Changes in environmental light can affect physiology, behavior, alertness, sleep propensity and the biological process directed by circadian rhythms such as the timing of digestion, sleep and performance. Humans and animals detect these light changes through novel photoreceptors in the eyes. Dr. Russell G. Foster is researching the extent to which these photoreceptors contribute to varied aspects of physiology and behavior and is working to define the relationship between photoreceptors, light, sleep state and levels of gene expression in the brain. The desired result of this study will provide a basis for drug development aimed at the manipulation of human circadian rhythms, sleep, mood and performance, and the design of new lighting sources as countermeasures.
The Role and Characterization of Novel Photoreceptor Mechanisms Regulating Circadian Rhythms, Sleep, Body Temperature and Heart Rate
Russell G. Foster, Ph.D.
University of Oxford
The long-term aims of this project are to provide effective countermeasures for the detrimental effects of the irregular and altered patterns of light exposure in space and on the surface of other planets. These countermeasures will depend upon an understanding of the basic mechanisms of how the eye perceives light. All photoreception within the eyes of mammals was considered the province of the rods and cones. However, our work has shown that varied aspects of physiology and behavior are regulated by gross changes in environmental light and that these irradiance changes are detected by non-rod, non-cone ocular photoreceptors. In 2003, we were able to demonstrate in the mouse that a small number (~ 1%) of retinal ganglion cells are directly photosensitive to light. It is these cells, termed photosensitive retinal ganglion cells (pRGCs) that seem to play a critical role in regulating varied aspects of our physiology and behavior. The central aims of the research that we have undertaken was to characterize the molecular mechanism of this unexplored photoreceptor system of the eye, and determine the extent to which the pRGCs contribute to varied aspects of physiology and behavior. In this regard, our proposal spans 1-4 of the Countermeasures Readiness Levels (CRL) of NASAs Human Research Program. By employing a unique transgenic mouse models and by taking advantage of the new opportunities created by a range of post-genomic technologies, we addressed two broad questions:
- What is the role of pRGCs in the regulation of general physiology and behavior?
- What are the molecular mechanisms of non-rod, non-cone ocular photoreceptors?
- Light detection by the eye is mediated by rods, cones and photosensitive retinal ganglion cells (pRGCs). The photopigment of the pRGCs has been the subject of considerable debate. From our previous data, the melanopsin gene and its protein product emerged as the strongest candidate for this photopigment. As part of our collaborative interactions, we have been able to show, using gene expression approaches, that melanopsin forms the photopigment of the pRGCs. This data was published in Nature.
- Light detection by the eye is mediated by rods, cones and photosensitive retinal ganglion cells (pRGCs), but it has remained unclear which of these photoreceptor classes modulate sleep and alertness. Our data provides the first direct physiological and behavioral evidence that pRGCs modulate sleep. Furthermore, we show that mice, which have rods and cone but lack melanopsin, no longer show sleep induction in response to light exposure. Thus, the pRGCs provide either the dominant or exclusive photic input into the sleep switch of the brain. This work is being prepared for a submission to Science.
- Cardiovascular performance, blood pressure and core body temperature can be modified by changes in ambient light. However, these responses have only been poorly characterised. Our ongoing studies suggest that the acute regulation of heart rate by environmental light in animal models arises from inputs from a time-dependent interaction between the classical rod and cone photoreceptor pathways and the pRGCs.
- To investigate the molecular mechanisms whereby light is transduced into a physiological response in pRGCs, we have undertaken a microarray project looking at light-induced gene expression. Eight genes have been identified (Gnas, Gnb2l1, Gnaq, Prkcz, Pik3r1, Inadl, Slc9a3r1, Drd1a) that co-localise with melanopsin pRGCs. The impact of genetic ablation of one of these, protein kinase C zeta (Prkcz), was assessed. Prkcz-/- animals show attenuated phase shifting responses to light, reduced period lengthening under constant light and attenuated pupillary responses at high irradiances as well as impaired light-induced gene expression in the suprachiasmatic nuclei (SCN). These attenuated responses are indistinguishable from the deficits observed in melanopsin knockout mice. This study is in press in Current Biology.
When our project was originally reviewed, support was enthusiastic but concerns were raised that we had been overly ambitious. We feel that over the duration of the grant we have more than fulfilled our set of goals. In brief, we have been able to show that the photic stimulation of pRGCs must be considered the primary target for the development of effective countermeasures for the detrimental effects of the irregular and altered patterns of light exposure in space and on the surface of other planets.
The cost to countries of working out of phase with the natural light environment, or working under inappropriate light conditions, is substantial in terms of poor performance, insomnia, altered mood and increased fatigue. For example, in the USA, the cost of accidents attributable to human fatigue is estimated at 16 billion per year. New approaches to address the clinical problems that either result from, or are affected by, inappropriate lighting conditions (e.g. depression, insomnia, reduced alertness and circadian maladjustment associated with shift work, blindness or jet-lag) will be critically dependent upon a detailed understanding of the basic mechanisms of the non-rod, non-cone ocular photoreceptors. Thus, a major benefit of the work outlined in this project will be to provide the mechanistic substrate for targeted drug development aimed at the manipulation of human circadian rhythms, sleep, mood and performance.