Russell G. Foster - US grants

The organization of the mammalian circadian system is receiving attention at the level of the hypothalamus, yet the photoreceptors that regulate these hypothalamic centers remain unknown. Our recent data on retinally degenerate (rd/rd) mice, suggest that circadian behavior is normally regulated by either a small number of cones which lack outer segments or alternatively, a novel class of photoreceptive cells in the mammalian retina which is unaffected by the rd/rd mutation. In these studies we utilize the rd/rd mouse which experiences a rapid loss of rod photoreceptors followed by a more protracted loss of cone cells. Our experiments propose to: 1) Correlate circadian behavioral responses to light with the presence or absence of retinal rods and cones. a) We will compare the spectral sensitivity of circadian responses in rd/rd and +/+ mice. Is the spectral sensitivity rod- or cone-like? b) Does circadian photosensitivity in rd/rd mice parallel the loss of photoreceptor perikarya? c) Are the irradiance levels required for entrainment to full photoperiods the same in rd/rd and +/+ mice? 2) Identify the circadian photoreceptive elements within the mammalian retina. Specifically, we aim to address whether circadian light detection can be attributed to rods, cones or neither. a) The type and location of the remaining photoreceptors within the retina of rd/rd mice will be determined using opsin antibodies, probes to opsin message, and quantification of the visual pigment chromophore 11-cis-retinaldehyde. b) The link between 11-cis-retinaldehyde and the photopigment mediating circadian light detection will be established using 11-cis-locked retinal analogs and SDS-PAGE analysis. 3) Compare the photoreceptors that regulate circadian responses and the photoreceptors that regulate pineal physiology. Do rods and cones regulate pineal melatonin synthesis? We will compare the sensitivity of suppression of melatonin by light in rd/rd, rds/rds and +/+ genotypes. Perturbation of human circadian physiology (jet-lag, shift-work fatigue, seasonal affective disorder) has transient but profoundly negative effects on individual health. A better understanding of mammalian circadian systems and specifically their regulation by light will provide much needed information on this complex area of biology and human health.

The organization of the mammalian circadian system is receiving attention at the level of the hypothalamus, yet the photoreceptors that regulate these hypothalamic centers remain unknown. Our recent data on retinally degenerate (rd/rd) mice, suggest that circadian behavior is normally regulated by either a small number of cones which lack outer segments or alternatively, a novel class of photoreceptive cells in the mammalian retina which is unaffected by the rd/rd mutation. In these studies we utilize the rd/rd mouse which experiences a rapid loss of rod photoreceptors followed by a more protracted loss of cone cells. Our experiments propose to: 1) Correlate circadian behavioral responses to light with the presence or absence of retinal rods and cones. a) We will compare the spectral sensitivity of circadian responses in rd/rd and +/+ mice. Is the spectral sensitivity rod- or cone-like? b) Does circadian photosensitivity in rd/rd mice parallel the loss of photoreceptor perikarya? c) Are the irradiance levels required for entrainment to full photoperiods the same in rd/rd and +/+ mice? 2) Identify the circadian photoreceptive elements within the mammalian retina. Specifically, we aim to address whether circadian light detection can be attributed to rods, cones or neither. a) The type and location of the remaining photoreceptors within the retina of rd/rd mice will be determined using opsin antibodies, probes to opsin message, and quantification of the visual pigment chromophore 11-cis-retinaldehyde. b) The link between 11-cis-retinaldehyde and the photopigment mediating circadian light detection will be established using 11-cis-locked retinal analogs and SDS-PAGE analysis. 3) Compare the photoreceptors that regulate circadian responses and the photoreceptors that regulate pineal physiology. Do rods and cones regulate pineal melatonin synthesis? We will compare the sensitivity of suppression of melatonin by light in rd/rd, rds/rds and +/+ genotypes. Perturbation of human circadian physiology (jet-lag, shift-work fatigue, seasonal affective disorder) has transient but profoundly negative effects on individual health. A better understanding of mammalian circadian systems and specifically their regulation by light will provide much needed information on this complex area of biology and human health.

DESCRIPTION (provided by applicant): Partial support is requested for the 13th Gordon Research Conference on Chronobiology, to be held in II Ciocco, Barga, Italy. In recent years, the significance of internal body clocks (circadian clocks) for the regulation and adjustment of temporal physiology has become increasingly clear and, as a consequence, much effort has been devoted to the analysis of the mechanisms underlying circadian processes. Recognition of the key role played by circadian rhythms in human health and disease and a recent series of landmark discoveries regarding the molecular mechanisms that both generate and regulate the circadian system has led to a remarkable expansion of the field. Today, chronobiological research attracts a host of researchers from a broad range of disciplines, including molecular genetics, photobiology, sleep medicine, psychiatry, and gerontology. The aims of the Gordon Conference on Chronobiology are: (1) To provide a forum for discussion and for seeking general principles in the rapidly expanding field of chronobiology. (2) To stimulate interactions among researchers working in the various sub-disciplines of chronobiology and thus to enhance the coherence of the research field as a whole. (3) To intensify interactions between young and established researchers and thus sustain high-quality chronobiological research. (4) To promote both national and international collaboration by bringing together scientists from many different groups and countries. (5) To promote translational research by bringing together researchers employing model organisms with researchers using human subjects for circadian research. The conference will achieve these goals by assembling approximately 130 scientists who will encompass individuals from different countries, age groups, genders, and using different research models. We are encouraging the active participation of minority groups by contacting minority colleges directly (e.g., Morehouse). The program will focus on new developments in key research areas (see Tentative Program). In accordance with the highly successful Gordon Conference format, a restricted number of lectures will be presented in 9 morning and evening sessions with ample time for discussions. Three late-afternoon poster sessions will allow participants to present additional data.