Light Reception: Discovering the Clock-Eye in Mammals (original) (raw)
Recent Developments in Circadian Photoreception: More Than Meets the Eye
O ur perception of the world is so dominated by our sense of vision that we have been reluctant to accept the fact that the vertebrate eye mediates another, quite separate photosensory task-the detection of light for the regulation of biological time. In this short article, we outline some of the recent experimental findings that show that the absence of rod and cone photoreceptors does not block the effects of light on the circadian system. Furthermore, we review the progress to date in identifying the photopigments that may mediate the effects of light on the mammalian biological clock.
Journal of Biological Rhythms, 1991
Acute light pulses as well as long-term light exposure may not only modulate photoreceptive properties, but also induce reversible or irreversible damage to the retina, depending on exposure conditions. Illuminance levels in laboratory animal colonies and manipulations of lighting regimens in circadian rhythm research can threaten retinal structure and physiology, and may therefore modify zeitgeber input to the central circadian system. Given the opportunity to escape light at any time, the nocturnal rat self-selects a seasonally varying "naturalistic skeleton photoperiod" that protects the eyes from potential damage by nonphysiological light exposures. Both rod outer-segment disk shedding and behavioral circadian phase shifts are elicited by low levels of twilight stimulation. From this vantage point, we hypothesize that certain basic properties of circadian rhythms (e.g., Aschoff's rule and splitting) may reflect modulation of retinal physiology by light. Pharmacological manipulations with or without the addition of lighting strategies have been used to analyze the neurochemistry of circadian timekeeping. Drug modulation of light input at the level of the retina may add to or interact with direct drug modulation of the central circadian pacemaking system.
Circadian biology: the physiology of inner retinal photoreceptors
2003
Non-traditional photoreceptors detect overall irradiance in the vertebrate retina. Such cells in the mouse inner retina show increased intracellular Ca 2+ levels following illumination. Neurons in the outer retina of fish also display characteristics appropriate for an irradiance detector.
Circadian phototransduction and the regulation of biological rhythms
2002
The vertebrate circadian system that controls most biological rhythms is composed of multiple oscillators with varied hierarchies and complex levels of organization and interaction. The retina plays a key role in the regulation of daily rhythms and light is the main synchronizer of the circadian system. To date, the identity of photoreceptors/photopigments responsible for the entrainment of biological rhythms is still uncertain; however, it is known that phototransduction must occur in the eye because light entrainment is lost with eye removal. The retina is also rhythmic in physiological and metabolic activities as well as in gene expression. Retinal oscillators may act like clocks to induce changes in the visual system according to the phase of the day by predicting environmental changes. These oscillatory and photoreceptive capacities are likely to converge all together on selected retinal cells. The aim of this overview is to present the current knowledge of retinal physiology in relation to the circadian timing system.
Localization of a circadian clock in mammalian photoreceptors
The FASEB Journal, 2007
Several studies have demonstrated that the mammalian retina contains an autonomous circadian clock. Dopaminergic and other inner retinal neurons express many of the clock genes, whereas some of these genes seem to be absent from the photoreceptors. This observation has led to the suggestion that in mammalian retina the circadian pacemaker driving retinal rhythms is located in the inner nuclear layer. However, other evidence points to the photoreceptor layer as the site of the mammalian retinal clock. The goal of the present study was to demonstrate the presence of a functional circadian clock in photoreceptors. First, using laser capture microdissection and reverse transcriptase-polymerase chain reaction, we investigated which of the clock genes are expressed in rat photoreceptors. We then prepared photoreceptor layer cultures from the retina to test whether these isolated cultures were viable and could drive circadian rhythms. Our data indicated that Per1, Per3, Cry1, Cry2, Clock, Bmal1, Rev-erb␣, and Rora RNAs were present in the photoreceptors, whereas we were unable to amplify mRNA for Per2 and Npas2. Photoreceptor layers obtained from Period1-luciferase rats expressed a robust circadian rhythm in bioluminescence and melatonin synthesis. These results demonstrate that mammalian photoreceptors contain the circadian pacemaker driving rhythmic melatonin synthesis.-Tosini, G., Davidson, A. J., Fukuhara, C., Kasamatsu, M., Castanon-Cervantes, O. Localization of a circadian clock in mammalian photoreceptors. FASEB J. 21, 3866 -3871 (2007)
The retinal clock in mammals: role in health and disease
ChronoPhysiology and Therapy
The mammalian retina contains an extraordinary diversity of cell types that are highly organized into precise circuits to perceive and process visual information in a dynamic manner and transmit it to the brain. Above this builds up another level of complex dynamic, orchestrated by a circadian clock located within the retina, which allows retinal physiology, and hence visual function, to adapt to daily changes in light intensity. The mammalian retina is a remarkable model of circadian clock because it harbors photoreception, self-sustained oscillator function, and physiological outputs within the same tissue. However, the location of the retinal clock in mammals has been a matter of long debate. Current data have shown that clock properties are widely distributed among retinal cells and that the retina is composed of a network of circadian clocks located within distinct cellular layers. Nevertheless, the identity of the major pacemaker, if any, still warrants identification. In addition, the retina coordinates rhythmic behavior by providing visual input to the master hypothalamic circadian clock in the suprachiasmatic nuclei (SCN). This light entrainment of the SCN to the light/dark cycle involves a network of retinal photoreceptor cells: rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs). Although it was considered that these photoreceptors synchronized both retinal and SCN clocks, new data challenge this view, suggesting that none of these photoreceptors is involved in photic entrainment of the retinal clock. Because circadian organization is a ubiquitous feature of the retina and controls fundamental processes, the coherence from cell to tissue is critical for circadian functions, and disruption of retinal clock organization or its response to light can potentially have a major impact on retinal pathophysiology and vision.
Retinal circadian clocks and control of retinal physiology
Journal of biological rhythms, 2004
Retinas of all classes of vertebrates contain endogenous circadian clocks that control many aspects of retinal physiology, including retinal sensitiv-ity to light, neurohormone synthesis, and cellular events such as rod disk shed-ding, intracellular signaling ...
Cell, 2007
Circadian clocks are widely distributed in mammalian tissues, but little is known about the physiological functions of clocks outside the suprachiasmatic nucleus of the brain. The retina has an intrinsic circadian clock, but its importance for vision is unknown. Here we show that mice lacking Bmal1, a gene required for clock function, had abnormal retinal transcriptional responses to light and defective inner retinal electrical responses to light, but normal photoreceptor responses to light and retinas that appeared structurally normal by light and electron microscopy. We generated mice with a retina-specific genetic deletion of Bmal1, and they had defects of retinal visual physiology essentially identical to those of mice lacking Bmal1 in all tissues and lacked a circadian rhythm of inner retinal electrical responses to light. Our findings indicate that the intrinsic circadian clock of the retina regulates retinal visual processing in vivo.
2020
The development of real-time bioluminescence recording using firefly luciferase as a reporter of clock gene expression has fundamentally revolutionized studies on circadian clocks [1,2]. This technique became a powerful tool and a common technique used in non-invasive and long-term assays of mammalian circadian rhythms in living cells, cultured tissues, and whole organisms [1-17]. The mammalian retina harbors many physiological and functional circadian rhythms, including photoreceptor disc shedding and phagocytosis by the retinal pigment epithelium, the expression of immediate early genes and opsin genes in photoreceptors, and dopamine/melatonin synthesis [18-26]; for a review, see also [27,28]. To investigate the core functioning and light properties of the mammalian retinal clock, Ruan and colleagues developed an in vitro retinal explant culture protocol using the Per2 Luc reporter mice [13]. In these mice, the luciferase coding sequence is inserted before the endogenous Per2 stop codon. The expression of the PER2::Luc fusion protein is then driven by the Per2 promoter [2]. It allows direct monitoring of molecular rhythms of the protein PER2 as a real-time reporter of circadian gene dynamics. This protocol was then used in several retinal studies [7-10,15,17,29-31]. However, to replicate experimental conditions and to enable meaningful comparisons between findings from different studies, the establishment of a standardized procedure is an essential prerequisite. The objective of this study is to highlight the important parameters that inf luence the retinal circadian
Photopic transduction implicated in human circadian entrainment
Neuroscience Letters, 1997
Despite the preeminence of light as the synchronizer of the circadian timing system, the phototransductive machinery in mammals which transmits photic information from the retina to the hypothalamic circadian pacemaker remains largely undefined. To determine the class of photopigments which this phototransductive system uses, we exposed a group (n = 7) of human subjects to red light below the sensitivity threshold of a scotopic (i.e. rhodopsin/rod-based) system, yet of sufficient strength to activate a photopic (i.e. cone-based) system. Exposure to this light stimulus was sufficient to reset significantly the human circadian pacemaker, indicating that the cone pigments which mediate color vision can also mediate circadian vision.
Identification of a circadian clock-controlled neural pathway in the rabbit retina
PloS one, 2010
Although the circadian clock in the mammalian retina regulates many physiological processes in the retina, it is not known whether and how the clock controls the neuronal pathways involved in visual processing. By recording the light responses of rabbit axonless (A-type) horizontal cells under dark-adapted conditions in both the day and night, we found that rod input to these cells was substantially increased at night under control conditions and following selective blockade of dopamine D(2), but not D(1), receptors during the day, so that the horizontal cells responded to very dim light at night but not in the day. Using neurobiotin tracer labeling, we also found that the extent of tracer coupling between rabbit rods and cones was more extensive during the night, compared to the day, and more extensive in the day following D(2) receptor blockade. Because A-type horizontal cells make synaptic contact exclusively with cones, these observations indicate that the circadian clock in the...
Circadian organization of the mammalian retina
Proceedings of the National Academy of Sciences of the United States of America, 2006
The mammalian retina contains an endogenous circadian pacemaker that broadly regulates retinal physiology and function, yet the cellular origin and organization of the mammalian retinal circadian clock remains unclear. Circadian clock neurons generate daily rhythms via cell-autonomous autoregulatory clock gene networks, and, thus, to localize circadian clock neurons within the mammalian retina, we have studied the cell type-specific expression of six core circadian clock genes in individual, identified mouse retinal neurons, as well as characterized the clock gene expression rhythms in photoreceptor degenerate rd mouse retinas. Individual photoreceptors, horizontal, bipolar, dopaminergic (DA) amacrines, catecholaminergic (CA) amacrines, and ganglion neurons were identified either by morphology or by a tyrosine hydroxylase (TH) promoter-driven red fluorescent protein (RFP) fluorescent reporter. Cells were collected, and their transcriptomes were subjected to multiplex single-cell RT-PCR for the core clock genes Period (Per) 1 and 2, Cryptochrome (Cry) 1 and 2, Clock, and Bmal1. Individual horizontal, bipolar, DA, CA, and ganglion neurons, but not photoreceptors, were found to coordinately express all six core clock genes, with the lowest proportion of putative clock cells in photoreceptors (0%) and the highest proportion in DA neurons (30%). In addition, clock gene rhythms were found to persist for >25 days in isolated, cultured rd mouse retinas in which photoreceptors had degenerated. Our results indicate that multiple types of retinal neurons are potential circadian clock neurons that express key elements of the circadian autoregulatory gene network and that the inner nuclear and ganglion cell layers of the mammalian retina contain functionally autonomous circadian clocks. circadian clock ͉ clock gene ͉ mouse retina ͉ photoreceptor ͉ real-time PCR
Frontiers in Neuroscience, 2021
The mammalian eye contains two systems for light perception: an image detecting system constituted primarily of the classical photoreceptors, rods and cones, and a non-image forming system (NIF) constituted of a small group of intrinsically photosensitive retinal ganglion cells driven by melanopsin (mRGCs). The mRGCs receive input from the outer retina and NIF mediates light entrainment of circadian rhythms, masking behavior, light induced inhibition of nocturnal melatonin secretion, pupillary reflex (PLR), and affect the sleep/wake cycle. This review focuses on the mammalian NIF and its anatomy in the eye as well as its neuronal projection to the brain. This pathway is known as the retinohypothalamic tract (RHT). The development and functions of the NIF as well as the knowledge gained from studying gene modified mice is highlighted. Furthermore, the similarities of the NIF between sighted (nocturnal and diurnal rodent species, monkeys, humans) and naturally blind mammals (blind mol...
Effect of Circadian Clock Gene Mutations on Nonvisual Photoreception in the Mouse
Investigative Ophthalmology & Visual Science, 2012
Mice lacking rods and cones retain pupillary light reflexes that are mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). Melanopsin is necessary and sufficient for this nonvisual photoreception. The mammalian inner retina also expresses the potential blue light photopigments cryptochromes 1 and 2. Previous studies have shown that outer retinal degenerate mice lacking cryptochromes have lower nonvisual photic sensitivity than retinal degenerate mice, suggesting a role for cryptochrome in inner retinal photoreception.
Circadian Photoreception in Vertebrates
Cold Spring Harbor Symposia on Quantitative Biology, 2007
To be adaptively useful, internal circadian clocks must be entrained (synchronized) to daily rhythms in the external world. The entraining process adjusts the period of the internal clock to 24 hours and its phase to a value that determines the organism's temporal niche (e.g., diurnal and nocturnal). For most vertebrates, the dominant environmental synchronizer is light. All vertebrates employ specialized photoreceptor cells to perceive synchronizing light signals, but mammals and nonmammalian vertebrates do this differently. Mammals concentrate circadian photoreceptors in the retina, employing rods, cones, and a subset of retinal ganglion cells that are directly photosensitive and contain an unusual photopigment (melanopsin). Nonmammalian vertebrates use photoreceptors located deep in the brain and in the pineal gland as well as others in the retina. Such photoreceptor extravagance is difficult to explain. It seems likely that the different photoreceptor classes in this elaborate sensory system may have specialized roles in entrainment. There is some evidence that this is in fact the case. Furthermore, this nonvisual "circadian" photoreceptive system also controls acute behavioral responses to light (masking), pupillary constriction, and photoperiodic regulation of reproductive state. We review some of the early work on birds and describe new findings that indicate specific roles for retinal rods, cones, and photosensitive retinal ganglion cells in mammals.
Circadian Photoentrainment in Mice and Humans
Biology, 2020
Light around twilight provides the primary entrainment signal for circadian rhythms. Here we review the mechanisms and responses of the mouse and human circadian systems to light. Both utilize a network of photosensitive retinal ganglion cells (pRGCs) expressing the photopigment melanopsin (OPN4). In both species action spectra and functional expression of OPN4 in vitro show that melanopsin has a λmax close to 480 nm. Anatomical findings demonstrate that there are multiple pRGC sub-types, with some evidence in mice, but little in humans, regarding their roles in regulating physiology and behavior. Studies in mice, non-human primates and humans, show that rods and cones project to and can modulate the light responses of pRGCs. Such an integration of signals enables the rods to detect dim light, the cones to detect higher light intensities and the integration of intermittent light exposure, whilst melanopsin measures bright light over extended periods of time. Although photoreceptor m...