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ScienceWeek
NEUROBIOLOGY: MELANOPSIN AND RETINAL CIRCUITRY
The following points are made by S. He et al (Science 2003 302:408):
1) The dream of many neuroscientists is to track a behavior right down to the activities of particular molecules. A small part of the dream came true in 2002 when a series of elegant studies firmly established that a photopigment-like molecule, melanopsin, located in a specific population of retinal ganglion cells (RGCs) is responsible for resetting the biological clock.
2) It had been clearly established that the entraining signal comes from the eyes (1,2), but that photoreceptors (rods and cones) are not needed (3,4). When Provencio et al (5) looked for a photopigment in frog skin using an antibody against bovine opsin, they identified a molecule in the dermal melanophores and named it "melanopsin". Melanopsin has also been localized in the eye of the mouse, monkey, and human and, more precisely, in the ganglion cell layer of the mouse and monkey (5). These results indicated that some RGCs might contain a potential photopigment and therefore could directly sense light. In situ hybridization localized the melanopsin message to the RGCs projecting to the suprachiasmatic nucleus (SCN), a center related to the biological clock, further linking the melanopsin RGCs with a role in regulating circadian rhythm. The melanopsin messenger RNA has also been found in the PACAP (pituitary adenylate cyclase-activating polypeptide)-containing RGCs that were previously shown to project to the SCN, indicating that PACAP might be used as a transmitter or modulator in this pathway.
3) Electrophysiological recordings from the SCN-projecting and melanopsin-containing RGCs (mcRGCs) revealed that they respond to light when synaptic transmission within the retina is blocked and even when they are isolated from the retina, directly demonstrating that the SCN-projecting mcRGCs are intrinsically light sensitive. The light responses of these RGCs show very long latency and little adaptation, properties inappropriate for coding dynamic images of vision. The spectral sensitivity of the mcRGCs is similar to the effective light spectrum of photo-entrainment. Construction of a transgenic mouse with labeled mcRGCs showed that they form a complete coverage of the retina, suggestive of a discrete population. In addition to the SCN, these cells project to several non-image forming brain centers related to pupillary responses and circadian rhythm. All of the evidence mentioned above suggested that this newly characterized RGC type participates in entraining the circadian clock.
4) In summary: Among 10 breakthroughs that the journal /Science/announced at the end of 2002 was the discovery of a photosensing (melanopsin-containing) retinal ganglion cell (RGC) and its role in entraining the circadian clock. This breakthrough exemplifies the ultimate goal of neuroscience: to understand the nervous system from molecules to behavior. Light-sensing RGCs constitute one of a dozen discrete RGC populations coding various aspects of visual scenes by virtue of their unique morphology, physiology, and coverage of the retina. Of interest is that the function of the melanopsin-containing RGCs in entraining the circadian clock need not involve much retinal processing, making it the simplest form of processing in the retina.
References (abridged):
1. R. J. Nelson, I. Zucker, Comp. Biochem. Physiol. A 69, 145 (1981)
2. D. M. Berson, Trends Neurosci. 26, 314 (2003)
3. M. S. Freedman et al., Science 284, 502 (1999)
4. R. J. Lucas et al., Behav. Brain. Res. 125, 97 (2001)
5. I. Provencio, G. Jiang, W. J. De Grip, W. P. Hayes, M. D. Rollag, Proc. Natl. Acad. Sci. U.S.A. 95, 340 (1998)
Science http://www.sciencemag.org
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NEUROBIOLOGY: MELANOPSIN AND ACCESSORY VISUAL FUNCTIONS
The following points are made by S. Hattar et al (Nature 2003 424:76):
1) Rods and cones have long been thought to be the exclusive photoreceptors in the retina. This hypothesis is now known to be untrue. An opsin-like protein called melanopsin, originally identified in Xenopus skin melanophores(1), is present in a small subset of mammalian retinal ganglion cells (RGCs)(1-5), and these cells are intrinsically photosensitive. The axons of these RGCs project predominantly to the suprachiasmatic nucleus (SCN), the intergeniculate leaflet (IGL) and the olivary pretectal nucleus (OPN) of the brain, which are key centers for circadian photo-entrainment and the pupillary light reflex.
2) In melanopsin knockout mice (Opn4-/-), those RGCs that would normally express melanopsin lose their intrinsic photosensitivity. Opn4-/- mice also have an incomplete pupillary light reflex at high illuminations. In independently produced melanopsin-knockout mice, others have found that the ability of light to phase-delay and lengthen the period of the circadian rhythm is also diminished. For the pupil reflex, this photic response can be quantitatively accounted for by a functional complementarity between the rod-cone system and the melanopsin system, without the need to invoke any additional light-detection system. Nonetheless, the proposal has persisted that cryptochromes -- flavoproteins reported to have a direct light-detecting role in Drosophila -- may have the same function in mammals despite earlier evidence to the contrary.
3) The authors investigated whether additional photoreceptive systems participate in various light responses. Using mice lacking rods and cones, the authors measured the action spectrum for phase-shifting the circadian rhythm of locomotor behavior. This spectrum matches that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. The authors have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, fail to entrain to light/dark cycles, and fail to show any masking response to light. Thus, the authors suggest, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.
References (abridged):
1. Provencio, I., Jiang, G., DeGrip, W. J., Hayes, W. P. & Rollag, M. D. Melanopsin: an opsin in melanophores, brain, and eye. Proc. Natl Acad. Sci. USA 95, 340-345 (1998)
2. Provencio, I. et al. A novel human opsin in the inner retina. J. Neurosci. 20, 600-605 (2000)
3. Gooley, J. J., Lu, J., Chou, T. C., Scammell, T. E. & Saper, C. B. Melanopsin in cells of origin of the retinohypothalamic tract. Nature Neurosci. 4, 1165 (2001)
4. Hannibal, J., Hindersson, P., Knudsen, S. M., Georg, B. & Fahrenkrug, J. The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. J. Neurosci. 22, RC191 (2002)
5. Provencio, I., Rollag, M. D. & Castrucci, A. M. Photoreceptive net in the mammalian retina. Nature 415, 493 (2002)
Nature http://www.nature.com/nature
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MELANOPSIN-CONTAINING RETINAL GANGLION CELLS: ARCHITECTURE, PROJECTIONS, AND INTRINSIC PHOTOSENSITIVITY
The following points are made by S. Hattar et al (Science 2002 295:1065):
1) Retinal rods and cones, with their light-sensitive, opsin-based pigments, are the primary photoreceptors for vertebrate vision. Visual signals are transmitted to the brain through retinal ganglion cells (RGCs), the output neurons whose axons form the optic nerve. This system, through its projections to the lateral geniculate nucleus and the midbrain, is responsible for interpreting and tracking visual objects and patterns. A separate visual circuit, running in parallel with this image-forming visual system, encodes the general level of environmental illumination and drives certain photic responses, including synchronization of the biological clock with the light-dark cycle (1), control of pupil size (2), acute suppression of locomotor behavior (3), melatonin release (4), and others (5).
2) Surprisingly, the non-image-forming system does not appear to originate from rods and cones. For example, rods and cones are not required for photoentrainment of circadian rhythms, a function mediated by the retinohypothalamic tract and its target, the suprachiasmatic nucleus (SCN), the brain's circadian pacemaker (1). Nor are rods and cones necessary for the pupillary light reflex, mediated by the retinal projection to the pretectal region of the brainstem (2). At present, the best candidate for a photopigment is an opsin-like protein called melanopsin, which is expressed by a subset of mouse and human RGCs. RGCs projecting to the SCN are directly sensitive to light. Thus, melanopsin may be the photopigment responsible for this intrinsic photosensitivity, and it may also trigger other non-image-forming visual functions.
3) In summary: The primary circadian pacemaker, in the suprachiasmatic nucleus (SCN) of the mammalian brain, is photoentrained by light signals from the eyes through the retinohypothalamic tract. Retinal rod and cone cells are not required for photoentrainment. Recent evidence suggests that the entraining photoreceptors are retinal ganglion cells (RGCs) that project to the SCN. The visual pigment for this photoreceptor may be melanopsin, an opsin-like protein whose coding messenger RNA is found in a subset of mammalian RGCs. By cloning rat melanopsin and generating specific antibodies, the authors demonstrate that melanopsin is present in cell bodies, dendrites, and proximal axonal segments of a subset of rat RGCs. In mice heterozygous for tau-lacZ targeted to the melanopsin gene locus, galactosidase-positive RGC axons projected to the SCN and other brain nuclei involved in circadian photoentrainment or the pupillary light reflex. Rat RGCs that exhibited intrinsic photosensitivity invariably expressed melanopsin. The authors conclude that melanopsin is most likely the visual pigment of phototransducing RGCs that set the circadian clock and initiate other non-image-forming visual functions.
References (abridged):
1. D. C. Klein, R. Y. Moore, S. M. Reppert, Suprachiasmatic Nucleus: The Mind's Clock (Oxford Univ. Press, New York, 1991)
2. R. J. Lucas, R. H. Douglas, R. G. Foster, Nature Neurosci. 4, 621 (2001)
3. N. Mrosovsky, Chronobiol. Int. 16, 415 (1999)
4. D. C. Klein and J. L. Weller, Science 177, 532 (1972)
5. P. Badia, B. Myers, M. Boecker, J. Culpepper, J. R. Harsh, Physiol. Behav. 50, 583 (1991)
Science http://www.sciencemag.org
ScienceWeek http://scienceweek.com
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