Exercise and the Neural Circadian System

Good sleep habits and regular physical exercise are a cornerstone of good health and longevity. The sleep-wake cycle is organised by the brain's daily or circadian clock. Cells of this brain area contain a molecular clock but must talk to each other to produce a unified ~24h output that controls other brain areas as well as body organs. These individual clock cells communicate using special brain chemicals called neuropeptides, each of which has its own role in timekeeping. Ordinarily, brain clock cells are reset by daylight, but interestingly, in a mouse model in which the brain clock was weakened by through the absence of a particular neuropeptide signal, we found that regular daily physical exercise was much more potent than light. In our work, we found that voluntary scheduled exercise in a running-wheel (6h/day) synchronises the clock cells and promotes stable ~24h rest-activity rhythms. This intriguing effect of exercise was absent in mice in which the molecular clock was deleted from all cells of the brain and body. Unfortunately, we do not know if physical exercise can compensate for the loss of other kinds of neuropeptides or the absence of the molecular clock in particular types of neuropeptide cells in brain clock. We also do not know if other areas of the brain receiving timekeeping signals from the brain clock contribute to these restorative actions of exercise. In this grant we shall address these important gaps in our knowledge and determine how voluntary physical exercise can improve synchronisation in the brain to promote well-being.

The brain's endogenous daily or circadian timekeeping system consists of the master clock in the suprachiasmatic nuclei (SCN) and downstream effectors in other parts of the brain. The SCN itself is composed of thousands of single clock cells that synthesise neuropeptides including vasoactive intestinal polypeptide (VIP) and arginine vasopressin (AVP). These clock cells communicate to one another through neuropeptide signalling and the resultant synchronised output signal is used to convey timekeeping signals to other brain regions that control behaviour and physiology. Daylight is considered the dominant cue acting on the SCN clock to synchronise our physiology and behaviour to the external world. However, in mice and humans, recurrent exposure to physical exercise and other so-called non-photic stimuli can strongly regulate circadian rhythms. Indeed, we have discovered that in mice lacking a key VIP receptor (Vipr2-/-), daily scheduled exercise in a running-wheel (6h/day) synchronises individual clock cells in the SCN and promotes long-term stable ~24h rhythms in behaviour. Using mouse models with targeted deficits in AVP and other neuropeptide signalling, we will determine if these contribute to the restorative actions of exercise on SCN synchrony and behaviour. Further, the SCN communicates with downstream brain areas such as the habenula to regulate behaviour and using a mouse model in which habenula function is compromised, we will evaluate the contributions of this structure to the restorative actions of scheduled exercise. Since the molecular clock and the neurochemical architecture of the circadian system are largely conserved from mouse to man, these findings will also be relevant to understanding basic human neurobiology and potentially reveal ways to treat circadian misalignment disorders.

The research questions within this proposal are of major interest to ACADEMIC GROUPINGS in Biological/medical sciences. The academic community will benefit from elucidation of neurochemical mechanisms of circadian clocks, which control numerous physiological and behavioural processes in humans as well as farm animals. Proper circadian clock function and synchronization with the natural environment contributes to our wellbeing as dysfunction (or desynchronisation) can cause severe sleep disorders, depression and obesity. As such, research findings on how physical exercise affects circadian rhythms in animals with neurochemical and molecular deficits will impact greatly on the HEALTH CARE COMMUNITY. For instance, it is becoming increasingly apparent that circadian rhythms influence a person's symptoms such as migraine, pain and asthma. Furthermore, heart attacks are more likely to occur in the morning and drug efficacy i.e. chemotherapy varies circadianly. We will disseminate findings by publishing primary papers and reviews in high impact journals, and presenting work at national and international meetings. We anticipate that the proposed work will produce 2-4 high-quality primary research papers.

Research on body clocks and sleep are of great interest to the GENERAL PUBLIC and specifically the large and ever-increasing proportion (about a third) of the population who have sleep problems. Our research findings will be delivered to the general public through public engagement activities (e.g. brain awareness week), as well as through mass media. For example, HP's article in Science was reported widely in national and international newspapers, on local radio, and on the intranet. HP has also been interviewed on BBC radio and television news for providing a Readers Digest view of recent work on human shift work and disruptions in gene expression. HP has also participated in the The Times Cheltenham Science Festival and delivered a talk 'Why Do We Sleep?'.

Generally sleep disorders are poorly treated therefore our research on neuropeptides and receptors (GPCRs are the No.1 drug target) will provide excellent targets for novel drugs to treat these disorders. The use of exercise could provide a non-invasive strategy to correct circadian rhythm abnormalities. The outcome of this research will impact on PHARMACEUTICAL COMPANIES that focus on this research area. Pharmaceutical industry investment into circadian biology is rapidly growing due to the fact that circadian dysfunction is linked to sleep disorders, cancer, inflammation, aging and mental disorders. In the context of "building partnerships to enhance take-up and impact, thereby contributing to the economic competitiveness of UK", HP's lab is involved in collaborations with IPSEN and Servier on circadian-related projects, and regular communication with these companies will ensure research findings impact upon industrial beneficiaries. The University of Manchester has taken a strong proactive role in developing links with major pharmaceutical companies, enhancing public communication of science, as well as development of commercialisation opportunities. There are dedicated members of staff employed within each university to assist in these areas.

Benefits of this research to the UK ECONOMY include detailed and basic understanding of circadian clock synchronization is important to better understand the problems related to shift work (~20% of the working population), jet lag and 24/7 culture both in terms of creating 'clock-friendly' work environments (e.g. sufficient illumination, designed time-tables), as well as treatment of people who suffer from it (e.g. light-therapy). Increased knowledge in this area will impact the health and safety recommendations of GOVERNMENT POLICY MAKERS regarding workplace requirements that need to provide a healthy working environment. Our public engagement and internship activities could help influence public policy.