Fig 7 - uploaded by Marion Sangster Eckmiller
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Processes in photoreceptor cells that involve motor functions performed by the intracellular cytoskeletons. (A) Retinomotor movements. In the retinas of many lower vertebrates, the relative positions of a rod (left) and a cone (right) are different in the dark and in the light. This occurs as a result of contraction or elongation (arrows) of the cell in the region of the myoid, the part of the IS just sclerad to the outer limiting membrane (OLM, indicated by the dotted line). Sclerad to the OLM the IS and OS of photoreceptors protrude into the subretinal space and have room in which to move, but vitread to the OLM the photoreceptor cell bodies and synaptic terminals are closely apposed by M . uller and other cells. During retinomotor movements those portions of photoreceptor cells sclerad to the myoid are displaced, while those vitread to the myoid remain stationary. (B) Slow protein translocations. After a photoreceptor (rod or cone) has received adequate light exposure, specific proteins (e.g., arrestin, a-and b-transducin) are slowly translocated (arrows) in the cytoplasm between the IS and the OS, via the CC. These proteins participate in the biochemical cascade of phototransduction, and the changes in their cytoplasmic concentrations within the OS modify the amplification of the photoresponse and thus constitute a slow form of adaptation. (C) Photoreceptor alignment. The alignment of the longitudinal axis of a (rod or cone) photoreceptor can be changed via a coordinated, differential bending (arrows) of the cell in the region of the IS myoid. The portion of a photoreceptor vitread to the myoid does not change its location, but the portion of a photoreceptor sclerad to the myoid moves as one unit.
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Macular degeneration (MD) is a puzzling disease characterized by disturbance, and then complete loss, of fine detailed vision in the central macular region of the human retina, as a result of disturbed function and then death of photoreceptor cells. This review describes a possible pathomechanism for MD that involves a causal relationship between m...
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Context 1
... the retinas of many lower vertebrate species (e.g., fish, amphibia, birds) the photoreceptors undergo coordinated retinomotor movements (Fig. 7A) as a form of adaptation to light and dark (Burnside, 2001). These movements position those cells that are functionally active closest to the incoming light: rods are uller and other cells. During retinomotor movements those portions of photoreceptor cells sclerad to the myoid are displaced, while those vitread to the myoid remain ...
Context 2
... that has allowed them to resolve this issue. Their results show conclusively that the proteins a-and b-transducin become redistributed within the cytoplasm of rodent rods during light and dark. Major translocations of these proteins between the rod IS and OS occur via their movement along the microtubule-based cytoskeleton of the CC axoneme (Fig. 7B). Furthermore, Sokolov et al. (2002) have shown that, in conjunction with these light-triggered translocations, the amplification factor of rod phototransduction is considerably reduced (by 80% in bright light), rendering the rods less sensitive to bright light. The signal for these events is presumed to be light absorption in the ...
Context 3
... alignment of photoreceptors can also be considered to be a process that involves motor functions, that is mediated by the intracellular cytoskeleton, and that contributes to photoreceptor adaptation (Fig. 7C). Little is known about the mechanisms involved in vertebrate photoreceptor alignment. There is convincing evidence that photoreceptor alignment is maintained actively, which suggests it is controlled by a feedback system. The presumed error signal for photoreceptor alignment is light that enters the pupil, is absorbed in the OS, and ...
Citations
... Cone photoreceptors function as sensors for bright light and various wavelengths in the retina, transmitting visual messages to multiple cone bipolar types rather than a single type, as observed in the rod system. Cone deficit can cause the loss of high-acuity vision and blindness, contributing to diseases such as macular degeneration (MD) (Eckmiller 2004) and retinitis pigmentosa (RP) (Ellis et al. 2023). Understanding the mechanisms underlying cone and cone pathway dysfunction is crucial. ...
synuclein, a member of the synuclein family, is frequently co-expressed with α-synuclein in the neural system, where it serves to inhibit abnormal aggregation of α-synuclein in neurodegenerative diseases. Beyond its role in pathological conditions, β-synuclein plays various functions independently of α-synuclein. In our investigation, we discovered a broader expression of β-synuclein in the mouse retina compared to α-synuclein. This widespread pattern implies its potential significance in the retina. Through detailed examination via light- and electron-microscopic immunocytochemistry, we identified β-synuclein expression from the inner segment (IS) and outer segment (OS) of photoreceptor cells to the ganglion cell layer (GCL). Our findings unveiled unique features, including β-synuclein immunoreactive IS and OS of cones, higher expression in cone pedicles than in rod spherules, absence in horizontal cells, limited expression in cone bipolar dendrites and somas, higher expression in cone bipolar terminals, presence in most amacrine cells, and expression in almost majority of somas in GCL with an absence in intrinsically photosensitive retinal ganglion cell (ipRGCs) processes. Notably, all cholinergic amacrine cells express high β- but not α-synuclein, while dopaminergic amacrine cells express α-synuclein exclusively. These distinctive expression patterns offer valuable insights for further exploration into the functions of β-synuclein and its potential role in synuclein pathology within the retina.
... For both observers, defocus changes are followed closely both during accommodation and relaxation at 1 • radial eccentricity. From 2 • to 6 • eccentricity, accommodation and relaxation are in the expected direction but with a reduced response with increasing eccentricity, which agrees with earlier studies [10,12,22,23]. At and beyond 7 • eccentricity, the accommodative response becomes negligible. ...
... An extra step (7.5 • ) between 7 • and 8 • radial eccentricity was taken to monitor the response closely at the point where accommodation is absent. eccentricity, accommodation and relaxation are in the expected direction but with a reduced response with increasing eccentricity, which agrees with earlier studies [10,12,22,23]. At and beyond 7° eccentricity, the accommodative response becomes negligible. ...
... Blur adaptation can improve visual acuity by approximately 0.2 logMAR within approximately an hour [30,31], and a related acuity reduction occurs after removing a prescribed correction [32]. This adaptation may partially be of optical origin, as photoreceptors dynamically adapt to the direction of incident light [22,23,33]. When it comes to the contrast of the stimuli, previous studies found that it does not have any influence on the accommodative response while reading on an electronic micro-display [34] or for near vision [35], and it has no significant impact on the accommodative lag [36]. ...
The accommodative response of the human eye is predominantly driven by foveal vision, but reacts also to off-foveal stimuli. Here, we report on monocular accommodation measurements using parafoveal and perifoveal annular stimuli centered around the fovea and extending up to 8° radial eccentricity for young emmetropic and myopic subjects. The stimuli were presented through a sequence of random defocus step changes induced by a pupil-conjugated tunable lens. A Hartmann–Shack wavefront sensor with an infrared beacon was used to measure real-time changes in ocular aberrations up to and including the fourth radial order across a 3 mm pupil at 20 Hz. Our findings show a significant reduction in accommodative response with increased radial eccentricity.
... For both observers, defocus changes are followed closely both during accommodation and relaxation at 1° radial eccentricity. From 2° to 6° eccentricity, accommodation and relaxation are in the expected direction but with a reduced response with increasing eccentricity which agrees with earlier studies [10,12,22,23]. At and beyond 7° eccentricity the accommodative response becomes negligible. ...
... Blur adaptation can improve visual acuity by approximately 0.2 logMAR within approximately an hour [28,29] and a related acuity reduction occurs after removing a prescribed correction [30]. This adaptation may partially be of optical origin as photoreceptors dynamically adapt to the direction of incident light [22,23,31]. A change in monocular vergence due to accommodation could result in reduced image contrast due to leakage from the cone outer segments [11,19,32]. ...
The accommodative response of the human eye is predominantly driven by foveal vision but reacts also to off-foveal stimuli. Here, we report on monocular accommodation measurements using parafoveal and perifoveal annular stimuli centered around the fovea and extending up to 8 degree radial eccentricity for young emmetropic and myopic subjects. The stimuli were presented through a sequence of random defocus step changes induced by a pupil-conjugated tunable lens. A Hartmann-Shack wavefront sensor with an infrared beacon was used to measure real-time changes of ocular aberrations up to and including the 4th radial order across a 3 mm pupil at 20 Hz. Our findings show a significant reduction in accommodative response with increased radial eccentricity.
... Charbel Issa and Heeren have recently shown that those eyes revealed a reduced "Stiles-Crawford-effect", which could be explained by a slight cone misalignment. [37] Eckmiller hypothesised that cone misalignment might result in metabolic stress [89] and metabolic changes might impair contrast sensitivity. [90] Another possibility might be that the misaligned cones might lead to reduced phototransduction. ...
Macular telangiectasia type 2 (macular telangiectasia type 2) is a bilateral neurodegenerative condition of the macula of the human eye which can lead to loss of central vision. There is evidence that metabolic dysfunction leads to slow degeneration of the retinal neuroglia, eventually leading to circumscribed loss of neuronal tissue (photoreceptor atrophy). A characteristic feature of macular telangiectasia type 2 is the temporal epicenter where the disease typically begins, and its limitation to a central oval shaped area of approximately five by ten degrees, called the macular telangiectasia type 2 area. Knowledge about visual function of people with macular telangiectasia type 2 was limited to visual acuity testing, investigations of reading performance, visual field testing with fundus-controlled perimetry (microperimetry), and scotopic perimetry (not fundus-controlled). This thesis summarises research aimed at exploring visual function in macular telangiectasia type 2 in more detail. In particular, visual acuity and reading performance are investigated in more detail, the (para)central scotomas are better characterised, and visual function in low light is elucidated by testing contrast sensitivity, low luminance visual acuity and dark-adapted microperimetry. Visual acuity data was collected as part of the international research collaboration The macular telangiectasia type 2 study, which started in 2005 and has since then accrued data of more than 3000 individuals with macular telangiectasia type 2. It was taken with Early Treatment of Diabetic Retinopathy Study (ETDRS) charts on a harmonised protocol. Distribution of visual acuity in the entire study cohort was investigated and eyes with low visual acuity were looked at in detail. It was found that only about half of eyes with very poor visual acuity showed evidence of neovascularisations, until recently still considered disease end stage, but nearly all eyes showed photoreceptor atrophy, which is therefore more likely to define the disease end stage. Scotomas were characterised further on retrospective analysis of microperimetry examinations from four large centers of the macular telangiectasia type 2 study. This analysis confirmed previous data which suggested mono-focality of the scotomas and the limitation to a specific size. Further microperimetry assessment was performed with a recently introduced new technology, allowing dark-adapted microperimetry with two wavelengths, aiding differentiation of cone and rod dysfunction. This test showed more general sensitivity reduction for blue light under low light conditions. This may be in keeping with the findings from contrast sensitivity testing in mesopic light conditions, showing strong impairment already in early disease stages, possibly indicating inner retinal dysfunction rather than photoreceptor dysfunction in those disease stages. Reading performance and the effect of binocularity was measured with Radner Reading charts. Reading was consistently slower when patients were using both eyes, strongly indicating binocular inhibition, in particular when arising from scotomas in left eyes. Based on the above, the findings resulted in new insights into visual function with implications on our understanding of the condition. Understanding visual impairment not only helps patient counselling, but also helps driving directions of future research.
... eye movement), and the optimal direction of alignment may be different in three types of cones. 41 The best strategy may be achromatizing the pupil position corresponding to the visual axis. However, this hypothesis must be tested. ...
Purpose:
The purpose of this study was to locate the visual axis and evaluate its correlation with the Stiles-Crawford effect (SCE) peak.
Methods:
Ten young, healthy individuals (20 eyes) were enrolled. An optical system was developed to locate the visual axis and measure SCE. To locate the visual axis, 2 small laser spots at 450 nm and 680 nm were co-aligned and delivered to the retina. The participants were asked to move a translatable pinhole until these spots were perceived to overlap each other. The same system assessed SCE at 680 nm using a bipartite, 2-channel (reference and test) Maxwellian-view optical system. The peak positions were estimated using a two-dimensional Gaussian fitting function and correlated with the visual axis positions.
Results:
Both the visual axis (x = 0.24 ± 0.35 mm, y = -0.16 ± 0.34 mm) and the SCE peak (x = 0.27 ± 0.35 mm, y = -0.15 ± 0.31 mm) showed intersubject variability among the cohort. The SCE peak positions were highly correlated in both the horizontal and vertical meridians to the visual axes (R2 = 0.98 and 0.96 for the x and y coordinates, respectively). Nine of the 10 participants demonstrated mirror symmetry for the coordinates of the visual axis and the SCE peak between the eyes (R2 = 0.71 for the visual axis and 0.76 for the SCE peak).
Conclusions:
The visual axis and SCE peak locations varied among the participants; however, they were highly correlated with each other for each individual. These findings suggest a potential mechanism underlying the foveal cone photoreceptor alignment.
... A similar reduction in both BCVA and LLVA could be secondary to mechanical disruption, disorientation of photoreceptors thereby reducing spatial resolution at both illuminance levels (Eckmiller, 2004;Gao et al., 2008;Hartmann et al., 2012). As LLD is a difference of BCVA and LLVA, any improvement or worsening in LLD has to be interpreted in the context of actual values of BCVA and LLVA (Sunness et al., 2008). ...
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the developed world among people over 50 years of age. Although AMD is clinically characterised by the presence of drusen, subretinal drusenoid deposits (SDD) have also been recognized as a distinct morphological feature that confers increased risk of developing advanced AMD. To date, there has been a lack of validated biomarkers that can capture early changes in visual function that strongly correlate to the anatomical alterations which also include SDD phenotype. This thesis aimed to explore functional and structural markers to differentiate between healthy eyes (n=11) and intermediate AMD (iAMD) with SDD (n=11) and without SDD (n=17) and non-foveal atrophic AMD (n=11). Firstly, I assessed scotopic thresholds using a novel dark-adapted chromatic (DAC) perimeter, in healthy aging and in varying AMD disease. Individuals with SDD had depressed retinal sensitivity centrally, particularly inferiorly and nasally. Functionally, eyes with SDD were comparable to eyes with non-foveal atrophy, but structurally differed in outer nuclear layer (ONL) and total retinal volumes and thicknesses. Importantly, only rod-mediated tests were able to distinguish iAMD with and without SDD. Another aim of this thesis was to explore the efficacy of 670nm light on aging and AMD. Although an improvement in scotopic thresholds was observed in healthy aged eyes (n=4) compared to younger eyes (n=5), a pilot study conducted in 40 participants over the age 55 years (12 control, 28 with intermediate AMD) refuted any clinical benefit. In conclusion, this thesis supports the need to re-classify the AMD severity scale by incorporating eyes with SDD as a separate group. This phenotype should be sub-analysed in clinical trials evaluating potential prophylactic agents to delay the progression. Scotopic sensitivity offers diagnostic value, but rod intercept time offers both prognostic and diagnostic value as candidate biomarkers.
... Photoreceptor cells are directionally sensitive, being sensitive to light travelling along their longitudinal axis. Eckmiller [35] hypothesized that changes in the macular cone cytoskeleton and associated proteins could be a basis for photoreceptor misalignment and death in AMD. In aging human retina, the photoreceptor microtubules undergo misalignment and partial disorganization [36], raising to the possibility that aging photoreceptor cells may suffer from interrupted axonal transport, which may make them vulnerable to death. ...
In human retina, photoreceptor cell death (PCD) is a slow but conspicuous event, which continues with aging. Rods die earlier than cones, the latter continue to alter in a subtle manner until advanced aging. This review summarizes the existing information on age-related changes in photoreceptor cells, especially cones and analyses the possible associated factors. Oxidative and nitrosative stress are involved in photoreceptor alterations, which may stem from light and iron toxicity and other sources. Lipid peroxidation in macular photoreceptor outer segments and mitochondrial aberrations are prominent in aging. It is important to understand how those changes ultimately trigger PCD. The redistribution of calbindin D-28K and long/middle-wavelength-sensitive opsin in the parafoveal and perifoveal cones, anomalies in their somata and axons are strong predictors of their increasing vulnerability with aging. Signs of reduced autophagy, with autophagosomes containing organelle remnants are seen in aging photoreceptor cells. Currently, mechanisms that lead to human PCD are unknown; some observations favour apoptosis as a pathway. Since cones appear to change slowly, there is an opportunity to reverse those changes before they die. Therefore, a full understanding of how cones alter and the molecular pathways they utilize for survival must be the future research goal. Recent approaches to prevent PCD in aging and diseases are highlighted.
... The outer segments of the photoreceptors are composed of infolded plasma membrane discs with photopigments that are properly aligned, and establish an anatomical association with the RPE (Johnson et al., 1986;Blanks et al., 1988). Several studies have shown the misalignment of the outer photoreceptor segments in aging and pathology (as AMD) (Green and Enger, 1993;Jackson et al., 2002;Liu et al., 2003;Eckmiller, 2004), and the discs are randomly oriented or disorganized into tubules and membranous whorls (Marshall et al., 1979;Nag and Wadhwa, 2012), as we observed in the 75-to 85-year-old human-equivalent aged mice (24-month-old mice), mainly for aged males. Their occurrence is possibly attributed to the vulnerability of mitochondria via oxidative stress, light, or toxic substances, contributing to energy depletion and cone loss in the human retina with aging (Curcio and Drucker, 1993). ...
Age and gender are two important factors that may influence the function and structure of the retina and its susceptibility to retinal diseases. The aim of this study was to delineate the influence that biological sex and age exert on the retinal structural and ultrastructural changes in mice and to identify the age-related miRNA dysregulation profiles in the retina by gender. Experiments were undertaken on male and female Balb/c aged 24 months (approximately 75–85 years in humans) compared to the control (3 months). The retinas were analyzed by histology, transmission electron microscopy, and age-related miRNA expression profile analysis. Retinas of both sexes showed a steady decline in retinal thickness as follows: photoreceptor (PS) and outer layers (p < 0.01 for the aged male vs. control; p < 0.05 for the aged female vs. control); the inner retinal layers were significantly affected by the aging process in the males (p < 0.01) but not in the aged females. Electron microscopy revealed more abnormalities which involve the retinal pigment epithelium (RPE) and Bruch’s membrane, outer and inner layers, vascular changes, deposits of amorphous materials, and accumulation of lipids or lipofuscins. Age-related miRNAs, miR-27a-3p (p < 0.01), miR-27b-3p (p < 0.05), and miR-20a-5p (p < 0.05) were significantly up-regulated in aged male mice compared to the controls, whereas miR-20b-5p was significantly down-regulated in aged male (p < 0.05) and female mice (p < 0.05) compared to the respective controls. miR-27a-3p (5.00 fold; p < 0.01) and miR-27b (7.58 fold; p < 0.01) were significantly up-regulated in aged male mice vs. aged female mice, whereas miR-20b-5p (−2.10 fold; p < 0.05) was significantly down-regulated in aged male mice vs. aged female mice. Interestingly, miR-27a-3p, miR-27b-3p, miR-20a-5p, and miR-20b-5p expressions significantly correlated with the thickness of the retinal PS layer (p < 0.01), retinal outer layers (p < 0.01), and Bruch’s membrane (p < 0.01). Our results showed that biological sex can influence the structure and function of the retina upon aging, suggesting that this difference may be underlined by the dysregulation of age-related mi-RNAs.
... Stockman and Sharpe explained that the visual acuity in a mesopic setting requires integrated cone function mediated by post-receptoral pathways and a disruption of this would lead to a drop in LLVA, worsening the LLD [20]. A similar reduction in both BCVA and LLVA could be secondary to mechanical disruption and disorientation of photoreceptors, thereby reducing spatial resolution at both illuminance levels [21][22][23]. As LLD is a difference of BCVA and LLVA, any improvement or worsening in LLD has to be interpreted in the context of actual values of BCVA and LLVA [14]. ...
Purpose:
To investigate the value of visual acuity and patient-perceived visual function test when subretinal drusenoid deposits (SDD) are incorporated into the classification of age-related macular degeneration (AMD). A total of 50 participants were recruited into the study in these groups: healthy ageing (n = 11), intermediate AMD (iAMD) with no SDD (n = 17), iAMD with SDD (n = 11) and non-foveal atrophic AMD (n = 11) confirmed by two retinal imaging modalities. Best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) were measured and low luminance deficit (LLD) was calculated. Participants were also interviewed with the low luminance questionnaire (LLQ). Linear regression was used to assess function-function relations. Compared with healthy participants, BCVA and LLVA scores were significantly reduced in the atrophic AMD group (p < 0.0001 and p = 0.00016, respectively) and in patients with SDD (p = 0.028 and p = 0.045, respectively). Participants with atrophy also had reduced BCVA (p = 0.001) and LLVA (p = 0.009) compared with the iAMD no SDD group. However, there were no differences in visual function tests between healthy aging and iAMD without SDD and between iAMD with SDD and atrophic AMD groups. The LLD score did not differ between groups. BCVA and LLVA correlated well. The LLQ did not correlate with visual function tests. This study shows that LLD is not a marker of disease severity as assessed clinically. Although LLQ is a good marker for disease severity using the current AMD classification, it does not differentiate between eyes with and without SDD. Eyes with non-macular geographic atrophy and SDD had lower function than eyes with no SDD and healthy controls.
... The COS, as a derivative of the cilium, begins at its base from the centriolar apparatus. This is the place where the light-sensitive membrane is forming constantly, folding into lamellae of the growing COS (Eckmiller, 1987(Eckmiller, , 2004. The IFBs follow from the CIS and along the COS to the cone tip, with single IFs separating from the IFBs, and touching and sometimes passing in-between the light-sensitive membrane lamellae of the COS. ...
We present unique ultrastructural data on avian retinal cells. Presently and earlier (Zueva et al., 2016) we explored distribution of intermediate filaments (IFs) in retinal cells of the Pied flycatcher (Ficedula hypoleuca, Passeriformes, Aves) in the central foveolar zone. This retinal zone only contains single and double cone photoreceptors. Previously we found that continuous IFs span Müller cells (MC) lengthwise from the retinal inner limiting membrane (ILM) layer up to the outer limiting membrane (OLM) layer. Here we describe long cylindrical bundles of IFs (IFBs) inside the cone inner segments (CIS) adjoining the cone plasma membrane, with these IFBs following along the cone lengthwise, and surrounding the cone at equal spacing one from the other. Double cones form a combined unit, wherein they are separated by their respective plasma membranes. Double cones thus have a common external ring of IFBs, surrounding both cone components. In the layer of cilia, the IFBs that continue into the cone outer segment (COS) follow on to the cone apical tip along the direction of incident light, with single IFs separating from the IFB, touching, and sometimes passing in-between the light-sensitive lamellae of the COS. These new data support our previous hypothesis on the quantum mechanism of light energy propagation through the vertebrate retina (Zueva et al., 2016, 2019).
