Mark Rollag - Academia.edu (original) (raw)
Papers by Mark Rollag
Methods in Enzymology, 2000
Journal of …, Jan 1, 2001
Journal of pineal research, Jan 26, 2015
The basic goal of this research is to determine the best combination of light wavelengths for use... more The basic goal of this research is to determine the best combination of light wavelengths for use as a lighting countermeasure for circadian and sleep disruption during space exploration, as well as for individuals living on Earth. Action spectra employing monochromatic light and selected monochromatic wavelength comparisons have shown that short wavelength visible light in the blue-appearing portion of the spectrum is most potent for neuroendocrine, circadian, and neurobehavioral regulation. The studies presented here tested the hypothesis that broad spectrum, polychromatic fluorescent light enriched in the short wavelength portion of the visible spectrum is more potent for pineal melatonin suppression in healthy men and women. A total of 24 subjects were tested across three separate experiments. Each experiment used a within-subjects study design that tested eight volunteers to establish the full-range fluence-response relationship between corneal light irradiance and nocturnal pl...
Science, 2002
like the latter two groups, mammals lack functional extraocular photoreceptors (28); thus, redund... more like the latter two groups, mammals lack functional extraocular photoreceptors (28); thus, redundancy in photoreception is confined to the retina. One challenge is to determine the relative contributions of melanopsin, rod/cone opsins, cryptochromes, and other currently uncharacterized photopigments in communicating photic information to the circadian system.
Proceedings of the National Academy of Sciences, 2001
The daily rhythm in melatonin levels is controlled by cAMP through actions on the penultimate enz... more The daily rhythm in melatonin levels is controlled by cAMP through actions on the penultimate enzyme in melatonin synthesis, arylalkylamine N-acetyltransferase (AANAT; serotonin N-acetyltransferase, EC 2.3.1.87). Results presented here describe a regulatory͞ binding sequence in AANAT that encodes a cAMP-operated binding switch through which cAMP-regulated protein kinasecatalyzed phosphorylation [RRHTLPAN 3 RRHpTLPAN] promotes formation of a complex with 14-3-3 proteins. Formation of this AANAT͞14-3-3 complex enhances melatonin production by shielding AANAT from dephosphorylation and͞or proteolysis and by decreasing the Km for 5-hydroxytryptamine (serotonin). Similar switches could play a role in cAMP signal transduction in other biological systems.
Proceedings of the National Academy of Sciences, 1998
We have identified an opsin, melanopsin, in photosensitive dermal melanophores of Xenopus laevis.... more We have identified an opsin, melanopsin, in photosensitive dermal melanophores of Xenopus laevis. Its deduced amino acid sequence shares greatest homology with cephalopod opsins. The predicted secondary structure of melanopsin indicates the presence of a long cytoplasmic tail with multiple putative phosphorylation sites, suggesting that this opsin's function may be finely regulated. Melanopsin mRNA is expressed in hypothalamic sites thought to contain deep brain photoreceptors and in the iris, a structure known to be directly photosensitive in amphibians. Melanopsin message is also localized in retinal cells residing in the outermost lamina of the inner nuclear layer where horizontal cells are typically found. Its expression in retinal and nonretinal tissues suggests a role in vision and nonvisual photoreceptive tasks, such as photic control of skin pigmentation, pupillary aperture, and circadian and photoperiodic physiology.
PLoS ONE, 2008
Non-image related responses to light, such as the synchronization of circadian rhythms to the day... more Non-image related responses to light, such as the synchronization of circadian rhythms to the day/night cycle, are mediated by classical rod/cone photoreceptors and by a small subset of retinal ganglion cells that are intrinsically photosensitive, expressing the photopigment, melanopsin. This raises the possibility that the melanopsin cells may be serving as a conduit for photic information detected by the rods and/or cones. To test this idea, we developed a specific immunotoxin consisting of an anti-melanopsin antibody conjugated to the ribosome-inactivating protein, saporin. Intravitreal injection of this immunotoxin results in targeted destruction of melanopsin cells. We find that the specific loss of these cells in the adult mouse retina alters the effects of light on circadian rhythms. In particular, the photosensitivity of the circadian system is significantly attenuated. A subset of animals becomes non-responsive to the light/dark cycle, a characteristic previously observed in mice lacking rods, cones, and functional melanopsin cells. Mice lacking melanopsin cells are also unable to show light induced negative masking, a phenomenon known to be mediated by such cells, but both visual cliff and light/ dark preference responses are normal. These data suggest that cells containing melanopsin do indeed function as a conduit for rod and/or cone information for certain non-image forming visual responses. Furthermore, we have developed a technique to specifically ablate melanopsin cells in the fully developed adult retina. This approach can be applied to any species subject to the existence of appropriate anti-melanopsin antibodies. Citation: Gö z D, Studholme K, Lappi DA, Rollag MD, Provencio I, et al. (2008) Targeted Destruction of Photosensitive Retinal Ganglion Cells with a Saporin Conjugate Alters the Effects of Light on Mouse Circadian Rhythms. PLoS ONE 3(9): e3153.
Journal of Pineal Research, 1993
single injection of adrenergic agonists enhances pineal melatonin production in Turkish hamsters.... more single injection of adrenergic agonists enhances pineal melatonin production in Turkish hamsters. J. Pineal Res. 1993:14:138-144. Abstract: The purpose of this study was to determine whether the pineal gland of Turkish hamsters (Mesocricetus brandti) responds to adrenergic agonists with an increase in melatonin production, and, if it does, whether the sensitivity of the pineal gland to agonists would differ throughout the dark phase. Adult Turkish hamsters weighing 110-210 g received a subcutaneous injection of isoproterenol (ISO, 1 mg/kg B.W.) or norepinephrine (NE, 1 mg/kg B.W.) at different times of night. Animals exposed to LD 16:8 responded to IS0 or NE with increased pineal melatonin content only when injected at dawn, when endogenous melatonin is at basal or near-basal levels. When the 8 hr scotophase was entirely replaced with light, the responsiveness to IS0 injections at dawn disappeared. In animals exposed to light from 30 min prior to melatonin content (P < 0.005, three-way ANOVA), which varied, depending on the specific time of injection (effect of time of night, P < 0.05, three-way ANOVA). These results demonstrate that adrenergic agonists enhance the production of pineal melatonin in Turkish hamsters, (2) this stimulatory effect takes place late, but not early in the 8 hr scotophase, and ( 3 ) the adrenergic induction of pineal melatonin production in Turkish hamsters requires priming by darkness during the appropriate circadian phase. I injection to the time of sacrifice, I S 0 injections increased pineal
Journal of Pineal Research, 2004
Journal of Neurochemistry, 2005
The avian retina and pineal gland contain autonomous circadian oscillators and photo-entrainment ... more The avian retina and pineal gland contain autonomous circadian oscillators and photo-entrainment pathways, but the photopigment(s) that mediate entrainment have not been definitively identified. Melanopsin (Opn4) is a novel opsin involved in entrainment of circadian rhythms in mammals. Here, we report the cDNA cloning of chicken melanopsin and show its expression in retina, brain and pineal gland. Like the melanopsins identified in amphibians and mammals, chicken melanopsin is more similar to the invertebrate retinaldehydebased photopigments than the retinaldehyde-based photopigments typically found in vertebrates. In retina, melanopsin mRNA is expressed in cells of all retinal layers. In pineal gland, expression was strong throughout the parenchyma of the gland. In brain, expression was observed in a few discrete nuclei, including the lateral septal area and medial preoptic nucleus. The retina and pineal gland showed distinct diurnal expression patterns. In pineal gland, melanopsin mRNA levels were highest at night at Zeitgeber time (ZT) 16. In contrast, transcript levels in the whole retina reached their highest levels in the early morning (ZT 0-4). Further analysis of melanopsin mRNA expression in retinal layers isolated by laser capture microdissection revealed different patterns in different layers. There was diurnal expression in all retinal layers except the ganglion cell layer, where heavy expression was localized to a small number of cells. Expression of melanopsin mRNA peaked during the daytime in the retinal pigment epithelium and inner nuclear layer but, like in the pineal, at night in the photoreceptors. Localization and regulation of melanopsin mRNA in the retina and pineal gland is consistent with the hypothesis that this novel photopigment plays a role in photic regulation of circadian function in these tissues.
Journal of Magnetic Resonance Imaging, 1994
Production of melatonin, a hormone synthesized and secreted by the pineal body, has been suppress... more Production of melatonin, a hormone synthesized and secreted by the pineal body, has been suppressed by electromagnetic fields in some but not all animal studies. Magnetic resonance (MR) imaging at 1.5 T was evaluated for its ability to modulate the level of melatonin in eight male volunteers. Subjects were exposed to three conditions, respectively, between 1:00 and 2:00 AM on different nights: (a) a series of routine MR pulse sequences for brain imaging in dark conditions, (b) dark control conditions, and (c) bright-light control conditions. Plasma was analyzed for melatonin and cortisol levels. Hormonal changes were analyzed by one-factor repeated measures within-subject analysis of variance. These conditions were associated with significant differences in melatonin levels: F(2, 6) = 7.95, and P = .021. Subjects exposed to darkness showed a typical increase in melatonin concentration. Subjects exposed to bright light showed a characteristic suppression of melatonin concentration. Those exposed to the MR imaging fields showed an increase in melatonin level similar to that seen in the dark control condition. Light and MR imaging had no significant effects on cortisol levels. Thus, MR imaging at field strengths known to modulate melatonin levels in rats did not suppress melatonin production in human subjects.
Journal of biological …, Jan 1, 2003
Journal of Biological Rhythms, 2003
An understanding of the retinal mechanisms in mammalian photoentrainment will greatly facilitate ... more An understanding of the retinal mechanisms in mammalian photoentrainment will greatly facilitate optimization of the wavelength, intensity, and duration of phototherapeutic treatments designed to phase shift endogenous biological rhythms. A small population of widely dispersed retinal ganglion cells projecting to the suprachiasmatic nucleus in the hypothalamus is the source of the critical photic input. Recent evidence has shown that many of these ganglion cells are directly photosensitive and serve as photoreceptors. Melanopsin, a presumptive photopigment, is an essential component in the phototransduction cascade within these intrinsically photosensitive ganglion cells and plays an important role in the retinal photoentrainment pathway. This review summarizes recent findings related to melanopsin and melanopsin ganglion cells and lists other retinal proteins that might serve as photopigments in the mammalian photoentrainment input pathway.
Journal of Affective Disorders, 2009
Background-Melanopsin, a non-visual photopigment, may play a role in aberrant responses to low wi... more Background-Melanopsin, a non-visual photopigment, may play a role in aberrant responses to low winter light levels in Seasonal Affective Disorder (SAD). We hypothesized that functional sequence variation in the melanopsin gene (Opn4) could contribute to increasing the light needed for normal functioning during winter in SAD.
Chronobiology International, 2006
Early studies on rodents indicated that the long-wavelength portion of the spectrum (orange- and ... more Early studies on rodents indicated that the long-wavelength portion of the spectrum (orange- and red-appearing light) could influence circadian and neuroendocrine responses. Since then, both polychromatic and analytic action spectra in various rodent species have demonstrated that long-wavelength light is very weak, if not entirely inactive, for regulating neurobehavioral responses. Since testing of monochromatic light wavelengths above 600 nm is uncommon, many researchers have assumed that there is little to no effect of red light on the neuroendocrine or circadian systems. The aims of the following studies were to test the efficacy of monochromatic light above 600 nm for melatonin suppression in hamsters and humans. Results in hamsters show that 640 nm monochromatic light at 1.1 x 10(17) photons/cm2 can acutely suppress pineal melatonin levels. In normal healthy humans, equal photon density exposures of 1.9 x 10(18) photons/cm2 at 460, 630, and 700 nm monochromatic light elicited a significant melatonin suppression at 460 nm and small reductions of plasma melatonin levels at 630 and 700 nm. These findings are discussed relative to the possible roles of classical visual photoreceptors and the recently discovered intrinsically photosensitive retinal ganglion cells for circadian phototransduction. That physiology, and its potential for responding to red light, has implications for domestic applications involving animal care, the lighting of typical human environments, and advanced applications such as space exploration.
Cancer Research, 2005
The increased breast cancer risk in female night shift workers has been postulated to result from... more The increased breast cancer risk in female night shift workers has been postulated to result from the suppression of pineal melatonin production by exposure to light at night. Exposure of rats bearing rat hepatomas or human breast cancer xenografts to increasing intensities of white fluorescent light during each 12-hour dark phase (0-345 MW/cm 2 ) resulted in a dose-dependent suppression of nocturnal melatonin blood levels and a stimulation of tumor growth and linoleic acid uptake/metabolism to the mitogenic molecule 13-hydroxyoctadecadienoic acid. Venous blood samples were collected from healthy, premenopausal female volunteers during either the daytime, nighttime, or nighttime following 90 minutes of ocular bright, white fluorescent light exposure at 580 MW/cm 2 (i.e., 2,800 lx). Compared with tumors perfused with daytimecollected melatonin-deficient blood, human breast cancer xenografts and rat hepatomas perfused in situ, with nocturnal, physiologically melatonin-rich blood collected during the night, exhibited markedly suppressed proliferative activity and linoleic acid uptake/metabolism. Tumors perfused with melatonin-deficient blood collected following ocular exposure to light at night exhibited the daytime pattern of high tumor proliferative activity. These results are the first to show that the tumor growth response to exposure to light during darkness is intensity dependent and that the human nocturnal, circadian melatonin signal not only inhibits human breast cancer growth but that this effect is extinguished by short-term ocular exposure to bright, white light at night. These mechanistic studies are the first to provide a rational biological explanation for the increased breast cancer risk in female night shift workers. (Cancer Res 2005; 65(23): 11174-84)
Molecular Brain Research, 2000
Canavan disease is caused by mutations in aspartoacylase, the enzyme that degrades N-acetylaspart... more Canavan disease is caused by mutations in aspartoacylase, the enzyme that degrades N-acetylaspartate (NAA) into acetate and aspartate. Murine aspartoacylase (mASPA) was cloned using sequence information from mouse expressed sequence tags homologous to the human cDNA. The open reading frame was cloned into a thioredoxin fusion vector, overexpressed in bacteria, and the protein was purified using affinity chromatography to near homogeneity. Recombinant human ASPA (hASPA) was prepared by a similar method. Both recombinant enzymes were highly specific to NAA, with about 10% of the NAA activity toward N-acetylasparagine. More interestingly, the product of N-acetylasparagine was aspartate but not asparagine, indicating that ASPA catalyzed deacetylation as well as hydrolysis of the b acid amide. Our success in preparing the recombinant ASPA in high purity should permit multiple lines of investigations to understand the pathogenic mechanisms of Canavan disease and the functional roles of NAA.
Acta Astronautica, 2005
Light is being used as a pre-launch countermeasure to circadian and sleep disruption in astronaut... more Light is being used as a pre-launch countermeasure to circadian and sleep disruption in astronauts. The effect of light on the circadian system is readily monitored by measurement of plasma melatonin. Our group has established an action spectrum for human melatonin regulation and determined the region of 446-477 nm to be the most potent for suppressing plasma melatonin. The aim of this study was to compare the efficacy of 460 and 555 nm for suppressing melatonin using a within-subjects design. Subjects (N = 12) were exposed to equal photon densities (7.18 × 10 12 photons/cm 2 /s) at 460 and 555 nm. Melatonin suppression was significantly stronger at 460 nm (p < 0.02). An extension to the action spectrum showed that 420 nm light at 16 and 32 W/cm 2 significantly suppressed melatonin (p < 0.04 and p < 0.002). These studies will help optimize lighting countermeasures to circadian and sleep disruption during spaceflight.
Journal of Biological Rhythms, 2008
The circadian and neurobehavioral effects of light are primarily mediated by a retinal ganglion c... more The circadian and neurobehavioral effects of light are primarily mediated by a retinal ganglion cell photoreceptor in the mammalian eye containing the photopigment, melanopsin.
Methods in Enzymology, 2000
Journal of …, Jan 1, 2001
Journal of pineal research, Jan 26, 2015
The basic goal of this research is to determine the best combination of light wavelengths for use... more The basic goal of this research is to determine the best combination of light wavelengths for use as a lighting countermeasure for circadian and sleep disruption during space exploration, as well as for individuals living on Earth. Action spectra employing monochromatic light and selected monochromatic wavelength comparisons have shown that short wavelength visible light in the blue-appearing portion of the spectrum is most potent for neuroendocrine, circadian, and neurobehavioral regulation. The studies presented here tested the hypothesis that broad spectrum, polychromatic fluorescent light enriched in the short wavelength portion of the visible spectrum is more potent for pineal melatonin suppression in healthy men and women. A total of 24 subjects were tested across three separate experiments. Each experiment used a within-subjects study design that tested eight volunteers to establish the full-range fluence-response relationship between corneal light irradiance and nocturnal pl...
Science, 2002
like the latter two groups, mammals lack functional extraocular photoreceptors (28); thus, redund... more like the latter two groups, mammals lack functional extraocular photoreceptors (28); thus, redundancy in photoreception is confined to the retina. One challenge is to determine the relative contributions of melanopsin, rod/cone opsins, cryptochromes, and other currently uncharacterized photopigments in communicating photic information to the circadian system.
Proceedings of the National Academy of Sciences, 2001
The daily rhythm in melatonin levels is controlled by cAMP through actions on the penultimate enz... more The daily rhythm in melatonin levels is controlled by cAMP through actions on the penultimate enzyme in melatonin synthesis, arylalkylamine N-acetyltransferase (AANAT; serotonin N-acetyltransferase, EC 2.3.1.87). Results presented here describe a regulatory͞ binding sequence in AANAT that encodes a cAMP-operated binding switch through which cAMP-regulated protein kinasecatalyzed phosphorylation [RRHTLPAN 3 RRHpTLPAN] promotes formation of a complex with 14-3-3 proteins. Formation of this AANAT͞14-3-3 complex enhances melatonin production by shielding AANAT from dephosphorylation and͞or proteolysis and by decreasing the Km for 5-hydroxytryptamine (serotonin). Similar switches could play a role in cAMP signal transduction in other biological systems.
Proceedings of the National Academy of Sciences, 1998
We have identified an opsin, melanopsin, in photosensitive dermal melanophores of Xenopus laevis.... more We have identified an opsin, melanopsin, in photosensitive dermal melanophores of Xenopus laevis. Its deduced amino acid sequence shares greatest homology with cephalopod opsins. The predicted secondary structure of melanopsin indicates the presence of a long cytoplasmic tail with multiple putative phosphorylation sites, suggesting that this opsin's function may be finely regulated. Melanopsin mRNA is expressed in hypothalamic sites thought to contain deep brain photoreceptors and in the iris, a structure known to be directly photosensitive in amphibians. Melanopsin message is also localized in retinal cells residing in the outermost lamina of the inner nuclear layer where horizontal cells are typically found. Its expression in retinal and nonretinal tissues suggests a role in vision and nonvisual photoreceptive tasks, such as photic control of skin pigmentation, pupillary aperture, and circadian and photoperiodic physiology.
PLoS ONE, 2008
Non-image related responses to light, such as the synchronization of circadian rhythms to the day... more Non-image related responses to light, such as the synchronization of circadian rhythms to the day/night cycle, are mediated by classical rod/cone photoreceptors and by a small subset of retinal ganglion cells that are intrinsically photosensitive, expressing the photopigment, melanopsin. This raises the possibility that the melanopsin cells may be serving as a conduit for photic information detected by the rods and/or cones. To test this idea, we developed a specific immunotoxin consisting of an anti-melanopsin antibody conjugated to the ribosome-inactivating protein, saporin. Intravitreal injection of this immunotoxin results in targeted destruction of melanopsin cells. We find that the specific loss of these cells in the adult mouse retina alters the effects of light on circadian rhythms. In particular, the photosensitivity of the circadian system is significantly attenuated. A subset of animals becomes non-responsive to the light/dark cycle, a characteristic previously observed in mice lacking rods, cones, and functional melanopsin cells. Mice lacking melanopsin cells are also unable to show light induced negative masking, a phenomenon known to be mediated by such cells, but both visual cliff and light/ dark preference responses are normal. These data suggest that cells containing melanopsin do indeed function as a conduit for rod and/or cone information for certain non-image forming visual responses. Furthermore, we have developed a technique to specifically ablate melanopsin cells in the fully developed adult retina. This approach can be applied to any species subject to the existence of appropriate anti-melanopsin antibodies. Citation: Gö z D, Studholme K, Lappi DA, Rollag MD, Provencio I, et al. (2008) Targeted Destruction of Photosensitive Retinal Ganglion Cells with a Saporin Conjugate Alters the Effects of Light on Mouse Circadian Rhythms. PLoS ONE 3(9): e3153.
Journal of Pineal Research, 1993
single injection of adrenergic agonists enhances pineal melatonin production in Turkish hamsters.... more single injection of adrenergic agonists enhances pineal melatonin production in Turkish hamsters. J. Pineal Res. 1993:14:138-144. Abstract: The purpose of this study was to determine whether the pineal gland of Turkish hamsters (Mesocricetus brandti) responds to adrenergic agonists with an increase in melatonin production, and, if it does, whether the sensitivity of the pineal gland to agonists would differ throughout the dark phase. Adult Turkish hamsters weighing 110-210 g received a subcutaneous injection of isoproterenol (ISO, 1 mg/kg B.W.) or norepinephrine (NE, 1 mg/kg B.W.) at different times of night. Animals exposed to LD 16:8 responded to IS0 or NE with increased pineal melatonin content only when injected at dawn, when endogenous melatonin is at basal or near-basal levels. When the 8 hr scotophase was entirely replaced with light, the responsiveness to IS0 injections at dawn disappeared. In animals exposed to light from 30 min prior to melatonin content (P < 0.005, three-way ANOVA), which varied, depending on the specific time of injection (effect of time of night, P < 0.05, three-way ANOVA). These results demonstrate that adrenergic agonists enhance the production of pineal melatonin in Turkish hamsters, (2) this stimulatory effect takes place late, but not early in the 8 hr scotophase, and ( 3 ) the adrenergic induction of pineal melatonin production in Turkish hamsters requires priming by darkness during the appropriate circadian phase. I injection to the time of sacrifice, I S 0 injections increased pineal
Journal of Pineal Research, 2004
Journal of Neurochemistry, 2005
The avian retina and pineal gland contain autonomous circadian oscillators and photo-entrainment ... more The avian retina and pineal gland contain autonomous circadian oscillators and photo-entrainment pathways, but the photopigment(s) that mediate entrainment have not been definitively identified. Melanopsin (Opn4) is a novel opsin involved in entrainment of circadian rhythms in mammals. Here, we report the cDNA cloning of chicken melanopsin and show its expression in retina, brain and pineal gland. Like the melanopsins identified in amphibians and mammals, chicken melanopsin is more similar to the invertebrate retinaldehydebased photopigments than the retinaldehyde-based photopigments typically found in vertebrates. In retina, melanopsin mRNA is expressed in cells of all retinal layers. In pineal gland, expression was strong throughout the parenchyma of the gland. In brain, expression was observed in a few discrete nuclei, including the lateral septal area and medial preoptic nucleus. The retina and pineal gland showed distinct diurnal expression patterns. In pineal gland, melanopsin mRNA levels were highest at night at Zeitgeber time (ZT) 16. In contrast, transcript levels in the whole retina reached their highest levels in the early morning (ZT 0-4). Further analysis of melanopsin mRNA expression in retinal layers isolated by laser capture microdissection revealed different patterns in different layers. There was diurnal expression in all retinal layers except the ganglion cell layer, where heavy expression was localized to a small number of cells. Expression of melanopsin mRNA peaked during the daytime in the retinal pigment epithelium and inner nuclear layer but, like in the pineal, at night in the photoreceptors. Localization and regulation of melanopsin mRNA in the retina and pineal gland is consistent with the hypothesis that this novel photopigment plays a role in photic regulation of circadian function in these tissues.
Journal of Magnetic Resonance Imaging, 1994
Production of melatonin, a hormone synthesized and secreted by the pineal body, has been suppress... more Production of melatonin, a hormone synthesized and secreted by the pineal body, has been suppressed by electromagnetic fields in some but not all animal studies. Magnetic resonance (MR) imaging at 1.5 T was evaluated for its ability to modulate the level of melatonin in eight male volunteers. Subjects were exposed to three conditions, respectively, between 1:00 and 2:00 AM on different nights: (a) a series of routine MR pulse sequences for brain imaging in dark conditions, (b) dark control conditions, and (c) bright-light control conditions. Plasma was analyzed for melatonin and cortisol levels. Hormonal changes were analyzed by one-factor repeated measures within-subject analysis of variance. These conditions were associated with significant differences in melatonin levels: F(2, 6) = 7.95, and P = .021. Subjects exposed to darkness showed a typical increase in melatonin concentration. Subjects exposed to bright light showed a characteristic suppression of melatonin concentration. Those exposed to the MR imaging fields showed an increase in melatonin level similar to that seen in the dark control condition. Light and MR imaging had no significant effects on cortisol levels. Thus, MR imaging at field strengths known to modulate melatonin levels in rats did not suppress melatonin production in human subjects.
Journal of biological …, Jan 1, 2003
Journal of Biological Rhythms, 2003
An understanding of the retinal mechanisms in mammalian photoentrainment will greatly facilitate ... more An understanding of the retinal mechanisms in mammalian photoentrainment will greatly facilitate optimization of the wavelength, intensity, and duration of phototherapeutic treatments designed to phase shift endogenous biological rhythms. A small population of widely dispersed retinal ganglion cells projecting to the suprachiasmatic nucleus in the hypothalamus is the source of the critical photic input. Recent evidence has shown that many of these ganglion cells are directly photosensitive and serve as photoreceptors. Melanopsin, a presumptive photopigment, is an essential component in the phototransduction cascade within these intrinsically photosensitive ganglion cells and plays an important role in the retinal photoentrainment pathway. This review summarizes recent findings related to melanopsin and melanopsin ganglion cells and lists other retinal proteins that might serve as photopigments in the mammalian photoentrainment input pathway.
Journal of Affective Disorders, 2009
Background-Melanopsin, a non-visual photopigment, may play a role in aberrant responses to low wi... more Background-Melanopsin, a non-visual photopigment, may play a role in aberrant responses to low winter light levels in Seasonal Affective Disorder (SAD). We hypothesized that functional sequence variation in the melanopsin gene (Opn4) could contribute to increasing the light needed for normal functioning during winter in SAD.
Chronobiology International, 2006
Early studies on rodents indicated that the long-wavelength portion of the spectrum (orange- and ... more Early studies on rodents indicated that the long-wavelength portion of the spectrum (orange- and red-appearing light) could influence circadian and neuroendocrine responses. Since then, both polychromatic and analytic action spectra in various rodent species have demonstrated that long-wavelength light is very weak, if not entirely inactive, for regulating neurobehavioral responses. Since testing of monochromatic light wavelengths above 600 nm is uncommon, many researchers have assumed that there is little to no effect of red light on the neuroendocrine or circadian systems. The aims of the following studies were to test the efficacy of monochromatic light above 600 nm for melatonin suppression in hamsters and humans. Results in hamsters show that 640 nm monochromatic light at 1.1 x 10(17) photons/cm2 can acutely suppress pineal melatonin levels. In normal healthy humans, equal photon density exposures of 1.9 x 10(18) photons/cm2 at 460, 630, and 700 nm monochromatic light elicited a significant melatonin suppression at 460 nm and small reductions of plasma melatonin levels at 630 and 700 nm. These findings are discussed relative to the possible roles of classical visual photoreceptors and the recently discovered intrinsically photosensitive retinal ganglion cells for circadian phototransduction. That physiology, and its potential for responding to red light, has implications for domestic applications involving animal care, the lighting of typical human environments, and advanced applications such as space exploration.
Cancer Research, 2005
The increased breast cancer risk in female night shift workers has been postulated to result from... more The increased breast cancer risk in female night shift workers has been postulated to result from the suppression of pineal melatonin production by exposure to light at night. Exposure of rats bearing rat hepatomas or human breast cancer xenografts to increasing intensities of white fluorescent light during each 12-hour dark phase (0-345 MW/cm 2 ) resulted in a dose-dependent suppression of nocturnal melatonin blood levels and a stimulation of tumor growth and linoleic acid uptake/metabolism to the mitogenic molecule 13-hydroxyoctadecadienoic acid. Venous blood samples were collected from healthy, premenopausal female volunteers during either the daytime, nighttime, or nighttime following 90 minutes of ocular bright, white fluorescent light exposure at 580 MW/cm 2 (i.e., 2,800 lx). Compared with tumors perfused with daytimecollected melatonin-deficient blood, human breast cancer xenografts and rat hepatomas perfused in situ, with nocturnal, physiologically melatonin-rich blood collected during the night, exhibited markedly suppressed proliferative activity and linoleic acid uptake/metabolism. Tumors perfused with melatonin-deficient blood collected following ocular exposure to light at night exhibited the daytime pattern of high tumor proliferative activity. These results are the first to show that the tumor growth response to exposure to light during darkness is intensity dependent and that the human nocturnal, circadian melatonin signal not only inhibits human breast cancer growth but that this effect is extinguished by short-term ocular exposure to bright, white light at night. These mechanistic studies are the first to provide a rational biological explanation for the increased breast cancer risk in female night shift workers. (Cancer Res 2005; 65(23): 11174-84)
Molecular Brain Research, 2000
Canavan disease is caused by mutations in aspartoacylase, the enzyme that degrades N-acetylaspart... more Canavan disease is caused by mutations in aspartoacylase, the enzyme that degrades N-acetylaspartate (NAA) into acetate and aspartate. Murine aspartoacylase (mASPA) was cloned using sequence information from mouse expressed sequence tags homologous to the human cDNA. The open reading frame was cloned into a thioredoxin fusion vector, overexpressed in bacteria, and the protein was purified using affinity chromatography to near homogeneity. Recombinant human ASPA (hASPA) was prepared by a similar method. Both recombinant enzymes were highly specific to NAA, with about 10% of the NAA activity toward N-acetylasparagine. More interestingly, the product of N-acetylasparagine was aspartate but not asparagine, indicating that ASPA catalyzed deacetylation as well as hydrolysis of the b acid amide. Our success in preparing the recombinant ASPA in high purity should permit multiple lines of investigations to understand the pathogenic mechanisms of Canavan disease and the functional roles of NAA.
Acta Astronautica, 2005
Light is being used as a pre-launch countermeasure to circadian and sleep disruption in astronaut... more Light is being used as a pre-launch countermeasure to circadian and sleep disruption in astronauts. The effect of light on the circadian system is readily monitored by measurement of plasma melatonin. Our group has established an action spectrum for human melatonin regulation and determined the region of 446-477 nm to be the most potent for suppressing plasma melatonin. The aim of this study was to compare the efficacy of 460 and 555 nm for suppressing melatonin using a within-subjects design. Subjects (N = 12) were exposed to equal photon densities (7.18 × 10 12 photons/cm 2 /s) at 460 and 555 nm. Melatonin suppression was significantly stronger at 460 nm (p < 0.02). An extension to the action spectrum showed that 420 nm light at 16 and 32 W/cm 2 significantly suppressed melatonin (p < 0.04 and p < 0.002). These studies will help optimize lighting countermeasures to circadian and sleep disruption during spaceflight.
Journal of Biological Rhythms, 2008
The circadian and neurobehavioral effects of light are primarily mediated by a retinal ganglion c... more The circadian and neurobehavioral effects of light are primarily mediated by a retinal ganglion cell photoreceptor in the mammalian eye containing the photopigment, melanopsin.