Using colour to tell time

How do animals tell time of day? This is an important question because internal circadian clocks, which drive daily rhythms in practically every aspect of physiology and behaviour, must be aligned with external time. For many years its been accepted that the most important external signal is the huge day:night difference in ambient illumination. There is a great deal of evidence that the retina sends information about environmental brightness to the circadian clock in a part of the brain called the suprachiasmatic nuclei (SCN) and that this signal can reset clock phase. However, we have recently shown that this is not the only way in which light can be used to tell time. Across twilight there is a big change in the spectral composition of natural light with shorter wavelengths enriched at low solar angles. As a result, light appears progressively bluer as solar angle decreases. We can perceive this change in colour ourselves and, in fact, because it is relatively unaffected by clouds, it provides a more reliable indicator of time across dawn and dusk transitions than does brightness. Now, using a range of sophisticated visual stimuli, we have shown that the mammalian SCN is sensitive to changes in colour and that including changes in colour improves the phase of entrainment of mice exposed to naturalistic light cycles. Those data represent the first demonstration that mammals can use colour to tell time. We now would like to know how the SCN comes to be colour sensitive; how the clock's response to light is defined by its intensity and colour; and whether the clock of diurnal animals is also colour sensitive.

Answering these questions will provide basic information about this newly discovered component of sensory biology. It also represents the key knowledge that we need in order to define the practical importance of our discovery. Disruptions to entrainment of the clock (e.g. in shift-work, ageing and various diseases) in both humans and animals are associated with range of negative effects on mental/physical performance, health and well-being. There is already substantial interest in how modern visual displays and artificial lights affect the clock. On the one hand, there is concern that too much light at night and/or too little natural light during the day (as e.g. for indoor reared animals) impact clock phase. On the other, there is excitement in the possibility that by changing the characteristics of light one could design systems that better support natural rhythms. Until now that effort has concentrated on the impact of different light intensities. Its colour has been considered but only insofar as some wavelengths more effectively induce a 'brightness' response in the clock. Our data also argue that we should think about its true colour. The experiments described here represent the essential steps in determining whether and how we can modulate colour to support appropriate circadian physiology in man and domestic animals.

Circadian clocks are critical for organisms to adapt their physiology/behaviour in anticipation of changing demands across the day. In mammals, this relies on retinal input to a master clock in the suprachiasmatic nuclei (SCN). Since inappropriate alignment of the clock (e.g. in shift-workers) is associated with negative effects on health, safety and productivity, understanding the precise nature of the sensory signals supplied to the clock is now a vital goal.

Although both the amount ('brightness') and spectral composition ('colour') of ambient light varies across the day/night, existing work has focused on the premise that the SCN tells time simply by measuring brightness. Our recent findings show that in fact, by comparing signals from short and longer wavelength sensitive cones, the SCN also uses colour to tell time. Here we propose a set of experiments that will reveal the biological significance of this arrangement and provide the critical information required to use colour to manipulate circadian timing.

We will first exploit our sophisticated new tools for selectively manipulating colour in mice, alongside large-scale electrophysiological recordings from retina and SCN, and behavioural monitoring under a range of analytical, practically and ecologically relevant lighting conditions. Together these approaches will tell us the biological origins of colour input to the clock and how information about brightness and colour are combined to determine circadian responses to light. We will next test whether the reduced sensitivity to UV light characteristic of diurnal mammals makes colour a less important temporal signal for this group of animals, by employing similar approaches in a day-active rodent with a more human-like visual system. Together these data will reveal whether using colour to tell time is q conserved strategy amongst mammals and allow us to predict how best to translate our findings into practical applications for human and/or animal use.

This proposal aligns closely with BBSRC priorities and has potential for significant impact with respect to Animal and Human Health.

It is well known that appropriate circadian alignment is important for health and well-being. Thus, there have already been many attempts to enhance artificial lighting to achieve this goal (e.g. in schools, offices and hospitals, light therapy for depression, dementia and in the elderly). At present however, there is no solid scientific foundation laying out exactly how best to manipulate light to control its effect on the clock. Our work will define precisely such information for species with visual systems representative of the major mammalian groupings (nocturnal and diurnal) and thus provide the theoretical underpinnings necessary to extrapolate our findings to any other mammal. Since there is abundant evidence that circadian misalignment negatively impacts the health and fitness of all organisms, we foresee relatively direct practical applications:

With respect to managed/domestic animals we will be able to define artificial lighting cycles where changes in colour and brightness best recapitulate those experienced by animals in nature (minimising stress/increasing productivity) and/or provide the most robust synchronisation of the circadian system (reducing individual variability). Similarly, our work will inform the design of lighting environments that ensure appropriate circadian alignment in humans and thus promote healthy sleep, learning and productivity. As part of this work, we hope to reveal ways of manipulating lighting or visual displays that enable robust circadian entrainment without impairing the ability to perform visually guided tasks (especially important for environments like hospitals). As such our data are potentially of benefit across wide sections of society, including shift workers, the elderly and those with chronic health conditions. Given recent advances in lighting (providing cost-effective means to control colour/brightness throughout the day), translating our research findings into practical applications in the areas listed above is readily achievable. Accordingly, we have two main strategies for achieving impact.

Direct commercial applications:
We will first approach established leaders in the lighting industries to gauge interest (where the project team already have extensive contacts). Working closely with our institutional knowledge transfer organisation to protect our IP, we will then formally approach industrial contacts with a view to developing any technology commercially. We anticipate it will be possible to make an initial filling on a potential application before the project completes and that, given the fairly clear path to translate our basic science findings to the human visual system, it is reasonable to expect a commercial device within 3-5 years of this initial filing. We can also seek industrial/academic partners for collaborative research and/or proof of concept funding where potential commercial applications need further development.

Lighting design/regulatory change:
An important first step is to publicise our findings to academic, lighting and regulatory communities (by presenting at scientific and applied lighting meetings, via contacts in the lighting industry and regulators, and via coverage in national/international media). A second key step will be for the relevant biological experts to agree some consensus advice (an area where we have already had significant success). We propose to achieve this by organising a meeting of leading experts and relevant regulatory/government bodies. We will consolidate these activities with review articles and research publications in top quality peer reviewed journals. Our recent work in related areas has garnered international media coverage and we expect the important new findings arising from this project to do likewise, further increasing the impact of our work among the public.