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  • Visual and circadian responses to light in aged retinally degenerate mice.

    27 November 2018

    The progression of photoreceptor degeneration in retinally degenerate (rd) mice commences early in postnatal development resulting in the complete loss of rods by 60-70 days of age followed by the more protracted loss of cones. We have previously shown that rd mice 80 days of age are capable of phase shifting their circadian locomotor rhythms in response to brief pulses of light and these animals show the same sensitivity as wild-type (+/+) controls. If surviving cones mediate these circadian responses, then one would expect the sensitivity of the circadian system in rd mice to decline with age and parallel the loss of cones. We demonstrate that aging rd mice (80-767 days of age) remain capable of photically regulating circadian locomotor rhythms in a manner indistinguishable from +/+ mice. Circadian responses to light do not parallel cone cell degeneration in rd mice. In contrast to the circadian responses to light, old (> 210 days of age) rd mice show no visually-evoked behavioral or electroretinogram (ERG) responses.

  • Circadian photoreception in the retinally degenerate mouse (rd/rd).

    27 November 2018

    We have examined the effects of light on circadian locomotor rhythms in retinally degenerate mice (C57BL/6J mice homozygous for the rd allele: rd/rd). The sensitivity of circadian photoreception in these mice was determined by varying the irradiance of a 15 min light pulse (515 nm) given at circadian time 16 and measuring the magnitude of the phase shift of the locomotor rhythm. Experiments were performed on animals 80 days of age. Despite the loss of visual photoreceptors in the rd/rd retina, animals showed circadian responses to light that were indistinguishable from mice with normal retinas (rd/+ and +/+). While no photoreceptor outersegments were identified in the retina of rd/rd animals (80-100 days of age), we did identify a small number of perikarya that were immunoreactive for cone opsins, and even fewer cells that contained rod opsin. Using HPLC, we demonstrated the presence and photoisomerization of the rhodopsin chromophore 11-cis retinaldehyde. The rd/rd retinas contained about 2% of 11-cis retinaldehyde found in +/+ retinas. We have yet to determine whether the opsin immunoreactive perikarya or some other unidentified cell type mediate circadian light detection in the rd/rd retina.

  • Absence of phosphoglucose isomerase-1 in retinal photoreceptor, pigment epithelium and Muller cells.

    27 November 2018

    Macroarray analysis was used to compare equal amounts of cDNA from wild-type and rd/rd (retinal degeneration) mice, collected at P90 when photoreceptor degeneration is virtually complete. A stronger signal for the glycolytic enzyme phosphoglucose isomerase (Gpi1) was observed in the rd/rd sample. Extracellularly, Gpi1 may act as a cytokine, independently described as neuroleukin and autocrine motility factor. Retinal Gpi1 expression was investigated by Northern and Western blot analysis and immunohistochemistry. Double-labelling was performed with antibodies against Gpi1 and calbindin-D, glutamine synthetase, RPE65, calretinin and ultraviolet opsin in order to provide positive cell type identification. Northern and Western blots showed double expression levels per microgram of RNA and protein, respectively, in the rd/rd retina compared with wild-type. However, the total amount of Gpi1 protein per retina was indistinguishable. Gpi1 immunoreactivity was found in ganglion, amacrine, horizontal and bipolar cells, but not in rods, cones, pigment epithelium and Muller cells. This distribution explains why the absolute amounts of Gpi1 protein were not appreciably different between wild-type and the rd/rd phenotype, where rods and cones are absent, whilst the relative contribution of Gpi1 to the total protein and RNA pools differed. Some extracellular immunoreactivity was observed in the photoreceptor matrix around cones in freshly fixed tissue only, which could possibly reflect a role as a cytokine. We propose that glycolysis in Gpi1-negative cells proceeds entirely through the pentose phosphate pathway, creating NADPH at the cost of organic carbon. We hypothesize that the unique metabolic needs of photoreceptors justify this trade-off.

  • Inner retinal photoreceptors (IRPs) in mammals and teleost fish.

    27 November 2018

    Research over the past decade has provided overwhelming evidence that photoreception in the vertebrate eye is not confined to the rods and cones. The discovery of non-rod, non-cone ocular photoreceptors in mammals and fish arose from quite different lines of investigation. In transgenic mice entirely lacking functional rod and cone photoreceptors a range of responses to light, including the regulation of the circadian system and a pupillary light reflex, are preserved. Electrophysiological and imaging approaches were then able to characterise a coupled plexus of directly light sensitive ganglion cells. Most recently action spectroscopy has shown that a novel 'blue-light' sensitive photopigment based upon opsin/vitamin A (OP480) mediates these responses to light. Several candidate genes have emerged for OP480, with melanopsin being by far the strongest. A definitive link, however, between this gene and OP480 has still to be established. In contrast to the mammals, the discovery of inner retinal photoreceptors (IRPs) in fish started with the discovery of a new gene family (VA opsin). The teleost VA opsins form functional photopigments and are expressed in several different types of inner retinal neuron, including retinal horizontal cells. Recent studies have investigated the electrical properties of these photosensitive neurones, but their light-sensing role remains a matter of speculation. Thus the study of IRP is developing along quite separate lines. In the mammals the research is directed towards a molecular identification of the photopigment (OP480) and its cascade, whilst in fish the major effort is directed towards identifying a role for these novel photoreceptors using physiological approaches. The discovery of IRPs in the vertebrates tells us that despite 150 years of research, we still have much to learn about how the eye processes light.

  • Characterization of an ocular photopigment capable of driving pupillary constriction in mice.

    27 November 2018

    This work demonstrates that transgenic mice lacking both rod and cone photoreceptors (rd/rd cl) retain a pupillary light reflex (PLR) that does not rely on local iris photoreceptors. These data, combined with previous reports that rodless and coneless mice show circadian and pineal responses to light, suggest that multiple non-image-forming light responses use non-rod, non-cone ocular photoreceptors in mice. An action spectrum for the PLR in rd/rd cl mice demonstrates that over the range 420-625 nm, this response is driven by a single opsin/vitamin A-based photopigment with peak sensitivity around 479 nm (opsin photopigment/OP479). These data represent the first functional characterization of a non-rod, non-cone photoreceptive system in the mammalian CNS.

  • Vertebrate ancient (VA) opsin and extraretinal photoreception in the Atlantic salmon (Salmo salar).

    27 November 2018

    A member of a new photopigment family first isolated from teleost fish, vertebrate ancient (VA) opsin, has recently been shown to form a functional photopigment and to be expressed within a subset of horizontal and amacrine cells of the inner retina. These sites of expression (and structural features) of VA opsin suggest that this photopigment might mediate non-image-forming light-detection tasks. We attempted to gain support for this hypothesis by examining the expression of VA opsin within the central nervous system (CNS) (pineal and deep brain) of the Atlantic salmon Salmo salar. In addition, we examined the sites of rod-opsin, cone-opsin and &agr; -transducin expression within the salmon CNS to provide a more complete description of the extraretinal photoreceptors of a teleost vertebrate. We show that multiple populations of cells within the salmon CNS appear to contain photoreceptors: VA opsin was strongly expressed in the pineal organ and in bilateral columns of subependymal cells in the epithalamus; anti-cone-opsin antibodies labelled cells within the pineal and numerous cells in the anterior hypothalamus (suprachiasmatic nucleus, nucleus preopticus magnocellularis, nucleus preopticus parvocellularis); anti-rod-opsin antibodies labelled cells within the pineal but no other areas within the central brain; and anti- &agr; -transducin antibodies labelled cells within the pineal and the ventral telencephalon. Collectively, our results suggest that VA opsin is a photopigment specialised for irradiance detection tasks within the eye, pineal and central brain, and that the salmon has multiple and varied populations of photoreceptors within the CNS. We review the significance of these findings within the broad context of vertebrate extraretinal photoreception.

  • The rhythm of rest and excess.

    27 November 2018

    There is a stark contrast between our attitudes to sleep and those of the pre-industrial age. In Shakespeare's Julius Caesar we are told to "Enjoy the honey-heavy dew of slumber". There seems little chance of this today, as we crave more, work more and expect more, and, in the process, abandon sleep. Our occupation of the night is having unanticipated costs for both our physical and mental health, which, if continued, might condemn whole sectors of our society to a dismal future.

  • Melanopsin retinal ganglion cells and the maintenance of circadian and pupillary responses to light in aged rodless/coneless (rd/rd cl) mice.

    27 November 2018

    Melanopsin-expressing ganglion cells have been proposed as the photoreceptors mediating non-rod, non-cone ocular responses to light. Here we use the aged (approximately 2 years) rodless and coneless (rd/rd cl) mouse to assess the impact of progressive inner retinal cell loss on melanopsin expression, circadian entrainment and pupillary constriction. Aged rd/rd cl mice show substantial transneuronal retinal degeneration leaving only the ganglion cell layer and little of the inner nuclear layer. Despite this loss, quantitative reverse transcriptase-polymerase chain reaction showed normal levels of melanopsin expression, and immunocytochemistry demonstrated both the presence and normal cellular appearance of these cells. Furthermore, the optic nerves of the two genotypes (rd/rd cl and +/+) were not obviously different in animals older than 2 years. However, this massive level of retinal degeneration left both pupillary and circadian responses to light intact, even in rd/rd cl mice older than 2 years. Our data provide the first positive correlation between the persistence of melanopsin-expressing cells and the maintenance of both circadian and pupillary responses to light in the absence of rods and cones. These findings, together with recent studies on melanopsin knockout mice, are consistent with the hypothesis that melanopsin-expressing ganglion cells are photosensitive and mediate a range of irradiance-detection tasks.

  • Neurodegeneration and Inflammation Research Group

    15 January 2013

    DCN

    We explore the neuropathology of multiple sclerosis and other inflammatory and neurodegenerative diseases using a multidisciplinary team approach to post-mortem brain and spinal cord tissue. The aim is that the understanding derived from these studies will translate into ideas for improved treatments for living patients.

  • Experimental Neurology

    15 January 2013

    DCN

    Our goal is to define how activity in large populations of neurons is coordinated in healthy movement and how such coordination may go awry in diseases, translating this information in to improved treatment for Parkinson’s Disease and other disorders of movement.

  • Neuromuscular Disorders

    15 January 2013

    DCN

    We work to translate an understanding of the molecular mechanisms of disease at the neuromuscular synapse into treatments. Our work led us to be commissioned to provide a National Advisory and Diagnostic Service for congenital myasthenic syndromes.

  • Neural Injury Group

    19 February 2013

    DCN

    Our aim is to gain a better understanding of the response of the peripheral nervous system to injury in order to develop strategies to promote peripheral nerve repair and to prevent the development of neuropathic pain. To do this we employ a variety of multi-disciplinary techniques ranging from transgenic models to human psychophysical studies and genetics.

  • Pain, Palliative and Supportive Care (PaPaS) Review Group

    15 January 2013

    NDA

    The Cochrane Pain, Palliative and Supportive Care (PaPaS) Review Group is based at the Oxford Pain Relief Unit, Churchill Hospital.

  • Oxford Respiratory Group

    15 January 2013

    NDA

    The Oxford Respiratory Group works collaboratively on a range of projects dedicated to Respiratory Control. Professor Pandit's group studies anaesthetic effects on oxygen sensing and also focusses on clinical research related to effects of anaesthetics on respiration and anaesthetic techniques on the lungs and airway.

  • Oxford Airway Group

    15 January 2013

    NDA

    We strive to continually improve airway management in anaesthesia with a focus on minimising risk associated with difficult airways.

  • Circadian and Visual Neuroscience (Foster)

    15 January 2013

    NLO

    Our research interests range across the neurosciences but with specific interests in circadian, visual and behavioural neuroscience.

  • Circadian and Visual Neuroscience (Peirson)

    15 January 2013

    NLO

    Our research focuses on the non-image forming function of the eye, including how the light environment regulates sleep and circadian rhythms and how these responses are affected in disease.