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Russell Foster BSc PhD FRS

Chair of Circadian Neuroscience, Nicholas Kurti Fellow, Brasenose College, Head of Department
Circadian and Visual Neuroscience
All life on earth has evolved under a rhythmically changing cycle of light and darkness, and organisms from single-celled bacteria up to man possess an internal representation of time. These 24 hour cycles, termed circadian rhythms, persist in the absence of external cues, and provide a means of anticipating changes in the environment rather than passively responding to them. In mammals, including man, light provides the critical input to the circadian system, synchronising the body clock to prevailing conditions. The photoreceptors providing this input are found in the retina, consisting of the classical rods and cones which enable image-formation, as well as a recently identified subset of photosensitive retinal ganglion cells (pRGCs). The research interests of our group range across the neurosciences but with specific interests in circadian, visual and behavioural neuroscience. This covers such topics as how circadian rhythms are generated, the diverse functions these rhythms serve, how this system is regulated by light, the role of classical and novel photoreceptors in both visual and circadian light perception, and genetic disorders of these systems. This work includes a range of molecular, cellular, anatomical and behavioural aspects, as well as addressing the implications for human performance, productivity and health. Research is divided into three groupings, with a broad overlap and extensive collaborations between each. Circadian Biology Retinal Neurobiology Ocular Genetics

Group Members

Collaborators

  • Dr Matthew Wood
  • Dr Jeremy Taylor
  • Prof. Kay Davies
  • Prof. Guy Goodwin
  • Prof. Robert Lucas, University of Manchester
  • Prof. Ronald Douglas, City University
  • Dr. David Whitmore, UCL
  • Dr. Pat Nolan, MRC Harwell
  • Dr. Samar Hatter, Johns Hopkins
Web Personal Website
Department Department of Ophthalmology
College Brasenose College
Russell Foster

Russell Foster

My research interest’s span both visual and circadian neurobiology with the main focus on the mechanisms whereby light regulates vertebrate circadian rhythms. Several of our key findings are listed below, but of these I consider the discovery of non-rod, non-cone retinal photoreceptors to be the most important to date. 

1) The discovery and characterisation of a third class of photoreceptor in the vertebrate eye.

Little more than a decade ago discussion that the eye might contain a non-rod, non-cone photoreceptor generated either polite amusement or hostile rebuttal by most vision scientists. Since the eye had been the subject of intense research for two centuries it seemed inconceivable that such a system could have been overlooked. The dogma was that all photoreception took place in the rods and cones of the outer retina whilst the cells of the inner retina provide the initial stages of signal processing prior to complex visual processing in the brain. However, two separate lines of study from my group showed that the inner retina also contains photosensory neurones.

1A – Studies in Mammals: In the early 1990’s we used retinally degenerate and transgenic animal models to understand how the circadian system in rodents is regulated by light.  The approach used mice which carry gene defects resulting in blindness (greatly diminished or undetectable visual responses) and monitor the impact of this loss on the ability of these rodents to adjust (entrain) their circadian rhythm system to a light/dark cycle. We showed that despite massive rod and cone photoreceptor loss these mice were not only able to entrain their circadian rhythms, but could do so with the same sensitivity as fully sighted animals (4). These, and a host of subsequent experiments (1), showed that the processing of light information by the circadian and visual systems was different and suggested that there might be another class of photoreceptor within the eye.  But because we could not preclude the possibility that only a very small number of rods and/or cones are required for photoentrainment, we engineered mice (rd/rd cl) in which all the rods and cones were functionally ablated. Circadian entrainment (6), the regulation of pineal melatonin (10, 11), and a variety of other responses to environmental irradiance (e.g. pupil constriction, (9), were preserved in rd/rd cl mice and these data provided unambiguous evidence for a third class of ocular photoreceptor, quite different from the rods and cones, within the mammalian retina. To localise these photoreceptors Mark Hankins, Sum Sakaran, Rob Lucas and I utilised the isolated rd/rd cl mouse retina in combination with Ca2+ - imaging techniques. This approach showed that the retina contains a plexus of electrically coupled photosensitive ganglion cells (pRGCs) and that Ca2+ is likely to play an important role in the phototransduction cascade (16).  Most recently this approach has shown that these pRGCs are photosensitive at birth and convey light information to the brain (17).  Parallel studies on the rd/rd cl mouse employed action spectroscopy to characterise a novel opsin/vitamin A photopigment (OP) with a maximum sensitivity in the “blue” part of the spectrum (λmax 479nm/ OP479) (7, 9). Although we had deduced the biochemistry of the photopigment, the molecular identity of OP479 remained a mystery. In collaboration with collegues in the USA, notably King-Wai Yau and Samar Hatter we then showed that melanopsin is likely to be this photopigment. Melanopsin is expressed in the pRGCs, and its genetic ablation in mice lacking all functional rods and cones abolishes circadian and pupillary responses to light (7, 12). The functional properties of melanopsin have been assessed very recently by members of our group (and independently by two other laboratories in the USA) by combining the expression of melanopsin protein with physiological assays of cellular photosensitivity. Remarkably, Mark Hankins has shown that melanopsin can confer photosensitivity to a variety of non-photosensitive cell types (see Melyan et. al. 2005). Our recent and unpublished work has shown that pRGCs regulate multiple areas of physiology including sleep propensity and cardiac function (work in progress). Finally, novel microarray approaches developed by Stuart Peirson and studies in gene knock-out models by Henrik Oster in the group have identified new and unexpected proteins in the melanopsin phototransduction cascade (15).

1B – Studies in Teleost Fish:  In parallel with our studies in mammals, we discovered non-rod, non-cone ocular photoreception in fish by using a very different set of approaches. In 1997 we isolated a novel opsin gene family from teleost fish that we termed the VA (vertebrate ancient)-opsins (18). This gene encodes a functional VA opsin photopigment and is expressed in a sub-set of retinal horizontal and amacrine/ganglion cells (19). Since this discovery pre-dated our findings in mammals it represents the first demonstration of a non-rod, non-cone ocular photopigment in any vertebrate. Subsequent collaborative work with Mark Hankins has combined electrophysiological, molecular and anatomical approaches to study the cell biology of these novel retinal photoreceptors. They respond to environmental irradiance, integrate light information from rods and cones, and contain a photopigment with a maximum sensitivity in the “blue” part of the spectrum (λmax 477nm) (8). 

Significance of these discoveries: The eye has been considered the best characterised part of the central nervous system. The fundamental questions about the eye were considered answered, with only the details left to resolve. Our discovery of novel ocular photoreceptors in mammals and fish has forced a major reassessment of how the eye processes light information to regulate a variety of different photosensory tasks, and it is likely that much of this work will have important clinical implications. Not least on the classification of human blindness. Ophthalmologists are now beginning to appreciate the full consequences of eye loss, a state that deprives an individual of both their sense of space and time (also see 5 – below). 

 

2) The discovery of opsin/vitamin A based photopigments in extraretinal photoreceptors. 

Non-mammalian vertebrates possess a diverse complement of photoreceptors including the pineal organ, deep encephalic photoreceptors, and dermal/peripheral tissue photoreceptors. Although these photoreceptors were first recognised in the early part of the 19th century, the basis for their photosensitivity remained (and to a degree still remains) poorly understood. My work provided overwhelming evidence that these diverse photoreceptors use broadly conserved mechanisms based upon opsin/vitamin A photopigments. Two of my early Nature papers, summarise these conceptual breakthroughs: (i) the photosensitive dermal pigment cells of certain teleost fish utilize an opsin-based photopigment system (13). This was shown by generating antibodies against visual pigment opsins, and localising opsin protein in the photosensitive membranes of the dermal iridophores.  In 2003 we isolated a new opsin gene family (tmt-opsin) from fish that probably encodes the specific opsin for this peripheral tissue photosensitivity (14). This work is ongoing;  (ii)  A study published in 1985, addressed a long-standing question in seasonal physiology. In the 1930’s birds had been shown to use a photoreceptor located deep within the brain to detect daylength changes and regulate seasonal physiology, but nothing was known of how this photoreceptor might function. By using action spectroscopy we established that these encephalic receptors utilize an opsin/vitamin A based photopigment system (2). We were also able to show how the detection of these daylength changes are translated into neuroendocrine changes of the reproductive axis (3).

 

3) Circadian rhythms and schizophrenia.

Patients with schizophrenia frequently complain of poor sleep and are commonly observed to shift their rest-activity cycle. Despite the introduction of new antipsychotic drugs, sleep-wake abnormalities remain a major complaint. Of the few previous studies undertaken, all have suggested that abnormal rest-activity or EEG sleep profiles in schizophrenic patients are associated with an increase in severity of psychotic symptoms, a decrease in cognitive performance, and poor psychosocial outcomes. Katharina Wulff and I, working with Eileen Joyce (UCL) and Derk-Jan Dijk (Surrey) have initiated a detailed study of this phenomenon. Our results show that the circadian timing of the sleep-wake profile and endocrine rhythms are either severely delayed or free-running with respect to time of day in patients with schizophrenia. This work is currently being prepared for publication. We feel that a greater understanding of circadian disturbance in schizophrenia will not only increase our understanding of the neurobiology and neurogenetics of the disorder, but also provide the substrate for the development of clinical and pharmacological interventions. This will improve rehabilitation potential and the quality of life of patients and their families. Future studies will address whether a correction of these sleep-wake abnormalities will result in a reduction in psychotic episodes and the abnormalities of neurocognition, emotion and social isolation that are intrinsic to the disorder (5).

 

Key Papers Cited:

1.     David-Gray ZK, Janssen JW, DeGrip WJ, Nevo E, and Foster RG. Light detection in a 'blind' mammal. Nat Neurosci 1: 655-656, 1998.

2.     Foster RG, Follett BK, and Lythgoe JN. Rhodopsin-like sensitivity of extra-retinal photoreceptors mediating the photoperiodic response in quail. Nature 313: 50-52, 1985.

3.     Foster RG, Plowman G, Goldsmith AR, and Follett BK. Immunocytochemical demonstration of marked changes in the LHRH system of photosensitive and photorefracory European starlings (Sturnus vulgaris). Journal of Endocrinology 115: 211-220, 1987.

4.     Foster RG, Provencio I, Hudson D, Fiske S, DeGrip W, and Menaker M. Circadian photoreception in the retinally degenerate mouse (rd/rd). J Comp Physiol [A] 169: 39-50, 1991.

5.     Foster RG, and Wulff K. The rhythm of rest and excess. Nat Rev Neurosci 6: 407-414, 2005.

6.     Freedman MS, Lucas RJ, Soni B, von Schantz M, Munoz M, David-Gray ZK, and Foster RG. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 284: 502-504, 1999.

7.     Hattar S, Lucas RJ, Mrosovsky N, Thompson S, Douglas RH, Hankins MW, Lem J, Biel M, Hofmann F, Foster RG, and Yau KW. Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424: 75-81, 2003.

8.     Jenkins A, Munoz M, Tarttelin EE, Bellingham J, Foster RG, and Hankins MW. VA opsin, melanopsin, and an inherent light response within retinal interneurons. Curr Biol 13: 1269-1278, 2003.

9.     Lucas RJ, Douglas RH, and Foster RG. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nat Neurosci 4: 621-626, 2001.

10.   Lucas RJ, and Foster RG. Neither functional rod photoreceptors nor rod or cone outer segments are required for the photic inhibition of pineal melatonin. Endocrinology 140: 1520-1524, 1999.

11.   Lucas RJ, Freedman MS, Munoz M, Garcia-Fernandez JM, and Foster RG. Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 284: 505-507, 1999.

12.   Lucas RJ, Hattar S, Takao M, Berson DM, Foster RG, and Yau KW. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 299: 245-247, 2003.

13.   Lythgoe JN, Shand J, and Foster RG. Visual pigment in fish iridocytes. Nature 308: 83-84, 1984.

14.   Moutsaki P, Whitmore D, Bellingham J, Sakamoto K, David-Gray ZK, and Foster RG. Teleost multiple tissue (tmt) opsin: a candidate photopigment regulating the peripheral clocks of zebrafish? Brain Res Mol Brain Res 112: 135-145, 2003.

15.   Peirson SN, Oster H, Jones SL, Leitges M, Hankins MW, and Foster RG. Microarray analysis and functional genomics identify novel components of melanopsin signaling. Curr Biol 17: 1363-1372, 2007.

16.   Sekaran S, Foster RG, Lucas RJ, and Hankins MW. Calcium imaging reveals a network of intrinsically light-sensitive inner-retinal neurons. Curr Biol 13: 1290-1298, 2003.

17.   Sekaran S, Lupi D, Jones SL, Sheely CJ, Hattar S, Yau KW, Lucas RJ, Foster RG, and Hankins MW. Melanopsin-dependent photoreception provides earliest light detection in the Mammalian retina. Curr Biol 15: 1099-1107, 2005.

18.   Soni BG, and Foster RG. A novel and ancient vertebrate opsin. FEBS Let 406: 279-283, 1997.

19.   Soni BG, Philp AR, Knox BE, and Foster RG. Novel retinal photoreceptors. Nature 394: 27-28, 1998.

 

Biography

Russell Foster is Professor of Circadian Neuroscience and the Head of Department of Ophthalmology. He is also a Nicholas Kurti Senior Fellow at Brasenose College.  His group, Circadian and Visual Neuroscience, have been based at the Wellcome Trust Centre for Human Genetics at the Old Road campus since May 2005, but will be moving to the JR campus in Spring 2008.  Prior to this, Russell was at Imperial College where Russell was Chair of Molecular Neuroscience within the Faculty of Medicine.  Russell Foster’s research spans basic and applied circadian and photoreceptor biology.  He received his education at the University of Bristol under the supervision of Professor Sir Brian Follett. from 1988–1995 he was a member of the National Science Foundation Center for Biological Rhythms at the University of Virginia and worked closely with Michael Menaker.  In 1995 he returned to the UK and established his group at Imperial College.  For his discovery of non-rod, non-cone ocular photoreceptors he has been awarded the Honma prize (Japan), Cogan award (USA), and Zoological Society Scientific & Edride-Green Medals (UK). He is the co-author of “Rhythms of Life” a popular science book on circadian rhythms.

Awards Training and Qualifications

  • 2007- 2012 Visiting Chair, School of Animal Biology, University of Western Australia
  • 2007- N/A Head, Department of Ophthalmology, University of Oxford
  • 2007- 2012 Chair, healthy Organism Panel, BBSRC
  • 2006- N/A Chair of Circadian Neurosceince, Nuffield Laboratory of Ophthalmology, University of Oxford
  • 2006- 2011 Nicholas Kurti Senior Fellow, Brasenose College, Oxford
  • 2006- 2011 Visiting Chair, Department of Biology, Imperial College, London
  • 2006- 2011 Visiting Chair, Department of Biomedical and Molecular Sciences, University of Surrey
  • 2006- N/A Member UKPanel for Research Integrity in Health and Biomedical Sciences, Universities UK
  • 2005- N/A Guest speaker, Montagskolloquium, Max Planck Institute, Tubingen germany
  • 2005- N/A Edridge Green Lecture and Medal, Royal College of Ophthalmologists
  • 2004- N/A Plenary Lecture, Opening of EDAB, European DANA Alliance
  • 2003- 2006 Deputy Chair, Department of Visual Neuroscience, Imperial College, London
  • 2003- N/A Chair, Gordon Research Conference on Chronobiology 2003, GRC Organisation
  • 2002- 2006 Chair, Animal Sciences Committee, BBSRC
  • 2002- N/A Member, Strategy Board, BBSRC
  • 2001- N/A Cogan Award, Association for Research in Vision and Ophthalmology (SUA)
  • 2000- 2003 Chair, Department of Integrative Neuroscience, Imperial College, London
  • 1999- 1999 ZSL Scientific Medal, Zoological Society London
  • 1997- N/A Honma Prize in Biological Rhythms Research, Honma (Japan)
  • 1995- 2002 Senior Fellow, NSF Centre for Biological Timimg (USA)
  • 1980- 1984 PhD Neuroscience, University of Bristol
  • 1977- 1980 BSc Zoology, University of Bristol
Medical Sciences Office, John Radcliffe Hospital, Oxford, OX3 9DU - email : neuroscience@medsci.ox.ac.uk