Neurons and biological timing

Lead Research Organisation: MRC Laboratory of Molecular Biology

Abstract

Common experience confirms the role of our daily (circadian) "body clock" in determining our abilities to act and to think and the daily changes in mood and how we feel. Conditions that affect the smooth operation of the body clock, such as shift-work, jet-lag and old-age, bring problems for the individual, and across Society are a major and growing cause of industrial accidents and systemic disease. Loss of daily control to the sleep/wake cycle is a primary complaint of old-age and the commonest cause of referrals to nursing homes. The recent discovery of the genes that code for the circadian clockwork in the brain now makes it possible to unravel the cellular processes that sustain our daily cycles of physiology and behaviour. In particular, the "clock genes" of mice and humans appear to operate in very much the same way and so we are able to manipulate the genes in mice to understand how the human clock works. Our analysis has revealed unanticipated biochemical and genetic links between the daily clock and disease-relevant processes, for example the cell division cycle that underpins normal growth and cancer. The aim of this project is to examine the core molecular mechanism of the brain's principal circadian clock, the suprachiasmatic nucleus (SCN). We shall examine the interplay between the different "clock proteins" produced by the clock genes, and how the proteins control the activity of their own and other clock genes, in order that the activity of the brain and the body changes in a predictable and very regular way over the course of day and night. Understanding this normal function will better enable us to manage the body clock when it is disturbed or even breaks down. To this end we are particularly eager to examine clock mechanisms in mouse models of human diseases such as Huntington’s and Alzheimer’s diseases, patients of which have severe sleep problems and difficulties staying awake.

Technical Summary

Our daily rhythms of sleep and wakefulness, hormone secretion and metabolic activity are driven by the brain’s circadian pacemaker: the suprachiasmatic nucleus (SCN) of the hypothalamus. These rhythms dominate the pattern of our lives and set the tempo of Society. Disruption of circadian structure underlies, or is associated with, many major contemporary health problems, including sleep disorders, metabolic syndrome, dementia and psychiatric illness. The current molecular model of the circadian oscillator within the SCN is one of interlocked transcriptional/post-translational feedback loops, which sustain autonomous 24 h cycles of gene expression. Notwithstanding its success, our knowledge of its components is far from complete and the model is heavily based on evidence and inferences of the properties and behaviour of clock factors in heterologous systems, far removed from the SCN. Our objective, therefore, is to conduct a series of definitive experiments to identify novel components of the SCN clockwork, define their activities in relation to known SCN properties and thereby expand, correct and enhance the current model. We aim to identify how daily time is defined both at the level of individual SCN neurons and across the SCN circuit. Moreover, we shall explore how this central time-keeper co-ordinates subordinate circadian clocks across the brain and thus consolidates the cycle of sleep and wakefulness.
Technically, we shall develop and exploit a combination of neurobiological, molecular genetic, biochemical and behavioural approaches, both in vitro and in vivo. An important feature is extensive use of genetically modified mice. These are used for fluorescent and bioluminescent real-time imaging of circadian gene and protein expression in organotypic cultures of SCN and other tissues. Some mice carry targeted or random mutations of clock genes whilst others act as genetic models of diseases with a pronounced circadian disturbance. As a test of our evolving models of cell-autonomous and circuit-level timekeeping, it should be possible to accelerate or slow down the clock, to control circadian phase, and indeed to stop and start the cycle at will, by temporally regulated expression of core components of the loop and inter-neuronal signalling pathways. The second aim of the work will be to elucidate the molecular and cellular mechanisms downstream from the core oscillator that are responsible for circadian regulation of SCN targets in the brain, and thence to peripheral, tissue-based clocks. Finally, with growing knowledge of circadian molecular neurobiology, it will be possible to explore the relevance of circadian timing to neurological disease, in particular by examining circadian function in animal models of such diseases, including Huntington's disease (HD) and Alzheimer's disease (AD), as well as disorders arising from genetic (several sleep disorders) or environmental (e.g. shift-work) disturbance of circadian physiology. It is in this regard that new knowledge of the circadian timing system offers considerable scope for translational development.

Publications


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Anderson KN (2009) Disrupted sleep and circadian patterns in frontotemporal dementia. in European journal of neurology
Brancaccio M (2014) Network-mediated encoding of circadian time: the suprachiasmatic nucleus (SCN) from genes to neurons to circuits, and back. in The Journal of neuroscience : the official journal of the Society for Neuroscience
Cribbet MR (2016) Circadian rhythms and metabolism: from the brain to the gut and back again. in Annals of the New York Academy of Sciences
Dolatshad H (2006) Developmental and reproductive performance in circadian mutant mice. in Human reproduction (Oxford, England)
 
Description BBSRC Project Grant
Amount £410,583 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Description EMF (NS)
Amount £200,000 (GBP)
Funding ID BRT 15/52 
Organisation The EMF Biological Research Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 05/2015 
End 04/2018
 
Description EMF Project Grant
Amount £137,846 (GBP)
Funding ID BRT 10/39 
Organisation The EMF Biological Research Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2010 
End 09/2014
 
Description EU-FP6 grant
Amount € 82,000 (EUR)
Organisation Sixth Framework Programme (FP6) 
Sector Public
Country European Union (EU)
Start  
 
Description Sir Henry Wellcome Trust Fellowship (JK)
Amount £250,000 (GBP)
Funding ID 106096/z/14/z 
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 12/2015 
End 12/2019
 
Description The Danish Research Council for Independent Research (TH)
Amount kr 609,987 (DKK)
Funding ID Aarhus University 
Organisation Danish National Research Foundation (DNRF) 
Sector Public
Country Denmark, Kingdom of
Start 03/2013 
End 09/2015
 
Description Trinity Internal Research Studentship
Amount £41,700 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Description e-Gap Conference grant
Amount £800 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Title Bioluminescence imaging system 
Description Equipment and software to record long term cycles of gene expression by bioluminescence. 
Type Of Material Improvements to research infrastructure 
Year Produced 2007 
Provided To Others? Yes  
Impact Take up of development by other groups. Advice on developing their own in-house facility. 
 
Description Casein kinase 
Organisation University of Manchester
Department Faculty of Life Sciences
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Exploitation of molecules and mice in our studies complementing the Manchester work
Collaborator Contribution Access to novel small molecules for use in experimental studies Access to novel genetically modified mice for use in experimental studies
Impact PMID: 18400165 PMID: 19458106, PMID: 20696890
 
Description Clocks and sleep 
Organisation Imperial College London (ICL)
Department Department of Life Sciences (encompassing Biology)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Research collaboration
Collaborator Contribution Research collaboration
Impact Pending
Start Year 2013
 
Description Proteomics 
Organisation College of Medicine, Biological Sciences and Psychology
Department Department of Genetics
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Identification of genes of interest
Collaborator Contribution Exploited fly genetics to advance our mammalian work
Impact PMID: 16753565, PMID: 17538967, PMID: 19913422
 
Title Inhibitor of Adenylyl Cyclase for Treating a Disorder of the Circadian Rhythm 
Description Using Inhibitor of Adenylyl Cyclase to Treat Disorders of the Circadian Rhythm, including jet-lag, shift work and sleep disturbance. 
IP Reference US2009264383 
Protection Patent granted
Year Protection Granted 2009
Licensed No
Impact None yet
 
Description STEM Careers day with GCSE level students in Cambridge, organised by Murray Edwards College - Nicola Smyllie 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact STEM Careers day with GCSE level students in Cambridge, organised by Murray Edwards College
Involved one-two-one "speed-dating" sessions where students could ask about what it's like to be a scientist and advice moving into A-levels.
Year(s) Of Engagement Activity 2016
 
Description BBC Radio - Studio phone-ins 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Taken part in studio phone-ins for "The Naked Scientist" and other BBC Radio Cambridgeshire programmes

Public interest and some education about "Body Clocks" and their relevance to helath and disease.
Year(s) Of Engagement Activity 2007,2008
 
Description BBC Radio 4 Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Gave an interview on BBC Radio 4 on the subject of body clocks
Year(s) Of Engagement Activity 2015
URL http://www.bbc.co.uk/news/magazine-33638905
 
Description Broadcast Interview on Body Clocks 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact In July 2016 I gave a Broadcast interview on Body Clocks and Health for a radio station in Dublin
Year(s) Of Engagement Activity 2016
 
Description Consultant to TV production 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Consultant to "The Seasons", a four-part television production by Tiger Aspect for ITV

Awaiting broadcast. Anticipate public interest and some education about "Body Clocks" and their relevance to health and disease.
Year(s) Of Engagement Activity 2008,2009
 
Description Crisp Lecture, University of Leeds 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact In December 2016 I have the Crisp Lecture at the University of Leeds on Body Clocks and Health
Year(s) Of Engagement Activity 2016
 
Description Exhibition at Cambridge Science Week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Designed, prepared and presented a full day exhibition on "Body Clocks" for Cambridge Science Week

Widspread public interest in "Body Clocks" Public interest and some education about "Body Clocks" and their relevance to health and disease.
Year(s) Of Engagement Activity 2007
 
Description Hills Road VIth Form College talk on Body Clocks to A-level Biology Students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Gave a talk at Hills Road VIth Form College to A-level Biology Students. The talk was on Body Clocks.
Year(s) Of Engagement Activity 2016
 
Description Horizon Programme BBC2 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Filmed and interviewed for the BBC2 Horizon programme on "The Secret Life of Your Body Clock"

Lots of media and public interest in "Body Clocks". Public interest and some education about "Body Clocks" and their relevance to health and disease.
Year(s) Of Engagement Activity 2008
 
Description LMB Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Lab open day - > 1000 general public

Public presented with LMB science
Year(s) Of Engagement Activity 2013
 
Description MRC festival of Medical Research - Nicola Smyllie 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Nicola hosted a class of primary school (aged 10) giving them an interactive presentation about body clocks, followed by a guided tour of the laboratories.
When asked who wanted to be scientist before and after the presentation, more students expressed interest after the presentation, than before the presentation.
Nicola also worked with the MRC-LMB artists in residence to aid them in creating a body-clocks inspired art activity to do with the students.
Year(s) Of Engagement Activity 2016
 
Description Public Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact ca. 80 6th formers and adults. Lecture then Q & A session.

School asked for lab visit for sixth form pupils and reported higher than expected interest from pupils in GCSE scien........
Year(s) Of Engagement Activity 2011
 
Description Public Lecture and school workship on "Body Clocks", King William's College, Isle of Man 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Gave a public lecture and was part of the school workshop on "Body Clocks" at King William's College, Isle of Man
Year(s) Of Engagement Activity 2015
 
Description Public exhibition on body clocks, University Technical College, Addenbrooke's Site, Cambridge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Was involved in a public exhibition on body clocks at the University Technical College Addenbrooke's site, Cambridge
Year(s) Of Engagement Activity 2014
 
Description Radio interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact BBC World Service

Explanation of recent research finding
Year(s) Of Engagement Activity 2013
 
Description Royal Society Summer Exhibitions 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Designed, prepared and presented "The Body's Daily Clock" for the Royal Society Summer Exhibitions of Science in London and Glasgow and gave a series of associated broadecast interviews.

Wide public interest in "Body Clocks" Public interest and some education about "Body Clocks" and their relevance to health and disease.
Year(s) Of Engagement Activity 2006
 
Description Soapbox Science - Nicola Smyllie 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Nicola was a speaker at an event promoting women and science as well as bringing science into the streets of Cambridge.
Involved standing on a "soapbox" for one hour (event was 4-hours in total) giving an interactive presentation about body clocks.

The event happened in a prominent location so that all members of the public could engage with the speakers.
Audience included families with children, and adults of all ages.

Soapbox science volunteers took questionnaires to assess interest from the public. On average, 85% found the event enjoyable/extremely enjoyable and over a third of people said it had an effect on their awareness of women in science.
Total audience number of audience members was difficult to estimate, but from the volunteers estimated that several thousand people passed through the event over the course of the 4 hours.

In the run up to the event, Nicola used social and traditional media to publicise the event. This included writing a Q&A blog post, Twitter, providing quotes for the local newspaper and giving an interview on BBC Radio Cambridgeshire.
Year(s) Of Engagement Activity 2016
 
Description Summer School, India 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Invited Faculty, Indian Government-sponsored Summer School on Chronobiology, North Eastern hill University, Shillong, India

Established excellent collaborative/ personal links with Indian scienctists and graduate students. Raised profile of "Circadian Clocks" within Indian Bioscience
Year(s) Of Engagement Activity 2009