Extraocular Photoreception and Circadian Entrainment in Nonmammalian Vertebrates

In mammals both the regulation of circadian rhythms and photoperiodic responses depend exclusively upon photic information provided by the lateral eyes; however, nonmammalian vertebrates can also rely on multiple extraocular photoreceptors to perform the same tasks. Extraocular photoreceptors include deep brain photoreceptors located in several distinct brain sites and the pineal complex, involving intracranial (pineal and parapineal) and extracranial (frontal organ and parietal eye) components. This review updates the research field of the most recent acquisitions concerning the roles of extraocular photoreceptors on circadian physiology and behavior, particularly photic entrainment and sun compass orientation.     

Extraocular Photoreception and Circadian Entrainment in Nonmammalian Vertebrates

In mammals both the regulation of circadian rhythms and photoperiodic responses depend exclusively upon photic information provided by the lateral eyes; however, nonmammalian vertebrates can also rely on multiple extraocular photoreceptors to perform the same tasks. Extraocular photoreceptors include deep brain photoreceptors located in several distinct brain sites and the pineal complex, involving intracranial (pineal and parapineal) and extracranial (frontal organ and parietal eye) components. This review updates the research field of the most recent acquisitions concerning the roles of extraocular photoreceptors on circadian physiology and behavior, particularly photic entrainment and sun compass orientation.     

Extraocular photoreception and circadian entrainment in nonmammalian vertebrates

In mammals both the regulation of circadian rhythms and photoperiodic responses depend exclusively upon photic information provided by the lateral eyes; however, nonmammalian vertebrates can also rely on multiple extraocular photoreceptors to perform the same tasks. Extraocular photoreceptors include deep brain photoreceptors located in several distinct brain sites and the pineal complex, involving intracranial (pineal and parapineal) and extracranial (frontal organ and parietal eye) components. This review updates the research field of the most recent acquisitions concerning the roles of extraocular photoreceptors on circadian physiology and behavior, particularly photic entrainment and sun compass orientation.     

No evidence for extraocular photoreceptors in the circadian system of the Syrian hamster.

Campbell and Murphy reported recently that 3 h of bright light (13,000 lux) exposure to the area behind the knee caused phase shifts of the circadian rhythms of both body temperature and saliva melatonin in humans. The authors tested the hypothesis that extraocular photoreception is also involved in the circadian system of the Syrian hamster. Hamsters were bilaterally enucleated (eyes removed), and their backs were shaved. Hamsters with stable free-running rhythms in constant darkness were exposed to direct sunlight for 1 or 3 hours during their subjective night. Intact (control) animals showed phase shifts as expected, but the locomotor activity of enucleated animals was unaffected by the exposure to sunlight. The authors also measured the pineal melatonin content after exposure to sunlight. Pineal melatonin content in intact animals declined markedly as expected, but no decline was observed in the enucleated hamsters. The authors conclude that extraocular phototransduction is not capable of shifting the phase of the hamster's locomotor activity rhythm or of suppressing pineal melatonin synthesis.     

An Unexpected Diversity of Photoreceptor Classes in the Longfin Squid,Doryteuthis pealeii

Cephalopods are famous for their ability to change color and pattern rapidly for signaling and camouflage. They have keen eyes and remarkable vision, made possible by photoreceptors in their retinas. External to the eyes, photoreceptors also exist in parolfactory vesicles and some light organs, where they function using a rhodopsin protein that is identical to that expressed in the retina. Furthermore, dermal chromatophore organs contain rhodopsin and other components of phototransduction (including retinochrome, a photoisomerase first found in the retina), suggesting that they are photoreceptive. In this study, we used a modified whole-mount immunohistochemical technique to explore rhodopsin and retinochrome expression in a number of tissues and organs in the longfin squid, Doryteuthis pealeii. We found that fin central muscles, hair cells (epithelial primary sensory neurons), arm axial ganglia, and sucker peduncle nerves all express rhodopsin and retinochrome proteins. Our findings indicate that these animals possess an unexpected diversity of extraocular photoreceptors and suggest that extraocular photoreception using visual opsins and visual phototransduction machinery is far more widespread throughout cephalopod tissues than previously recognized.     

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.     

Tales from the crypt(ochromes)

Cryptochromes are a family of flavoproteins found in organisms ranging from Arabidopsis to man. Across phylogeny, these proteins have been used for pleiotropic functions ranging from blue-light-dependent development in plants and blue-light-mediated phase shifting of the circadian clock in insects to a core circadian clock component in mammals. Review of the roles of cryptochromes in model organisms reveals several common themes: Multiple cryptochrome family members within individual organisms have redundant functions; cryptochromes used in photic entrainment pathways of the circadian clock are partially redundant with other photopigments; and cryptochromes may function in circadian phototransduction and core clock mechanisms in the same organism, with different functions in different tissues. The present review summarizes recent research on the functions of cryptochrome in the circadian timekeeping and photic entrainment pathways.     

Photoreception for circadian, neuroendocrine, and neurobehavioral regulation

In the art and science of lighting, four traditional objectives have been to provide light that: 1) is optimum for visual performance; 2) is visually comfortable; 3) permits aesthetic appreciation of the space; and 4) conserves energy. Over the past 25 years, it has been demonstrated that there are nonvisual, systemic effects of light in healthy humans. Furthermore, light has been used to successfully treat patients with selected affective and sleep disorders as well as healthy individuals who have circadian disruption due to shift work, transcontinental jet travel, or space flight. Recently, there has been an upheaval in the understanding of photoreceptive input to the circadian system of humans and other mammals. Analytical action spectra in rodents, primates, and humans have identified 446-484 nm (predominantly the blue part of the spectrum) as the most potent wavelength region for neuroendocrine, circadian, and neurobehavioral responses. Those studies suggested that a novel photosensory system, distinct from the visual rods and cones, is primarily responsible for this regulation. Studies have now shown that this new photosensory system is based on a small population of widely dispersed retinal ganglion cells that are intrinsically responsive to light, and project to the suprachiasmatic nuclei and other nonvisual centers in the brain. These light-sensitive retinal ganglion cells contain melanopsin, a vitamin A photopigment that mediates the cellular phototransduction cascade. Although light detection for circadian and neuroendocrine phototransduction seems to be mediated principally by a novel photosensory system in the eye, the classic rod and cone photoreceptors appear to play a role as well. These findings are important in understanding how humans adapt to lighting conditions in modern society and will provide the basis for major changes in future architectural lighting strategies.     

The circadian timing system and reproduction in mammals.

Circadian systems in a wide variety of organisms all appear to include three basic components: 1) biological oscillators that maintain a self-sustained circadian periodicity in the absence of environmental time cues; 2) input pathways that convey environmental information, especially light cues, that can entrain the circadian oscillations to local time; and 3) output pathways that drive overt circadian rhythms, such as the rhythms of locomotor activity and a variety of endocrine rhythms. In mammals, the circadian system is employed in the regulation of reproductive physiology and behavior in two very important ways. 1) In some species, there is a strong circadian component in the timing of ovulation and reproductive behavior, ensuring that these events will occur at a time when the animal is most likely to encounter a potential mate. 2) Many mammals exhibit seasonal reproductive rhythms that are largely under photoperiod regulation; in these species, the circadian system and the pineal gland are crucial components of the mechanism that is used to measure day length. The rhythm of pineal melatonin secretion is driven by a neural pathway that includes the circadian oscillator(s) in the suprachiasmatic nuclei. Melatonin is secreted at night in all mammals, and the duration of each nocturnal episode of melatonin secretion is inversely related to day length. The pineal melatonin rhythm appears to serve as an internal signal that represents day length and that is capable of regulating a variety of seasonal variations in physiology and behavior.     

Quantifying light-dependent circadian disruption in humans and animal models

Although circadian disruption is an accepted term, little has been done to develop methods to quantify the degree of disruption or entrainment individual organisms actually exhibit in the field. A variety of behavioral, physiological and hormonal responses vary in amplitude over a 24-h period and the degree to which these circadian rhythms are synchronized to the daily light–dark cycle can be quantified with a technique known as phasor analysis. Several studies have been carried out using phasor analysis in an attempt to measure circadian disruption exhibited by animals and by humans. To perform these studies, species-specific light measurement and light delivery technologies had to be developed based upon a fundamental understanding of circadian phototransduction mechanisms in the different species. When both nocturnal rodents and diurnal humans, experienced different species-specific light–dark shift schedules, they showed, based upon phasor analysis of the light–dark and activity–rest patterns, similar levels of light-dependent circadian disruption. Indeed, both rodents and humans show monotonically increasing and quantitatively similar levels of light-dependent circadian disruption with increasing shift-nights per week. Thus, phasor analysis provides a method for quantifying circadian disruption in the field and in the laboratory as well as a bridge between ecological measurements of circadian entrainment in humans and parametric studies of circadian disruption in animal models, including nocturnal rodents.     

Gene duplication and complex circadian clocks in mammals

The circadian clock arose early in the evolution of life to enable organisms to adapt to the cycle of day and night. Recently, the extent and importance of circadian regulation of behaviour and physiology has come to be more fully realized. Core molecular cogs of circadian oscillators appear to have been largely conserved between such diverse organisms as Drosophila melanogaster and mammals. However, gene duplication events have produced multiple copies of many clock genes in mammals. Recent studies suggest that genome duplication has lead to increased circadian complexity and local tissue regulation. This has important implications for temporal regulation of behaviour via multiple clocks in the central nervous system, and also extends to the local physiology of major body organs and tissues.     

Mammalian photoperiodic system: formal properties and neuroendocrine mechanisms of photoperiodic time measurement

Photoperiodism is a process whereby organisms are able to use both absolute measures of day length and the direction of day length change as a basis for regulating seasonal changes in physiology and behavior. The use of day length cues allows organisms to essentially track time-of-year and to "anticipate" relatively predictable annual variations in important environmental parameters. Thus, adaptive types of seasonal biological changes can be molded through evolution to fit annual environmental cycles. Studies of the formal properties of photoperiodic mechanisms have revealed that most organisms use circadian oscillators to measure day length. Two types of paradigms, designated as the external and internal coincidence models, have been proposed to account for photoperiodic time measurement by a circadian mechanism. Both models postulate that the timing of light exposure, rather than the total amount of light, is critical to the organism's perception of day length. In mammals, a circadian oscillator(s) in the suprachiasmatic nucleus of the hypothalamus receives photic stimuli via the retinohypothalamic tract. The circadian system regulates the rhythmic secretion of the pineal hormone, melatonin. Melatonin is secreted at night, and the duration of secretion varies in inverse relation to day length; thus, photoperiod information is "encoded" in the melatonin signal. The melatonin signal is presumably "decoded" in melatonin target tissues that are involved in the regulation of a variety of seasonal responses. Variations in photoperiodic response are seen not only between species but also between breeding populations within a species and between individuals within single breeding populations. Sometimes these variations appear to be the result of differences in responsiveness to melatonin; in other cases, variations in photoperiod responsiveness may depend on differences in patterns of melatonin secretion related to circadian variation. Sites of action for melatonin in mammals are not yet well characterized, but potential targets of particular interest include the pars tuberalis of the pituitary gland and the suprachiasmatic nuclei. Both these sites exhibit uptake of radiolabeled melatonin in various species, and there is some evidence for direct action of melatonin at these sites. However, it appears that there are species differences with respect to the importance and specific functions of various melatonin target sites.     

微小RNA和长链非编码RNA介导的昼夜节律调控

非编码RNA(ncRNA)是生物体细胞内一类重要的调控分子,其介导的昼夜节律调控日益受到研究者的重视。本文主要以黑腹果蝇Drosophila melanogaster和哺乳动物的相关研究为背景,阐述了微小RNA(miRNA)和长链非编码RNA(lncRNA)对昼夜节律的调控。miRNA介导的昼夜节律调控包括:生物体内(尤其是钟神经元中)具有节律性表达的miRNA;输入系统和miRNA存在相互调控,这主要是通过光照这个授时因子起作用;miRNA可直接调控核心振荡器,还可以调控其他基因而间接影响到核心振荡器;miRNA对输出系统的调控主要集中在代谢取食节律、运动节律、睡眠节律等。昼夜节律可调控lncRNA的表达,同时lncRNA也可调控昼夜节律,且lncRNA对基因调控范围广,作用机制复杂,这些都具有广阔的研究前景。本文将有助于进一步深入研究ncRNA对昼夜节律的调控。     

Circadian organization in Aplysia californica.

Substantial progress has been made in unraveling the organization of the circadian system of Aplysia californica. There are at least three circadian pacemakers in Aplysia. One has been localized in each eye and a third lies outside the eyes. Removal of the eyes disrupts the free-running locomotor activity rhythm; however, an extraocular oscillator can mediate a free-running rhythm in some eyeless animals. Although photoreceptors sufficient for entrainment of the ocular oscillator have been localized in the retina, photoreceptors outside the eyes are capable of "driving" a diurnal rhythm of locomotor activity and may also influence entrainment of ocular pacemakers. Finally, attention has been focused on the optic nerve as a coupling pathway between various parts of the system. The evidence suggests that information transmitted in the optic nerves is involved in entrainment of the ocular pacemaker by light, and in ocular control of the locomotor activity rhythm.     

Does a biological clock reside in the eye of quail?

The site (intra- vs. extraocular) of the circadian clock driving an ocular melatonin rhythm in Japanese quail was investigated by alternately covering the left and right eyes of individual quail, otherwise held in constant light (LL), for 12-hr periods. This procedure exposed each eye to a light-dark (LD) 12:12 light cycle 180 degrees (12 hr) out of phase with the LD 12:12 light cycle experienced by the other eye. This protocol entrained the melatonin rhythm in the left eye of quail 180 degrees out of phase with the rhythm expressed in the right eye. These results are compatible with the hypothesis that an independent light-entrainable circadian pacemaker resides in each eye; they are incompatible with the hypothesis that a single (or functionally single) extraocular pacemaker drives the ocular melatonin rhythm in both eyes. However, the results are also compatible with a model in which two independent extraocular circadian pacemakers, each with an exclusive photic input from one eye, drive the ocular melatonin rhythm.     

Additivity in murine circadian phototransduction

Additivity in the circadian phototransduction system of the mouse has not been tested directly. Because of this, accurate prediction of circadian phase shifts elicited by polychromatic light stimuli cannot be derived from the results of studies using monochromatic light stimuli. This limitation also makes it impossible to deduce the relative contributions of the photoreceptive mechanisms (rods, cones and melanopsin-containing retinal ganglion cells) underlying circadian phototransduction in the mouse. Using nearly monochromatic light stimuli of different spectral composition, and combinations thereof, we demonstrated that murine circadian phototransduction exhibits additivity. Based on the locomotor activity phase shifts elicited by these stimuli, we developed the first quantitative assessment of the relative contributions of conventional and novel photoreceptive mechanisms for circadian functioning in the mouse.     

Photons, clocks, and consciousness

Light profoundly impacts human consciousness through the stimulation of the visual system and powerfully regulates the human circadian system, which, in turn, has a broad regulatory impact on virtually all tissues in the body. For more than 25 years, the techniques of action spectroscopy have yielded insights into the wavelength sensitivity of circadian input in humans and other mammalian species. The seminal discovery of melanopsin, the photopigment in intrinsically photosensitive retinal ganglion cells, has provided a significant turning point for understanding human circadian phototransduction. Action spectra in humans show that the peak wavelength sensitivity for this newly discovered sensory system is within the blue portion of the spectrum. This is fundamentally different from the three-cone photopic visual system, as well as the individual rod and cone photoreceptor peaks. Studies on rodents, nonhuman primates, and humans indicate that despite having a different wavelength fingerprint, these classic visual photoreceptors still provide an element of input to the circadian system. These findings open the door to innovations in light therapy for circadian and affective disorders, as well as possible architectural light applications.     

Non-ocular circadian oscillators and photoreceptors modulate long term memory formation in Aplysia

In Aplysia californica, memory formation for long-term sensitization (LTS) and for a more complex type of associative learning, learning that food is inedible (LFI), is modulated by a circadian clock. For both types of learning, formation of long-term memory occurs during the day and significantly less during the night. Aplysia eyes contain a well-characterized circadian oscillator that is strongly coupled to the locomotor activity rhythm. Thus, the authors hypothesized that the ocular circadian oscillator was responsible for the circadian modulation of LFI and LTS. To test this hypothesis, they investigated whether the eyes were necessary for circadian modulation of LFI and LTS. Eyeless animals trained during the subjective day and tested 24 h later demonstrated robust long-term memory for both LFI and LTS, while eyeless animals trained and tested during the subjective night showed little or no memory for LFI or LTS. The amplitude of the rhythm of modulation in eyeless animals was similar to that of intact Aplysia, suggesting that extraocular circadian oscillators were mainly responsible for the circadian rhythms in long-term memory formation. Next, the authors investigated whether the eyes played a role in photic entrainment for circadian regulation of long-term memory formation. Eyeless animals were exposed to a reversed LD cycle for 7 days and then trained and tested for long-term memory using the LFI paradigm. Eyeless Aplysia formed significant long-term memory when trained during the projected shifted day but not during the projected shifted night. Thus, the extraocular circadian oscillator responsible for the rhythmic modulation of long-term memory formation can be entrained by extraocular photoreceptors.     

High-intensity red light suppresses melatonin

Early studies on rodents indicated that the long-wavelength portion of the spectrum (orange- and red-appearing light) could influence circadian and neuroendocrine responses. Since then, both polychromatic and analytic action spectra in various rodent species have demonstrated that long-wavelength light is very weak, if not entirely inactive, for regulating neurobehavioral responses. Since testing of monochromatic light wavelengths above 600 nm is uncommon, many researchers have assumed that there is little to no effect of red light on the neuroendocrine or circadian systems. The aims of the following studies were to test the efficacy of monochromatic light above 600 nm for melatonin suppression in hamsters and humans. Results in hamsters show that 640 nm monochromatic light at 1.1 x 10(17) photons/cm2 can acutely suppress pineal melatonin levels. In normal healthy humans, equal photon density exposures of 1.9 x 10(18) photons/cm2 at 460, 630, and 700 nm monochromatic light elicited a significant melatonin suppression at 460 nm and small reductions of plasma melatonin levels at 630 and 700 nm. These findings are discussed relative to the possible roles of classical visual photoreceptors and the recently discovered intrinsically photosensitive retinal ganglion cells for circadian phototransduction. That physiology, and its potential for responding to red light, has implications for domestic applications involving animal care, the lighting of typical human environments, and advanced applications such as space exploration.