A Broad Role for Melanopsin in Nonvisual Photoreception

The rod and cone photoreceptors that mediate visual phototransduction in mammals are not required for light-induced circadian entrainment, negative masking of locomotor activity, suppression of pineal melatonin, or the pupillary light reflex. The photopigment melanopsin has recently been identified in intrinsically photosensitive retinal ganglion cells (RGCs) that project to the suprachiasmatic nucleus (SCN), intergeniculate leaflet (IGL), and olivary pretectal nucleus, suggesting that melanopsin might influence a variety of irradiance-driven responses. We have found novel projections from RGCs that express melanopsin mRNA to the ventral subparaventricular zone (vSPZ), a region involved in circadian regulation and negative masking, and the sleep-active ventrolateral preoptic nucleus (VLPO) and determined the subsets of melanopsin-expressing RGCs that project to the SCN, the pretectal area (PTA), and the IGL division of the lateral geniculate nucleus (LGN). Melanopsin was expressed in the majority of RGCs that project to the SCN, vSPZ, and VLPO and in a subpopulation of RGCs that innervate the PTA and the IGL but not in RGCs projecting to the dorsal LGN or superior colliculus. Two-thirds of RGCs containing melanopsin transcript projected to each of the SCN and contralateral PTA, and one-fifth projected to the ipsilateral IGL. Double-retrograde tracing from the SCN and PTA demonstrated a subpopulation of RGCs projecting to both sites, most of which contained melanopsin mRNA. Our results suggest that melanopsin expression defines a subset of RGCs that play a broad role in the regulation of nonvisual photoreception, providing collateralized projections that contribute to circadian entrainment, negative masking, the regulation of sleep-wake states, and the pupillary light reflex.

[1]  T. Yoshimura,et al.  Spectral sensitivity of photoreceptors mediating phase-shifts of circadian rhythms in retinally degenerate CBA/J (rd/rd) and normal CBA/N (+/+) mice , 1996, Journal of Comparative Physiology A.

[2]  H. Ikeda,et al.  Luminance and darkness detectors in the olivary and posterior pretectal nuclei and their relationship to the pupillary light reflex in the rat , 2004, Experimental Brain Research.

[3]  K. Yau,et al.  Diminished Pupillary Light Reflex at High Irradiances in Melanopsin-Knockout Mice , 2003, Science.

[4]  R. V. Van Gelder,et al.  Reduced Pupillary Light Responses in Mice Lacking Cryptochromes , 2003, Science.

[5]  Satchidananda Panda,et al.  Melanopsin (Opn4) Requirement for Normal Light-Induced Circadian Phase Shifting , 2002, Science.

[6]  Bruce F O'Hara,et al.  Role of Melanopsin in Circadian Responses to Light , 2002, Science.

[7]  H. Quigley,et al.  Gene delivery to the eye using adeno-associated viral vectors. , 2002, Methods.

[8]  A. R. Harvey,et al.  Intravitreal Injection of Adeno-associated Viral Vectors Results in the Transduction of Different Types of Retinal Neurons in Neonatal and Adult Rats: A Comparison with Lentiviral Vectors , 2002, Molecular and Cellular Neuroscience.

[9]  Jun Lu,et al.  Selective Activation of the Extended Ventrolateral Preoptic Nucleus during Rapid Eye Movement Sleep , 2002, The Journal of Neuroscience.

[10]  A. Loewy,et al.  CNS inputs to the suprachiasmatic nucleus of the rat , 2002, Neuroscience.

[11]  K. Yau,et al.  Melanopsin-Containing Retinal Ganglion Cells: Architecture, Projections, and Intrinsic Photosensitivity , 2002, Science.

[12]  D. Berson,et al.  Phototransduction by Retinal Ganglion Cells That Set the Circadian Clock , 2002, Science.

[13]  M. Hankins,et al.  The Primary Visual Pathway in Humans Is Regulated According to Long-Term Light Exposure through the Action of a Nonclassical Photopigment , 2002, Current Biology.

[14]  Jun Lu,et al.  Afferents to the Ventrolateral Preoptic Nucleus , 2002, The Journal of Neuroscience.

[15]  M. Rollag,et al.  Anatomy: Photoreceptive net in the mammalian retina , 2002, Nature.

[16]  Scarla J. Weeks,et al.  Anatomy: Photoreceptive net in the mammalian retina , 2002, Nature.

[17]  J. Hannibal,et al.  The Photopigment Melanopsin Is Exclusively Present in Pituitary Adenylate Cyclase-Activating Polypeptide-Containing Retinal Ganglion Cells of the Retinohypothalamic Tract , 2002, The Journal of Neuroscience.

[18]  C. Weitz,et al.  Regulation of Daily Locomotor Activity and Sleep by Hypothalamic EGF Receptor Signaling , 2001, Science.

[19]  G. Kobinger,et al.  Exchange of surface proteins impacts on viral vector cellular specificity and transduction characteristics: the retina as a model. , 2001, Human molecular genetics.

[20]  N. Mrosovsky,et al.  Persistence of Masking Responses to Light in Mice Lacking Rods and Cones , 2001, Journal of biological rhythms.

[21]  S. Thanos,et al.  Lens-Injury-Stimulated Axonal Regeneration throughout the Optic Pathway of Adult Rats , 2001, Experimental Neurology.

[22]  Jun Lu,et al.  Melanopsin in cells of origin of the retinohypothalamic tract , 2001, Nature Neuroscience.

[23]  T. Aleman,et al.  Long-term protection of retinal structure but not function using RAAV.CNTF in animal models of retinitis pigmentosa. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[24]  G. Brainard,et al.  Action Spectrum for Melatonin Regulation in Humans: Evidence for a Novel Circadian Photoreceptor , 2001, The Journal of Neuroscience.

[25]  D. Skene,et al.  An action spectrum for melatonin suppression: evidence for a novel non‐rod, non‐cone photoreceptor system in humans , 2001, The Journal of physiology.

[26]  C. Saper,et al.  Contrasting Effects of Ibotenate Lesions of the Paraventricular Nucleus and Subparaventricular Zone on Sleep–Wake Cycle and Temperature Regulation , 2001, The Journal of Neuroscience.

[27]  Robert J. Lucas,et al.  Characterization of an ocular photopigment capable of driving pupillary constriction in mice , 2001, Nature Neuroscience.

[28]  N. Mrosovsky.  FURTHER CHARACTERIZATION OF THE PHENOTYPE OF mCry1/mCry2-DEFICIENT MICE , 2001, Chronobiology international.

[29]  Izzo,et al.  SUPPRESSION OF MELATONIN SECRETION IN SOME BLIND PATIENTS BY EXPOSURE TO BRIGHT LIGHT , 2001 .

[30]  S. Geuna.  Appreciating the difference between design‐based and model‐based sampling strategies in quantitative morphology of the nervous system , 2000, The Journal of comparative neurology.

[31]  C. Saper,et al.  Effect of Lesions of the Ventrolateral Preoptic Nucleus on NREM and REM Sleep , 2000, The Journal of Neuroscience.

[32]  R. Moore,et al.  Efferent projections of the intergeniculate leaflet and the ventral lateral geniculate nucleus in the rat , 2000, The Journal of comparative neurology.

[33]  H. Meissl,et al.  Responses of neurones of the rat suprachiasmatic nucleus to retinal illumination under photopic and scotopic conditions , 2000, The Journal of physiology.

[34]  C. Novak,et al.  A sparse projection from the suprachiasmatic nucleus to the sleep active ventrolateral preoptic area in the rat , 2000, Neuroreport.

[35]  W. P. Hayes,et al.  A Novel Human Opsin in the Inner Retina , 2000, The Journal of Neuroscience.

[36]  J. Bennett,et al.  Infection with adeno-associated virus may protect against excitotoxicity. , 1999, Neuroreport.

[37]  G. Acland,et al.  Persistent transgene product in retina, optic nerve and brain after intraocular injection of rAAV , 1999, Vision Research.

[38]  W. Hauswirth,et al.  Reporter expression persists 1 year after adeno-associated virus-mediated gene transfer to the optic nerve. , 1999, Archives of ophthalmology.

[39]  C. Saper,et al.  Retinal input to the sleep-active ventrolateral preoptic nucleus in the rat , 1999, Neuroscience.

[40]  R. Foster,et al.  Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. , 1999, Science.

[41]  R. Foster,et al.  Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. , 1999, Science.

[42]  N. Mrosovsky,et al.  Thresholds for masking responses to light in three strains of retinally degenerate mice , 1999, Journal of Comparative Physiology A.

[43]  N. Mrosovsky,et al.  Masking by light in hamsters with SCN lesions , 1999, Journal of Comparative Physiology A.

[44]  R. Benca,et al.  Effects of lighting conditions on sleep and wakefulness in albino Lewis and pigmented Brown Norway rats. , 1998, Sleep.

[45]  C. Saper,et al.  Innervation of Histaminergic Tuberomammillary Neurons by GABAergic and Galaninergic Neurons in the Ventrolateral Preoptic Nucleus of the Rat , 1998, The Journal of Neuroscience.

[46]  A. Sancar,et al.  Vitamin B2-based blue-light photoreceptors in the retinohypothalamic tract as the photoactive pigments for setting the circadian clock in mammals. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Raymond D. Lund,et al.  The retinal ganglion cells that drive the pupilloconstrictor response in rats , 1998, Brain Research.

[48]  D. Hunt,et al.  Adeno-associated virus gene transfer to mouse retina. Human Gene Therapy , 1998 .

[49]  D. Hunt,et al.  Adeno-associated virus gene transfer to mouse retina. , 1998, Human gene therapy.

[50]  M. Harrington.  The Ventral Lateral Geniculate Nucleus and the Intergeniculate Leaflet: Interrelated Structures in the Visual and Circadian Systems , 1997, Neuroscience & Biobehavioral Reviews.

[51]  R. Moore,et al.  Organization of neural inputs to the suprachiasmatic nucleus in the rat , 1997, The Journal of comparative neurology.

[52]  E. Maywood,et al.  Non‐photic signalling in the suprachiasmatic nucleus , 1997, Biology of the cell.

[53]  S. Ponnazhagan,et al.  Evaluation of recombinant adeno-associated virus as a gene transfer vector for the retina. , 1997, Current eye research.

[54]  C. Saper,et al.  Activation of neurons projecting to the paraventricular hypothalamic nucleus by intravenous lipopolysaccharide , 1996, The Journal of comparative neurology.

[55]  N. Mrosovsky.  LOCOMOTOR ACTIVITY AND NON‐PHOTIC INFLUENCES ON CIRCADIAN CLOCKS , 1996, Biological reviews of the Cambridge Philosophical Society.

[56]  R. Benca,et al.  Increased Basal REM Sleep But No Difference in Dark Induction or Light Suppression of REM Sleep in Flinders Rats with Cholinergic Supersensitivity , 1996, Neuropsychopharmacology.

[57]  R. McCarley,et al.  Activation of Ventrolateral Preoptic Neurons During Sleep , 1996, Science.

[58]  R. Foster,et al.  Circadian rhythms in mice can be regulated by photoreceptors with cone-like characteristics , 1995, Brain Research.

[59]  J. Klooster,et al.  Efferent projections of the olivary pretectal nucleus in the albino rat subserving the pupillary light reflex and related reflexes a light microscopic tracing study , 1995, Brain Research.

[60]  N. Mrosovsky.  In praise of masking: behavioural responses of retinally degenerate mice to dim light. , 1994, Chronobiology international.

[61]  R. Lund,et al.  The anatomical substrates subserving the pupillary light reflex in rats: Origin of the consensual pupillary response , 1994, Neuroscience.

[62]  L. P. Morin.  The circadian visual system , 1994, Brain Research Reviews.

[63]  M. Weiss,et al.  Retinohypothalamic tract in the female albino rat: A study using horseradish peroxidase conjugated to cholera toxin , 1991, The Journal of comparative neurology.

[64]  L. P. Morin,et al.  Retinohypothalamic projections in the hamster and rat demonstrated using cholera toxin , 1988, Brain Research.

[65]  L W Swanson,et al.  Efferent projections of the suprachiasmatic nucleus: I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat , 1987, The Journal of comparative neurology.

[66]  G. E. Pickard.  Bifurcating axons of retinal ganglion cells terminate in the hypothalamic suppachiasmatic nucleus and the intergeniculate leaflet of the thalamus , 1985, Neuroscience Letters.

[67]  J. Takahashi,et al.  Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms , 1984, Nature.

[68]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[69]  H. Roffwarg,et al.  REM sleep inhibition by light in the albino rat. , 1972, Experimental neurology.

[70]  M. Abercrombie.  Estimation of nuclear population from microtome sections , 1946, The Anatomical record.