The Importance of Biological Oscillators for Hypothalamic‐Pituitary‐Adrenal Activity and Tissue Glucocorticoid Response: Coordinating Stress and Neurobehavioural Adaptation

The hypothalamic-pituitary-adrenal (HPA) axis is critical for life. It has a circadian rhythm that anticipates the metabolic, immunoregulatory and cognitive needs of the active portion of the day, and retains an ability to react rapidly to perceived stressful stimuli. The circadian variation in glucocorticoids is very 'noisy' because it is made up from an underlying approximately hourly ultradian rhythm of glucocorticoid pulses, which increase in amplitude at the peak of circadian secretion. We have shown that these pulses emerge as a consequence of the feedforward-feedback relationship between the actions of corticotrophin hormone (ACTH) on the adrenal cortex and of endogenous glucocorticoids on pituitary corticotrophs. The adrenal gland itself has adapted to respond preferentially to a digital signal of ACTH and has its own feedforward-feedback system that effectively amplifies the pulsatile characteristics of the incoming signal. Glucocorticoid receptor signalling in the body is also adapted to respond in a tissue-specific manner to oscillating signals of glucocorticoids, and gene transcriptional and behavioural responses depend on the pattern (i.e. constant or pulsatile) of glucocorticoid presentation. During major stressful activation of the HPA, there is a marked remodelling of the pituitary-adrenal interaction. The link between ACTH and glucocorticoid pulses is maintained, although there is a massive increase in the adrenal responsiveness to the ACTH signals.