Principal Investigators


Dr MH Hastings

Institution


MRC Laboratory of Molecular Biology

Contact information of lead PI


Country


United Kingdom

Title of project or programme


Neurons and biological timing

Source of funding information


MRC

Total sum awarded (Euro)


€ 7,771,965

Start date of award


01/10/2011

Total duration of award in years


5.0

The project/programme is most relevant to:


Neurodegenerative disease in general

Keywords


body clock| circadian| suprachiasmatic nuclei| Alzheimer's disease| Huntington's disease| corticosteroids| sleep| biological rhythms| mutant mice| shift-work

Research Abstract


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. 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 Huntingtons disease (HD) and Alzheimers 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.

Lay Summary


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, cause 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 the cell division cycle that underpins normal growth and cancer. The aim of this project is to examine the core clock 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 Huntingtons and Alzheimers diseases, patients of which have severe sleep problems and difficulties staying awake.

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