Clocks Exercise and Cognition: A new approach

It is popularly held that the way to a long life is through regular exercise, good sleeping habits and a healthy diet. Indeed, regular exercise is beneficial for the brain and body and can stimulate the production of new brain cells and improve our problem solving abilities. A key to having good sleeping and dietary habits is to make sure that we maintain regular bed-times and meal times. Daily regularity in sleeping and feeding arises because our body clock, which tells us when to awaken and when to eat, is synchronized to the 24h changes in daylight. Unfortunately, this synchronization can go wrong in individuals with weak body clocks, resulting in disruptions in sleep, wake, eating and impaired problem solving abilities. Recently, we found a new effect of exercise: scheduling voluntary exercise for 6 hours at a particular time of day restored daily patterns in sleeping, waking, and drinking in mice with weakened body clocks. This suggests that recovery of clock function in these animals is possible, but we do not know if different schedules of this exercise have different restorative effects on daily rhythms. We will test this by limiting the amount of time that mice can spend exercising. We predict that these animals will benefits less when compared to other mice that have free access to exercise. Unfortunately, we do not know if scheduled exercise also stimulates the brain and improves learning and memory in mice with weakened body clocks. We also do not know whether aged animals would benefit from this schedule of exercise. Aged mice, like ageing humans, have deteriorating body clocks and, consequently, they have disrupted daily patterns of sleep and rest, eating and reduced learning and memory capabilities. It is possible that regular exercise may also strengthen the body clock and restore daily patterns of sleeping, waking, and eating in aged mice. It is also possible that regular exercise will stimulate the ageing brain to produce new cells and improve problem solving capabilities. Through this research project, we will establish new ways of restoring brain and body rhythms to promote good health and longevity.

Synchronization of body clock rhythms and regular physical exercise are important for good health. In transgenic Vipr2-/- mice which lack a key neuropeptide receptor, VPAC2, the brain's main circadian clock in the suprachiasmatic nuclei (SCN) is weakened and these animals do not synchronize to the external light-dark cycle. Instead, these mice have very disrupted rhythms in sleeping, eating and drinking and they show reduced performance on cognitive tasks. Recently, we reported that scheduled voluntary exercise (SVE) in a running-wheel for 6h/day over 3 weeks restored 24h rhythms in locomotor activity and drinking in Vipr2-/- mice and boosted rhythms of a key clock gene in the SCN. We do not, however, know the optimal 'dose' of SVE needed to restore SCN and behavioural rhythms. In healthy wild-type rodents with fully functional circadian clocks, exercise stimulates neurogenesis in the dentate gyrus (a brain region important for learning and memory) and improves spatial cognition. Whether SVE also stimulates neurogenesis and improves spatial cognition in Vipr2-/- mice remains to be determined. The beneficial effects of SVE may also ameliorate deficits in other mice, such as those lacking the cryptochrome genes; these mice do not have a functioning molecular circadian clock and they manifest several circadian and other impairments. In addition, aged mice have reduced expression of the VPAC2 receptor in the SCN and show reduced circadian competence, while Vipr2-/- mice show accelerated ageing. Whether SVE is an appropriate intervention to restore circadian and cognitive function in these mice has yet be explored. This project will, therefore, reveal the utility of SVE in promoting circadian and cognitive function across a range of wild-type and transgenic animal models. Through these studies, we shall determine the potential utility of SVE in promoting mental and physical health in animals.

Who will benefit from this research? In addition to academic researchers in the fields of neuroscience, exercise physiology, cognitive science, and circadian biology, there are several potential parties who could benefit from this research including: 1) Pharma, particularly drug companies with interests in developing anti-ageing, and cognitive enhancing compounds. 2) Scientific instrument manufacturers, such as those companies designing and building cages for housing laboratory rodents in research and commercial sectors. 3) NHS clinic managers could also benefit for the management of sleep-wake activities in disturbed or aged patients. 4) Policy makers for best practice in laboratory animal housing. 5) Policy makers in the determining the patterns of shift-workers. 6) Educationalists seeking to determine how best to match school policies on recreational fitness and studying. 7) Members of general public interested in how to improve their physical and mental fitness as well as longevity. How will they benefit? A potential major benefit from the proposed work is the determination how voluntary scheduled exercise in a running wheel aligns intrinsic body rhythms in physiology including sleeping and ingestive activities and improves cognitive function of laboratory rodents. The vast majority of laboratory animals are housed in cages in which they lack the opportunity to engage in vigorous exercise. Companies designing devices for housing animals, both in the research sector as well as the commercial sector, could use the findings of this proposed work to improve cage designs that better promote animal health. Such cages could include new apparati that permit animals to exercise vigorously. This could lead to new financial opportunities for such companies. Pharma could use such cages coupled with the design of the experiments in this proposed work to improve validity and accuracy in the assessment of positive and negative effects of new compounds. This could lead to both a reduction and refinement in animal usage. Similarly, this could lead to new government legislation and the introduction of new guidelines for the housing of rodents in pet shops and in the home. Additionally, data from the proposed work, could inform health-care professionals as the design of non-invasive physical therapies that could aid in treatment of long-stay patients in hospitals. This may be of key importance with aged patients who often have disrupted sleep-wake patterns and are difficult to manage on wards. Further the introduction of exercise regimes may benefit hospital staff who are particular shift work cycles. Shift workers have disruptions in the alignment of their circadian rhythms and are known to be prone to elevated risks of cardiovascular diseases and certain cancers. Appropriately timed physical exercise could be of benefit, in both the short- and long-term. Within the education sector, curricula designers could use findings of this research to incorporate a daily 'games' session to facilitate learning performance of primary and secondary school students. Finally, the general public should be of interest of exercise timed to occur at a certain time of the day could facilitate improvements in physical and cognitive function as well as ameliorating age-related decrements in such functions. Similarly, athletes who suffer from sleep disorders may find it beneficial to exercise at certain times of their circadian cycles.