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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Behavioral Neuroscience Review Committee (BNR)
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University of Virginia
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