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1.
Proc Natl Acad Sci U S A ; 117(29): 17320-17329, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632006

RESUMO

Second only to headache, photophobia is the most debilitating symptom reported by people with migraine. While the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to play a role, how cone and melanopsin signals are integrated in this pathway to produce visual discomfort is poorly understood. We studied 60 people: 20 without headache and 20 each with interictal photophobia from migraine with or without visual aura. Participants viewed pulses of spectral change that selectively targeted melanopsin, the cones, or both and rated the degree of visual discomfort produced by these stimuli while we recorded pupil responses. We examined the data within a model that describes how cone and melanopsin signals are weighted and combined at the level of the retina and how this combined signal is transformed into a rating of discomfort or pupil response. Our results indicate that people with migraine do not differ from headache-free controls in the manner in which melanopsin and cone signals are combined. Instead, people with migraine demonstrate an enhanced response to integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an enhancement of pupil responses was not seen in the migraine group, nor were group differences found in surveys of other behaviors putatively linked to ipRGC function (chronotype, seasonal sensitivity, presence of a photic sneeze reflex). By revealing a dissociation in the amplification of discomfort vs. pupil response, our findings suggest a postretinal alteration in processing of ipRGC signals for photophobia in migraine.


Assuntos
Transtornos de Enxaqueca/metabolismo , Fotofobia/metabolismo , Células Ganglionares da Retina/fisiologia , Adulto , Feminino , Humanos , Masculino , Estimulação Luminosa , Pupila/fisiologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Opsinas de Bastonetes/fisiologia
2.
Science ; 368(6495): 1108-1113, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32499439

RESUMO

Enabling near-infrared light sensitivity in a blind human retina may supplement or restore visual function in patients with regional retinal degeneration. We induced near-infrared light sensitivity using gold nanorods bound to temperature-sensitive engineered transient receptor potential (TRP) channels. We expressed mammalian or snake TRP channels in light-insensitive retinal cones in a mouse model of retinal degeneration. Near-infrared stimulation increased activity in cones, ganglion cell layer neurons, and cortical neurons, and enabled mice to perform a learned light-driven behavior. We tuned responses to different wavelengths, by using nanorods of different lengths, and to different radiant powers, by using engineered channels with different temperature thresholds. We targeted TRP channels to human retinas, which allowed the postmortem activation of different cell types by near-infrared light.


Assuntos
Cegueira/terapia , Ouro , Raios Infravermelhos , Nanotubos , Degeneração Retiniana/terapia , Limiar Sensorial/efeitos da radiação , Canais de Cátion TRPC/fisiologia , Visão Ocular/efeitos da radiação , Animais , Cegueira/fisiopatologia , Modelos Animais de Doenças , Potenciais Evocados Visuais/fisiologia , Potenciais Evocados Visuais/efeitos da radiação , Engenharia Genética , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estimulação Luminosa , Ratos , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Fotorreceptoras Retinianas Cones/efeitos da radiação , Degeneração Retiniana/fisiopatologia , Células Ganglionares da Retina/fisiologia , Células Ganglionares da Retina/efeitos da radiação , Limiar Sensorial/fisiologia , Serpentes , Canais de Cátion TRPC/genética , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/fisiologia , Visão Ocular/fisiologia , Córtex Visual/fisiopatologia , Córtex Visual/efeitos da radiação
3.
J Vis ; 20(3): 7, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32232377

RESUMO

Color constancy involves disambiguating the spectral characteristics of lights and surfaces, for example to distinguish red in white light from white in red light. Solving this problem appears especially challenging for bluish tints, which may be attributed more often to shading, and this bias may underlie the individual differences in whether people described the widely publicized image of #thedress as blue-black or white-gold. To probe these higher-level color inferences, we examined neural correlates of the blue-bias, using frequency-tagging and high-density electroencephalography to monitor responses to 3-Hz alternations between different color versions of #thedress. Specifically, we compared relative neural responses to the original "blue" dress image alternated with the complementary "yellow" image (formed by inverting the chromatic contrast of each pixel). This image pair produced a large modulation of the electroencephalography amplitude at the alternation frequency, consistent with a perceived contrast difference between the blue and yellow images. Furthermore, decoding topographical differences in the blue-yellow asymmetries over occipitoparietal channels predicted blue-black and white-gold observers with over 80% accuracy. The blue-yellow asymmetry was stronger than for a "red" versus "green" pair matched for the same component differences in L versus M or S versus LM chromatic contrast as the blue-yellow pair and thus cannot be accounted for by asymmetries within either precortical cardinal mechanism. Instead, the results may point to neural correlates of a higher-level perceptual representation of surface colors.


Assuntos
Vestuário , Percepção de Cores/fisiologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Neurônios Retinianos/fisiologia , Adulto , Eletroencefalografia , Feminino , Humanos , Individualidade , Iluminação/normas , Masculino , Adulto Jovem
4.
Invest Ophthalmol Vis Sci ; 61(4): 26, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32315379

RESUMO

Purpose: Cone photoreceptor function loss 3 (Gnat2cpfl3/cpfl3 or cpfl3) is a mouse model commonly used as a functional cones null from a naturally occurring mutation in the α-subunit of cone transducin (Gnat2). We nevertheless detected robust cone-mediated light responses from cpfl3 animals, which we now explore. Methods: Recordings were made from whole retina and from identified cones with whole-cell patch clamp in retinal slices. Relative levels of GNAT2 protein and numbers of cones in isolated retinas were compared between cpfl3, rod transducin knockout (Gnat1-/-), cpfl3/Gnat1-/- double mutants, and control C57Bl/6J age-matched mice at 4, 9, and 14 weeks of age. Results: Cones from cpfl3 and cpfl3/Gnat1-/- mice 2 to 3 months of age displayed normal dark currents but greatly reduced sensitivity and amplification constants. Responses decayed more slowly than in control (C57Bl/6J) mice, indicating an altered mechanism of inactivation. At dim light intensities rod responses could be recorded from cpfl3 cones, indicating intact rod/cone gap junctions. The cpfl3 and cpfl3/Gnat1-/- mice express two-fold less GNAT2 protein compared with C57 at 4 weeks, and a four-fold decrease by 14 weeks. This is accompanied by a small decrease in the number of cones. Conclusions: Cplf3 cones can respond to light with currents of normal amplitude and cannot be assumed to be a Gnat2 null. The decreased sensitivity and amplification rate of cones is not explained by a reduction in GNAT2 protein level, but instead by abnormal interactions of the mutant transducin with rhodopsin and the effector molecule, cGMP phosphodiesterase.


Assuntos
Regulação da Expressão Gênica , Proteínas Heterotriméricas de Ligação ao GTP/genética , Doenças Retinianas/genética , Transducina/genética , Visão Ocular/genética , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Estimulação Luminosa , Células Fotorreceptoras Retinianas Cones/fisiologia , Doenças Retinianas/fisiopatologia , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Transdução de Sinais/genética
5.
Invest Ophthalmol Vis Sci ; 61(3): 53, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32232344

RESUMO

Purpose: To investigate clinical characteristics of RDH5-related fundus albipunctatus (FAP) in a Japanese cohort. Methods: Twenty-five patients from 22 pedigrees with RDH5-related FAP were studied. Ophthalmic medical records were reviewed. For genetic analysis, either Sanger sequencing of the RDH5 gene or whole-exome sequencing was performed. Results: Genetic analysis identified eight different RDH5 variants, including seven known RDH5 variants (p.G35S, p.G107R, p.R167H, p.A240GfsX19, p.R278X, p.R280H, and p.L310delinsEV) and a novel variant: c.259C>T (p.Q87X). The most frequently observed variant was p.L310delinsEV (65.2%, 30/46 alleles). Of 50 eyes examined, 44 eyes (88.0%) showed logMAR best-corrected visual acuity (BCVA) of 0.10 or better. In optical coherence tomography, macular involvement was observed in 12 patients (24 eyes). Ten patients (83.3%) who had good BCVA (0.10 or better) exhibited diffuse disruption of the outer retina with foveal sparing, and two patients (16.7%) exhibited diffuse disruption throughout the macula and decreased BCVA. Among the 24 eyes, ring-or crescent-shaped hyperautofluorescence or irregular autofluorescence around the fovea was observed in 15 eyes (83.3%) of 18 eyes examined by fundus autofluorescence imaging. Full-field electroretinography showed extinguished or severely decreased rod responses in all 23 examined patients, whereas decreased cone responses were seen in 17 patients (73.9%). Conclusions: Multimodal imaging and electroretinography of RDH5-related FAP revealed high frequencies of macular involvement in older patients and decreased cone responses. Our findings suggest that progressive macular/cone dysfunction, as well as delayed rod function, may be key phenotypic features of RDH5-related FAP.


Assuntos
Oxirredutases do Álcool/genética , Grupo com Ancestrais do Continente Asiático/genética , Células Fotorreceptoras Retinianas Cones/fisiologia , Doenças Retinianas/genética , Doenças Retinianas/fisiopatologia , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Adolescente , Adulto , Idoso , Criança , Eletrorretinografia , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Linhagem , Doenças Retinianas/diagnóstico por imagem , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Sequenciamento Completo do Genoma , Adulto Jovem
6.
PLoS One ; 15(3): e0229142, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32134934

RESUMO

Migratory birds can detect the direction of the Earth's magnetic field using the magnetic compass sense. However, the sensory basis of the magnetic compass still remains a puzzle. A large body of indirect evidence suggests that magnetic compass in birds is localized in the retina. To confirm this point, an evidence of visual signals modulation by magnetic field (MF) should be obtained. In a previous study we showed that MF inclination impacts the amplitude of ex vivo electroretinogram (ERG) recorded from isolated pigeon retina. Here we present the results of an analysis of putative MF effect on one component of ERG, the photoreceptor's response, isolated from the total ERG by adding sodium aspartate and barium chloride to the perfusion solution. Photoresponses were recorded from isolated retinae of domestic pigeons Columba livia. The retinal samples were placed in MF that was modulated by three pairs of orthogonal Helmholtz coils. Light stimuli (blue and red) were applied under two inclinations of MF, 0° and 90°. In all the experiments, preparations from two parts of retina were used, red field (with dominant red-sensitive cones) and yellow field (with relatively uniform distribution of cone color types). In contrast to the whole retinal ERG, we did not observe any effect of MF inclination on either amplitude or kinetics of pharmacologically isolated photoreceptor responses to blue or red half-saturating flashes. A possible explanations of these results could be that magnetic compass sense is localized in retinal cells other than photoreceptors, or that photoreceptors do participate in magnetoreception, but require some processing of compass information in other retinal layers, so that only whole retina signal can reflect the response to changing MF.


Assuntos
Migração Animal/fisiologia , Columbidae/anatomia & histologia , Campos Magnéticos , Orientação Espacial/fisiologia , Células Fotorreceptoras de Vertebrados/fisiologia , Retina/anatomia & histologia , Resposta Táctica/fisiologia , Animais , Cor , Eletrorretinografia/veterinária , Fundo de Olho , Luz , Magnetismo , Estimulação Luminosa , Células Fotorreceptoras de Vertebrados/citologia , Retina/citologia , Retina/diagnóstico por imagem , Células Fotorreceptoras Retinianas Cones/citologia , Células Fotorreceptoras Retinianas Cones/fisiologia
7.
PLoS Comput Biol ; 16(3): e1007691, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32150546

RESUMO

Nervous systems are incredibly diverse, with myriad neuronal subtypes defined by gene expression. How binary and graded fate characteristics are patterned across tissues is poorly understood. Expression of opsin photopigments in the cone photoreceptors of the mouse retina provides an excellent model to address this question. Individual cones express S-opsin only, M-opsin only, or both S-opsin and M-opsin. These cell populations are patterned along the dorsal-ventral axis, with greater M-opsin expression in the dorsal region and greater S-opsin expression in the ventral region. Thyroid hormone signaling plays a critical role in activating M-opsin and repressing S-opsin. Here, we developed an image analysis approach to identify individual cone cells and evaluate their opsin expression from immunofluorescence imaging tiles spanning roughly 6 mm along the D-V axis of the mouse retina. From analyzing the opsin expression of ~250,000 cells, we found that cones make a binary decision between S-opsin only and co-expression competent fates. Co-expression competent cells express graded levels of S- and M-opsins, depending nonlinearly on their position in the dorsal-ventral axis. M- and S-opsin expression display differential, inverse patterns. Using these single-cell data, we developed a quantitative, probabilistic model of cone cell decisions in the retinal tissue based on thyroid hormone signaling activity. The model recovers the probability distribution for cone fate patterning in the mouse retina and describes a minimal set of interactions that are necessary to reproduce the observed cell fates. Our study provides a paradigm describing how differential responses to regulatory inputs generate complex patterns of binary and graded cell fates.


Assuntos
Opsinas dos Cones , Modelos Biológicos , Retina , Células Fotorreceptoras Retinianas Cones , Animais , Biologia Computacional , Opsinas dos Cones/análise , Opsinas dos Cones/química , Opsinas dos Cones/metabolismo , Feminino , Processamento de Imagem Assistida por Computador , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Retina/citologia , Retina/crescimento & desenvolvimento , Células Fotorreceptoras Retinianas Cones/citologia , Células Fotorreceptoras Retinianas Cones/fisiologia
8.
Invest Ophthalmol Vis Sci ; 61(3): 5, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32150247

RESUMO

Purpose: Activating the cell survival modulator sigma 1 receptor (Sig1R) delays cone photoreceptor cell loss in Pde6ßrd10/J (rd10) mice, a model of retinitis pigmentosa. Beneficial effects are abrogated in rd10 mice lacking NRF2, implicating NRF2 as essential to Sig1R-mediated cone neuroprotection. Here we asked whether activation of NRF2 alone is sufficient to rescue cones in rd10 mice. Methods: Expression of antioxidant genes was evaluated in 661W cells and in mouse retinas after treatment with monomethylfumarate (MMF), a potent NRF2 activator. Rd10 mice were administered MMF (50 mg/kg) or the Sig1R ligand (+)-pentazocine (PTZ; 0.5 mg/kg) intraperitoneally (every other day, P14-42). Mice were evaluated for visual acuity (optokinetic tracking response), retinal function (electroretinography) and architecture (SD-OCT); histologic retinal sections were evaluated morphometrically. Results: MMF treatment increased Nrf2, Nqo1, Cat, Sod1, and Hmox1 expression in vitro and in vivo. Visual acuity of (+)-PTZ-treated rd10 mice was similar to wild-type mice; however, MMF treatment did not alter acuity compared with nontreated rd10 mice. Cone electroretinography b-wave amplitudes were greater in PTZ-treated than nontreated or MMF-treated rd10 mice. SD-OCT assessment of retinal thickness was greater in (+)-PTZ-treated mice versus nontreated or MMF-treated rd10 mice. Morphometric assessment of the outer nuclear layer revealed approximately 18 cells/100 µm retinal length in (+)-PTZ-treated rd10 mice, but only approximately 10 to 12 cells/100 µm in MMF-treated and nontreated rd10 retinas. Conclusions: Activation of NRF2 using MMF, at least at our dosing regimen, is insufficient to attenuate catastrophic photoreceptor damage characteristic of rd10 mice. The data prompt investigation of additional mechanisms involved in Sig1R-mediated retinal neuroprotection.


Assuntos
Fumaratos/uso terapêutico , Maleatos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Receptores sigma/fisiologia , Retinite Pigmentosa/prevenção & controle , Animais , Antioxidantes/metabolismo , Modelos Animais de Doenças , Eletrorretinografia/métodos , Fumaratos/farmacologia , Hidroquinonas/farmacologia , Maleatos/farmacologia , Camundongos Knockout , Fator 2 Relacionado a NF-E2/fisiologia , Neuroproteção/fisiologia , Fármacos Neuroprotetores/farmacologia , Pentazocina/farmacologia , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/efeitos dos fármacos , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Retinite Pigmentosa/patologia , Retinite Pigmentosa/fisiopatologia , Tomografia de Coerência Óptica/métodos , Regulação para Cima/efeitos dos fármacos , Acuidade Visual/efeitos dos fármacos
9.
Invest Ophthalmol Vis Sci ; 61(2): 13, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32049342

RESUMO

Purpose: Exposure to short-wavelength light influences refractive development and inhibits myopic development in many animal models. Retinal mechanisms underlying this response remain unknown. This study used a mouse model of lens-induced myopia to evaluate the effect of different wavelength light on refractive development and dopamine levels in the retina. A possible retinal pathway is tested using a mutant mouse with dysfunctional cones. Methods: Wild-type C57BL/6J (WT) and ALS/LtJ/Gnat2cpfl3 (Gnat2-/-) mice were exposed to one of three different light conditions beginning at postnatal day 28: broad-spectrum "white" (420-680 nm), medium wavelength "green" (525 ± 40 nm), and short wavelength "violet" (400 ± 20 nm). One-half of the mice received hyperopic lens defocus. All mice were exposed to the light for 4 weeks; animals were measured weekly for refractive error and axial parameters. Retinal dopamine and the dopamine metabolite 3,4-dihydroxyphenylacetic acid were measured by HPLC. Results: In WT mice, short-wavelength violet light induced hyperopia and violet light inhibited lens-induced myopia when compared with mice exposed to white light. Hyperopia could be attributed to shallower vitreous chambers in WT animals. There were no changes in the levels of dopamine or its metabolite. In Gnat2-/- mice, violet light did not induce hyperopia or inhibit lens-induced myopia. Conclusions: These findings show that short-wavelength light slows refractive eye growth, producing hyperopic responses in mice and inhibiting lens-induced myopia. The lack of inhibition in mice with dysfunctional cones suggests that cone signaling plays a role in the hyperopic response to short-wavelength (violet) light.


Assuntos
Luz , Miopia/prevenção & controle , Fototerapia , Células Fotorreceptoras Retinianas Cones/fisiologia , Transdução de Sinais/fisiologia , Animais , Dopamina/metabolismo , Feminino , Proteínas Heterotriméricas de Ligação ao GTP/deficiência , Doenças do Cristalino/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Refração Ocular/fisiologia , Retina/metabolismo
10.
PLoS Biol ; 18(1): e3000570, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31971946

RESUMO

Stimuli that modulate neuronal activity are not always detectable, indicating a loss of information between the modulated neurons and perception. To identify where in the macaque visual system information about periodic light modulations is lost, signal-to-noise ratios were compared across simulated cone photoreceptors, lateral geniculate nucleus (LGN) neurons, and perceptual judgements. Stimuli were drifting, threshold-contrast Gabor patterns on a photopic background. The sensitivity of LGN neurons, extrapolated to populations, was similar to the monkeys' at low temporal frequencies. At high temporal frequencies, LGN sensitivity exceeded the monkeys' and approached the upper bound set by cone photocurrents. These results confirm a loss of high-frequency information downstream of the LGN. However, this loss accounted for only about 5% of the total. Phototransduction accounted for essentially all of the rest. Together, these results show that low temporal frequency information is lost primarily between the cones and the LGN, whereas high-frequency information is lost primarily within the cones, with a small additional loss downstream of the LGN.


Assuntos
Macaca fascicularis/fisiologia , Córtex Visual/citologia , Córtex Visual/fisiologia , Vias Visuais/fisiologia , Percepção Visual/fisiologia , Animais , Núcleo de Edinger-Westphal/citologia , Núcleo de Edinger-Westphal/fisiologia , Núcleo de Edinger-Westphal/efeitos da radiação , Fenômenos Eletrofisiológicos , Corpos Geniculados/citologia , Corpos Geniculados/fisiologia , Luz , Iluminação , Masculino , Neurônios/fisiologia , Neurônios/efeitos da radiação , Estimulação Luminosa , Células Fotorreceptoras Retinianas Cones/citologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Fotorreceptoras Retinianas Cones/efeitos da radiação , Movimentos Sacádicos/fisiologia , Fatores de Tempo , Córtex Visual/efeitos da radiação , Vias Visuais/efeitos da radiação , Percepção Visual/efeitos da radiação
11.
Doc Ophthalmol ; 140(2): 95-101, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31749034

RESUMO

The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum procedure for testing generalized retinal function but encourages more extensive testing. This extended protocol describes a method of assessing the function of the short-wavelength-sensitive cone (S-cone) retinal pathway, using a short-wavelength flash superimposed on a background that saturates the rods and adapts the L/M-cones to elicit a response, known as the S-cone ERG. Stimulus parameters such as the strength and luminance of the flash and background, respectively, and their spectral and temporal characteristics are specified. As a complement to the ISCEV standard, testing the S-cone ERG enables further characterization of light-adapted retinal function and may refine diagnosis of some retinal disorders. Typical applications are described including use in the diagnosis of rod monochromacy and S-cone monochromacy, identification and investigation of cone On-bipolar cell dysfunction and use of the technique to confirm the diagnosis of enhanced S-cone syndrome.


Assuntos
Eletrofisiologia/normas , Eletrorretinografia/normas , Células Fotorreceptoras Retinianas Cones/fisiologia , Opsinas de Bastonetes/fisiologia , Sociedades Médicas/normas , Adaptação Ocular , Calibragem/normas , Protocolos Clínicos , Humanos , Agências Internacionais , Estimulação Luminosa , Distrofias Retinianas/fisiopatologia , Visão Ocular
12.
Doc Ophthalmol ; 140(1): 31-42, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31512016

RESUMO

PURPOSE: To define the relationship between abnormalities in the activation phase of cone phototransduction and the oscillatory potentials (OPs) of the light-adapted electroretinogram in diabetics who have mild or no retinopathy. METHODS: Subjects included 20 non-diabetic controls and 40 type-2 diabetics (20 had no clinically apparent diabetic retinopathy [NDR] and 20 had mild nonproliferative DR). Single flash responses for a series of stimulus retinal illuminances were measured under light-adapted conditions using conventional techniques. The a-waves of the responses were fit with a delayed Gaussian model to derive Rmp3 (maximum amplitude of the massed photoreceptor response) and S (phototransduction sensitivity). OPs were extracted from the responses by conventional band-pass filtering. RESULTS: Analysis of variance (ANVOA) indicated that both diabetic groups had significant OP amplitude and S reductions compared to the controls, whereas Rmp3 did not differ significantly among the groups. Although log OP amplitude and log Rmp3 were significantly correlated for the control subjects for each flash retinal illuminance (all r > 0.49, p < 0.03), log OP amplitude and log Rmp3 were not correlated for either diabetic group for any flash retinal illuminance (all r ≤ 0.36, p ≥ 0.13). Log OP amplitude and log S were generally not correlated significantly for the control or diabetic groups. CONCLUSION: OP amplitude losses do not appear to be related to reduced cone sensitivity in early-stage diabetic retinopathy. This suggests that diabetes may separately affect cone function, as evidenced by cone phototransduction sensitivity losses, and inner-retina function, as evidenced by OP amplitude losses.


Assuntos
Retinopatia Diabética/fisiopatologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Visão Ocular/fisiologia , Adaptação Ocular/fisiologia , Adulto , Diabetes Mellitus Tipo 2/fisiopatologia , Eletrorretinografia/métodos , Feminino , Humanos , Masculino , Oscilometria , Estimulação Luminosa/métodos
13.
Doc Ophthalmol ; 140(2): 147-157, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31583501

RESUMO

PURPOSE: A single variant (p.G38D) in the GNAT1 gene, encoding the rod-specific transducin α-subunit in phototransduction, has been reported only in one French family with Nougaret-type autosomal dominant congenital stationary night blindness (CSNB). We identified a Japanese family with Nougaret-type CSNB and cone-rod dystrophy (CORD). METHODS: Five patients with CSNB and two patients with childhood-onset CORD were recruited. We performed a comprehensive ophthalmic examination including electroretinography (ERG). Disease-causing variants were identified by whole exome sequencing, with candidates confirmed by Sanger sequencing in nine family members. RESULTS: The GNAT1 variant (p.G38D) was identified in all four CSNB patients, whereas the two CORD patients carried biallelic truncated known ABCA4 variants as well as the GNAT1 variant. Clinically, no remarkable findings were observed in fuduscopy, fundus autofluorescence, or optical coherence tomography images from the CSNB patients. No response was detectable by rod ERG. The a-waves of standard and bright flash ERG were delayed and broadened rather than biphasic, and b/a-wave amplitude ratio was negative. Cone and 30-Hz flicker responses were normal, and overall, the ERG findings were compatible with previous descriptions of Nougaret-type CSNB. ERG of the CORD patients with macular atrophy showed non-recordable rod response and severely decreased standard flash, cone and 30-Hz flicker responses. CONCLUSIONS: This is the second report of a Nougaret-type CSNB family with the GNAT1 variant. Our novel findings suggest that coexistence of the GNAT1 and biallelic ABCA4 variants is associated with an overlapping phenotype with both Nougaret-type CSNB and CORD.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Distrofias de Cones e Bastonetes/genética , Oftalmopatias Hereditárias/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Miopia/genética , Cegueira Noturna/genética , Polimorfismo de Nucleotídeo Único , Transducina/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Distrofias de Cones e Bastonetes/fisiopatologia , Eletrorretinografia , Oftalmopatias Hereditárias/fisiopatologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Miopia/fisiopatologia , Cegueira Noturna/fisiopatologia , Linhagem , Fenótipo , Estimulação Luminosa , Retina/fisiologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Sequenciamento Completo do Exoma
14.
Am J Ophthalmol ; 214: 72-85, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31883465

RESUMO

PURPOSE: Limited information is available on morphologic and functional regeneration of photoreceptors after retinal detachment (RD) surgery. This observational clinical study compared morphologic and functional changes of cones after vitrectomy for macula-off retinal detachment. DESIGN: Prospective, fellow-eye comparative case series. METHODS: StudyPopulation: Five eyes after vitrectomy with gas for macula-off retinal detachment (retinal detachment eyes, RDE) and 5 healthy fellow eyes (HFE) of 5 patients (mean age 59.8 years, macula-off duration 0.5 days to 5.5 days). ObservationProcedures: Eyes were examined with adaptive-optics optical coherence tomography (AO-OCT), spectral-domain OCT (SDOCT), and microperimetry (MP) at 6 (baseline, BL) and 56 weeks (follow-up, FUP) after 23 gauge pars plana vitrectomy and SF6 gas tamponade. Eight corresponding regions at foveal eccentricities of 2.5° (ecc 2.5°) and 6.5° (ecc 6.5°) were analyzed in every eye. AO-OCT en face images and SD-OCT B-scans were graded regarding irregularity and loss of photoreceptor signals ranging from none to severe changes. The number of detectable cones at height of the inner-outer segment junction (IS/OS) and cone outer segment tips (COST) was counted manually in AO-OCT images. MP with a custom grid was used to assess retinal sensitivity at these locations. MainOutcomeMeasures: Cone density, cone pattern regularity and signal attenuation, retinal sensitivity. RESULTS: In comparison to HFE, RDE showed highly irregular cone patterns in AO-OCT and irregular outer retinal bands in SDOCT. Despite significant improvement of cone pattern regularity compared to BL (P < .001), 63% of AO images showed remaining cone pattern irregularity and 45.5% of SDOCT B-scans showed severe signal reduction at FUP. In HFE, mean cone density retrieved from IS/OS and COST remained around 20,000/mm2 (ecc 2.5°) and 16,000/mm2 (ecc 6.5°) at BL and FUP. Cone density of RDE was significantly reduced and ranged between 200/mm2 and 15,600/mm2 (P < .001) at BL. Despite improvement at FUP (P < .001), mean cone density at IS/OS and COST was still lower compared to HFE and ranged between 7790 and 9555 cones/mm2 (P < .001). Mean retinal sensitivity of all measured locations remained 18 dB in HFE and was significantly lower in RDE, with 14.30 dB at BL and 14.64 dB at FUP. Both SDOCT grading and microperimetry sensitivity showed strong correlation with AO-OCT grading and cone density (rho values > 0.750). CONCLUSIONS: The combination of AO-OCT, SDOCT, and microperimetry is a powerful tool to capture cone regeneration after vitreoretinal surgery. Our study shows that cone morphology and function improve within 56 weeks after RD surgery but structural and functional impairment is still present.


Assuntos
Células Fotorreceptoras Retinianas Cones/fisiologia , Descolamento Retiniano/fisiopatologia , Descolamento Retiniano/cirurgia , Tomografia de Coerência Óptica , Testes de Campo Visual , Vitrectomia , Idoso , Comprimento Axial do Olho , Contagem de Células , Tamponamento Interno , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Óptica e Fotônica , Estudos Prospectivos , Descolamento Retiniano/diagnóstico por imagem , Acuidade Visual/fisiologia , Campos Visuais/fisiologia
15.
Science ; 366(6470): 1251-1255, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31806815

RESUMO

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are a subset of cells that participate in image-forming and non-image-forming visual responses. Although both functional and morphological subtypes of ipRGCs have been described in rodents, parallel functional subtypes have not been identified in primate or human retinas. In this study, we used a human organ donor preparation method to measure human ipRGCs' photoresponses. We discovered three functional ipRGC subtypes with distinct sensitivities and responses to light. The response of one ipRGC subtype appeared to depend on exogenous chromophore supply, and this response is conserved in both human and mouse retinas. Rods and cones also provided input to ipRGCs; however, each subtype integrated outer retina light signals in a distinct fashion.


Assuntos
Células Fotorreceptoras Retinianas Cones , Células Ganglionares da Retina/fisiologia , Animais , Humanos , Luz , Camundongos , Estimulação Luminosa , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/fisiologia
16.
Adv Exp Med Biol ; 1185: 483-487, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884658

RESUMO

Retinal degenerative diseases are genetically diverse and rare inherited disorders that cause the death of rod and cone photoreceptors, resulting in progressive vision loss and blindness. This review will focus on two retinal degeneration-causing genes: prominin-1 (prom1) and photoreceptor cadherin (prCAD). We will discuss protein localization, potential roles in photoreceptor outer segment disc morphogenesis, and areas for future investigation.


Assuntos
Antígeno AC133/genética , Caderinas/genética , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Animais , Degeneração Retiniana , Xenopus laevis
17.
Curr Biol ; 29(24): 4260-4267.e4, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31846668

RESUMO

In humans, short-wavelength light evokes larger circadian responses than longer wavelengths [1-3]. This reflects the fact that melanopsin, a key contributor to circadian assessments of light intensity, most efficiently captures photons around 480 nm [4-8] and gives rise to the popular view that "blue" light exerts the strongest effects on the clock. However, in the natural world, there is often no direct correlation between perceived color (as reported by the cone-based visual system) and melanopsin excitation. Accordingly, although the mammalian clock does receive cone-based chromatic signals [9], the influence of color on circadian responses to light remains unclear. Here, we define the nature and functional significance of chromatic influences on the mouse circadian system. Using polychromatic lighting and mice with altered cone spectral sensitivity (Opn1mwR), we generate conditions that differ in color (i.e., ratio of L- to S-cone opsin activation) while providing identical melanopsin and rod activation. When biased toward S-opsin activation (appearing "blue"), these stimuli reliably produce weaker circadian behavioral responses than those favoring L-opsin ("yellow"). This influence of color (which is absent in animals lacking cone phototransduction; Cnga3-/-) aligns with natural changes in spectral composition over twilight, where decreasing solar angle is accompanied by a strong blue shift [9-11]. Accordingly, we find that naturalistic color changes support circadian alignment when environmental conditions render diurnal variations in light intensity weak/ambiguous sources of timing information. Our data thus establish how color contributes to circadian entrainment in mammals and provide important new insight to inform the design of lighting environments that benefit health.


Assuntos
Ritmo Circadiano/fisiologia , Percepção de Cores/fisiologia , Opsinas dos Cones/metabolismo , Animais , Cor , Opsinas dos Cones/fisiologia , Transdução de Sinal Luminoso/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Opsinas/metabolismo , Estimulação Luminosa , Células Fotorreceptoras Retinianas Cones/fisiologia
18.
Invest Ophthalmol Vis Sci ; 60(13): 4397-4407, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639826

RESUMO

Purpose: Retinitis pigmentosa (RP), a retinal photoreceptor degeneration, typically affects rod function and subsequently cones. Activation of sigma 1 receptor (Sig1R) has been shown to preserve cone function through 6 weeks in the rd10 mouse model of RP, when mice were treated systemically with the Sig1R ligand (+)-pentazocine (PTZ). This study determined the extent to which cone function is preserved in rd10 mice when Sig1R is activated. Methods: Rd10 mice were administered (+)-PTZ (alternate days beginning at postnatal day [P]14) over a period of 180 days. Mouse visual function and structure were measured in vivo using optokinetic tracking response, scotopic and photopic electroretinography plus photopic assessment using "natural" noise stimuli, and optical coherence tomography (OCT). Immunofluorescent methods were used to detect cones in retinal cryosections. Results: Visual acuity was maintained in rd10(+)-PTZ-treated mice through P56, whereas rd10 nontreated mice showed marked decline by P28. Cone responses were detected in (+)-PTZ-treated mice through P60, which were more robust when tested with natural noise stimuli; cone responses were minimal in nontreated rd10 mice. OCT revealed significantly thicker retinas in (+)-PTZ-treated rd10 mice through P60 compared to nontreated mice. Cones were detected by immunofluorescence in (+)-PTZ-treated rd10 retinas through P120. Conclusions: The extent to which cone rescue could be sustained in (+)-PTZ-treated rd10 mice was evaluated comprehensively, showing that activation of Sig1R is associated with prolonged visual acuity, extended detection of cone function, and detection of cones in retinal histologic sections. The data reflect promising long-term neuroprotection when Sig1R is activated.


Assuntos
Analgésicos Opioides/uso terapêutico , Modelos Animais de Doenças , Pentazocina/uso terapêutico , Receptores sigma/metabolismo , Células Fotorreceptoras Retinianas Cones/fisiologia , Retinite Pigmentosa/tratamento farmacológico , Acuidade Visual/efeitos dos fármacos , Animais , Sobrevivência Celular/fisiologia , Visão de Cores/fisiologia , Eletrorretinografia , Pressão Intraocular , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Visão Noturna/fisiologia , Nistagmo Optocinético/fisiologia , Retina/metabolismo , Retina/fisiopatologia , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/fisiopatologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia
19.
J Vis ; 19(12): 23, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31658357

RESUMO

Scientists and engineers have created computations and made measurements that characterize the first steps of seeing. ISETBio software integrates such computations and data into an open-source software package. The initial ISETBio implementations modeled image formation (physiological optics) for planar or distant scenes. The ISET3d software described here extends that implementation, simulating image formation for three-dimensional scenes. The software system relies on a quantitative computer graphics program that ray traces the scene radiance through the physiological optics to the retinal irradiance. We describe and validate the implementation for several model eyes. Then, we use the software to quantify the impact of several physiological optics parameters on three-dimensional image formation. ISET3d is integrated with ISETBio, making it straightforward to convert the retinal irradiance into cone excitations. These methods help the user compute the predictions of optics models for a wide range of spatially rich three-dimensional scenes. They can also be used to evaluate the impact of nearby visual occlusion, the information available to binocular vision, or the retinal images expected from near-field and augmented reality displays.


Assuntos
Gráficos por Computador , Simulação por Computador , Imageamento Tridimensional/métodos , Óptica e Fotônica , Retina/fisiologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Visão Ocular , Cor , Desenho de Equipamento , Humanos , Cristalino/fisiologia , Luz , Software , Adulto Jovem
20.
Exp Eye Res ; 189: 107827, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31600486

RESUMO

Under cone-mediated (photopic) conditions, an "instantaneous" flash of light, including both stimulus onset and offset, will simultaneously activate both "ON" and "OFF" bipolar cells, which either depolarize (ON) or hyperpolarize (OFF) in response and, respectively, produce positive-going and negative-going deflections in the electroretinogram (ERG). The stimulus-response (SR) relationship of the photopic ON response demonstrates logistic growth, like that manifested in the rod-mediated (scotopic) b-wave, which is driven by a single class of depolarizing bipolar cell. However, the photopic b-wave SR function is importantly shaped by OFF responses, leading to a "photopic hill." Furthermore, both on and off stimuli elicit activity in both ON and OFF bipolar cells. This has made it difficult to produce meaningful parameters for ready interpretation of the photopic b-wave SR relationship. Therefore, we evaluated whether the sum of sigmoidal SR functions, as descriptors of the depolarizing and hyperpolarizing components of the photopic flash ERG, could be used to elucidate and quantitate the mechanisms that produce the photopic hill. We used a novel fitting routine to optimize a sum of simple sigmoidal curves to SR data in five groups of subjects: Healthy adult, 10-week-old infant, congenital stationary night blindness (CSNB), X-linked juvenile retinoschisis (XJR), and preterm-born, both without and with a history of retinopathy of prematurity (ROP). Differences in ON and OFF amplitude, sensitivity, and implicit time among the groups were then compared using parameters extracted from these fits. We found that our modeling procedure enabled plausible derivations of ON and OFF pathway contributions to the ERG, and that the parameters produced appeared to have physiological relevance. In adult subjects, the ON and OFF amplitudes were similar in magnitude with respectively longer and shorter implicit times. Infant, CSNB, and XJR subjects showed significant ON pathway deficits. History of preterm-birth, without or with a diagnosis of ROP, did not much affect cone responses.


Assuntos
Visão de Cores , Adaptação à Escuridão/fisiologia , Eletrorretinografia/métodos , Oftalmopatias Hereditárias/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Miopia/fisiopatologia , Cegueira Noturna/fisiopatologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Retinopatia da Prematuridade/fisiopatologia , Adulto , Oftalmopatias Hereditárias/metabolismo , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Miopia/metabolismo , Cegueira Noturna/metabolismo , Estimulação Luminosa , Retinopatia da Prematuridade/metabolismo
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