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, 16 (10), 435-46

The Emerging Roles of Melanopsin in Behavioral Adaptation to Light


The Emerging Roles of Melanopsin in Behavioral Adaptation to Light

Megumi Hatori et al. Trends Mol Med.


The adaptation of behavior and physiology to changes in the ambient light level is of crucial importance to life. These adaptations include the light modulation of neuroendocrine function and temporal alignment of physiology and behavior to the day:night cycle by the circadian clock. These non-image-forming (NIF) responses can function independent of rod and cone photoreceptors but depend on ocular light reception, suggesting the participation of novel photoreceptors in the eye. The discovery of melanopsin in intrinsically photosensitive retinal ganglion cells (ipRGCs) and genetic proof for its important role in major NIF responses have offered an exciting entry point to comprehend how mammals adapt to the light environment. Here, we review the recent advances in our understanding of the emerging roles of melanopsin and ipRGCs. These findings now offer new avenues to understand the role of ambient light in sleep, alertness, dependent physiologies and potential pharmacological intervention as well as lifestyle modifications to improve the quality of life.


Figure I
Figure I. (Box 2) Phototransduction mechanisms of classical vertebrate and invertebrate rhodopsins
The vertebrate rod/cone opsin phototransduction signaling cascade (a) is distinct from that of invertebrate rhodopsin (b).
Figure 1
Figure 1. Melanopsin expressing RGCs and their spectral properties
(a) Schematic diagram of the mammalian retina showing different cell types and their connectivity. The rod and cone photoreceptors densely packed in the outer retina are the primary photoreceptors supporting IF vision. Light activated signals originating from the rod/cone cells are processed in the horizontal (H), bipolar (B) and amacrine cells (A) before reaching the RGC of the inner retina. A small percentage of RGCs express melanopsin and are intrinsically photosensitive (ipRGCs). The ipRGCs, like other RGCs also receive signals originating from the outer retina rod/cone photoreceptors. RPE: retinal pigment epithelium; OPL: outer plexiform layer; INL: inner nuclear layer; IPL: inner plexiform layer; GCL: ganglion cell layer. (b) Melanopsin expressing RGCs in rodents exhibit diversity in their cellular architecture , . Dendrites of the M1 subtype primarily arborize in the outer half of the IPL, the sublamina a (OFF sublamina). Dendrites of the M2 subtype stratify in the inner sublamina of the IPL, the sublamina b (ON sublamina), whereas the M3 subtype stratify in both sublaminae a and b. In general, ON and OFF bipolar cells have its terminals in the sublamina b (ON sublamina) and sublamina a (OFF sublamina), respectively. However, the ON bipolar cells have unusual ectopic synaptic contacts with the M1 cell type in the OFF sublamina . (c) Mouse retina flat mount stained with anti-melanopsin antibody (red). The distribution of melanopsin-staining cells is almost uniform across the mouse retina, whereas in the primate retina, the fovea is largely devoid of ipRGCs . The somata of melanopsin-positive RGCs have sparsely branching dendrites that are relatively long (up to several hundred microns). The dendritic fields of these RGCs in primate and mouse retina have an average diameter of 0.5 mm and 0.3 mm , respectively. Thus, despite the limited expression of melanopsin in only 1–2% of RGCs, these RGCs form a diffuse photosensitive web that covers virtually the entire retina. Melanopsin immunoreactivity is found throughout the dendrites, soma and axons, which contrasts with rods and cones whose photopigment expression is restricted to the outer segments. (d) Spectral sensitivity of rod, cones and ipRGCs and the spectral composition of indoor fluorescent lamps and sunlight. Maximum light sensitivities of human rods (R), S cones, M cones and L cones are to ∼500 nm, ∼420 nm, ∼530 nm and ∼560 nm wavelengths, respectively. The ipRGCs exhibit peak sensitivity at ∼480 nm. The emission spectra for popular fluorescent lamps (black line) used for indoor lighting and sunlight (grey line; two hours after sunrise in San Diego, April 2010) were measured and analyzed by EPP2000 UV-VIS spectrometer and SpectraWiz software (StellarNet Inc.).
Figure 2
Figure 2. The visual cycle and phototranduction in the vertebrate retina
In the rod outer segment (ROS), light converts 11-cis retinal chromophore of rhodopsin to all-trans retinal. All-trans retinal is released from rhodopsin and undergoes an elaborate multistep enzymatic process (visual cycle) to regenerate 11-cis retinal. All-trans retinal is first reduced to all-trans retinol by retinol dehydrogenase 8 (RDH8) and RDH12. In the RPE, all-trans retinol is esterified by LRAT to all-trans retinyl esters. RPE65 mediates the conversion of all-trans retinyl esters to 11-cis retinol, which is oxidized to 11-cis retinal by RDH5. 11-cis retinal returns to the ROS where it binds to opsin to regenerate rhodopsin photopigment. In the ipRGCs, melanopsin is found in complex with 11-cis retinal . The source of this chromophore and the mechanism for regeneration of 11-cis- from all-trans- retinal photoproduct is currently not known. Evidence points to both photoisomerization of all-trans retinal to 11-cis by melanopsin itself and use of the RPE visual cycle.
Figure 3
Figure 3. The ipRGCs as the site of signal integration
The rod and cone photoreceptors of the outer retina signal via multisynaptic pathways to the RGCs of the inner retina. The RGCs, in turn, transfer the visual signals from the eye to the brain via their axonal projections. For NIF visual functions, the light information originating from the rods and cones are exclusively transmitted through the ipRGCs. The ipRGCs function as the node for integrating melanopsin and rod/cone initiated photoresponses. ipRGCs likely participate in the IF vision by two potential mechanisms. In the retina they also affect function of the dopamine-responsive amacrine cells, which then affect adaptation of the rod/cone-initiated signals under prolonged illumination. The ipRGCs also send projections to the dorsal LGN (lateral geniculate nucleus) in the brain, which receives extensive innervations from other RGCs .
Figure 4
Figure 4. Central projections of the ipRGCs
A schematic diagram of summarizing the brain regions innervated with the ipRGC axons. SCN: suprachiasmatic nucleus; LH: lateral hypothalamus; AH: anterior hypothalamus, SPZ: subparaventricular zone; OPN: olivary pretectal nucleus; IGL: intergeniculate leaf; dLGN: dorsal lateral geniculate nucleus; vLGN: ventral lateral geniculate nucleus; SC: superior colliculus.

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