provide additional evidence for the concept of a deterministic sub-hypothalamic oscillator regulating the ultradian glucocorticoid rhythm, which constitutes a highly responsive peripheral hormone system that interacts dynamically with hypothalamic inputs to regulate the overall hormonal response to stress.
    PLoS ONE 01/2012; 7(2):e30978. · 3.53 Impact Factor
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    ABSTRACT: The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates the circulating levels of vital glucocorticoid hormones. The activity of the HPA axis is characterized not only by a classic circadian rhythm, but also by an ultradian pattern of discrete pulsatile release of glucocorticoids. A number of psychiatric and metabolic diseases are associated with changes in glucocorticoid pulsatility, and it is now clear that glucocorticoid responsive genes respond to these rapid fluctuations in a biologically meaningful way. Theoretical modelling has enabled us to identify and explore potential mechanisms underlying the ultradian activity in this axis, which to date have not been identified successfully. We demonstrate that the combination of delay with feed-forward and feedback loops in the pituitary-adrenal system is sufficient to give rise to ultradian pulsatility in the absence of an ultradian source from a supra-pituitary site. Moreover, our model enables us to predict the different patterns of glucocorticoid release mediated by changes in hypophysial-portal corticotrophin-releasing hormone levels, with results that parallel our experimental in vivo data.
    Proceedings of the Royal Society B: Biological Sciences 06/2010; 277(1688):1627-33. · 5.68 Impact Factor