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The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration


The classical concept of hypothalamus–pituitary–adrenal (HPA) homeostasis comprises a feedback system within which circulating levels of glucocorticoid hormones maintain the brain and body in an optimal steady state. However, studies involving new techniques for investigating the real-time dynamics of both glucocorticoid hormones and glucocorticoid receptor function paint a different picture — namely, of continuous dynamic equilibration throughout this neuroendocrine system. This dynamic state is dictated by feedforward and feedback regulatory loops and by stochastic interactions at the level of DNA binding. We propose that this continuous oscillatory activity is crucial for optimal responsiveness of glucocorticoid-sensitive neural processes.

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Figure 1: Plasticity in the glucocorticoid ultradian secretory profile.
Figure 2: Stress responsiveness during the ultradian rhythm.
Figure 3: GR action during ultradian glucocorticoid treatment.
Figure 4: A model of GR intranuclear recycling activity.
Figure 5: Pulsatile responses and regulation of the clock gene Period 1 in rat hippocampus.


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We gratefully acknowledge funding from the Wellcome Trust (Programme Grant 089647/Z/09/Z), the Biotechnology and Biological Sciences Research Council and the Neuroendocrine Charitable Trust.

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Supplementary information S1 (figure)

Schematic of the automated infusion and ABS system. (PDF 295 kb)

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Allostatic load

The physiological costs of chronic exposure to a fluctuating or heightened neural or neuroendocrine response that results from repeated or chronic stress.

Circadian cycle

The regular cycling of biological processes in an organism over a 24-hour period that occurs regardless of the zeitgeber.

Frequency encoding

The encoding of the information in a system by the frequency of the input.

Heteronuclear RNA

The immediate transcript of a gene, which is subsequently processed into mRNA.

Numerical continuation

A method of computing approximate solutions of a system of parameterized nonlinear equations.

Portal blood

The blood in the portal venous system that connects the hypothalamus and the anterior pituitary.


A condition that disturbs the physiological (or psychological) homeostasis of an animal.


A temperature sensor.

Ultradian rhythm

A rhythm with a shorter period than a circadian rhythm — that is, with a frequency greater than one cycle in 24 hours.

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Lightman, S., Conway-Campbell, B. The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nat Rev Neurosci 11, 710–718 (2010).

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