Investigating the role of pulsatile hypothalamic signals in regulating the dynamics of the hypothalamic-pituitary-adrenal (HPA) axis

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The major hormonal system that enables an organism to respond rapidly and effectively to stressful situations is the hypothalamic-pituitary-adrenal (HPA) axis. This complex neuroendocrine network regulates the secretion of vital glucocorticoid hormones from the adrenal glands, and a critical aspect of its function is an ultradian oscillation (i.e. pulsatile pattern) in hormone release. Neurons throughout the central nervous system are exposed to these glucocorticoid pulses. In hippocampal cells, for example, these rapid changes in glucocorticoid levels regulate gene transcription and modulate synaptic transmission. Significantly, alterations in these oscillations are associated with a wide variety of physiological and pathological conditions, including ageing and chronic stress. Elucidating the mechanisms regulating this pulsatile activity will not only help to understand the normal physiological function of the stress axis, but will also help to understand how this function is altered in disease.Despite the importance of glucocorticoid pulses, the mechanisms through which the HPA axis generates and regulates this pulsatile activity remain largely unknown. The long-held hypothesis has been that pulsatile activity in the system is controlled by a neural "pulse generator" within the hypothalamus, but recent studies have shown that the way in which this system generates oscillations is more complex. Most significantly, recent work has now shown that the pituitary-adrenal system can generate its own pulsatile activity independently of hypothalamic pulses. This suggests that the pulsatile activity emerging from the system is the result of a dynamic interaction between two oscillatory components: a pulsatile hypothalamic neural network and an endogenously-pulsatile pituitary-adrenal system.Our hypothesis is that changes in this dynamic interaction will result in disrupted hormone pulsatility emerging from the system. In this project, we will explore this idea by considering two key questions:(1) How does the amplitude, frequency and mean concentration of hormone pulses released from the hypothalamus influence the pulsatile activity of the pituitary-adrenal system?(2) How does pulsatile glucocorticoid feedback at the hypothalamus influence the system's dynamics?To answer these questions, we will employ an array of techniques: in vivo (whole animal, rat) experimental physiology and in vitro electrophysiology/imaging to assess the effects of hypothalamic pulsatility on the pituitary-adrenal system, and the effects of glucocorticoid feedback on hypothalamus; and mathematical modelling to untangle the dynamic interactions between these components. This multidisciplinary approach will enable us to study the dynamics of the system at multiple scales, and to understand the key mechanisms underpinning oscillatory hormone release.