Non-visual Photoreception Research Articles

Shedding light on photoperiodism

In mammals, photoreception is restricted to the eye. By contrast, nonmammalian vertebrates possess photoreceptors in a wide array of extraocular tissues, including the pineal complex and brain (1). The identity of the deep brain photoreceptors has remained elusive. They continue to be the least studied of all nonvisual photoreceptor classes, although their existence in the vertebrates has been known for nearly a century. In this issue of PNAS, the Yoshimura laboratory presents a study that represents a significant stride toward identifying and characterizing encephalic photoreceptors (2).

Light Activation of the Phosphoinositide Cycle in Intrinsically Photosensitive Chicken Retinal Ganglion Cells

In vertebrates, intrinsically photosensitive retinal ganglion cells (ipRGCs) acting as nonvisual photoreceptors transmit environmental illumination information to the brain, regulating diverse non-image-forming tasks. The phototransduction cascade in chicken ipRGCs has been shown to resemble that of rhabdomeric photoreceptors and involves phospholipase C (PLC) activation. The current work was an investigation of the participation of the phosphoinositide (PIP) cycle in this mechanism and of whether changes in activities of inositol 1,4,5-trisphosphate (IP(3)) and PIP kinase are triggered by light. Primary cultures of Thy-1 immunopurified chicken embryonic RGCs were exposed to bright light pulses or kept in the dark, to assess intracellular Ca(2+) mobilization by Fluo-3 AM fluorescence microscopy, IP(3) levels, and enzymatic activities of diacylglycerol, phosphatidylinositol, and phosphatidylinositol phosphate kinases (DAGK, PIK, and PIPK, respectively), by radioactive assays. The presence of different melanopsins (Opn4m and Opn4x) and other photopigments was determined by RT-PCR and immunochemistry. Cultured RGCs expressing different nonvisual photopigments displayed a significant and rapid increase in IP(3) levels (1.3-fold) and Ca(2+) mobilization by light, which was reversed by administration of the PLC inhibitor U73122 (5 μM). Brief light pulses also caused a very rapid and transient activation of DAGK, PIK, and PIPK compared with that in the dark control. The results indicate for the first time that light stimulation of chicken RGC cultures activates the PIP cycle, causing an increase in intracellular levels of IP(3), changes in levels of phosphatidic acid, PIP, and PIP(2); and mobilization of Ca(2+).

PACAP-Deficient Mice Exhibit Light Parameter–Dependent Abnormalities on Nonvisual Photoreception and Early Activity Onset

BackgroundThe photopigment melanopsin has been suggested to act as a dominant photoreceptor in nonvisual photoreception including resetting of the circadian clock (entrainment), direct tuning or masking of vital status (activity, sleep/wake cycles, etc.), and the pupillary light reflex (PLR). Pituitary adenylate cyclase-activating polypeptide (PACAP) is exclusively coexpressed with melanopsin in a small subset of retinal ganglion cells and is predicted to be involved extensively in these responses; however, there were inconsistencies in the previous reports, and its functional role has not been well understood.Methodology/Principal FindingsHere we show that PACAP-deficient mice exhibited severe dysfunctions of entrainment in a time-dependent manner. The abnormalities in the mutant mice were intensity-dependent in phase delay and duration-dependent in phase advance. The knockout mice also displayed blunted masking, which was dependent on lighting conditions, but not completely lost. The dysfunctions of masking in the mutant mice were recovered by infusion of PACAP-38. By contrast, these mutant mice show a normal PLR. We examined the retinal morphology and innervations in the mutant mice, and no apparent changes were observed in melanopsin-immunoreactive cells. These data suggest that the dysfunctions of entrainment and masking were caused by the loss of PACAP, not by the loss of light input itself. Moreover, PACAP-deficient mice express an unusually early onset of activities, from approximately four hours before the dark period, without influencing the phase of the endogenous circadian clock.Conclusions/SignificanceAlthough some groups including us reported the abnormalities in photic entrainments in PACAP- and PAC1-knockout mice, there were inconsistencies in their results [1], [2], [3], [4]. The time-dependent dysfunctions of photic entrainment in the PACAP-knockout mice described in this paper can integrate the incompatible data in previous reports. The recovery of impaired masking by infusion of PACAP-38 in the mutant mice is the first direct evidence of the relationship between PACAP and masking. These results indicate that PACAP regulates particular nonvisual light responses by conveying parametric light information—that is, intensity and duration. The “early-bird” phenotype in the mutant mice originally reported in this paper supposed that PACAP also has a critical role in daily behavioral patterns, especially during the light-to-dark transition period.

Transcriptome Analysis of the Circadian Regulatory Network in the Coral Acropora millepora

Entrained circadian rhythms control many biological processes. These cyclical systems are synchronized by environmental signals but continue to free run for a considerable time when the synchronizing stimuli are removed. In scleractinian corals that reproduce by broadcast spawning, timing processes are essential in ensuring successful fertilization. It is not known whether spawn timing is regulated directly by environmental signals or if it is entrained and regulated by circadian or circalunar rhythms. The genetic components of circadian systems have been studied in considerable detail in microbes, plants, and animals. To identify potential participants in regulating scleractinian circadian systems, we have undertaken a bioinformatic analysis of the transcriptome of larvae of the coral Acropora millepora. Acropora contigs assembled from more than 600,000 sequencing reads from larval mRNA were searched via NCBI BLAST for matches to 24 key insect and mammalian circadian genes. Matches were found to all queried genes, with 22 of 24 of these matches having strong confidence levels. An Acropora match to the nonvisual photoreceptor melanopsin was also identified. The high level of conservation of circadian gene networks implies that the regulatory interactions between pathway members are also likely to be conserved and to regulate entrained processes in corals.

Short-wavelength sensitive nonvisual photoreceptors, their role in the pathological effects of night illumination

Event Abstract Back to Event Short-wavelength sensitive nonvisual photoreceptors, their role in the pathological effects of night illumination Bela Vigh1*, Maria J. Silva2, Vincze Csilla1, Attila Magyar1, Laszlo Szabo1 and Szel Agoston1 1 Department of Human Morphology and Developmental Biology, Semmelweis University, Hungary 2 Occupational Health Service, Centro Hospitalar de Lisboa Ocidental, Hospital Egas Moniz, Portugal Night-illumination disturbs normal diurnal periodicity thereby increases health risks e.g. gastro-intestinal or cardiovascular disorders, overweight, depression, disturbed sexual activity, brest cancer and colorectal cancer. Normal diurnal periodicity is driven by a genetical self-regulating clock-system present in several organs and having approximately 24 hour-long periods. This clock-system is synchronized by the suprachiasmatic nucleus and adapted to circadian and circannual light periods of the actual environment by nonvisual retinal, pineal and deep brain photoreceptors. The hormone melatonin produced by the pineal organ at night plays a fundamental role in the circadian and circannual periodic synchronization of biologic functions. Short wavelenght light was found to result a melatonin suppression and is an important factor producing pathological events caused by night illumination. In the present work we immunocytochemically localized blue-light sensitive molecules in nonvisual photo-receptors of various experimental animals. Cryptochrome-1, 2, pinopsin and OS-2 being short-wavelength-sensitive molecules were localized in retinal, pineal and deep encephalic photoreceptors. In the retina cryptochrome-2 was localized in nuclei of some photoreceptors, in the inner and outer granular layer, while cryptochrome-1 was found in the cytoplasm of a population of photoreceptors. Pinopsin and OS-2 were localized in the outer segment of some cone-like photoreceptors. The pineal organ representing the main nonvisual photoreceptor in submammalians has a retina-like structure. In the pineal photoreceptors – among other photoreceptor molecules – cryptochrome-2, pinopsin and OS-2 were found. Cryptochrome-2 and Pinopsin was also demonstrated in the suprachiasmatic nucleus being the main circadian pacemaker of the body and in the deep encephalic photoreceptors of lower vertebrates. Our immunocytochemical studies localize and confirm the presence of pinopsin, cryptochromes and OS-2 being blue light sensitive molecules in all nonvisual photoreceptor areas. These results strengthen the view that blue light-free-illumination or vearing blue-light-filtering glasses may reduce health risks caused by reduced melatonin secretion during night-illumination. As also high-intensity red light supresses melatonin secretion, filtered light at night should be of low intensity. Conference: 12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009. Presentation Type: Poster Presentation Topic: Behavioural neuroscience Citation: Vigh B, Silva MJ, Csilla V, Magyar A, Szabo L and Agoston S (2009). Short-wavelength sensitive nonvisual photoreceptors, their role in the pathological effects of night illumination. Front. Syst. Neurosci. Conference Abstract: 12th Meeting of the Hungarian Neuroscience Society. doi: 10.3389/conf.neuro.01.2009.04.131 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Mar 2009; Published Online: 04 Mar 2009. * Correspondence: Bela Vigh, Department of Human Morphology and Developmental Biology, Semmelweis University, Semmelweis, Hungary, vigh@ana2.sote.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Bela Vigh Maria J Silva Vincze Csilla Attila Magyar Laszlo Szabo Szel Agoston Google Bela Vigh Maria J Silva Vincze Csilla Attila Magyar Laszlo Szabo Szel Agoston Google Scholar Bela Vigh Maria J Silva Vincze Csilla Attila Magyar Laszlo Szabo Szel Agoston PubMed Bela Vigh Maria J Silva Vincze Csilla Attila Magyar Laszlo Szabo Szel Agoston Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Gq‐coupled Rhodopsin Subfamily Composed of Invertebrate Visual Pigment and Melanopsin†

Rhodopsins (rhodopsins and their related photopigments) are phylogenetically classified into at least seven subfamilies, which are also roughly discriminated by molecular function. The Gq-coupled rhodopsin subfamily, members of which activate the Gq type G protein upon light absorption, contains pigments which underlie both visual and nonvisual physiologic functions. Gq-coupled visual pigments have been found in the rhabdomeric photoreceptor cells of varied protostomes, and those of molluskans and arthropods have been extensively investigated. Recently, a novel photopigment, melanopsin, and its homologs have been identified in varied vertebrates. In mammals, melanopsin is localized in retinal ganglion cells and is involved in nonvisual systems, including circadian entrainment and pupillary light responses. More recently, we discovered a melanopsin homolog in amphioxus, the closest living invertebrate to vertebrates. Amphioxus melanopsin is localized in putative nonvisual photoreceptor cells with rhabdomeric morphology and exhibits molecular properties almost identical to those of invertebrate Gq-coupled visual pigments. The localization and properties of amphioxus melanopsin bridged the functional and evolutionary gap between invertebrate Gq-coupled visual pigments and vertebrate circadian photopigment melanopsins. Research into the Gq-coupled rhodopsin subfamily, especially invertebrate melanopsins, will provide an opportunity to investigate the evolution of various physiologic functions, based on orthologous genes, during animal evolution.

34.2. Comparative characterization of bistable pigments in visual and non-visual photoreception

34.2. Comparative characterization of bistable pigments in visual and non-visual photoreception

Mitochondrial Dysfunction as the Molecular Basis of Bipolar Disorder

Multiple lines of evidence, such as impaired energy metabolism in the brain detected by magnetic resonance spectroscopy, a possible role of maternal inheritance, co-morbidity with mitochondrial diseases, the effects of mood stabilisers on mitochondria, increased mitochondrial DNA (mtDNA) deletion in the brain, and association with mtDNA mutations/polymorphisms or nuclear-encoded mitochondrial genes, suggest that mitochondrial dysfunction is an important component of bipolar disorder. Global reduction of mitochondria-related gene expression in the postmortem brains of patients with bipolar disorder may also be an indicator, but such findings are affected by sample pH and thus need to be interpreted with caution. A recently developed animal model carrying mtDNA deletion in neurons suggested that accumulation of mtDNA deletions causes bipolar disorder-like phenotypes. The next step in the study of mitochondrial dysfunction in bipolar disorder should be clarification of how mitochondrial dysfunction, a nonspecific risk factor, can cause specific symptoms of bipolar disorder. Two hypothetical mechanisms are mtDNA neuroplasticity and nonvisual photoreception impairment. Further study of mitochondrial dysfunction in bipolar disorder is expected to be useful for the development of new mood stabilisers.

An invertebrate‐like phototransduction cascade mediates light detection in the chicken retinal ganglion cells

Prebilaterian animals perceived ambient light through nonvisual rhabdomeric photoreceptors (RPs), which evolved as support of the chordate visual system. In vertebrates, the identity of nonvisual photoreceptors and the phototransduction cascade involved in nonimage forming tasks remain uncertain. We investigated whether chicken retinal ganglion cells (RGCs) could be nonvisual photoreceptors and the nature of the photocascade involved. We found that primary cultures of chicken embryonic RGCs express such RP markers as transcription factors Pax6 and Brn3, photopigment melanopsin, and G-protein q but not markers for ciliary photoreceptors (alpha-transducin and Crx). To investigate the photoreceptive capability of RGCs, we assessed the direct effect of light on 3H-melatonin synthesis in RGC cultures synchronized to 12:12 h light-dark cycles. In constant dark, RGCs displayed a daily variation in 3H-melatonin levels peaking at subjective day, which was significantly inhibited by light. This light effect was further increased by the chromophore all-trans-retinal and suppressed by specific inhibitors of the invertebrate photocascade involving phosphoinositide hydrolysis (100 microM neomycin; 5 microM U73122) and Ca2+ mobilization (10 mM BAPTA; 1 mM lanthanum). The results demonstrate that chicken RGCs are intrinsically photosensitive RPs operating via an invertebrate-like phototransduction cascade, which may be responsible for early detection of light before vision occurs.

Nonvisual light responses in the Rpe65 knockout mouse: Rod loss restores sensitivity to the melanopsin system

Intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin (OPN4), together with rods and cones, provide light information driving nonvisual light responses. We examined nonvisual photoreception in mice lacking RPE65, a protein that is required for regeneration of visual chromophore in rods and cones. Although Rpe65 knockouts retain a small degree of rod function, we show here that circadian phase shifting responses in Rpe65(-/-) mice are attenuated far beyond what has been reported for rodless/coneless mice. Furthermore, the number of melanopsin-immunoreactive perikarya and the extent of dendritic arborizations were decreased in Rpe65 knockout mice compared with controls. To assess the nature of the photoreceptive defect in Rpe65 null mice, we eliminated either rods or melanopsin from Rpe65(-/-) retinas by generating (i) Rpe65(-/-) mice carrying a transgene (rdta) that results in selective elimination of rods and (ii) double knockout Rpe65(-/-);Opn4(-/-) mice. Surprisingly, rod loss in Rpe65 knockout mice resulted in restoration of circadian photosensitivity. Normal photoentrainment was lost in Rpe65(-/-);Opn4(-/-) mice, and, instead, a diurnal phenotype was observed. Our findings demonstrate that RPE65 is not required for ipRGC function but reveal the existence of a mechanism whereby rods may influence the function of ipRGCs.

Photoreceptors in Vertebrates

Cryptochromes function as photoreceptors for circadian rhythm entrainment in insects and in plants. Tu et al. provide evidence that cryptochromes may function similarly in vertebrates. The isolated iris sphincter muscle from chicks will constrict strongly and rapidly in light and redilate in the dark in the absence of any extrinsic neural input. The characteristics of the photopigment underlying this activity did not fit the template for an opsin photoreceptor, but instead matched the known absorption spectra for cryptochromes. Antisense knockdown of cryptochromes, but not melanopsin, caused a proportional loss of intrinsic iris photosensitivity. D. C. Tu, M. L. Batten, K. Palczewski, R. N. Van Gelder, Nonvisual photoreception in the chick iris. Science 306 , 129-131 (2004). [Abstract] [Full Text]

Expression of melanopsin during development of the rat retina

There is accumulating evidence that the new opsin-like protein, melanopsin, in adult rodents functions as non-visual photoreceptor. Here we report using immunohistochemistry and in situ hybridisation that melanopsin during rat retinal development is expressed already at prenatal day 18 in cells of the inner neuroblast layer. Perinatally the melanopsin positive cells increase in number and migrate towards the ganglion cell layer. During early postnatal development a melanopsin immunoreactive dendritic network is formed in the inner plexiform layer. Melanopsin is exclusively expressed in PACAP-containing cells which in adults become the retinal ganglion cells constituting the retinohypothalamic tract. The early expression of melanopsin argues for a photoreceptor role in the developing retinohypothalamic tract which is functional as early as the first day after birth.

Further evidence for the role of cryptochromes in retinohypothalamic photoreception/phototransduction

Cryptochrome is a blue-light absorbing photopigment that has been proposed to act as a photoreceptor for a variety of nonvisual light-responsive tasks. While mouse models have suggested an important role for cryptochrome in nonvisual photoreception, there are no biochemical data demonstrating the functional photoreceptive capability of cryptochrome in mice. There are two models that describe the effect of cryptochrome on light responsive events: (1) cryptochrome is a photoreceptor or (2) cryptochrome is required for either normal phototransduction from the retina to the brain or for normal transcriptional regulation in the brain, irrespective of light. To differentiate between these two models, we have examined the integrity of the regulatory mechanism of c-fos in cryptochromeless cell lines and in the suprachiasmatic nucleus (SCN) of cryptochromeless mice. Photoinduction of c-fos mRNA in the SCN can be used as a marker for circadian photoreception/phototransduction and it is drastically reduced in mice lacking cryptochromes. Our results indicate that light-independent transcription regulatory system of c-fos is normal in cryptochromeless mice and that the reduced c-fos light responsiveness in the absence of cryptochromes is due to a loss of photoreceptor function.

Expression of the blue-light receptor cryptochrome in the human retina.

To analyze the patterns of expression of the cryptochromes, CRY1 and CRY2, in the human retina and to correlate expression of these putative blue-light receptors with nonvisual photoreceptor localization. CRY1 and CRY2 mRNA expression was analyzed in 4-mm diameter punches of macula and midperipheral human retina by quantitative RT-PCR. CRY2 protein expression was examined by immunohistochemistry in cross sections of human retina, and its subcellular localization was determined by immunoblot analysis of fractionated human retinal extracts. CRY2 mRNA was 11 times more abundant than CRY1 throughout adult human retina. CRY2 immunoreactivity was detected in most cells in the ganglion cell layer (GCL) and in a subset of cells in the inner nuclear layer (INL) in both the macula and periphery. Immunoperoxidase staining further revealed that CRY2 was localized throughout the cytoplasm of cells in the GCL as well as within nuclei. This intracellular localization of CRY2 was confirmed by immunoblot analysis of fractionated human retinal extracts. Photopigments governing circadian photoreception have been localized to the inner retina. The relative abundance of CRY2 transcripts, coupled with CRY2 localization to the inner retina, supports a photoreceptive role for CRY2 in human retina. Furthermore, the discovery that CRY2 is also localized within the cytoplasm of some cells in the GCL, suggests it may perform a function separate from its known nuclear role in the transcriptional feedback loop underlying the molecular circadian clock.

A Broad Role for Melanopsin in Nonvisual Photoreception

The rod and cone photoreceptors that mediate visual phototransduction in mammals are not required for light-induced circadian entrainment, negative masking of locomotor activity, suppression of pineal melatonin, or the pupillary light reflex. The photopigment melanopsin has recently been identified in intrinsically photosensitive retinal ganglion cells (RGCs) that project to the suprachiasmatic nucleus (SCN), intergeniculate leaflet (IGL), and olivary pretectal nucleus, suggesting that melanopsin might influence a variety of irradiance-driven responses. We have found novel projections from RGCs that express melanopsin mRNA to the ventral subparaventricular zone (vSPZ), a region involved in circadian regulation and negative masking, and the sleep-active ventrolateral preoptic nucleus (VLPO) and determined the subsets of melanopsin-expressing RGCs that project to the SCN, the pretectal area (PTA), and the IGL division of the lateral geniculate nucleus (LGN). Melanopsin was expressed in the majority of RGCs that project to the SCN, vSPZ, and VLPO and in a subpopulation of RGCs that innervate the PTA and the IGL but not in RGCs projecting to the dorsal LGN or superior colliculus. Two-thirds of RGCs containing melanopsin transcript projected to each of the SCN and contralateral PTA, and one-fifth projected to the ipsilateral IGL. Double-retrograde tracing from the SCN and PTA demonstrated a subpopulation of RGCs projecting to both sites, most of which contained melanopsin mRNA. Our results suggest that melanopsin expression defines a subset of RGCs that play a broad role in the regulation of nonvisual photoreception, providing collateralized projections that contribute to circadian entrainment, negative masking, the regulation of sleep-wake states, and the pupillary light reflex.

Melanopsin is required for non-image-forming photic responses in blind mice.

Although mice lacking rod and cone photoreceptors are blind, they retain many eye-mediated responses to light, possibly through photosensitive retinal ganglion cells. These cells express melanopsin, a photopigment that confers this photosensitivity. Mice lacking melanopsin still retain nonvisual photoreception, suggesting that rods and cones could operate in this capacity. We observed that mice with both outer-retinal degeneration and a deficiency in melanopsin exhibited complete loss of photoentrainment of the circadian oscillator, pupillary light responses, photic suppression of arylalkylamine-N-acetyltransferase transcript, and acute suppression of locomotor activity by light. This indicates the importance of both nonvisual and classical visual photoreceptor systems for nonvisual photic responses in mammals.

Nonvisual Photoreceptors in Arthropods with Emphasis on Their Putative Role as Receptors of Natural Zeitgeber Stimuli

In various insect and arachnid species, three different types of photoreceptors that do not serve image processing have been discovered and analyzed by means of neurobiological methods: They can be found for example: (1) as lamina and lobula organs (LaOs and LoOs) next to the optic neuropils in the optic lobes of holo‐ and hemimetabolous insects; (2) inside the last ganglia of the cord of the scorpion and a marine midge; and (3) as modified visual photoreceptors in metamorphosized larval stemmata and the lateral eyes of scorpions, which have been compound eyes in fossil scorpion relatives. Immunocytology with various antibodies against proteins of the phototransduction cascade, the rhabdom turnover cycle and neurotransmitters of afferent and efferent pathways, was combined with light‐ and ultrastructural investigations in well‐defined adaptational states, in order to study their photoreceptive function and neuronal wiring. Pilot chronobiological experiments with a newly developed twilight simulating lamp, behavioral studies, and model calculations provide evidence that these photoreceptors may well serve a role in the complex task of detecting time cues out of natural dawn and dusk.“…Clearly more work will be necessary before truly informed judgements can be made about the functional significance of the diversity in photoreception for entrainment. A first step will be the precise identification of photoreceptors and investigations of the mechanisms of transduction, processing and transmission of temporal information provided by the daily light cycle.…” ()

Nonvisual photoreceptors of the deep brain, pineal organs and retina.

The role of the nonvisual photoreception is to synchronise periodic functions of living organisms to the environmental light periods in order to help survival of various species in different biotopes. In vertebrates, the so-called deep brain (septal and hypothalamic) photoreceptors, the pineal organs (pineal- and parapineal organs, frontal- and parietal eye) and the retina (of the "lateral" eye) are involved in the light-based entrain of endogenous circadian clocks present in various organs. In humans, photoperiodicity was studied in connection with sleep disturbances in shift work, seasonal depression, and in jet-lag of transmeridional travellers. In the present review, experimental and molecular aspects are discussed, focusing on the histological and histochemical basis of the function of nonvisual photoreceptors. We also offer a view about functional changes of these photoreceptors during pre- and postnatal development as well as about its possible evolution. Our scope in some points is different from the generally accepted views on the nonvisual photoreceptive systems. The deep brain photoreceptors are hypothalamic and septal nuclei of the periventricular cerebrospinal fluid (CSF)-contacting neuronal system. Already present in the lancelet and representing the most ancient type of vertebrate nerve cells ("protoneurons"), CSF-contacting neurons are sensory-type cells sitting in the wall of the brain ventricles that send a ciliated dendritic process into the CSF. Various opsins and other members of the phototransduction cascade have been demonstrated in telencephalic and hypothalamic groups of these neurons. In all species examined so far, deep brain photoreceptors play a role in the circadian and circannual regulation of periodic functions. Mainly called pineal "glands" in the last decades, the pineal organs actually represent a differentiated form of encephalic photoreceptors. Supposed to be intra- and extracranially outgrown groups of deep brain photoreceptors, pineal organs also contain neurons and glial elements. Extracranial pineal organs of submammalians are cone-dominated photoreceptors sensitive to different wavelengths of light, while intracranial pineal organs predominantly contain rod-like photoreceptor cells and thus scotopic light receptors. Vitamin B-based light-sensitive cryptochromes localized immunocytochemically in some pineal cells may take part in both the photoreception and the pacemaker function of the pineal organ. In spite of expressing phototransduction cascade molecules and forming outer segment-like cilia in some species, the mammalian pineal is considered by most of the authors as a light-insensitive organ. Expression of phototransduction cascade molecules, predominantly in young animals, is a photoreceptor-like characteristic of pinealocytes in higher vertebrates that may contribute to a light-percepting task in the perinatal entrainment of rhythmic functions. In adult mammals, adrenergic nerves--mediating daily fluctuation of sympathetic activity rather than retinal light information as generally supposed--may sustain circadian periodicity already entrained by light perinatally. Altogether three phases were supposed to exist in pineal entrainment of internal pacemakers: an embryological synchronization by light and in viviparous vertebrates by maternal effects (1); a light-based, postnatal entrainment (2); and in adults, a maintenance of periodicity by daily sympathetic rhythm of the hypothalamus. In addition to its visual function, the lateral eye retina performs a nonvisual task. Nonvisual retinal light perception primarily entrains genetically-determined periodicity, such as rod-cone dominance, EEG rhythms or retinomotor movements. It also influences the suprachiasmatic nucleus, the primary pacemaker of the brain. As neither rods nor cones seem to represent the nonvisual retinal photoreceptors, the presence of additional photoreceptors has been supposed. Cryptochrome 1, a photosensitive molecule identified in retinal nerve cells and in a subpopulation of retinal photoreceptors, is a good candidate for the nonvisual photoreceptor molecule as well as for a member of pacemaker molecules in the retina. When comparing various visual and nonvisual photoreceptors, transitory, "semi visual" (directional) light-perceptive cells can be detected among them, such as those in the parietal eye of reptiles. Measuring diffuse light intensity of the environment, semivisual photoreceptors also possess some directional light perceptive capacity aided by complementary lens-like structures, and screening pigment cells. Semivisual photoreception in aquatic animals may serve for identifying environmental areas of suitable illumination, or in poikilotermic terrestrial species for measuring direct solar irradiation for thermoregulation. As directional photoreceptors were identified among nonvisual light perceptive cells in the lancelet, but eyes are lacking, an early appearance of semivisual function, prior to a visual one (nonvisual --> semivisual --> visual?) in the vertebrate evolution was supposed.

The spatio-temporal pattern of photoreceptor degeneration in the aged rd/rd mouse retina.

Photoreceptor degeneration in the retina of the rd/rd (retinal degeneration) mice has been studied using immunocytochemistry with antisera against cone- and rod-opsin. The rd/rd mice exhibited different regional specific rates of degeneration for rods and cones. As early as postnatal day 25, cells labelled with the rod-opsin and cone-opsin antisera disappeared preferently from the central retina. Whereas in the inferior half of the retina, degeneration subsequently proceeded towards the periphery, this did not occur in the dorsal hemisphere. By the age of 100 days, many cells immunoreactive for the cone-opsin antiserum and a few cells immunoreactive for the rod-opsin antiserum were located in an area of the dorsal retina. The ventral retina lacked labelled elements at this age. Finally, rd/rd mice at one year or 600 days of age contained a similar number of cone-opsin immunopositive cells (approximately 2000-2800 cells), occupying almost the same area in the retina as that found at 100 days of age. A photoreceptor candidate for the entrainment of non-visual photoreception probably remains in the cone population in aged rd/rd mice.

Photopigments and circadian systems of vertebrates

In the retinal degeneration (rd) mouse the absence of rod cells and the progressive loss of cones does not result in a decrease in circadian phase shifting responses to light. By contrast, rd/rd mice are unable to perform simple visual tasks. In addition, rodless transgenic mice, and mice homozygous for the retinal degeneration slow (rds) mutation, show unattenuated circadian responses to light. Collectively these data suggest that cone cells lacking outer segments are sufficient to maintain normal circadian responses to light, or some unidentified photoreceptor within the retina. An action spectrum for circadian responses to light in rd/rd mice, and molecular analysis of retinally degenerate mice and blind mole rat eyes, suggests the involvement of a mid-to-long wavelength sensitive cone opsin in photoentrainment. Extraocular photoreceptors of non-mammalian vertebrates are currently being analyzed in order to identify functional and evolutionary similarities between visual and non-visual photoreceptor systems.