Hypothalamic-pituitary modulation of corticosterone pulsatility

The hypothalamic-pituitary-adrenal axis is critical for the maintenance of life, and is the major hormonal system that protects the body in response to stress. A very important aspect of this system is that is must be able to respond rapidly to emergency situations. We should like to investigate whether an important factor in maintaining this rapid reactivity is the fact that hormone levels are always changing in an ultradian manner, which prevents the system from desensitising or downregulating. We propose that this ultradian rhythmicity is actually built into the way the pituitary and the adrenal glands interact - in both feedforward and feedback regulation, and that the activation from the hypothalamus simply increases the built-in pulsatility of this system. This we shall test by artificially altering hypothalamic drive by giving different patterns and concentrations of CRF. We also propose that the ultradian rhythmicity of ACTH is critical for maintaining adrenal gland responsiveness to stress. Furthermore we believe that this responsiveness will vary over the day in a manner dependent upon the activity of the sympathetic innovation to the adrenal gland. We shall investigate this by giving differential patterns of ACTH at different times of day and measuring both the intra-adrenal enzymes involves in corticosterone synthesis and the release of corticosterone into the plasma. These studies should provide important information as to how the hypothalamic-pituitary axis is able to respond rapidly to stressful situations and will provide the basis for understanding abnormalities of HPA function which have been detected in a number of diseases such as depression, as well as providing a rationale why treatment with synthetic steroids might have particularly bad side effects. With respect to BBSRC strategic priorities, our proposal uses a systems approach to investigate the mechanisms underlying the oscillatory activity of HPA activity and its impact on the effectiveness of this neuroendocrine system to react rapidly to internal and external stress stimuli. The use of our automated whole animal infusion and sampling systems to answer questions about hypothalamic-pituitary-adrenal interactions, is therefore closely in line with the BBSRC strategic priority 'Systems Approach to Biological Research'.

There has been considerable dispute as to whether there is a pulse generator in the hypothalamus responsible for the ultradian rhythmicity of the HPA axis. We believe that this type of central mechanism is unnecessary, and have been able to model the pituitary-adrenal axis using well characterised feedforward and feedback features. This has allowed us to identify a natural oscillatory rhythm which closely resembles our biological data - and has major implications not only for the HPA axis but also for the ultradian regulation of many ultradian endocrine systems. We now need to test the predictions resulting from our mathematical model. In particular, we predict that increasing CRH - even if infused in a constant manner - will actually increase pituitary-adrenal pulsatility. This we plan to perform in intact animals at the nadir of their endogenous CRH rhythm and also in animals with disconnection of the pituitary from the hypothalamic paraventricular nucleus. We also plan to test our hypothesis that ultradian rhythmicity is vital for the maintenance of adrenal sensitivity to ACTH - and that steady levels of ACTH would lead to down regulation of adrenal steroidogenic mechanisms. This will be tested by comparing both adrenal enzyme and plasma corticosterone responses following chronic or episodic elevation of ACTH. Furthermore, we shall use this opportunity to assess whether the autonomic innervation of the adrenal alters the responsivity to ACTH in a circadian manner.

Both academic and non-academic stakeholders will benefit from the impact of the project outcomes on our understanding of adrenocortical regulation in health and disease. There will be an immediate impact demonstrating the added value of collaboration between mathematicians and biological scientists, with a clear demonstration that the use of mathematical modeling can make predictions that change our preconceptions of biological processes. With respect to the biological data we shall obtain, this will provide fundamental. Information in our understanding of an essential biological mechanism and will serve as a foundation to stimulate further research and innovation. In the medium to long-term, private commercial sector (biotechnology and pharmaceutical companies) should benefit as the results of this project could provide pertinent new targets for the development of new therapeutic drugs/strategies in the areas of glucocorticoid therapy and in diseases resulting from disregulation of the hypothalamic-pituitary adrenal axis. In particular this research could have an impact on the wider societal issues of public health, including mental health, particularly in respect to stress and affective disorders such as major depression. The results of the work, including continued development of the techniques used, will be promptly and effectively disseminated in high quality scientific journals (open-access wherever possible) and national and international conferences and symposia. Although being predominantly basic research, we will promote both the general field and our specific findings to the non-academic stakeholders identified above, especially the general public. We will work in partnership with the University Centre for Public Engagement (CPE) to ensure that all relevant findings from the project can be shared in an accessible format with the wider public. Prof. Lightman has substantial experience organising and participating in public engagement activities. Prof. Lightman also has substantial experience in establishing industrial collaborations. Dr Terry has been involved in the organization of a number of public engagement activities. He has recently established collaboration with a large pharmaceutical company, whom are funding a PhD student commencing studies in October 2009 Dr Spiga has participated in educational events such as the Brain Awareness Week. She has also experience on industrial collaborations. Dr Spiga will undergo University and Research Council training in preparation for those impact and public engagement activities.