foster.qxp 24/9/08 02:13 Page 86
Posterior Segment Retina
excitatory input.
14
The explanation for this opponent interaction photoreceptors may contribute to an individual’s ability to detect or
remains unclear.
22
even experience some awareness of light, triggering either a conscious
response or, in the absence of a percept, a response analogous to
Research on the pRGCs has been largely confined to animal models, blindsight – defined as an above chance ability to detect the presence of
and the extent to which the findings in rodents and non-human a light stimulus in the absence of a conscious percept. Therefore, a
primates are mirrored in humans has been the subject of much debate. rodless/coneless subject was examined to determine whether a given
The participation of two profoundly blind subjects lacking functional light stimulus could be detected when presented in the first or second
rods and cones has allowed an exploration of this question. The first of two temporal intervals in a two-alternative forced-choice paradigm
finding was that human subjects lacking rods and cones are still (2AFC). After some initial hesitancy on being asked to report the
capable of regulating their circadian physiology and behaviour.
26
On presence of visual stimuli of which she was nominally unaware, the
the basis of these findings, and by analogy to the studies in rodents,
8
subject was able to correctly identify the interval in which a 481nm test
it was reasoned that some pupil reactivity to bright light should also light (at threshold intensity) appeared, but failed to detect light at longer
be retained, despite the clinical reports that subjects are unresponsive or shorter wavelengths (420, 460, 500, 515, 540, 560 and 580nm).
to the brief light exposure from a pen torch.
Collectively, these results provide strong evidence that pRGCs can, at
One individual was examined in detail and clearly possessed a some level, contribute to our awareness of environmental light. These
functioning pupillomotor system responsive to bright light. surprising findings suggest a greater functional overlap of the pRGCs
Furthermore, the pupil constriction response was spectrally tuned, and rod/cone subsystems than was previously assumed.
26
peaking (λ
max
) around 480nm, which corresponds well to the action
spectra for pRGCs in both human (483nm)
15
and non-human primates The discovery of a third photoreceptor system within the eye based on
(482nm),
14
but not the λ
max
of human rods (~498nm) or S-, M- and L- melanopsin pRGCs argues that the clinical diagnosis of ‘complete’
wavelength cones (λ
max
~420, 534 and 563nm, respectively). blindness should assess the state of both the rod/cone and pRGC
photoreceptive systems. We now appreciate that eye loss plunges
Humans appear to possess a pRGC system that to a high degree individuals into a world that lacks both vision and a proper sense of
resembles that of rodents and non-human primates. Furthermore, the time, and clinical guidelines should incorporate this information. If a
demonstration of a pupil response in a rodless/coneless individual ‘blind’ individual shows a bright-light-dependent pupil constriction,
raises important issues regarding the significance of this assay in he or she should be encouraged to expose his or her eyes to sufficient
defining blindness. Currently, unreactive pupils in response to brief daytime light to maintain normal circadian entrainment and
torch pen examination are considered clinically to be a sine qua non of sleep–wake timing.
profound blindness of retinal origin.
26
Ideally, such an examination
should involve exposure to bright light over many seconds. Furthermore, patients with diseases of the inner retina that result in RGC
death (e.g. glaucoma) are at particular risk of circadian rhythm and sleep
What else may the pRGCs regulate in humans? Recent findings in disruption. Such individuals should receive counselling regarding the
primates showed that the pRGCs project to the dorsal lateral geniculate problems of sleep disruption
27
and would be strong candidates for
nucleus (dLGN), which is the thalamic relay that provides a direct input treatment with appropriately timed melatonin, which has been shown to
to the visual cortex.
14
This raised the possibility that these consolidate sleep timing in patients suffering eye loss.
28,29
■
1. Foster RG, Helfrich-Forster C, The regulation of circadian clocks 1070–73. 20. Qiu X, Kumbalasiri T, Carlson SM, et al., Induction of
by light in fruitflies and mice, Philos Trans R Soc Lond B Biol Sci, 11. Sekaran S, Foster RG, Lucas RJ, Hankins MW, Calcium imaging photosensitivity by heterologous expression of melanopsin,
2001;356:1779–89. reveals a network of intrinsically light-sensitive inner-retinal Nature, 2005;433:745–9.
2. Foster RG, Provencio I, Hudson D, et al., Circadian neurons, Curr Biol, 2003;13:1290–98. 21. Panda S, Provencio I, Tu DC, et al., Melanopsin Is Required for
photoreception in the retinally degenerate mouse (rd/rd), 12. Peirson SN, Thompson S, Hankins MW, Foster RG, Mammalian Non-Image-Forming Photic Responses in Blind Mice, Science,
J Comp Physiol, 1991;169:39–50. photoentrainment: results, methods, and approaches, Methods 2003;301(5632):525–7.
3. David-Gray ZK, Janssen JW, DeGrip WJ, et al., Light detection Enzymol, 2005;393:697–726. 22. Peirson S, Foster RG, Melanopsin: another way of signaling
in a ‘blind’ mammal, Nat Neurosci, 1998;1:655–6. 13. Hattar S, Lucas RJ, Mrosovsky N,et al., Melanopsin and rod- light, Neuron, 2006;49:331–9.
4. Czeisler CA, Shanahan TL, Klerman EB, et al., Suppression of cone photoreceptive systems account for all major accessory 23. Peirson SN, Oster H, Jones SL, et al., Microarray analysis and
melatonin secretion in some blind patients by exposure to visual functions in mice, Nature, 2003;424:75–81. functional genomics identify novel components of melanopsin
bright light, N Engl J Med, 1995;332:6–11. 14. Dacey DM, Liao HW, Peterson BB, et al., Melanopsin-expressing signaling, Curr Biol, 2007;17:1363–72.
5. Freedman MS, Lucas RJ, Soni B, et al., Regulation of ganglion cells in primate retina signal colour and irradiance and 24. Sekaran S, Lall GS, Ralphs KL, et al., 2-Aminoethoxydiphenyl-
mammalian circadian behavior by non-rod, non-cone, ocular project to the LGN, Nature, 2005;433:749–54. borane is an acute inhibitor of directly photosensitive retinal
photoreceptors, Science, 1999;284:502–4. 15. Hankins MW, Lucas RJ, The primary visual pathway in humans ganglion cell activity in vitro and in vivo, J Neurosci, 2007;27:
6. Lucas RJ, Freedman MS, Munoz M, et al., Regulation of the is regulated according to long-term light exposure through the 3981–6.
mammalian pineal by non-rod, non-cone, ocular photo- action of a non-classical photopigment, Curr Biol, 2002;12: 25. Hankins MW, Peirson SN, Foster RG, Melanopsin: an exciting
receptors, Science, 1999;284,505–7. 191–8. photopigment, Trends Neurosci, 2008;31:27–36.
7. Whiteley SJ, Young MJ, Litchfield TM,et al., Changes in the 16. Provencio I, Jiang G, DeGrip WJ, et al., Melanopsin: An opsin in 26. Zaidi FH, Hull JT, Peirson SN, et al., Short-wavelength light
pupillary light reflex of pigmented royal college of surgeons rats melanophores, brain and eye, Proc Natl Acad Sci U S A, 1998; sensitivity of circadian, pupillary, and visual awareness in
with age, Exp Eye Res, 1998;66:719–30. 95:340–45. humans lacking an outer retina, Curr Biol, 2007;17:2122–8.
8. Lucas RJ, Douglas RH, Foster RG, Characterization of an ocular 17. Bellingham J, Whitmore D, Philp AR, et al., Zebrafish 27. Foster RG, Wulff K, The rhythm of rest and excess, Nat Rev
photopigment capable of driving pupillary constriction in mice, melanopsin: isolation, tissue localisation and phylogenetic Neurosci, 2005;6:407–14.
Nat Neurosci, 2001;4:621–6. position, Brain Res Mol Brain Res, 2002;107:128–36. 28. Lockley SW, Skene DJ, James K, et al., Melatonin administration
9. Provencio I, Cooper HM, Foster RG, Retinal projections in mice 18. Provencio I, Rodriguez IR, Jiang G, et al., A novel human opsin can entrain the free-running circadian system of blind subjects,
with inherited retinal degeneration: implications for circadian in the inner retina, J Neurosci, 2000;20:600–605. J Endocrinol, 2000;164:R1–R6.
photoentrainment, J Comp Neurol, 1998;395:417–39. 19. Melyan Z, Tarttelin EE, Bellingham J, et al., Addition of human 29. Sack RL, Brandes RW, Kendall AR, Lewy AJ, Entrainment of
10. Berson DM, Dunn FA, Takao M, Phototransduction by retinal melanopsin renders mammalian cells photoresponsive, Nature, free-running circadian rhythms by melatonin in blind people,
ganglion cells that set the circadian clock, Science, 2002;295: 2005;433:741–45. N Engl J Med, 2000;343:1070–77.
86 EUROPEAN OPHTHALMIC REVIEW
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100