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The chronosense – what light tells man about biological time
Medical Hypotheses (2004) 63, 1074–1080
http://intl.elsevierhealth.com/journals/mehy
The chronosense – what light tells man about biological time Thomas C. Errena,*, Russel J. Reiterb, Andreas Pingera, Claus Piekarskia, Michael Errenc a
Institute and Polyclinic for Occupational and Social Medicine, School of Medicine and ¨ln, Lindenthal, Germany Dentistry, University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Ko b Department of Cellular and Structural Biology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, USA c Institute of Clinical Chemistry and Laboratory Medicine, Westphalian Wilhelms-University of ¨nster, Mu ¨nster, Germany Mu Received 31 March 2004; accepted 6 April 2004
Summary In the past 10 years, experimental studies have provided further evidence for the suggestion that the eye serves man as a dual sense organ, viz as a sense organ for sight but also for time and the regulation of biological rhythms. A small group of scientists interested in the adjustment of biological rhythms to the key Zeitgeber light wanted to answer the question whether rods and/or cones and/or other uncharacterized retinal photoreceptors contribute to this function in mammals. Intriguingly, in the course of elegant research, a number of laboratories around the world have been zeroing in on a novel non-rod, non-cone ocular photopigment which serves a number of responses to non-image-forming (NIF) photoreception in mammals. This paper intends to draw attention to possible implications of photoreception and phototransduction research for other scientific disciplines which study health and diesase effects in man. We therefore review the pivotal role of the photoreceptors – old and new – for the light-related timing and coordination of the interplay of otherwise less efficient biological rhythms. To distinguish our focus on time- and timing-related effects from classic image-forming (IF) and other NIF responses to ambient light, we refer informatively to chronoreceptors which mediate the sense of time, or chronosense. We conclude that syndisciplinary research into the physiology and pathophysiological implications of the chronosense is warranted and summarize a series of research questions. c 2004 Elsevier Ltd. All rights reserved.
*
Corresponding author. Tel.: +49-478-5819; fax: +49-4785119. E-mail address: [email protected] (T.C. Erren).
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.04.028
The chronosense – what light tells man about biological time
Introduction Each mechanism or special faculty by which man and other organisms are able to react to changes in their external or internal environment can be understood as a ‘sense’, and the specialized bodily structures which receive or are sensitive to external or internal stimuli through nerve endings are called sense organs. The common denominator for all higher animals’ senses is the process of transduction, i.e., within sense organs external or internal stimuli are converted into nerve impulses which then travel via sensory neurons to specialized areas of the brain. After analysis of the information, higher organisms can react to the stimuli. Transduction processes for all known human senses share four features: (i) sense organs contain receptor or sensor cells which are responsive to one specific type of stimulus or energy change; (ii) sensor cells are often located at a membrane which receives the specific stimulus; (iii) primary sensor cells are often connected to secondary nerve cells so that energy impulses are carried along threadlike axons; (iv) usually, afferent (ingoing) nerves connect with pathways that lead to deeper, specialized parts in the brain and to the cerebral cortex. In applying these ‘‘four criteria’’ to abundant research data we review why the eye is not only the sense organ of vision but can be also considered as a sense organ for time. Finally, we draw attention to implications of and questions regarding the sense of time, or ‘chronosense’.
The eye – a sense organ for time (i) The eye To explain the eye’s role for vision, similarities with a camera have been pointed out: images of the environment are constantly formed on the retina in the same way as they are formed on a film of a camera. To appreciate that the eye is also a sense organ for time, the reference to a clock is suggestive. Indeed, as part of a sun or light clock, specific photosensitive cells in the retinas provide deeper parts of the brain with a series of light readings which depend on the changes of the intensity of both natural and artificial light over time. In this vein, retinal cells constitute gates for photic information which travels down specific pathways to specialized parts of the brain where internal or biological time and rhythms are adjusted to external or environmental time.
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(ii) Non-rod, non-cone photoreceptors in the retina That the complex retina constitutes a ‘‘true nervous centre’’ was indicated by Ramo ´n y Cajal when he revealed the structural beauty of an intricate retinal nerve net in the late 19th century [1] and it is likewise suggested by its embryological development from the brain. Key elements of the retina are photoreceptive structures which Leeuwenhoek noticed microscopically as early as in 1684 and which have been known as rods and cones since the 1800s. In 1854, Mueller showed that photoreception occurs in these light-sensitive nerve cells and in view of their crucial role for vision, rods and cones have been considered as the retina’s most important sensory cells until very recently. In fact, only in the past couple of years, researchers have concentrated on photoreceptors that may serve another purpose and sense which is the focus of this paper. In view of serious interest and abundant research into the eye and the retina since the 1800s, it is astonishing that, apart from the ‘‘classical’’ rods and cones, there are important non-rod, non-cone photoreceptors which were overlooked until very recently. Only a few years ago, a small group of scientists interested in the adjustment of biological rhythms to the key Zeitgeber 1 light have posed the question whether rods and/or cones and/or other uncharacterized retinal photoreceptors perform this function in mammals [2]. Elegant experimental studies followed and provided substantial evidence of photoreceptive cells that mediate non-image-forming processes [3–9]. In the current quest for the specific sensory cells which appear to initiate a cascade of temporal information transfer within the human body, results from investigations in different species have been brought together. In 2002, Glickman et al. [10] compared the action spectra (which describe the relative effectiveness of different spectral bandwidths to elicit a given photobiological response) for physiological effects in humans [suppression of melatonin [5,7]; time-of-day adaptations of primary visual pathways [8]], mice [pupillary constriction in mice lacking both rod and cone receptors [6]] and rats [intrinsic photosensitivity of retinal ganglion cells [9]] and suggested that there be a common region of peak sensitivity (446–484 nm) for these non-visual effects. This comparison of
1
German for time-giver, a synchronizer which provides stimuli for setting or resetting biological clocks and thus determines the arrangement of rhythms in time.
1076 different biological responses to light across different species may not justify generalisations and the authors clearly state so. Nevertheless, their approach may be justified if ‘‘non-classical’’ lightsensitive receptors, which provide biological clocks with information about environmental time, constitute – or are crucial part of – a common sensory principle of some, perhaps many, representatives of the animal world. Moreover, another within-species comparison of the three human action spectra has suggested that there is one opsin photopigment with a common peak sensitivity around 480 nm [2]. In any case, it is clear now that a ‘‘novel’’ non-rod, non-cone photopigment in the retinas processes light information for the regulation of biological rhythms in mammals, and a series of ongoing experiments promises identification of the receptor in the near future. This will also contribute to the characterization of the chemical nature of the pigment(s) sensitive to ambient light. In fact, in the past 6 years, a number of opsins, namely vertebrate ancient (VA) opsin [11,12], encephalopsin [13] and melanopsin [14,15], and cryptochrome [16,17] have been discussed as candidate photopigments. Among the opsins, considerable focus is currently placed on the pivotal role of the retinas’ melanopsin [9,15,18,19] for the photoentrainment of mammalian systems over time [20–22]. Interestingly, in genetically engineered melanopsin-deficient mice, the adjustment of biological rhythms to light completely disappeared [23]. And yet, since the latter mice were also engineered with disabled rod and cone phototransduction pathways, we can not rule out the possibility that the ‘‘classical’’ photoreceptors may be involved in the regulation of biological rhythms (for an overview see [2]; for further experimental evidence see [24]). That they are not necessary for these tasks was demonstrated in mice who, with melanopsin but no rods and cones, appeared to have a normal adjustment of biological rhythms to external light [25]. That rods and cones could nevertheless have a contributing role may help to explain the observation that in mice without melanopsin but with intact rods and cones, circadian responses to environmental light, albeit diminished ones, could be recorded [20,21]. On logical grounds, in addition to a contributing role of rods and cones for photoentrainment, there might be still another, as yet unrecognized, photosensitive complex or mechanism involved: on its own, the latter is not sufficient for the adjustment of biological rhythms to light under extreme experimental conditions but together with rods and cones, i.e., without melanopsin, it may contrib-
Erren et al. ute to fulfill this task to a certain and together with melanopsin i.e., without rods and cones, to a full extent. What degree of temporal resolution photoreceptors in the retinas provide is not clear at this stage but, in principle, we would expect that a resolution of external or environmental time mediated by the eye is crude so that the adjustment of internal or biological time would be rather inert: indeed, it would not only seem sufficient but desirable if light were to convey rather crude temporal information about day and night and seasons because too detailed temporal resolution of ambient light exposures could confuse the timing of biological rhythms in man, e.g., a cloud which passes over the sun should not suggest a fairly sudden dusk and thus abrupt change of time.
(iii) Retinofugal fibers Conveying the sense of time, or chronosense, from the specialized retinal photoreceptors to the master biological clock, the suprachiasmatic nuclei (SCN), in the antero-basal hypothalamus is accomplished by the retinohypothalamic tract (RHT) [26]. This retinofugal pathway is constituted by axons of ganglion cells, located in the inner cell layer of the retina, which receive neural impulses from the specialized photoreceptors [19]. The RHT traverses the optic nerve and, at the level of the optic chiasm, it diverges to enter the SCN. The retinofugal fibers of the RHT probably constitute the most important afferent pathway to the biological clock. In the optic nerve the RHT is accompanied by nerves that subserve classic visual processes.
(iv) The suprachiasmatic nuclei (SCN) in the forebrain and the coordination of biological rhythms The timing information conveyed by the RHT has at least two important actions on the SCN, i.e., (a) it stimulates the activity of the majority of neurons with which the fibers make synaptic contact [27,28] and, (b), it phase shifts the intrinsic endogenous rhythm (which is normally slightly longer than the 24 h light/dark cycle [29]) of the SCN neurons [30]. A major neurotransmitter released from the RHT terminals, which provides timing information to the SCN, is believed to be glutamate [31,32]. This excitatory stimulus, via a yet ill-defined cascade of intracellular events that probably involve pituitary adenylate cyclase-activating polypeptide (PACAP), is involved in providing the biological clock with a sense of time as perceived by
The chronosense – what light tells man about biological time the retina [33]. An understanding of how the SCN neurons transfer the electrical signal they receive from the RHT to the clock genes – PER1, PER2, CRY1 and CRY2 [34] – remains unknown and is the subject of intensive investigation. Glutamate is by no means the only neurotransmitter located in the SCN. Indeed, a dozen or more chemical mediators are known to function in coordinating the electrical activity of this group of neurons [3]. While both excitatory and inhibitory neurotransmitters have been identified in the clock, unraveling their specific functions is an unfinished task. Of all the chemical mediators uncovered in the SCN, only vasopressin (VP) exhibits a clear circadian rhythm [35], but how these changes relate to the function of the clock has yet to be established. VP is believed, however, to be a component of the efferent outflow of the SCN [36,37]. That the SCN exhibits intrinsic circadian rhythmicity, with a period of a little longer than 24 h, is beyond debate. As a master oscillator, the SCN retains its circadian pattern of activity even when its neural connections to the brain are surgically disrupted [38] or when it is placed in organ culture [39]. Furthermore, even single isolated SCN neurons continue to fire in a circadian manner [40]. Finally, transplantation of a functional SCN from a donor animal into one that is arrhythmic after its biological clock has been electrolytically destroyed causes the recipient animal to develop circadian rhythmicity with the precise properties of the transplanted donor clock [41]. Once the clock integrates signals from the retinas into its complex neuronal networks, it must then pass the information to the remainder of the body. The nature of this efferent message as well as the mechanisms involved are almost totally unknown. It has been suggested that the clock genes influence expression of post-translational ion channels to generate day-night rhythms in electrical activity of neurons in the SCN [42]. This, of course, makes the presumption that the output from the clock is neuronal. In the studies mentioned above, in which the transplanted SCN determined the locomotor rhythm of the recipient animal [41], examination of the grafted tissue revealed very little neuronal outgrowth from the transplanted tissue. This leaves open the possibility that at least one efferent message may be humoral [43]. Some of the SCN outputs are, however, clearly dependent on neuronal signaling. The neuronal projects from the SCN to areas within and outside the hypothalamus are extensive [37,44]. Via these connections and possibly by means of humoral factors, the clock influences the cyclic events of a wide variety of processes,
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e.g., the autonomic nervous system, pineal melatonin synthesis, adrenocorticosterone cycle, body temperature rhythms, sleep and wakefulness, etc. While the SCN exhibits a circadian rhythm in general electrical activity, with high levels during the subjective day and low levels at night, it is not at all clear how this single diurnal rhythm determines the complex diversity of rhythms seen in such a wide variety of organs. Rhythms in these numerous organs differ in terms of their shape and the timing of their peaks and troughs. These differential output messages may be determined by different neurotransmitters [45], neuromodulators, as well as by regional differentiation [46]. It is possible that specialized subdivisions in the SCN may determine specific rhythms in other organs. Considering the current primitive state of knowledge, the mechanisms by which the master clock governs the timing of functions in such a multitude of organs are not likely to be identified in the near future.
Conclusions The material presented indicates why the eye can be considered as a sense organ for time. A sense organ is usually able to receive only a certain kind of stimulus, and thus only certain kinds of communication from the environment. In the case of the human eye, a very limited band of the known electromagnetic spectrum is actually detected. In fact, visible light from the Sun or man-made sources – in particular the blue-green spectrum – provides specific electromagnetic stimuli for photoreceptors in the retinas and thus mediates temporal information about external day and night and season to a master clock in the forebrain. This information is then used by the SCN to adjust otherwise less efficient internal biological rhythms to the environmental light/dark cycle. Therefore, in addition to photoreceptors which primarily serve vision, i.e., rods and cones, man has photoreceptors which – apart from a series of further NIF responses to light – convey crucial information about environmental time. In this paper’s context of time- and timing-related effects of phototransduction in man, and to distinguish from IF and other NIF photoresponses, the novel temporal photoreceptors may be referred to informatively as chronoreceptors. Clearly, the novel ocular receptors are sensitive to light but, equally clearly, receptors have been referred to appropriately with regard to their effect rather than the type of stimulus before. For instance, nocireceptors can be sensitive to mechanical, thermal and chemical stimuli but they are nevertheless identified
1078 Table 1
Erren et al. Research questions regarding the physiology of the chronosense
Is there more than one type of chronoreceptor? Accordingly, i.e., for one (or more) chronoreceptor(s): What wavelength is the chronoreceptor’s peak sensitivity? What is the chronoreceptor chemically? What are the chronoreceptor’s precursors? How does the chronoreceptor work? What amount of light initiates a reaction in the chronoreceptor? What molecular transformation/s – isomerization/s is/are induced in the chronoreceptor by light? What molecular re-transformation/s – re-isomerization/s occurr/s in the chronoreceptor after reception of light? What is the spatial distribution of the chronoreceptor? What is the temporal resolution of the chronoreceptor? What is the temporal resolution of the chronoreceptive retinal net? Do chronoreceptors interact with rods and cones? And, if so, how? What gene/s encode/s the chronoreceptor? Are there – as yet unidentified – retinofugal fibers for time? Are there – as yet unidentified – temporal nerves [within or outside of the optic nerves]? Are there – as yet unidentified – temporal tracts [within or outside of the optic tracts]? How does the SCN convey time information to a multitude of organs? Do we have to re-evaluate research in view of information reviewed in this paper?
Table 2
Research questions regarding pathophysiological implications of the chronosense
How does anthropogenic light act on the chronoreceptor(s)? Do drugs affect the chronoreceptor(s)? Does diet/do nutrients affect the chronoreceptor(s)? Are there diseases which affect the chronreceptor(s)? Are there diseases which affect the retinofugal transmission of temporal information? Are there diseases which affect the SCN’s use of temporal information? How can the chronosense affect health and disease? How robust is the chronosense [i.e., what variations of light in terms of spectral distribution, intensity and duration suffice to affect the continuum from health to disease?]? Do we have to re-evaluate research in view of information reviewed in this paper?
informatively by reference to their ultimate effect, i.e., the perception of pain.
Perspectives In 1864 and 1865, Holmgren discovered the retina’s electrical response to light [47]. Thereafter, retinal electrophysiology contributed substantially to our understanding of vision. Importantly, the research material synthesized in this paper shows that the electrical responses of the retina to light mediate effects way beyond the complex processes of vision. To understand the many implications of the chronosense, targeted studies from photoreception research and further disciplines are clearly warranted. Indeed, research questions arise at each link along the suspected chain between the stimulus,
the sensor, the neuronal pathway(s) to and from the principal effector, viz the SCN, and with regard to the ultimately mediated effects. With regard to the latter, we have to examine links between light, the timing of biological rhythms and health and between light, the timing of biological rhythms and disease. That relevant disturbances of the timing of biological rhythms can lead to manifest chronic processes and adverse health effects is reasonable to expect [48] 2 and explored in more detail in a companion paper [49]: as a descriptive term for a significant disturbance of the coordination of biological rhythms over days and seasons and years, we suggest the term chronodisruption there. As one example for chronodisruption in man, we dis-
2 ‘‘. . .circadian systems are inherent in and pervade the living system to an extent that they are fundamental features of its organization; and to an extent that if deranged they impair it.’’ (48; p. 159).
The chronosense – what light tells man about biological time cuss the possibility that aging and cancer may be chronic processes which belong to one light- and rhythm-related effect entity. A series of research questions which can be of interest regarding the underlying physiology and pathophysiologic implications of the chronosense are summarized in Tables 1 and 2, respectively. In summary, it is remarkable that ubiquitous light serves as specific stimulus for two senses which are mediated via one sense organ, viz, the eye. The nexus of light and time in man’s intricate neuronal network is clearly intriguing. When Granit referred to ‘‘our noblest sense organ’’ [50] such qualification was certainly justified in view of how the complex interpretation of the world of light, form and color is organized. But this wording has even more weight today considering the implications of the eye being a dual sense organ which not only links light and vision but also light and time. We hope that this paper can provide context and further impetus for syndisciplinary research into the physiology and pathophysiological implications of the chronosense in man.
Acknowledgement We thank Dr. Rob Lucas for his valuable comments on earlier drafts of this paper.
References [1] Ramo ´n y Cajal S. Die Retina der Wirbelthiere [The retina of vertebrates]. Wiesbaden: Bergmann; 1894. [2] Foster RG, Hankins MW. Non-rod, non-cone photoreception in the vertebrates. Prog Retin Eye Res 2002;21:507–27. [3] Freedman MS, Lucas RJ, Soni B, von Schantz M, Munoz M, David-Gray Z et al. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 1999;284:502–4. [4] Lucas RJ, Freedman MS, Munoz M, Garcia-Fernandez JM, Foster RG. Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 1999;284:505–7. [5] Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E et al. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci 2001;21:6405–12. [6] Lucas RJ, Douglas RH, Foster RG. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nat Neurosci 2001;4:621–6. [7] Thapan K, Arendt J, Skene DJ. An action spectrum for melatonin suppression: evidence for a novel non-rod, noncone photoreceptor system in humans. J Physiol 2001;535:261–7. [8] Hankins MW, Lucas RJ. The primary visual pathway in humans is regulated according to long-term light exposure through the action of a nonclassical photopigment. Curr Biol 2002;12:191–8.
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[9] Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 2002;295:1070–3. [10] Glickman G, Levin R, Brainard GC. Ocular input for human melatonin regulation: relevance to breast cancer. Neuroendocrinol Lett 2002;23(Suppl 2):17–22. [11] Soni BG, Foster RG. A novel and ancient vertebrate opsin. FEBS Lett 1997;406:279–83. [12] Soni BG, Philp AR, Foster RG, Knox BE. Novel retinal photoreceptors. Nature 1998;394:27–8. [13] Blackshaw S, Snyder SH. Encephalopsin: a novel mammalian extraretinal opsin discretely localized in the brain. J Neurosci 1999;19:3681–90. [14] Provencio I, Cooper HM, Foster RG. Retinal projections in mice with inherited retinal degeneration: implications for circadian photoentrainment. J Comp Neurol 1998;395:417–39. [15] Provencio I, Rodriguez IR, Jiang G, Hayes WP, Moreira EF, Rollag MD. A novel human opsin in the inner retina. J Neurosci 2000;20:600–5. [16] Miyamoto Y, Sancar A. Vitamin B2-based blue-light photoreceptors in the retinohypothalamic tract as the photoactive pigments for setting the circadian clock in mammals. Proc Natl Acad Sci USA 1998;95:6097–102. [17] Thresher RJ, Vitaterna MH, Miyamoto Y, Kazantsev A, Hsu C, Petit C et al. Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 1998;282:1490–4. [18] Provencio I, Rollag MD, Castrucci AM. Photoreceptive net in the mammalian retina. This mesh of cells may explain how some blind mice can still tell day from night. Nature 2002;415:493. [19] Hattar S, Liao HW, Takao M, Berson DM, Yau KW. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 2002;295:1065–70. [20] Ruby NF, Brennan TJ, Xie X, Cao V, Franken P, Heller HC et al. Role of melanopsin in circadian responses to light. Science 2002;298:2211–3. [21] Panda S, Sato TK, Castrucci AM, Rollag MD, DeGrip WJ, Hogenesch JB et al. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 2002;298:2213–6. [22] Lucas RJ, Hattar S, Takao M, Berson DM, Foster RG, Yau KW. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 2003;299:245–7. [23] Hattar S, Lucas RJ, Mrosovsky N, Thompson S, Douglas RH, Hankins MW et al. Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 2003;424:76–81. [24] Panda S, Provencio I, Tu DC, Pires SS, Rollag MD, Castrucci AM et al. Melanopsin is required for non-image-forming photic responses in blind mice. Science 2003;301:525–7. [25] Semo M, Peirson S, Lupi D, Lucas RJ, Jeffery G, Foster RG. Melanopsin retinal ganglion cells and the maintenance of circadian and pupillary responses to light in aged rodless/ coneless (rd/rd cl) mice. Eur J Neurosci 2003;17:1793–801. [26] Moore RY, Spek JC, Card JP. The retinohypothalamic tract originates from a distinct subset of retinal ganglion cells. J Comp Neurol 1995;352:351–66. [27] Meijer JH, Rusak B, Harrington ME. Photically responsive neurons in the hypothalamus of a diurnal ground squirrel. Brain Res 1989;501:315–23. [28] Meijer JH, Watanabe K, Schaap J, Albus H, Detari L. Light responsiveness of the suprachiasmatic nucleus: long-term multi single-unit recordings in freely moving rats. J Neurosci 1998;18:9078–87.
1080 [29] Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF, Rimmer DW et al. Stability, precision, and near-24-h period of the human circadian pacemaker. Science 1999;284:2177–81. [30] Foster RG. The regulation of mammalian circadian rhythms by light. In: Holick MF, Jung EG, editors. Biological effects of light. Berlin, Germany: Walter de Gruyter; 1996. p. 372–9. [31] Ding JM, Chen D, Weber ET, Faiman LE, Rea MA, Gillette MV. Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO. Science 1994;266:1713–7. [32] Vries MJD, Treep JA, Pauw SEDD, Meyer JH. The effects of electrical stimulation of the optic nerves and the anterior optic chiasm on the circadian activity rhythm of the Syrian hamster: involvement of excitatory amino acids. Brain Res 1994;642:206–12. [33] Harrington ME, Hoque S, Hall A, Golombek D, Biello S. Pituitary adenylate cyclase activating peptide phase shifts circadian rhythms in a manner similar to light. J Neurosci 1999;19:6637–42. [34] van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao M et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 1999;398:627–30. [35] van Esseveldt KE, Lehman MN, Boer GJ. The suprachiasmatic nucleus and the circadian time-keeping system revisited. Brain Res Rev 2000;33:34–77. [36] Kalsbuk A, van der Vliet J, Buijs RM. Decrease of endogenous vasopressin release necessary for expression of the circadian rise in plasma corticosterone: a reverse microdialysis study. J Neuroendocrinol 1996;8:299–307. [37] Palm IF, van der Beek EM, Wiegant VM, Buijs RM, Kalsbeek A. Vasopressin induces a luteinizing hormone surge in ovariectomized, estradiol-treated rats with lesion of the suprachiasmatic nucleus. Neuroscience 1999;93:659–66. [38] Inouye SIT, Kawamura H. Persistence of circadian rhythmicity in a mammalian hypothalamic ‘‘island’’ containing the suprachiasmatic nucleus. Proc Natl Acad Sci USA 1979;76:5962–6. [39] Gillette MV, Medanic M, Mc Arthur AJ, Liu C, Ding JM, Faiman LE et al. Intrinisic neuronal rhythms in the suprachiasmatic and their adjustment. Ciba Fnd Symp 1995;183:134–53.
Erren et al. [40] Welsh DK, Logothets DE, Meister M, Reppert SM. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phase circadian firing rhythms. Neuron 1995;14:697–706. [41] Ralph MR, Foster RG, Davis FC, Menaker M. Transplanted suprachiasmatic nucleus determines circadian period. Science 1990;247:975–8. [42] Pennartz GM, de Jeu MT, Bos NP, Schaap J, Geurtsen AM. Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock. Nature 2002;416:286–90. [43] Meyer-Bernstein EL, Jetton AE, Matsumoto SI, Markuns MN, Lehman MN, Bittman EL. Effects of suprachiasmatic transplants on circadian rhythms of neuroendocrine function in golden hamsters. Endocrinology 1999;140:207–18. [44] Ruijs RM, Wortel J, Van Heerikhuize JJ, Feenstra MGP, Ter Horst GY, Romijn HJ et al. Anatomical and functional demonstration of multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur J Neurosci 1999;11:1534–5. [45] Cui LN, Coderre E, Ranaud LP. Glutamate and GABA mediate suprachiasmatic nucleus inputs to spinal-projecting paraventricular neurons. Am J Physiol 2001;281: R1283–9. [46] Schaap J, Albus H, Eilers PH, Datari L, Meijer JM. Phase differences in electrical discharge rhythms between neuronal population of the left and right suprachiasmatic nuclei. Neuroscience 2001;108:359–63. [47] Holmgren AF. Method att objectivera effecten af Ljusintryck pa ˚retina. Upsala La ¨karefo ¨renings Fo ¨rhandlingar 1865–1866;1:177–91. [48] Pittendrigh CS. Circadian rhythms and circadian organization of the living systems. In: Cold Spring Harbor Symposium on Quantitative Biology. Biological clocks, vol. XXV. New York: Cold Spring Harbor Press; 1960. p. 159–84. [49] Erren TC, Reiter RJ, Piekarski C. Light, timing of biological rhythms, and chronodisruption in man. Naturwissenschaften 2003;90:485–94. [50] Granit R. The development of retinal neurophysiology. Nobel Lecture, December 12, 1967. In: Nobel Lectures, Physiology or Medicine 1963–1970. Amsterdam: Elsevier Publishing Company; 1972. p. 255–65. Available from: http://www.nobel.se/medicine/laureates/1967/granitlecture.html.
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The chronosense – what light tells man about biological time Thomas C. Errena,*, Russel J. Reiterb, Andreas Pingera, Claus Piekarskia, Michael Errenc a
Institute and Polyclinic for Occupational and Social Medicine, School of Medicine and ¨ln, Lindenthal, Germany Dentistry, University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Ko b Department of Cellular and Structural Biology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, USA c Institute of Clinical Chemistry and Laboratory Medicine, Westphalian Wilhelms-University of ¨nster, Mu ¨nster, Germany Mu Received 31 March 2004; accepted 6 April 2004
Summary In the past 10 years, experimental studies have provided further evidence for the suggestion that the eye serves man as a dual sense organ, viz as a sense organ for sight but also for time and the regulation of biological rhythms. A small group of scientists interested in the adjustment of biological rhythms to the key Zeitgeber light wanted to answer the question whether rods and/or cones and/or other uncharacterized retinal photoreceptors contribute to this function in mammals. Intriguingly, in the course of elegant research, a number of laboratories around the world have been zeroing in on a novel non-rod, non-cone ocular photopigment which serves a number of responses to non-image-forming (NIF) photoreception in mammals. This paper intends to draw attention to possible implications of photoreception and phototransduction research for other scientific disciplines which study health and diesase effects in man. We therefore review the pivotal role of the photoreceptors – old and new – for the light-related timing and coordination of the interplay of otherwise less efficient biological rhythms. To distinguish our focus on time- and timing-related effects from classic image-forming (IF) and other NIF responses to ambient light, we refer informatively to chronoreceptors which mediate the sense of time, or chronosense. We conclude that syndisciplinary research into the physiology and pathophysiological implications of the chronosense is warranted and summarize a series of research questions. c 2004 Elsevier Ltd. All rights reserved.
*
Corresponding author. Tel.: +49-478-5819; fax: +49-4785119. E-mail address: [email protected] (T.C. Erren).
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.04.028
The chronosense – what light tells man about biological time
Introduction Each mechanism or special faculty by which man and other organisms are able to react to changes in their external or internal environment can be understood as a ‘sense’, and the specialized bodily structures which receive or are sensitive to external or internal stimuli through nerve endings are called sense organs. The common denominator for all higher animals’ senses is the process of transduction, i.e., within sense organs external or internal stimuli are converted into nerve impulses which then travel via sensory neurons to specialized areas of the brain. After analysis of the information, higher organisms can react to the stimuli. Transduction processes for all known human senses share four features: (i) sense organs contain receptor or sensor cells which are responsive to one specific type of stimulus or energy change; (ii) sensor cells are often located at a membrane which receives the specific stimulus; (iii) primary sensor cells are often connected to secondary nerve cells so that energy impulses are carried along threadlike axons; (iv) usually, afferent (ingoing) nerves connect with pathways that lead to deeper, specialized parts in the brain and to the cerebral cortex. In applying these ‘‘four criteria’’ to abundant research data we review why the eye is not only the sense organ of vision but can be also considered as a sense organ for time. Finally, we draw attention to implications of and questions regarding the sense of time, or ‘chronosense’.
The eye – a sense organ for time (i) The eye To explain the eye’s role for vision, similarities with a camera have been pointed out: images of the environment are constantly formed on the retina in the same way as they are formed on a film of a camera. To appreciate that the eye is also a sense organ for time, the reference to a clock is suggestive. Indeed, as part of a sun or light clock, specific photosensitive cells in the retinas provide deeper parts of the brain with a series of light readings which depend on the changes of the intensity of both natural and artificial light over time. In this vein, retinal cells constitute gates for photic information which travels down specific pathways to specialized parts of the brain where internal or biological time and rhythms are adjusted to external or environmental time.
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(ii) Non-rod, non-cone photoreceptors in the retina That the complex retina constitutes a ‘‘true nervous centre’’ was indicated by Ramo ´n y Cajal when he revealed the structural beauty of an intricate retinal nerve net in the late 19th century [1] and it is likewise suggested by its embryological development from the brain. Key elements of the retina are photoreceptive structures which Leeuwenhoek noticed microscopically as early as in 1684 and which have been known as rods and cones since the 1800s. In 1854, Mueller showed that photoreception occurs in these light-sensitive nerve cells and in view of their crucial role for vision, rods and cones have been considered as the retina’s most important sensory cells until very recently. In fact, only in the past couple of years, researchers have concentrated on photoreceptors that may serve another purpose and sense which is the focus of this paper. In view of serious interest and abundant research into the eye and the retina since the 1800s, it is astonishing that, apart from the ‘‘classical’’ rods and cones, there are important non-rod, non-cone photoreceptors which were overlooked until very recently. Only a few years ago, a small group of scientists interested in the adjustment of biological rhythms to the key Zeitgeber 1 light have posed the question whether rods and/or cones and/or other uncharacterized retinal photoreceptors perform this function in mammals [2]. Elegant experimental studies followed and provided substantial evidence of photoreceptive cells that mediate non-image-forming processes [3–9]. In the current quest for the specific sensory cells which appear to initiate a cascade of temporal information transfer within the human body, results from investigations in different species have been brought together. In 2002, Glickman et al. [10] compared the action spectra (which describe the relative effectiveness of different spectral bandwidths to elicit a given photobiological response) for physiological effects in humans [suppression of melatonin [5,7]; time-of-day adaptations of primary visual pathways [8]], mice [pupillary constriction in mice lacking both rod and cone receptors [6]] and rats [intrinsic photosensitivity of retinal ganglion cells [9]] and suggested that there be a common region of peak sensitivity (446–484 nm) for these non-visual effects. This comparison of
1
German for time-giver, a synchronizer which provides stimuli for setting or resetting biological clocks and thus determines the arrangement of rhythms in time.
1076 different biological responses to light across different species may not justify generalisations and the authors clearly state so. Nevertheless, their approach may be justified if ‘‘non-classical’’ lightsensitive receptors, which provide biological clocks with information about environmental time, constitute – or are crucial part of – a common sensory principle of some, perhaps many, representatives of the animal world. Moreover, another within-species comparison of the three human action spectra has suggested that there is one opsin photopigment with a common peak sensitivity around 480 nm [2]. In any case, it is clear now that a ‘‘novel’’ non-rod, non-cone photopigment in the retinas processes light information for the regulation of biological rhythms in mammals, and a series of ongoing experiments promises identification of the receptor in the near future. This will also contribute to the characterization of the chemical nature of the pigment(s) sensitive to ambient light. In fact, in the past 6 years, a number of opsins, namely vertebrate ancient (VA) opsin [11,12], encephalopsin [13] and melanopsin [14,15], and cryptochrome [16,17] have been discussed as candidate photopigments. Among the opsins, considerable focus is currently placed on the pivotal role of the retinas’ melanopsin [9,15,18,19] for the photoentrainment of mammalian systems over time [20–22]. Interestingly, in genetically engineered melanopsin-deficient mice, the adjustment of biological rhythms to light completely disappeared [23]. And yet, since the latter mice were also engineered with disabled rod and cone phototransduction pathways, we can not rule out the possibility that the ‘‘classical’’ photoreceptors may be involved in the regulation of biological rhythms (for an overview see [2]; for further experimental evidence see [24]). That they are not necessary for these tasks was demonstrated in mice who, with melanopsin but no rods and cones, appeared to have a normal adjustment of biological rhythms to external light [25]. That rods and cones could nevertheless have a contributing role may help to explain the observation that in mice without melanopsin but with intact rods and cones, circadian responses to environmental light, albeit diminished ones, could be recorded [20,21]. On logical grounds, in addition to a contributing role of rods and cones for photoentrainment, there might be still another, as yet unrecognized, photosensitive complex or mechanism involved: on its own, the latter is not sufficient for the adjustment of biological rhythms to light under extreme experimental conditions but together with rods and cones, i.e., without melanopsin, it may contrib-
Erren et al. ute to fulfill this task to a certain and together with melanopsin i.e., without rods and cones, to a full extent. What degree of temporal resolution photoreceptors in the retinas provide is not clear at this stage but, in principle, we would expect that a resolution of external or environmental time mediated by the eye is crude so that the adjustment of internal or biological time would be rather inert: indeed, it would not only seem sufficient but desirable if light were to convey rather crude temporal information about day and night and seasons because too detailed temporal resolution of ambient light exposures could confuse the timing of biological rhythms in man, e.g., a cloud which passes over the sun should not suggest a fairly sudden dusk and thus abrupt change of time.
(iii) Retinofugal fibers Conveying the sense of time, or chronosense, from the specialized retinal photoreceptors to the master biological clock, the suprachiasmatic nuclei (SCN), in the antero-basal hypothalamus is accomplished by the retinohypothalamic tract (RHT) [26]. This retinofugal pathway is constituted by axons of ganglion cells, located in the inner cell layer of the retina, which receive neural impulses from the specialized photoreceptors [19]. The RHT traverses the optic nerve and, at the level of the optic chiasm, it diverges to enter the SCN. The retinofugal fibers of the RHT probably constitute the most important afferent pathway to the biological clock. In the optic nerve the RHT is accompanied by nerves that subserve classic visual processes.
(iv) The suprachiasmatic nuclei (SCN) in the forebrain and the coordination of biological rhythms The timing information conveyed by the RHT has at least two important actions on the SCN, i.e., (a) it stimulates the activity of the majority of neurons with which the fibers make synaptic contact [27,28] and, (b), it phase shifts the intrinsic endogenous rhythm (which is normally slightly longer than the 24 h light/dark cycle [29]) of the SCN neurons [30]. A major neurotransmitter released from the RHT terminals, which provides timing information to the SCN, is believed to be glutamate [31,32]. This excitatory stimulus, via a yet ill-defined cascade of intracellular events that probably involve pituitary adenylate cyclase-activating polypeptide (PACAP), is involved in providing the biological clock with a sense of time as perceived by
The chronosense – what light tells man about biological time the retina [33]. An understanding of how the SCN neurons transfer the electrical signal they receive from the RHT to the clock genes – PER1, PER2, CRY1 and CRY2 [34] – remains unknown and is the subject of intensive investigation. Glutamate is by no means the only neurotransmitter located in the SCN. Indeed, a dozen or more chemical mediators are known to function in coordinating the electrical activity of this group of neurons [3]. While both excitatory and inhibitory neurotransmitters have been identified in the clock, unraveling their specific functions is an unfinished task. Of all the chemical mediators uncovered in the SCN, only vasopressin (VP) exhibits a clear circadian rhythm [35], but how these changes relate to the function of the clock has yet to be established. VP is believed, however, to be a component of the efferent outflow of the SCN [36,37]. That the SCN exhibits intrinsic circadian rhythmicity, with a period of a little longer than 24 h, is beyond debate. As a master oscillator, the SCN retains its circadian pattern of activity even when its neural connections to the brain are surgically disrupted [38] or when it is placed in organ culture [39]. Furthermore, even single isolated SCN neurons continue to fire in a circadian manner [40]. Finally, transplantation of a functional SCN from a donor animal into one that is arrhythmic after its biological clock has been electrolytically destroyed causes the recipient animal to develop circadian rhythmicity with the precise properties of the transplanted donor clock [41]. Once the clock integrates signals from the retinas into its complex neuronal networks, it must then pass the information to the remainder of the body. The nature of this efferent message as well as the mechanisms involved are almost totally unknown. It has been suggested that the clock genes influence expression of post-translational ion channels to generate day-night rhythms in electrical activity of neurons in the SCN [42]. This, of course, makes the presumption that the output from the clock is neuronal. In the studies mentioned above, in which the transplanted SCN determined the locomotor rhythm of the recipient animal [41], examination of the grafted tissue revealed very little neuronal outgrowth from the transplanted tissue. This leaves open the possibility that at least one efferent message may be humoral [43]. Some of the SCN outputs are, however, clearly dependent on neuronal signaling. The neuronal projects from the SCN to areas within and outside the hypothalamus are extensive [37,44]. Via these connections and possibly by means of humoral factors, the clock influences the cyclic events of a wide variety of processes,
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e.g., the autonomic nervous system, pineal melatonin synthesis, adrenocorticosterone cycle, body temperature rhythms, sleep and wakefulness, etc. While the SCN exhibits a circadian rhythm in general electrical activity, with high levels during the subjective day and low levels at night, it is not at all clear how this single diurnal rhythm determines the complex diversity of rhythms seen in such a wide variety of organs. Rhythms in these numerous organs differ in terms of their shape and the timing of their peaks and troughs. These differential output messages may be determined by different neurotransmitters [45], neuromodulators, as well as by regional differentiation [46]. It is possible that specialized subdivisions in the SCN may determine specific rhythms in other organs. Considering the current primitive state of knowledge, the mechanisms by which the master clock governs the timing of functions in such a multitude of organs are not likely to be identified in the near future.
Conclusions The material presented indicates why the eye can be considered as a sense organ for time. A sense organ is usually able to receive only a certain kind of stimulus, and thus only certain kinds of communication from the environment. In the case of the human eye, a very limited band of the known electromagnetic spectrum is actually detected. In fact, visible light from the Sun or man-made sources – in particular the blue-green spectrum – provides specific electromagnetic stimuli for photoreceptors in the retinas and thus mediates temporal information about external day and night and season to a master clock in the forebrain. This information is then used by the SCN to adjust otherwise less efficient internal biological rhythms to the environmental light/dark cycle. Therefore, in addition to photoreceptors which primarily serve vision, i.e., rods and cones, man has photoreceptors which – apart from a series of further NIF responses to light – convey crucial information about environmental time. In this paper’s context of time- and timing-related effects of phototransduction in man, and to distinguish from IF and other NIF photoresponses, the novel temporal photoreceptors may be referred to informatively as chronoreceptors. Clearly, the novel ocular receptors are sensitive to light but, equally clearly, receptors have been referred to appropriately with regard to their effect rather than the type of stimulus before. For instance, nocireceptors can be sensitive to mechanical, thermal and chemical stimuli but they are nevertheless identified
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Erren et al. Research questions regarding the physiology of the chronosense
Is there more than one type of chronoreceptor? Accordingly, i.e., for one (or more) chronoreceptor(s): What wavelength is the chronoreceptor’s peak sensitivity? What is the chronoreceptor chemically? What are the chronoreceptor’s precursors? How does the chronoreceptor work? What amount of light initiates a reaction in the chronoreceptor? What molecular transformation/s – isomerization/s is/are induced in the chronoreceptor by light? What molecular re-transformation/s – re-isomerization/s occurr/s in the chronoreceptor after reception of light? What is the spatial distribution of the chronoreceptor? What is the temporal resolution of the chronoreceptor? What is the temporal resolution of the chronoreceptive retinal net? Do chronoreceptors interact with rods and cones? And, if so, how? What gene/s encode/s the chronoreceptor? Are there – as yet unidentified – retinofugal fibers for time? Are there – as yet unidentified – temporal nerves [within or outside of the optic nerves]? Are there – as yet unidentified – temporal tracts [within or outside of the optic tracts]? How does the SCN convey time information to a multitude of organs? Do we have to re-evaluate research in view of information reviewed in this paper?
Table 2
Research questions regarding pathophysiological implications of the chronosense
How does anthropogenic light act on the chronoreceptor(s)? Do drugs affect the chronoreceptor(s)? Does diet/do nutrients affect the chronoreceptor(s)? Are there diseases which affect the chronreceptor(s)? Are there diseases which affect the retinofugal transmission of temporal information? Are there diseases which affect the SCN’s use of temporal information? How can the chronosense affect health and disease? How robust is the chronosense [i.e., what variations of light in terms of spectral distribution, intensity and duration suffice to affect the continuum from health to disease?]? Do we have to re-evaluate research in view of information reviewed in this paper?
informatively by reference to their ultimate effect, i.e., the perception of pain.
Perspectives In 1864 and 1865, Holmgren discovered the retina’s electrical response to light [47]. Thereafter, retinal electrophysiology contributed substantially to our understanding of vision. Importantly, the research material synthesized in this paper shows that the electrical responses of the retina to light mediate effects way beyond the complex processes of vision. To understand the many implications of the chronosense, targeted studies from photoreception research and further disciplines are clearly warranted. Indeed, research questions arise at each link along the suspected chain between the stimulus,
the sensor, the neuronal pathway(s) to and from the principal effector, viz the SCN, and with regard to the ultimately mediated effects. With regard to the latter, we have to examine links between light, the timing of biological rhythms and health and between light, the timing of biological rhythms and disease. That relevant disturbances of the timing of biological rhythms can lead to manifest chronic processes and adverse health effects is reasonable to expect [48] 2 and explored in more detail in a companion paper [49]: as a descriptive term for a significant disturbance of the coordination of biological rhythms over days and seasons and years, we suggest the term chronodisruption there. As one example for chronodisruption in man, we dis-
2 ‘‘. . .circadian systems are inherent in and pervade the living system to an extent that they are fundamental features of its organization; and to an extent that if deranged they impair it.’’ (48; p. 159).
The chronosense – what light tells man about biological time cuss the possibility that aging and cancer may be chronic processes which belong to one light- and rhythm-related effect entity. A series of research questions which can be of interest regarding the underlying physiology and pathophysiologic implications of the chronosense are summarized in Tables 1 and 2, respectively. In summary, it is remarkable that ubiquitous light serves as specific stimulus for two senses which are mediated via one sense organ, viz, the eye. The nexus of light and time in man’s intricate neuronal network is clearly intriguing. When Granit referred to ‘‘our noblest sense organ’’ [50] such qualification was certainly justified in view of how the complex interpretation of the world of light, form and color is organized. But this wording has even more weight today considering the implications of the eye being a dual sense organ which not only links light and vision but also light and time. We hope that this paper can provide context and further impetus for syndisciplinary research into the physiology and pathophysiological implications of the chronosense in man.
Acknowledgement We thank Dr. Rob Lucas for his valuable comments on earlier drafts of this paper.
References [1] Ramo ´n y Cajal S. Die Retina der Wirbelthiere [The retina of vertebrates]. Wiesbaden: Bergmann; 1894. [2] Foster RG, Hankins MW. Non-rod, non-cone photoreception in the vertebrates. Prog Retin Eye Res 2002;21:507–27. [3] Freedman MS, Lucas RJ, Soni B, von Schantz M, Munoz M, David-Gray Z et al. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 1999;284:502–4. [4] Lucas RJ, Freedman MS, Munoz M, Garcia-Fernandez JM, Foster RG. Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 1999;284:505–7. [5] Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E et al. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci 2001;21:6405–12. [6] Lucas RJ, Douglas RH, Foster RG. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nat Neurosci 2001;4:621–6. [7] Thapan K, Arendt J, Skene DJ. An action spectrum for melatonin suppression: evidence for a novel non-rod, noncone photoreceptor system in humans. J Physiol 2001;535:261–7. [8] Hankins MW, Lucas RJ. The primary visual pathway in humans is regulated according to long-term light exposure through the action of a nonclassical photopigment. Curr Biol 2002;12:191–8.
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[9] Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 2002;295:1070–3. [10] Glickman G, Levin R, Brainard GC. Ocular input for human melatonin regulation: relevance to breast cancer. Neuroendocrinol Lett 2002;23(Suppl 2):17–22. [11] Soni BG, Foster RG. A novel and ancient vertebrate opsin. FEBS Lett 1997;406:279–83. [12] Soni BG, Philp AR, Foster RG, Knox BE. Novel retinal photoreceptors. Nature 1998;394:27–8. [13] Blackshaw S, Snyder SH. Encephalopsin: a novel mammalian extraretinal opsin discretely localized in the brain. J Neurosci 1999;19:3681–90. [14] Provencio I, Cooper HM, Foster RG. Retinal projections in mice with inherited retinal degeneration: implications for circadian photoentrainment. J Comp Neurol 1998;395:417–39. [15] Provencio I, Rodriguez IR, Jiang G, Hayes WP, Moreira EF, Rollag MD. A novel human opsin in the inner retina. J Neurosci 2000;20:600–5. [16] Miyamoto Y, Sancar A. Vitamin B2-based blue-light photoreceptors in the retinohypothalamic tract as the photoactive pigments for setting the circadian clock in mammals. Proc Natl Acad Sci USA 1998;95:6097–102. [17] Thresher RJ, Vitaterna MH, Miyamoto Y, Kazantsev A, Hsu C, Petit C et al. Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 1998;282:1490–4. [18] Provencio I, Rollag MD, Castrucci AM. Photoreceptive net in the mammalian retina. This mesh of cells may explain how some blind mice can still tell day from night. Nature 2002;415:493. [19] Hattar S, Liao HW, Takao M, Berson DM, Yau KW. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 2002;295:1065–70. [20] Ruby NF, Brennan TJ, Xie X, Cao V, Franken P, Heller HC et al. Role of melanopsin in circadian responses to light. Science 2002;298:2211–3. [21] Panda S, Sato TK, Castrucci AM, Rollag MD, DeGrip WJ, Hogenesch JB et al. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 2002;298:2213–6. [22] Lucas RJ, Hattar S, Takao M, Berson DM, Foster RG, Yau KW. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 2003;299:245–7. [23] Hattar S, Lucas RJ, Mrosovsky N, Thompson S, Douglas RH, Hankins MW et al. Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 2003;424:76–81. [24] Panda S, Provencio I, Tu DC, Pires SS, Rollag MD, Castrucci AM et al. Melanopsin is required for non-image-forming photic responses in blind mice. Science 2003;301:525–7. [25] Semo M, Peirson S, Lupi D, Lucas RJ, Jeffery G, Foster RG. Melanopsin retinal ganglion cells and the maintenance of circadian and pupillary responses to light in aged rodless/ coneless (rd/rd cl) mice. Eur J Neurosci 2003;17:1793–801. [26] Moore RY, Spek JC, Card JP. The retinohypothalamic tract originates from a distinct subset of retinal ganglion cells. J Comp Neurol 1995;352:351–66. [27] Meijer JH, Rusak B, Harrington ME. Photically responsive neurons in the hypothalamus of a diurnal ground squirrel. Brain Res 1989;501:315–23. [28] Meijer JH, Watanabe K, Schaap J, Albus H, Detari L. Light responsiveness of the suprachiasmatic nucleus: long-term multi single-unit recordings in freely moving rats. J Neurosci 1998;18:9078–87.
1080 [29] Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF, Rimmer DW et al. Stability, precision, and near-24-h period of the human circadian pacemaker. Science 1999;284:2177–81. [30] Foster RG. The regulation of mammalian circadian rhythms by light. In: Holick MF, Jung EG, editors. Biological effects of light. Berlin, Germany: Walter de Gruyter; 1996. p. 372–9. [31] Ding JM, Chen D, Weber ET, Faiman LE, Rea MA, Gillette MV. Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO. Science 1994;266:1713–7. [32] Vries MJD, Treep JA, Pauw SEDD, Meyer JH. The effects of electrical stimulation of the optic nerves and the anterior optic chiasm on the circadian activity rhythm of the Syrian hamster: involvement of excitatory amino acids. Brain Res 1994;642:206–12. [33] Harrington ME, Hoque S, Hall A, Golombek D, Biello S. Pituitary adenylate cyclase activating peptide phase shifts circadian rhythms in a manner similar to light. J Neurosci 1999;19:6637–42. [34] van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao M et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 1999;398:627–30. [35] van Esseveldt KE, Lehman MN, Boer GJ. The suprachiasmatic nucleus and the circadian time-keeping system revisited. Brain Res Rev 2000;33:34–77. [36] Kalsbuk A, van der Vliet J, Buijs RM. Decrease of endogenous vasopressin release necessary for expression of the circadian rise in plasma corticosterone: a reverse microdialysis study. J Neuroendocrinol 1996;8:299–307. [37] Palm IF, van der Beek EM, Wiegant VM, Buijs RM, Kalsbeek A. Vasopressin induces a luteinizing hormone surge in ovariectomized, estradiol-treated rats with lesion of the suprachiasmatic nucleus. Neuroscience 1999;93:659–66. [38] Inouye SIT, Kawamura H. Persistence of circadian rhythmicity in a mammalian hypothalamic ‘‘island’’ containing the suprachiasmatic nucleus. Proc Natl Acad Sci USA 1979;76:5962–6. [39] Gillette MV, Medanic M, Mc Arthur AJ, Liu C, Ding JM, Faiman LE et al. Intrinisic neuronal rhythms in the suprachiasmatic and their adjustment. Ciba Fnd Symp 1995;183:134–53.
Erren et al. [40] Welsh DK, Logothets DE, Meister M, Reppert SM. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phase circadian firing rhythms. Neuron 1995;14:697–706. [41] Ralph MR, Foster RG, Davis FC, Menaker M. Transplanted suprachiasmatic nucleus determines circadian period. Science 1990;247:975–8. [42] Pennartz GM, de Jeu MT, Bos NP, Schaap J, Geurtsen AM. Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock. Nature 2002;416:286–90. [43] Meyer-Bernstein EL, Jetton AE, Matsumoto SI, Markuns MN, Lehman MN, Bittman EL. Effects of suprachiasmatic transplants on circadian rhythms of neuroendocrine function in golden hamsters. Endocrinology 1999;140:207–18. [44] Ruijs RM, Wortel J, Van Heerikhuize JJ, Feenstra MGP, Ter Horst GY, Romijn HJ et al. Anatomical and functional demonstration of multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur J Neurosci 1999;11:1534–5. [45] Cui LN, Coderre E, Ranaud LP. Glutamate and GABA mediate suprachiasmatic nucleus inputs to spinal-projecting paraventricular neurons. Am J Physiol 2001;281: R1283–9. [46] Schaap J, Albus H, Eilers PH, Datari L, Meijer JM. Phase differences in electrical discharge rhythms between neuronal population of the left and right suprachiasmatic nuclei. Neuroscience 2001;108:359–63. [47] Holmgren AF. Method att objectivera effecten af Ljusintryck pa ˚retina. Upsala La ¨karefo ¨renings Fo ¨rhandlingar 1865–1866;1:177–91. [48] Pittendrigh CS. Circadian rhythms and circadian organization of the living systems. In: Cold Spring Harbor Symposium on Quantitative Biology. Biological clocks, vol. XXV. New York: Cold Spring Harbor Press; 1960. p. 159–84. [49] Erren TC, Reiter RJ, Piekarski C. Light, timing of biological rhythms, and chronodisruption in man. Naturwissenschaften 2003;90:485–94. [50] Granit R. The development of retinal neurophysiology. Nobel Lecture, December 12, 1967. In: Nobel Lectures, Physiology or Medicine 1963–1970. Amsterdam: Elsevier Publishing Company; 1972. p. 255–65. Available from: http://www.nobel.se/medicine/laureates/1967/granitlecture.html.