Light synchronizes mammalian circadian rhythms with environmental time by modulating retinal input to the circadian pacemaker-the suprachiasmatic nucleus (SCN) of the hypothalamus. Such photic entrainment requires neither rods nor cones, the only known retinal photoreceptors. Here, we show that retinal ganglion cells innervating the SCN are intrinsically photosensitive. Unlike other ganglion cells, they depolarized in response to light even when all synaptic input from rods and cones was blocked. The sensitivity, spectral tuning, and slow kinetics of this light response matched those of the photic entrainment mechanism, suggesting that these ganglion cells may be the primary photoreceptors for this system.

http://science.sciencemag.org/content/sci/295/5557/1070.full.pdf

Phototransduction by retinal ganglion cells that set the circadian clock.

The primary circadian pacemaker, in the suprachiasmatic nucleus (SCN) of the mammalian brain, is photoentrained by light signals from the eyes through the retinohypothalamic tract. Retinal rod and cone cells are not required for photoentrainment. Recent evidence suggests that the entraining photoreceptors are retinal ganglion cells (RGCs) that project to the SCN. The visual pigment for this photoreceptor may be melanopsin, an opsin-like protein whose coding messenger RNA is found in a subset of mammalian RGCs. By cloning rat melanopsin and generating specific antibodies, we show that melanopsin is present in cell bodies, dendrites, and proximal axonal segments of a subset of rat RGCs. In mice heterozygous for tau-lacZ targeted to the melanopsin gene locus, beta-galactosidase-positive RGC axons projected to the SCN and other brain nuclei involved in circadian photoentrainment or the pupillary light reflex. Rat RGCs that exhibited intrinsic photosensitivity invariably expressed melanopsin. Hence, melanopsin is most likely the visual pigment of phototransducing RGCs that set the circadian clock and initiate other non-image-forming visual functions.

http://science.sciencemag.org/content/sci/295/5557/1065.full.pdf

Melanopsin-Containing Retinal Ganglion Cells: Architecture, Projections, and Intrinsic Photosensitivity

The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for light-induced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 +/- 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects' pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n = 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence-response curves (R(2) = 0.81-0.95). The action spectrum constructed from these data fit an opsin template (R(2) = 0.91), which identifies 446-477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.

https://www.jneurosci.org/content/jneuro/21/16/6405.full.pdf

Action Spectrum for Melatonin Regulation in Humans: Evidence for a Novel Circadian Photoreceptor

Circadian rhythms of behavior are driven by oscillators in the brain that are coupled to the environmental light cycle. Circadian rhythms of gene expression occur widely in peripheral organs. It is unclear how these multiple rhythms are coupled together to form a coherent system. To study such coupling, we investigated the effects of cycles of food availability (which exert powerful entraining effects on behavior) on the rhythms of gene expression in the liver, lung, and suprachiasmatic nucleus (SCN). We used a transgenic rat model whose tissues express luciferase in vitro. Although rhythmicity in the SCN remained phase-locked to the light-dark cycle, restricted feeding rapidly entrained the liver, shifting its rhythm by 10 hours within 2 days. Our results demonstrate that feeding cycles can entrain the liver independently of the SCN and the light cycle, and they suggest the need to reexamine the mammalian circadian hierarchy. They also raise the possibility that peripheral circadian oscillators like those in the liver may be coupled to the SCN primarily through rhythmic behavior, such as feeding.

https://science.sciencemag.org/content/sci/291/5503/490.full.pdf

Entrainment of the Circadian Clock in the Liver by Feeding

Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus. Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases. Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature. At the level of individual tissues, thousands of genes are brought to unique phases through the actions of a local transcription/translation-based feedback oscillator and systemic cues. In this molecular clock, the proteins CLOCK and BMAL1 cause the transcription of genes which ultimately feedback and inhibit CLOCK and BMAL1 transcriptional activity. Finally, there are also other molecular circadian oscillators which can act independently of the transcription-based clock in all species which have been tested.

https://www.springer.com/cda/content/document/cda_downloaddocument/9783642259494-c1.pdf?SGWID=0-0-45-1387410-p174273964

Molecular components of the mammalian circadian clock

Circadian rhythms of mammals are entrained by light to follow the daily solar cycle (photoentrainment). To determine whether retinal rods and cones are required for this response, the effects of light on the regulation of circadian wheel-running behavior were examined in mice lacking these photoreceptors. Mice without cones (cl) or without both rods and cones (rdta/cl) showed unattenuated phase-shifting responses to light. Removal of the eyes abolishes this behavior. Thus, neither rods nor cones are required for photoentrainment, and the murine eye contains additional photoreceptors that regulate the circadian clock.

https://science.sciencemag.org/content/sci/284/5413/502.full.pdf

Regulation of Mammalian Circadian Behavior by Non-rod, Non-cone, Ocular Photoreceptors

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2897%2900287-1

A novel and ancient vertebrate opsin

The rod and cone cells of the retina are thought to mediate all of the light responses of the vertebrate eye But here we show that salmon vertebrate ancient (VA) opsin forms a functional photopigment in vitro, and is expressed in a subset of retinal horizontal and amacrine cells in vivo These results indicate that retinal photoreception is not restricted to just rod and cone cells

Novel retinal photoreceptors

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 a -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- a -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.

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

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1016/S0014-5793%2800%2901550-7

Sequence, genomic structure and tissue expression of carp (Cyprinus carpio L.) vertebrate ancient (VA) opsin

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