The regulation of circadian and ultradian rhythmicity of circulating glucocorticoid hormones and their role in the optimisation of limbic activity

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

Abstract

Biological rhythms are critical for good health and the optimal function of many physiological systems. The daily-circadian-regulation of body rhythms is controlled by a group of cells in the suprachiasmatic nucleus (SCN) of the hypothalamus. These cells employ a specific molecular machinery of so-called clock genes, which use a self-regulating feedback system to maintain an approximate 24-hour rhythm of activity. This central clock / whose activity is fine tuned by external cues such as light / regulates multiple physiological systems including endocrine, metabolic, cardiovascular, cognitive and behavioural outputs. The discovery that clock genes are also found in other areas of the brain and in many peripheral tissues challenges the concept of a single SCN pacemaker. Unlike the SCN however, the clock genes in these other areas do not necessarily express independent long-term rhythms and need the SCN to entrain and maintain their rhythms. This immediately demands that we address the question of how the SCN can control these slave oscillators. One obvious candidate as a controller of the clock genes outside the SCN is the glucocorticoid secreted by the adrenal cortex, which is secreted in a circadian rhythm. This rhythm is under the control of the SCN, and we have recently shown that signalling through this system depends on both its circadian rhythm and the pulse character of its secretion. Furthermore, we know that a critically important clock gene / period 1 (per 1) / has the molecular signature that allows it to be regulated by glucocorticoids. In this application therefore, we want to define how the SCN effects glucocorticoid secretory dynamics, and how changes in these dynamics alter the regulation of clock genes in areas of the brain vital for cognitive function and anxiety behaviour. We shall then go on to investigate how these changes in clock genes alter the efficiency of neurones to interact (synaptic plasticity) and how this in turn alters the memory abilities of conscious animals.

Technical Summary

Although the role of the SCN in the regulation of circadian function has been appreciated for many years, the role and regulation of peripheral clocks both in the CNS and in peripheral tissues is poorly understood. What is clear is that many of these peripheral oscillators cannot maintain their episodic activity in the absence of the SCN, and thus there must be some form neural or circulating signal that can coordinate these slave oscillators. Since one of the major clock genes / period 1 (per 1) has glucocorticoid response elements in its five prime - upstream sequence, and its expression can be induced by glucocorticoids, this would suggest that circulating glucocorticoids which are secreted in both an ultradian and circadian rhythm, may be an important factor in setting the activity of these oscillators. We should like to test this hypothesis by: 1. Clarifying the effect of the SCN on ultradian as well and circadian rhythmicity of glucocorticoid secretion. 2. Revealing the effects of altering the glucocorticoid circadian rhythm on per 1 and/or per 2 activity. 3. Investigating how blocking the activation of per 1 and/or per 2 by glucocorticoid effects synaptic plasticity 4. Examining the role of PER 1 activation in cognitive function

Publications

10 25 50
 
Description Rapid glucocorticoid effects on synaptic function
Exploitation Route Help to understand the effect of stress on memory
Sectors Healthcare,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 10/2007 
End 09/2010
 
Description Circadian corticosterone infusion work 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution In vivo study to complement in vitro work done by collaborators
Start Year 2011
 
Description Radial arm maze 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution Help with behavioural work outlined in grant
Start Year 2011
 
Description Advances in glucocorticoid therapy - Importance of timing. 
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 Presentation at GlaxoSmithKline

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
Description Analysing and Modelling the Neural System in Health and Disease. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact To participate in Skills Exchange Forum Workshop UK Neuroinformatics Node

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
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 Glucocorticoid replacement therapy: What are we doing wrong? 
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 - Gairdner Endocrinology Visiting Professor, University of Perth

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
Description Nothing ever stands still: Move over homeostasis. 
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 4. Retirement Symposium for Professor Ron de Kloet.

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
URL http://www.synbio.group.shef.ac.uk/synbio/news/inaguralmeeting
 
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 Rhythms of the body 
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 The Royal Institution, Friday Evening Discourse

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
Description Rhythms of the body 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach local
Primary Audience Participants in your research or patient groups
Results and Impact Lecture - Merton College, Oxford

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
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 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 importance of rapid glucocorticoid signalling: Evidence for an intra nuclear GR shuttle 
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 Seminar at the William Harvey Research Institute, Barts and The London School of Medicine and Dentistry.

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
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 Postgraduate students
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