A model of phototransduction by the human circadian system

Brain Research Reviews 50 (2005) 213 – 228 www.elsevier.com/locate/brainresrev

Review

A model of phototransduction by the human circadian system Mark S. Rea*, Mariana G. Figueiro, John D. Bullough, Andrew Bierman Lighting Research Center, Rensselaer Polytechnic Institute, 21 Union Street, Troy, NY 12180, USA Accepted 11 July 2005 Available online 7 October 2005

Abstract The absolute and spectral sensitivities to light by the human circadian system, measured through melatonin suppression or phase shifting response, are beginning to emerge after a quarter century of active research. The present paper outlines a hypothesized model of human circadian phototransduction that is consistent with the known neuroanatomy and physiology of the human visual and circadian systems. Spectral opponency is fundamental to the model, providing a parsimonious explanation of some recently published data. The proposed model offers a framework for hypothesis testing and subsequent discussion of the practical aspects of architectural lighting with respect to light and health. D 2005 Elsevier B.V. All rights reserved. Theme: Sensory systems Topic: Retina and photoreceptors Keywords: Melatonin suppression; Melanopsin; Spectral sensitivity; Retinal ganglion cell; Spectral opponency; Retina; Photoreceptor; Circadian rhythm

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . Neuroanatomy . . . . . . . . . . . . . . . . . . . . 2.1. Melanopsin-containing retinal ganglion cells . 2.2. Neurons in the S cone pathway . . . . . . . . 2.3. Neurons in the rod system. . . . . . . . . . . 3. Electrophysiology . . . . . . . . . . . . . . . . . . . 4. Psychophysics . . . . . . . . . . . . . . . . . . . . 5. Modeling spectral opponency and high threshold . . 6. Predictions from the model for different light sources 6.1. Dose – response functions . . . . . . . . . . . 6.2. Spectral sensitivity . . . . . . . . . . . . . . . 7. Discussion . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . Appendix A . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author. Fax: +1 518 687 7120. E-mail address: [email protected] (M.S. Rea). URL: http://www.lrc.rpi.edu (M.S. Rea). 0165-0173/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2005.07.002

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1. Introduction The absolute and spectral sensitivities to light by the human circadian system, measured through melatonin suppression or phase shifting response, are beginning to emerge after a quarter century of active research. Lewy et al. [53] were the first to show that the human circadian system was photosensitive and that light suppressed melatonin at night, consistent with studies in animals (e.g., [82]). Early studies, as well as all subsequent research, have shown that much higher levels of white light were needed to affect human melatonin suppression and induce circadian phase shifts than were needed to stimulate the visual system [9,26,28,46,47,51,53,59,60,62,68,72,78,106]. McIntyre et al. [59], for example, showed a dose –response to a 60min pulse of white light suggesting that light levels two to three orders of magnitude higher than those found in electrically illuminated architectural spaces [78] were needed to reliably suppress human nocturnal melatonin. Early estimates of the spectral sensitivity of human circadian phototransduction suggested that the middle region of the visible spectrum was maximally effective in suppressing nighttime melatonin, implicating, in particular, rods as the primary photoreceptor for circadian phototransduction [12]. Subsequent studies argued that middle(M) [65] and long-wavelength (L) cones [105] were likely candidates. More recently, these early inferences have been shown to be incorrect [13,14,79,80,97], and there is now general consensus that human circadian phototransduction, measured, for example, through melatonin suppression by light, is maximally sensitive to visible short wavelengths between 440 nm and 500 nm. In concert with these efforts to characterize the absolute and the spectral responses of human circadian phototransduction, a great deal of attention was placed upon a search for novel photopigments in the inner plexiform layer (IPL) of the retina because genetically manipulated mice lacking rods and cones still showed circadian phase shifting to ocular light [34,55]. At first, both vitamin-A- and vitamin-B-based photopigments were proposed as candidates for the novel circadian photopigment, but recent work in neurophysiology [8], electrophysiology [76], and genetics [33,39,69] have converged on melanopsin, a vitamin-Abased opsin, found in a class of retinal ganglion cells (RGCs) that are intrinsically photosensitive (ipRGCs), as a leading photopigment candidate for phototransduction in mammalian circadian systems [32,61,71,77]. Furthermore, recent work has shown that both ipRGCs containing melanopsin and classic photoreceptors contribute to phototransduction by the circadian system in rodents [40,70]. Very recent findings have suggested that retinal photopigments are combined into a non-additive, spectrally opponent mechanism leading to nocturnal melatonin suppression in humans [31]. In the present paper, a spectral opponent model of human circadian phototransduction is proposed, incorporating all of the classic photoreceptors

[rods, L, M, and short-wavelength (S) cones] and melanopsin-containing ipRGCs into a comprehensive model that accounts for both the spectral sensitivity and the relatively high-threshold response to white light exhibited by the human circadian system through nocturnal melatonin suppression. Although the proposed model of human circadian phototransduction is based upon a synthesis of a wide range of existing literature in neuroanatomy, electrophysiology, and psychophysics, some emphasis has been placed upon human psychophysical studies incorporating nocturnal melatonin suppression by light. In particular, studies of nocturnal melatonin suppression in the bloodstream, using short-duration light exposures (0.5 to 1.5 h) presented near the time of maximum bloodstream melatonin concentrations, provided the experimental basis for the model, as well as evidence from neuroanatomy and neurophysiology. This emphasis simply reflects the fact that there are adequate data using this outcome measure relevant to characterizing human circadian phototransduction. More specifically, there are no fluence response curves for narrow-band spectra using any other outcome measure comparable to those from Brainard et al. [14] and Thapan et al. [97]. Clearly, light has many more measurable effects on the circadian system including changes in circadian timing [37,45,100– 102,106], alertness [16,17], core body temperature [17], heart rate [17,89,90], and cortisol production [88]. Despite obvious differences in neural and hormonal response functions caused or influenced by the circadian system, the characteristics of circadian phototransduction should be the same. This distinction between characterizing the input to the circadian system, the purpose of the present paper, and predicting responses emanating from the circadian system is essential for understanding the model proposed here.

2. Neuroanatomy 2.1. Melanopsin-containing retinal ganglion cells A unique class of mammalian RGCs central to circadian phototransduction has recently been discovered [8]. These ipRGCs are directly photosensitive and express melanopsin, a novel vertebrate opsin discovered by Provencio et al. [74,75]. Like other types of RGCs, the cell bodies of these neurons are located almost entirely in the ganglion cell layer of the retina. The ipRGCs project to a wide range of centers in the brain including the suprachiasmatic nucleus (SCN) [94] as well as the intergeniculate nucleus, the olivary pretectal nucleus, the superior colliculus, and the lateral geniculate nucleus (LGN) [25,41] and thus contribute to the retinohypothalamic tract (RHT) [64] as well as the optic nerve tract. It should be noted that a small proportion of RGCs making up the RHT are not photosensitive [94], carrying information only from rods or cones.

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The ipRGCs represent a small fraction of all retinal ganglion cells (1 to 3%) but are diffusely spread throughout the retina. They have large sparse dendritic trees (approximately 500 Am, 15- in diameter) that extend into the IPL [99]. Provencio et al. [76] showed that most of the dendrites terminate in the distal sublayer of the IPL, but some also terminate in the more proximal sublayer. (These sublayers are almost always associated with distinct electrophysiological responses to light; neurons forming synapses in the distal sublayer respond with a hyperpolarizing OFF response to light, whereas neurons forming synapses in the proximal sublayer exhibit a depolarizing ON response to light.) Since these dendrites are directly photosensitive [8], they form a large photoreceptive net covering most of the retina [76]. The ipRGCs have lower sensitivity to light than classical photoreceptors (rods and cones) and appear to be specialized to simply encode ambient light intensity [7]. Importantly, the dendrites of the ipRGCs receive input from rods and cones via bipolar cell and amacrine cell connections in the proximal sublayer of the IPL and amacrine cell connections in the distal sublayer of the IPL [5]. All photosensitive systems in the retina (cones, rods, and ipRGCs) therefore are believed to participate in circadian phototransduction [40,70]. These ipRGCs are central to the proposed model. 2.2. Neurons in the S cone pathway Among the three classes of cone photoreceptors, S cones and their neural connections are the most unusual. S cones are usually larger than L and M cones. There are substantially fewer S cones in the human retina than L and M cones (5 to 10% of all cones [22,49,56]), and they are much more diffusely distributed throughout the retina. In fact, S cones are not found in the central human fovea. Unlike the genetically older S cones, the L and M cones in Old World primates (including humans) are organized into spectrally opponent and spatially antagonistic receptive fields that dominate the fovea of these species. L cones are paired with M cones, and vice versa, into small centersurround receptive fields in the fovea. A single L cone or a single M cone forms the center of these receptive fields. This type of pairing forms the foundation for two major channels in the visual system of Old World primates, the red – green (r –g) color opponent channel and the high spatial resolution, contrast-enhancing (through lateral inhibition) achromatic channel [43,52]. The L and M cone spectral – spatial antagonism is largely restricted to the midget pathway in the fovea; surprisingly however, the exact neural foundation for this antagonism remains uncertain [22,23]. Few S cones are part of the midget system [22,23,48]. Unlike the L and M cones, they form distinctive vertical and lateral connections with neurons in the retina. The most common type of S cone bipolar cell projects deep

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into the proximal sublayer of the IPL forming an ON synapse with RGCs that project to the LGN. Other less common giant bistratified bipolar cells have dendritic connections in both the ON and OFF layers of the IPL and are presumed to be part of the S cone pathway [50]. Dacey and Packer [23] demonstrated that bistratified RGCs form blue – yellow (b– y) spectrally opponent connections with ON input from S cones and OFF input from the combination of L and M cones. These bistratified RGCs have large dendritic connections in both the ON and OFF sublayers of the IPL [22,24]. Furthermore, whereas both L and M cones serve as ON and OFF centers in the midget system, recordings of a y-ON and b-OFF bipolar cell in the S cone pathway are rare [25,48]. Finally, in contrast to the spatially opponent receptive fields of the midget system, the receptive fields of S cone pathway are relatively large and are not spatially antagonistic [36]. Thus, unlike the L and M midget RGCs, the ON and OFF receptive field regions of the b– y bistratified RGCs are spectrally opponent but spatially identical, leading to poor contrast sensitivity [23]. Originally, Dacey [22] speculated that the unique morphology of the small bistratified RGCs underlay the spectral opponent, spatially identical receptive field characteristics of the b– y system. More recent studies have shown, however, that color opponency in these cells is probably formed through a unique horizontal cell (HII) connection in the outer plexiform layer (OPL) that feeds back spectrally antagonistic L and M cone signals to the S cone directly [22]. Thus, it is suggested that color opponency in the S cone pathway is formed prior to the bistratified ganglion cells and is a characteristic of bipolar cells in the S cone pathway. The exact reason for the existence of bistratification in the S cone pathway remains unclear; however, this S cone pathway also plays a central role in the proposed model. 2.3. Neurons in the rod system The rod system is diffusely spread throughout the retina and, like the S cone pathway, is excluded from the human fovea which, again, is dominated by the L and M cone midget system. Indeed, the fovea is a photopic (L and M cone) retinal island on the center of the optic axis of the eye, largely unaffected by rods [42]. Rods and peripheral cones ultimately share a common pathway to the brain through the cone bipolar cells; that is, there is no direct connection between rod bipolars and RGCs. The best known link between the rod and cone systems is through the AII amacrine cell [50]. Rod photoreceptors connect to rod bipolar cells, which in turn connect to AII amacrine cells, cone bipolars, and finally to RGCs. Other connections between the rod and cone systems have been identified in the mammalian retina, including a gap– junction coupling between rods and cones [27]. Finally, a third pathway for rod signals was shown in the mouse and

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rat retina whereby rod photoreceptors appear to directly excite OFF cone bipolar cells through ionotropic signconserving glutamate receptors [38]. The best known rod pathway, though, AII amacrine cells, provides direct links to both the ON and the OFF pathways through synapses in both the proximal and the distal sublayers of the IPL, respectively. Through the AII amacrine cells, rods can connect to both ON and OFF RGCs. A primary role of AII amacrine cells then is to make a sign-inverting synapses on the OFF cone bipolars and thus OFF RGCs [19]. Generating OFF responses by RGCs cannot be the only role for amacrine cells in the retina, however. It has been estimated that there are 29 different types of amacrine cells with different pre- and post-synaptic connections, in different sub-lamina of the IPL, having different neurotransmitters, as well as large and small receptive fields [58]. Indeed, there are more types of amacrine cells in the retina than any other type of neuron. Although the exact role of this diverse population of the amacrine cells is unknown, they undoubtedly provide a rich and complicated framework for retinal neural processing, some of which likely are fundamentally important to the circadian system. In the proposed model, AII and A18 amacrine cells [50] provide links between the scotopic (rod) pathway and the photopic (S cone) pathways, both of which influence the behavior of ipRGCs.

3. Electrophysiology Electrophysiological recordings in rodents (rats and mice) and in macaque also show that there is a unique class of RGCs that is directly photosensitive. In particular, Berson et al. [8] have characterized in rats the electrophysiological characteristics of this unique type of RGC containing the novel opsin, melanopsin. Although slow to respond, these ipRGCs depolarize when exposed to light and always show sustained ON excitatory responses to light when isolated from rods and cones. In the intact retina, these cells reflect excitatory ON responses from both rods and cones through both bipolar and amacrine cell connections [5], demonstrating a plausible link between classical photoreceptors and the ipRGCs. Consistently, genetically manipulated mice lacking melanopsin still showed partial circadian entrainment to light and dark [69], indicating, again, that some photic input to the SCN originates from classical photoreceptors. Aggelopoulos and Meissl [1], making electrical recordings in the SCN of rat, showed that this species has both a scotopic (rod) response as well as a photopic (cone) response to light. In humans, only light levels well above cone threshold seem to affect the SCN as evidenced by several outcome measures such as nocturnal melatonin suppression [28,31,53,59,60,68,106]. Aggelopoulos and Meissl [1] showed two general types of responses under low scotopic light levels. Most of the SCN neurons

exhibited ON excitatory responses to light under scotopic conditions; however, others showed ON inhibitory responses to light. From these data, they were able to develop a scotopic-like luminous efficiency response function by the SCN. When they applied light under cone-only (i.e., complete rod bleaching) conditions, all SCN cells signal an ON excitatory response when the light stimulus is applied but generate a distinct OFF inhibitory response when the light was extinguished. They were also able to develop a double-peak photopic luminous efficiency function response to light, consistent with the two known cone photopigments in mouse [44]. Apparently, two photopigments are found in nearly every cone photoreceptor of mouse [4], so a photopic signal to the ipRGC in rodents would also be expected to exhibit a double-peaked spectral response under photopic conditions [15]. These findings from electrophysiology are consistent with the neuroanatomy in mouse from Belenky et al. [5]. They found that most dendrites of the ipRGCs terminate in the OFF distal layer of the IPL, but some also terminate in the ON proximal layer of the IPL. The former OFF layer connections are exclusively with amacrine dendrites, whereas the latter ON layer type has both bipolar and amacrine connections. It is still not known, however, whether the synapses recorded by Belenky et al. [5] are a second population of ipRGCs, different from the ones recorded by Berson et al. [8]. For example, recent data from Dacey and colleagues [25] showed that these ipRGCs also project to the LGN. Nevertheless, from Aggelopoulos and Meissl [1], it can be inferred that, in rodents, depolarizing cone bipolar cells and/or amacrine cells signal an ON depolarizing response to the ipRGCs under both scotopic and photopic conditions through the proximal ON layer of the IPL. It is also possible that, under scotopic conditions, the rod bipolar cells in rodent provide excitatory connections to the ipRGCs through synapses with the AII amacrine and the cone bipolar cells terminating in the proximal ON sublayer of the IPL [50,58]. Since AII amacrine cells also make contacts with RGCs in the distal OFF sublayer of the IPL, they can also provide inhibitory or shunting responses to light to the ipRGCs under photopic conditions. In diurnal humans, the effects on circadian outcome measures from retinal light exposure are very different than they are in nocturnal rodents, although the neural connections in the retina could be quite similar. Melatonin is not suppressed at very low (scotopic) light levels in humans [e.g., [3,53,59,60,79,80, 106]]. Indeed, the circadian systems of rodents, measured through melatonin suppression or phase shifting response, are more than 1000 times more sensitive to light than that of humans (Appendix A), although they have the same rod photopigment, rhodopsin. Thus, humans appear to have a high-threshold mechanism for circadian phototransduction not found in nocturnal rodents. Still, humans probably preserve much of the basic circadian neurology common to mammals.

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4. Psychophysics Lewy and colleagues [53] were the first to demonstrate nocturnal melatonin suppression in humans in response to light. More specifically, they showed in this early study that high light levels of white light were required to suppress nocturnal melatonin. Previous studies had limited success at showing these effects at typical electric lighting levels in buildings [78] because the lighting conditions and exposure durations were below those at which measurable circadian responses are found [53]. Other researchers [e.g., [51, 59,60]] presented results inconsistent with those provided by Lewy et al. [53] showing that nocturnal melatonin suppression could be achieved for relatively short (1 h) exposures to white light producing 500 lx at the cornea; Lewy et al. [53] were unable to show statistically significant nocturnal melatonin suppression at this same light level. Nevertheless, 500 lx at the cornea is comparable to light levels 3 to 5 times higher than those found in electrically illuminated architectural spaces [81], so, as Lewy et al. [53] suggested, light brighter than that commonly found in buildings is required to reliably suppress nocturnal melatonin. (500 lx at the cornea is comparable to about 1500 or 2500 lx measured on a horizontal work surface in an office illuminated by overhead electric lighting.) Lower light levels can, however, produce measurable levels of melatonin suppression if exposure durations are extended to several hours. For example, Zeitzer et al. [106] showed that white light levels comparable to those found in electrically illuminated building interiors (approximately 200 lx at the cornea) not only could suppress nocturnal melatonin but could completely saturate nocturnal melatonin suppression when provided for a duration of 6.5 h. In the same study, Zeitzer et al. [106] were also able to show similar results for shifting circadian phase to light durations of 6.5 h, although slightly higher light levels were required for saturation (approximately 500 lx at the cornea). These fundamental results (both nocturnal melatonin suppression and phase shifting) were obtained in a tightly controlled laboratory environment following several days of preconditioning. Thus, levels of white light higher than those found in electrically illuminated architectural spaces are generally necessary to reliably suppress human nocturnal melatonin unless light exposure durations are fairly long [106]. In general, those conclusions have been supported by a number of authors, such as McIntyre et al. [59,60], Aoki et al. [3], Laakso et al. [51], Owen and Arendt [68], Rea et al. [79,80], and Figueiro et al. [31] for melatonin suppression and Jewett et al. [45], Boivin et al. [11], and Middleton et al. [62] for phase shifting. Although these psychophysical studies showed a consistently high threshold to white light for measurable circadian responses, the mechanisms for phototransduction were impossible to deduce from these studies. It was natural to undertake more precise human psychophysical studies in an attempt to better understand the circadian phototrans-

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duction mechanisms. In parallel studies, published at the same time and providing remarkably consistent findings, Brainard et al. [14] and Thapan et al. [97] measured nocturnal melatonin suppression in response to several narrow-band light sources at different intensities. Several improvements over previous studies were employed by these two sets of authors. Both laboratories partially controlled for circadian phase in their subject population in these studies by applying light at a consistent clock [14] or circadian time [97] and either by screening subjects for shift work, jet lag, or inconsistent sleep patterns [14] or by isolating subjects in the laboratory and controlling their light exposure prior to study [97]. Despite the fact that circadian phase was not rigidly controlled, these procedures do reduce inter-subject variability in the data that would have been caused by large changes in the levels of nocturnal melatonin over the course of the night as well as those that might have resulted from changes in the spectral sensitivity of the circadian system over the night [29]. The two studies did differ in their light exposure durations; Brainard et al. [14] presented lights for 90 min starting at 02:00, while Thapan et al. [97] presented lights for 30 min starting between 23:30 and 02:30, depending upon the subject’s circadian time. Although different in exposure duration and thus expected absolute levels of melatonin suppression, the results for both studies were obtained well within stimulus conditions producing either threshold or saturation for nocturnal melatonin suppression and therefore should be directly comparable for a constant criterion methodology, as discussed below. Furthermore, blood samples for nocturnal melatonin suppression were taken before any possible effects of habituation from prolonged stimulus exposure [e.g., [98]] as evidenced by some of the data from Lockley et al. [54] following 6.5 h of light exposure at 555 nm. Both laboratories also provided well-controlled monochromatic light to the retinae of their subjects unlike many of the earlier studies of circadian phototransduction in humans that failed to properly specify the light stimulus. Often, the spectral power distributions (SPDs) of the light sources used in earlier studies were simply unreported [3,106]. Even when the SPD of the light source was reported, the exact SPD incident on the retina was not precisely known in some studies because of the possible use of optical elements that could modify the SPD of light reaching subjects’ eyes. Because of such limitations, conclusions about the spectral sensitivity of the circadian system based on these studies were compromised. Furthermore, unlike previous studies that utilized constant flux densities incident on the cornea to infer spectral sensitivity (e.g., [12,13]), both sets of authors correctly used criterion suppression values from the fitted dose – response curves from the different narrow-band light stimuli. Utilization of constant flux densities to infer a dose – response curve, as was done in the other studies, assumes a

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linear system of phototransduction. For isolated photopigments, this is a satisfactory approach, but, for in vivo psychophysical measurements, nonlinear post-receptor processes in humans will invariably affect the outcome measure (e.g., those leading to nocturnal melatonin suppression). By establishing a constant criterion response in the recent studies, both sets of authors were able to hold invariant nonlinear post-receptor processes leading to nocturnal melatonin suppression from monochromatic light. Perhaps at the expense of belaboring this important point, different stimulus conditions (e.g., stimulus durations), different experimental protocols (e.g., slight differences in circadian phase), or even different outcome measures (e.g., phase shifting) will, of course, result in different response functions to light stimuli, even if the circadian phototransduction mechanisms are the same. Adapting a constant criterion response methodology is fundamental to deducing the characteristics of circadian phototransduction because of the many differences in experimental procedures, stimuli, and subjects. Absent phenomena exhibited by the circadian system such as threshold and saturation [106] or habituation [54], a constant criterion response methodology obviates the nonlinear response functions to light subsequent to the phototransduction stage. In this regard, the differences between the experimental protocols by Brainard et al. [14] and by Thapan et al. [97] become inconsequential. Thus, as expected, the constant criterion response methodology provides mutual reinforcement between the two studies for representing circadian phototransduction to narrow-band spectra. Although the constant criterion technique utilizing narrow-band spectra is entirely appropriate for characterizing the spectral sensitivity of photoreceptors, even if there are nonlinear responses to light by the photoreceptors themselves, the technique does not isolate individual photoreceptor sensitivity from post-receptor neural interactions that might contribute to circadian phototransduction of polychromatic light. Clearly, there are many post-receptor neural interactions in the human retina, including mechanisms leading to spectral opponency prior to generating RGCs responses sent on to the brain. Of particular significance, the S cone pathway must be considered when trying to characterize the phototransduction mechanisms in the circadian system. Indeed, by employing both monochromatic and polychromatic stimuli, Figueiro et al. [31] showed that the additivity principle [86] appeared to be violated for nocturnal melatonin suppression in humans. Figueiro et al. [31] showed that a spectral opponent mechanism, most likely the b – y system, was necessary to account for nocturnal melatonin suppression measured in response to both monochromatic and polychromatic light. However, the opponent function used by Figueiro et al. [31] was generated without regard for the retinal neuroanatomy and neurophysiology and was completely silent with regard to the high-threshold behavior exhibited by the circadian system relative to the visual system. The model offered

presently attempts to rationalize all of these data into a comprehensive model of phototransduction by the human circadian system. It must be noted, however, that the model is based largely upon human nocturnal melatonin suppression data since they are the most complete and, thus, relevant for the purpose. We are assuming that the model for human circadian phototransduction proposed here is equally useful for characterizing the light stimulus for other outcome measures such as phase shifting and core body temperature as long as the stimulus conditions are between threshold activation and response saturation. One caveat, however, is the assumption that the spectral sensitivity of the circadian system does not change with circadian time. As previously noted, there is some weak evidence to this effect, but the data are not sufficiently robust to justify a more complicated model of circadian phototransduction at this time.

5. Modeling spectral opponency and high threshold Low light level (scotopic) stimulation to the rods does not provide a measurable circadian response in humans [3,53,59,60,62,79,80,106]. According to the proposed model, however, rods are hypothesized to play an important role in circadian phototransduction. Rods could set a high threshold for circadian phototransduction through shunting inhibitory AII amacrine cell connections on the ipRGC dendrites in the distal layer of the IPL [5,50]. The ipRGCs can only give a depolarizing ON response to light [7], so, under certain conditions, the shunting AII input would set a higher than expected threshold to light in the ipRGCs. Thus, despite direct photosensitivity in the ipRGCs [8,39], it is hypothesized that no response can be sent to the SCN until excitation in the ipRGCs exceeds rod inhibition via the AII amacrine cell connections. As light levels increase, the rod response would begin to saturate, reducing the net inhibition until, at still higher light levels, ipRGCs excitation exceeds inhibition. At this point, not only would the ipRGCs response to light begin to stimulate the circadian system at higher light levels, the effects of cones also begin to have an influence on this system. Humans show robust spectral opponency that leads to color vision. Color opponency is formed prior to the RGC layer [21], so a model of human circadian phototransduction must certainly deal with spectral opponency. Furthermore, recent findings by Figueiro et al. [31] have shown evidence for a b – y, but not r– g, spectral opponency in nocturnal melatonin suppression. Thus, one would not expect r– g dichromats (protans and deutans) to show large differences from color-normal individuals in nocturnal melatonin suppression as, in fact, shown by Ruberg et al. [84]. The S cone bipolar gives a bivalent depolarizing ON (blue) and hyperpolarizing OFF (yellow) response to light [21]. The depolarizing ON (blue) response is determined by the S cone with a peak spectral sensitivity near 440 nm; the hyperpolarizing OFF (yellow) response is determined by the sum

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of the L and M cones [91], the spectral sensitivity of which is characterized by V 10k [20,87]. In the proposed model, the S cone bipolar is a giant bistratified bipolar exhibiting b-ON versus y-OFF spectral opponency but not spatial opponency [21,57]. When the S cone bipolar is stimulated with shortwavelength radiation, it contributes to the excitatory depolarizing response of the ipRGC through a bipolar/ RGC synapse in the proximal ON layer of the IPL [5]. However, with long-wavelength radiation, the S cone bipolar cannot directly influence the ipRGC through the ON layer of the IPL because the ipRGC is a depolarizing ON RGC and cannot interpret a hyperpolarizing OFF signal from bipolar cells [58]. In the proposed model, the synapse between the S cone bipolar and the ipRGC in the ON sublayer serves as an electrical diode whereby only depolarizing ON signals, and never hyperpolarizing, OFF signals, are communicated from the S cone bipolar directly to the ipRGC. In this model, the hyperpolarizing OFF signals from the S cone bipolar would be communicated to A18 amacrine cells, a special class of dopaminergic amacrine cells in the OFF sublayer of the IPL. These amacrine cells form a diffuse net throughout the retina and are hypothesized to ‘‘decouple’’ the AII amacrine cells from the ipRGCs [50]. Thus, according to the model, under long-wavelength radiation, the hyperpolarizing OFF response from the S cone bipolar signals the A18 amacrine to release rod inhibition reaching the ipRGC through the AII amacrine cell. Like the synapse between the S cone bipolar and the ipRGC in the ON sublayer of the IPL, the connection between the S cone bipolar and the A18 amacrine cell in the OFF sublayer is also modeled to work like a diode, but, in this case, the diode provides hyperpolarizing OFF signals to the A18 amacrine cell, but never depolarizing ON signals. In the proposed model, the spectral opponent cross-point (near 500 nm [103]) is extremely important. At high light levels where cones are active and for radiation longer than the approximate 500-nm cross-point, the spectral response of the SCN is based upon the intrinsic photosensitive response of the ipRGC alone. Under these conditions, it is expected that the ipRGC would be entirely free from rod inhibition and is able to directly express its photosensitivity to light to the SCN. At high light levels where cones are active and for radiation shorter than the cross-point, the spectral response of the SCN is modeled as a combination of the response from the ipRGC, the S cone (via the S cone bipolar), and the loss of shunting inhibition by rods. It is important to explain this last input to the absolute and the spectral response of human circadian phototransduction in more detail. Rods are hypothesized not only to set the absolute threshold to light, they also would indirectly impact the spectral sensitivity of circadian phototransduction. As the inhibitory rod response begins to saturate, the combined excitatory responses from the S cone bipolar and the ipRGC can begin to grow. However, the neural signals to the SCN are hypothesized to be based not simply upon the excitatory responses of the S cone bipolar and the ipRGC, but on a loss

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of inhibition from the rods response as well. The spectral sensitivity of circadian phototransduction would reflect this loss of inhibition by the rod mechanism as a positive addition to overall spectral sensitivity. A loss of inhibition serves as a mathematical ‘‘double negative’’ contribution to spectral sensitivity and, thus, is identical to a positive contribution from rods to the overall spectral response of human circadian phototransduction. Significantly then, rod inhibition not only reduces overall sensitivity to light by the circadian system according to the model, but, after rod saturation begins, the loss of inhibition (i.e., the double negative) adds to its spectral sensitivity. Fig. 1a shows a diagram of the proposed model for human circadian phototransduction described above, and Eq. (1) provides a mathematical expression of the model constrained to be consistent with the neurophysiology and neuroanatomy illustrated in Fig. 1a. Fig. 1b shows an electrical circuit representation of the hypothesized model, unconstrained by the hypothesized neurology. As discussed below, the model is capable of predicting the available nocturnal melatonin suppression data obtained under both monochromatic [14,97] and polychromatic light stimulation [31,59,79,80].  Z  CS ¼ a1 Mk Pk dk  b1 / a2 Z     Z XVkV Pk dk rodSat  Sk Pk dk  k V10k Pk dk  b2  a3 1  e Z Z for Sk Pk dk  k V10k Pk dk  0 Z CS ¼ a1 Mk Pk dk  b1 Z Z for Sk Pk dk  k V10k Pk dk <0 ð1Þ where: / Mk

V 10k V kV Sk Pk Parameters k = 0.31, a 1 = 0.285, a 2 = 0.2, a 3 = 0.72 Constants b 1 = 0.01, b 2 = 0.001, rodSat = 6.5 CS

is a diode mathematical operator explained in the text, is the melanopsin-containing retinal ganglion cell spectral efficiency function peaking at 480 nm [92], is the large-field L + M cone spectral efficiency function [20,87], is the rod spectral efficiency function [20], is the S cone spectral efficiency function [91], is the spectral irradiance at the eye (W/m2/nm), represent the interactions among photoreceptor types,

represent the thresholds and dynamic characteristics of the photoreceptor types as described below, and (circadian stimulus) is in units of circadian spectrally weighted irradiance (weighted W/m2).

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The terms in Eq. (1) represent the responses of the ipRGC, the rods, and the b – y opponent signal. The magnitude of the ipRGC response is modeled by a simple linear equation with values a 1 and b 1. b 1 sets a sensitivity threshold, while a 1 determines the relative signal strength. The rod response is modeled by the exponential term which was obtained from fitting the rod bleaching data from Alpern and Ohba [2] (see Fig. 2). rodSat is the saturation

constant defining the irradiance level at which ¨63% of the rods are bleached. The b– y opponent signal is modeled by subtracting the L + M signal, with a spectral response given by V 10k from the S cone response. The L + M signal is multiplied by the constant k which is less than unity to be consistent with excitation being stronger than inhibition in the b – y opponent mechanism. As with the ipRGCs response, the magnitude and threshold of the b– y response are modeled by a linear equation with values a 2 and b 2. Fig. 2 plots the relative signal strengths according to the above equation terms for three monochromatic wavelengths. Evident from this figure are the different thresholds for the three wavelengths and the saturation of the rod signal for irradiance levels exceeding 10,000 scotopic lx. (Neither cone nor ipRGC saturation is modeled in Fig. 2, as these effects probably require irradiance levels above those used to test nocturnal melatonin suppression.) The relative positions of the curves change for different stimulus wavelengths, as do the crossover points due to the different spectral sensitivities of the photoreceptors involved. The mathematical operator, Q, is worth special mention. It symbolizes an electrical diode, a device that permits current flow in only one direction. When the b– y term to the right of the operator is positive, it is added to the equation, modeling the additional depolarization of the ipRGC in response to short wavelength (blue) radiation. When the b –y term is negative, however, it does not subtract from the right side of the equation, modeling the inability of the ipRGC to respond to a hyperpolarizing (yellow) signal. CS in Eq. (1) is the instantaneous circadian stimulus, in weighted irradiance units, that when applied over time produces a given circadian dose –response value. Although CS can be used to generate a spectral sensitivity to a particular SPD, it does not behave as a conventional action spectrum. Action spectra imply additivity in spectral sensitivity. Radiant power weighted by an action spectrum can be simply summed to predict response. According to the model represented by Eq. (1), however, additivity is not obeyed by human circadian phototransduction because of nonlinear characteristics affecting its spectral sensitivity. For example, the loss of inhibition by rods as light levels Fig. 1. (a) Rod bipolars (rb), through excitatory input (er) to the AII amacrine cells, provide shunting inhibition (s) to the dendrites of depolarizing (ON) melanopsin-containing retinal ganglion cell (ipRGC), elevating their intrinsic photosensitivity (ip) absolute threshold. The bistratified S cone bipolar (scb) signals ‘‘blue’’ (depolarization, eb) or ‘‘yellow’’ (hyperpolarization, ey) and has a cross-point (neutral or unique green) wavelength at 500 nm. The ‘‘blue’’ signal from the scb adds to the sensitivity of the ipRGC to gradually overcome the shunting inhibition as light levels increase. This gradual net loss of rod inhibition serves to add a double negative, or positive, response to the overall spectral response of the circadian system for wavelengths shorter than 500 nm. The ‘‘yellow’’ signal from the scb decouples (d) the rod inhibition via A18 amacrine cells and reveals the ip absolute threshold of the ipRGC for wavelengths longer than 500 nm. (b) Electrical circuit representation of the proposed model for circadian phototransduction.

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Fig. 2. Relative magnitudes of the signals involved with the circadian system as modeled by Eq. (1). The curve ‘‘Melanopsin’’ represents the ipRGCs. Each plot is for a different stimulus wavelength as indicated. The b – y signal is absent from the plot on the right because for that wavelength the signal is negative (hyperpolarizing).

increase affects the spectral sensitivity of human circadian phototransduction as a ‘‘double negative’’ addition of rod spectral sensitivity. The amount of ‘‘double negative’’ addition to the spectral sensitivity of human circadian phototransduction decreases as light levels increase. Thus, the stimulus to the circadian system varies from the threshold for circadian activation to the saturation of circadian response. This nonlinear feature of the model confounds simple multiplication of radiant power incident on the retina with a particular action spectrum. As a consequence, the spectral sensitivity of the circadian system will vary from threshold to saturation with the SPD of the source. The spectral opponency predicted by Eq. (1) also results in additivity failures. Nevertheless, for specific circadian response criteria (e.g., specific levels of nocturnal melatonin suppression), Eq. (1) makes it possible to generate predicted dose – response functions for both monochromatic and polychromatic light sources. Again, this should be true for any specific response (e.g., phase shifting) criterion despite potentially very different neural and hormonal responses subsequent to light-induced activation of the SCN.

6. Predictions from the model for different light sources 6.1. Dose –response functions The model predicts that rods set the threshold for circadian phototransduction exemplified by nocturnal melatonin suppression. Again, we are limiting our predictions to

those data most suitable for testing the model. Converging verifications of the model must wait until more data are obtained for other criterion response functions (e.g., phase shifting) or until data are gathered for different exposure conditions using nocturnal melatonin suppression (e.g., time to habituation). Fig. 3 shows the calculated relationship between rhodopsin bleaching in rods and circadian activation as white light levels increase. The rod saturation curve is from Alpern and Ohba [2], and the nocturnal melatonin suppression curve is from McIntyre et al. [59] and Rea et al. [79,80]. One way to relate the two sets of data is to relate the scotopic retinal illuminances from Alpern and Ohba [2] to the photopic illuminances on the cornea from McIntyre et al. [59] and Rea et al. [79,80] using the following procedures. McIntyre et al. [59] measured melatonin suppression from a light box containing ‘‘full spectrum’’ fluorescent lamps for 1 h over a range of photopic illuminance levels (measured at the cornea) from 200 to 3000 lx. The highest suppression value McIntyre et al. [59] found was 71% with 3000 lx. The circadian response function in Fig. 3 assumes a maximum possible suppression value of 75%, which is usually the highest level of nocturnal melatonin suppression observed in the literature from brief (0.5 to 1.5 h) light exposures [14,59,97] and, for this comparison, sets that absolute value as a 100% relative response value. Similarly, data from Rea et al. [79,80] are included in Fig. 3. Rea et al. [79,80] measured melatonin suppression at several times during their experimental sessions; only the data corresponding to light exposure for 1 h starting at 03:00 (the closest time to that used by Brainard et al. [14] and Thapan et al. [97]) are shown in Fig. 3.

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Fig. 3. Relative suppression of nocturnal melatonin from McIntyre et al. [59] and from Rea et al. [79,80], together with the percentage of rhodopsin bleached from Alpern and Ohba [2], as a function of photopic illuminance at the cornea.

Alpern and Ohba [2] related steady-state pupil size to scotopic retinal illuminance, in trolands (Td). Unit Td are defined as the product of field luminance, in cd/m2, and pupil area, in mm2 [78]. Given the full field of view in the Alpern and Ohba [2] study, the illuminance at the cornea was calculated from the scotopic luminances derived in turn from the scotopic Td [78]. To convert scotopic illuminance to photopic illuminance, these values are divided by the estimated scotopic/photopic ratio [6] of the tungsten filament source (1.4) used by Alpern and Ohba in their study [2]. Rushton [85,86] reported the fraction of bleached rhodopsin in the rod photoreceptors as a function of scotopic retinal illuminance (i.e., Td). With this information, it was possible to calculate the percentage of rhodopsin bleached in the Alpern and Ohba study [2] as a function of photopic illuminance at the cornea from the lamp spectrum assumed to be used by McIntyre et al. [59]. In similar manner, the relative melatonin suppression data of Rea et al. [79,80] are also included in Fig. 3. Despite the differences in SPDs among the lamps used by McIntyre et al. [59] and by Rea et al. [79,80], the relative melatonin suppression data fall closely along a single, monotonic function of illuminance, shown in Fig. 3. As can be seen in Fig. 3, the two curves share a common characteristic. Namely, both melatonin suppression and significant amounts (>1%) of rhodopsin bleaching begin at the same photopic illuminance incident on the cornea. This plot provides indirect evidence that melatonin suppression begins near the level of rod bleaching and, thereby, that the net level of rod inhibition might progressively

decline as more rhodopsin is bleached. As rod inhibition declines and excitation by the ipRGC increases, this compounding effect could rapidly lead to SCN-induced nocturnal melatonin suppression as light levels increase. This hypothesized compounding effect is exemplified in Fig. 3 by the much steeper nocturnal melatonin suppression response function than the rhodopsin bleaching function. Although Fig. 3 suggests that rods could be involved in setting threshold for circadian phototransduction, it is necessary for a successful model to predict an entire dose – response function like that shown in Fig. 3 (as described earlier, neither cone nor ipRGC saturation is incorporated into the model because of the high irradiances at which these phenomena occur, relative to rod saturation). The data from McIntyre et al. [59] as well as those from Rea et al. [79,80] using several different polychromatic light sources are plotted in Fig. 4, together with data from Brainard et al. [14] and Thapan et al. [97] using monochromatic sources. Because the data from Brainard et al. [14] and Thapan et al. [97] were not given in a tabular form, the values were determined from digitized versions of the published graphs, using a similar methodology described elsewhere [80]. All data are plotted as a function of CS, the magnitude of the circadian stimulus needed to produce a criterion level of melatonin suppression. Because Brainard et al. [14] and Thapan et al. [97] used dilated pupils in their studies, the irradiances in their studies are adjusted upward by a factor of 8.6 to account for the increased retinal illuminances in those studies. This factor assumes a 7.3 mm diameter dilated pupil, based on Gaddy et al. [35] who used pupil dilation, and a 2.5 mm average natural pupil diameter in the studies using polychromatic light based on measurements by Rea et al. [79]. Of note, the melatonin suppression data to the 555nm stimuli used by Brainard et al. [14] are not included in this figure. According to the dose – response curves published by Brainard et al. [14] for 530 and 555 nm, these two wavelengths (when approximately equated for irradiance) resulted in similar amounts of melatonin suppression, but the spectral sensitivity published by Brainard et al. [14] indicates that light at 555 nm is only about one-fourth as effective as light at 530 nm for melatonin suppression, which is consistent with the data of Thapan et al. [97]. Because of this unresolved discrepancy in the published report by Brainard et al. [14], the 555-nm data were excluded from the regression and from Fig. 4. Also included in this figure but not included in the analysis are the 600-nm data of Brainard et al. [14]. This wavelength is sufficiently long that the response of ipRGCs at this wavelength is very low, leading to a large ratio of the predicted to the measured sensitivity, even though the difference between the predicted and measured sensitivity is very low (a few percent). Measurements of outcome measures associated with such conditions result in low signal-to-noise ratios that make such outcome measures difficult to predict by any model.

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Fig. 4. Melatonin suppression data from McIntyre et al. [59], Rea et al. [79,80], Brainard et al. [14], Thapan et al. [97], and Figueiro et al. [31], plotted as a function of CS. Goodness of fit of the data to the sigmoid function (r 2) is 0.82. Where noted, data are indicated by first author (B: Brainard, T: Thapan). For Brainard et al. [14] (B) and Thapan et al. [97] (T), numbers indicate peak wavelengths used by those authors. For Rea et al. [79,80], SPDs are as follows: W: warm (3000 K), M: mixed (3000 K + 7500 K), C: cool (7500 K) fluorescent lamps.

Furthermore, the irradiances for the Thapan et al. [97] data are scaled down by an empirical factor of 1.8, to account for the shorter duration of light exposure in that study (30 min) compared to Brainard et al. [14] (90 min). Comparison of the data by Brainard et al. [14] and Thapan et al. [97] showed that the melatonin suppression data were consistently offset along the irradiance axis by about this factor of 1.8. The fact that this ratio is not equal to 3.0 (the ratio of light exposure duration) demonstrates a violation of time – intensity reciprocity for nocturnal melatonin suppression. Finally, Fig. 4 includes the melatonin suppression data of Figueiro et al. [31] who used a polychromatic and a nearly monochromatic light to test nocturnal melatonin suppression. In Fig. 4, nocturnal melatonin suppression values below 10% suppression were excluded because, for these values, the typical standard errors of the mean were large enough that these suppression values were not necessarily different from zero. As can be seen in Fig. 4, the model provides good predictions (r 2 = 0.82) of the data based upon nocturnal melatonin suppression from several monochromatic and polychromatic light sources, when the melatonin suppression data are fit to a logistic sigmoid [106] function of the CS value. As mentioned above, the model is also able to predict the rank order of the data from Figueiro et al. [31] who were able to show spectral opponency by human circadian phototransduction. Figueiro et al. [31] showed a surprising disparity between the flux densities needed to suppress human nocturnal melatonin after 1 h of exposures to narrow-band blue light (LED, k max = 470 nm) and to polychromatic white light (mercury vapor). The white light source required ¨170 AW/cm2 (450 lx) at the eye to suppress nocturnal melatonin by 18%, consistent with

earlier findings using white light [59,79,80], whereas the blue light source only required only ¨29 AW/cm2 (18 lx) to suppress nocturnal melatonin by 34%, consistent with earlier findings using nearly monochromatic light [14,97]. The model predicts greater nocturnal melatonin suppression for the blue light than for the white light exposure. 6.2. Spectral sensitivity According to the model, polychromatic light sources producing a net depolarizing response by the S cone bipolar could add to the ipRGC response to light, as with the blue LED, whereas polychromatic white light, such as a mercury vapor light, would produce no signal from the opponent S cone bipolar cell. In the latter case, as with sources producing a net hyperpolarizing response that is hypothesized to release rod inhibition, human circadian phototransduction is driven by the spectral sensitivity of the ipRGC alone (i.e., peaking at 480 nm). Spectral opponency from the S cone bipolar, however, is interpreted as a modulation of the depolarizing response sent by the S cone bipolar to the ipRGC. Thus, spectral opponency in circadian phototransduction can only be directly demonstrated for polychromatic light and only where the magnitude of the response by the ipRGC is affected by the level of the depolarization signal received from the S cone bipolar. Again, due to the nature of the ipRGC cells and the hypothesized diode connections from the S cone bipolar, spectral opponency in circadian phototransduction can only be exhibited as a decrease in the magnitude of depolarization, but not as a hyperpolarization. Brainard et al. [14] and Thapan et al. [97] developed their spectral sensitivities using monochromatic light sources. They selected the same melatonin suppression criterion, 35% suppression (half the maximum of about 70% they

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each found in their studies), and plotted the relative intensity required at each of the wavelengths they tested. When the model predictions for this criterion level of melatonin suppression are plotted as a function of single wavelength exposures (Fig. 5), they demonstrate close agreement with the data of Brainard et al. [14] and of Thapan et al. [97], as would be expected from a constant criterion response methodology. It should be noted that the sharp discontinuity between the predictions for 496 nm and 505 nm is an inherent feature of the model. For wavelengths longer than the cross-point for the S cone bipolar (about 500 nm [103]), circadian phototransduction is driven by the inherent photosensitivity of the ipRGC, having a peak spectral sensitivity at 480 nm [8,92]. For wavelengths shorter than the cross-point, the spectral stimulus of circadian phototransduction is the result of the ipRGC melanopsin, the S cone bipolar response, which is driven largely by the S cone peaking at 440 nm, and, finally, the double negative rod response which also lowers the overall sensitivity of the circadian system to light shorter than the cross-point at about 500 nm. It is worth emphasizing that the cross-point for the b – y system in color vision is at about 500 nm [103], consistent with the predictions from this model. The shaded area of Fig. 5 demonstrates the range of predictions with the model if the rod saturation through the A18 amacrine cell is modeled as an instantaneous switch as in Eq. (1) (the sharp discontinuity in Fig. 5) or if rod saturation gradually incorporates increasing activity of the ipRGCs (the curved ‘‘elbow’’ in Fig. 5). This gradual feature can be modeled by a diode-like action occurring at the A18 amacrine cell that controls rod inhibition of the ipRGCs. According to such a model, when the b– y signal becomes negative, it switches off rod inhibition gradually, eventually

allowing for full signal strength from the ipRGCs before rods are completely bleached, as modeled in Eq. (2), which replaces the exponential term in Eq. (1) with the term below:   R  R XVkVPk dk a3 1  e rodSat 1  e40 Sk Pk dkk V10k Pk dk

ð2Þ

As Fig. 5 indicates, some gradual incorporation of rod saturation is not inconsistent with the melatonin suppression data of Brainard et al. [14] and of Thapan et al. [97], but, clearly, there are insufficient data to resolve this feature of the model. The model predicts that polychromatic light sources will have their own unique spectral sensitivity functions for a criterion level of circadian response. Although the model predictions are based upon the best available information, it seems highly likely that the model will be revised as more information on circadian phototransduction is acquired. For example, there is some evidence from our laboratory that the spectral sensitivity of the circadian system changes throughout the night [29], and, thus, nocturnal melatonin suppression early in the circadian dark phase may have a different spectral sensitivity relative to that late in the dark phase. Photic light history also plays an important role in circadian sensitivity (e.g., [93]). Furthermore, it is not known for certain whether circadian phototransduction leading to phase shifting and to nocturnal melatonin suppression are the same [66], but there are no data available in the literature that would suggest otherwise. Nevertheless, this is the first complete model for framing phototransduction by the human circadian system and can serve as a basis for generating hypotheses about light exposures from different sources and at different intensities.

Fig. 5. Predictions of the model to the constant criterion spectral sensitivity data of Brainard et al. [14] and of Thapan et al. [97], bounded by the hypothesized modes of action by the A18 amacrine cell.

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7. Discussion The model proposed in the present paper was designed to be consistent with data obtained from psychophysics, electrophysiology, and neuroanatomy. Therefore, the mathematical model in Eq. (1) has the distinct virtue of being plausible with respect to human biology. The model also has the virtue of being parsimonious. The diode mathematical operator is quite simple, and there are very few coefficients modifying the relative magnitudes of the terms in Eq. (1). Although these coefficients may change as new data are acquired, at this early stage of model development, the virtues of a simple model outweigh those of a more complicated model based upon limited data. Finally, the model does not address the wide range of responses generated by the circadian system to all of the other very important aspects of the luminous stimulus, namely, spatial distribution, timing and duration of exposure, and history of previous photic exposure. Specification of these stimulus variables is obviously essential for accurately predicting the many biological responses to light by the circadian system [81]. The proposed model simply deals with characterizing the photic input to the circadian system, not its subsequent effects on the wide range of biological responses that could be measured (e.g., phase shifting, core body temperature, alertness). The proposed model may be further limited, as already noted, if the spectral sensitivity of the circadian system changes over the course of the night [29]. Nevertheless, the proposed model lays out a plausible architecture of the neural pathways that can be extended to accommodate new data and insights into human circadian phototransduction as they become available. Of some practical significance, the present model facilitates the discussion of practical aspects of architectural lighting and provides much better insight into the growing discussion of the relationship between light and health (e.g., [95]). In particular, it should now be possible to provide more precise characterization of the light stimulus to the circadian systems of individuals such as seniors who suffer from Alzheimer’s disease [30], premature infants in the neonatal intensive care unit [63,83], and shift workers [10]. It is hoped that the model will lead to more rapid progress in architectural applications where light can be an effective clinical tool or a promoter of productivity. Clearly, too, the model also helps to quantitatively frame the ongoing discussion about the impact of light at night (LAN) on circadian disruption [95].

Acknowledgements We appreciatively acknowledge Dennis Guyon from the Lighting Research Center (LRC) who assisted with the preparation of graphics and Judith B. Thorpe and Charles R. Fay from the LRC who provided bibliographic assistance.

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David Berson from Brown University provided helpful comments on a previous draft of this manuscript. We also gratefully acknowledge the two anonymous reviewers whose comments helped clarify our manuscript.

Appendix A Melatonin suppression in rodents Circadian regulation by light in mammals occurs through the retina [67]. Lucas et al. [55] reported data on nocturnal melatonin suppression in wild-type mice (with intact rod and cone photoreceptors) from a 15-min pulse of light at 506 nm. This wavelength is near the peak for spectral sensitivity of the circadian system in rodents [15,18,73, 96,104]. Lucas et al. [55] showed that a level of about 0.001 AW/cm2 resulted in about half the maximum level of melatonin suppression, while about 0.03 AW/cm2 resulted in a maximum amount of melatonin suppression. Reiter [82] summarized the time course of melatonin suppression from a series of studies in different rodent species and found the approximate time to achieve half the maximum suppression of melatonin that could be achieved with a particular irradiance was, on average, about 8 min (for Richardson’s ground squirrels and Sprague – Dawley rats), but it could be as short as 2 min (for cotton rats). Melatonin suppression in humans Brainard et al. [14] measured nocturnal melatonin suppression in humans from 460-nm light (this wavelength is near the peak for melatonin suppression in humans) and achieved a half-maximum suppression (after 90 min) with 3 AW/cm2 of light from this source. Brainard et al. [14] dilated subjects’ pupils, so the adjusted irradiance for someone with normally constricted pupils would be about eight times higher, or 24 AW/cm2. The maximum amount of suppression was achieved from the same source when its irradiance was about 10 times higher than that needed for the halfmaximum response, or about 240 AW/cm2. Comparison Using suppression of nocturnal melatonin as the criterion, humans require significantly more light (approaching four log units more) and for a longer duration (perhaps a log unit longer) than rodents to produce an equivalent percentage suppression of melatonin. These data underscore the importance of understanding differences between species when utilizing them as models for understanding circadian phototransduction in humans. Nevertheless, with care, a photometric link between humans and rodents can be calculated and used to quantitatively relate the impact of light exposure on circadian activation and melatonin suppression.

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