Hypothalamic-pituitary modulation of corticosterone pulsatility

Lead Research Organisation: University of Bristol
Department Name: Henry Wellcome LINE

Abstract

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'.

Technical Summary

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.

Planned Impact

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.

Publications

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Biddie SC (2012) Dynamic regulation of glucocorticoid signalling in health and disease. in Rheumatology (Oxford, England)

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Biddie SC (2011) Epigenetics: a lasting impression? in Journal of neuroendocrinology

 
Description Pulsatile ACTH is crucial for ultradian rhythm of glucocorticoids.



Steroidogenic proteins are expressed with a pulsatile pattern.



Ultradian rhythm of glucocorticoids is generated by a pituitary-adrenal feedforward-feedback mechanism.



Disruption of the light cycle leads to disruption of HPA axis circadian rhythm and disruption of circadian rhythm of steroidogenic proteins in the adrenal gland.
Exploitation Route Development of new drugs
Sectors Healthcare

Pharmaceuticals and Medical Biotechnology

 
Description They have altered the research questions and profiles of many groups working on the HPA axis
First Year Of Impact 2012
Sector Pharmaceuticals and Medical Biotechnology
 
Description Neonatal programming of pubertal delay: a novel neural interaction between corticotrophin-releasing hormone and kisspeptin
Amount £456,779 (GBP)
Funding ID BB/F007396/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2007 
End 09/2010
 
Description Addison's Disease Self-Help Group - Energy, memory, emotion and cortisol 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Discussion of scientific advances to help treatment of this patient group.

Better informed patients.
Year(s) Of Engagement Activity 2014
 
Description Bristol Neuroscience Festival - Lecture on "The importance of rhythm for stress and the brain" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Part of the University of Bristol's outreach programme.
Year(s) Of Engagement Activity 2016
 
Description British Neuroscience Roadshow - Stress and the brain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Talk sparked questions and discussion afterwards.

The local stimulation of neuroscience in Korea.
Year(s) Of Engagement Activity 2008
 
Description Cheltenham Science Festival - Hormone Fight Club 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Considerable discussion!

Contact from several media sources!
Year(s) Of Engagement Activity 2013
 
Description Public Lecture held at The Physiological Society in London and streamed world-wide on Facebook Live - The Physiology of Stress - Science of Stress. Lecture on "Mechanisms of stress" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This is the first time that The Physiological Society has streamed a public lecture for a world-wide audience.
Year(s) Of Engagement Activity 2017
 
Description Royal Institution, London - Science of Sleep 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This remains available on the Royal Institution website for all interested parties.
Year(s) Of Engagement Activity 2016
 
Description Talk to Bristol Pituitary Support Group at Southmead Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact An active discussion on recent advances in treating patients with disrupted hormone secretion
Year(s) Of Engagement Activity 2017
 
Description The Royal Institution Friday Evening Discourse - Rhythms of the body 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk sparked questions and discussion afterwards.

Discussion with membership of the Royal Institution and their friends.
Year(s) Of Engagement Activity 2010
 
Description The importance of hormone dynamics in therapies 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Presentation followed by discussion about the importance of patterns of hormone replacement for best patient wellbeing.
Year(s) Of Engagement Activity 2017
 
Description The origin and importance of HPA activity 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach international
Primary Audience Participants in your research or patient groups
Results and Impact Lecture at the University of Washington, Seattle, USA

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
Description University of Utrecht - Stress and Disorders of the Brain. Lecture on "Corticosteroid rhythms and replacement strategies" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Part of EU outreach programme
Year(s) Of Engagement Activity 2016