Quantification of the early pupillary dilation kinetic to assess rod and cone activity.
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ABSTRACT:
SUBMITTER: Kostic C
PROVIDER: S-EPMC8099900 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:This study aims to identify which aspects of the pupil light reflex are most influenced by rods and cones independently by analyzing pupil recordings from different mouse models of photoreceptor deficiency.One-month-old wild type (WT), rodless (Rho-/-), coneless (Cnga3-/-), or photoreceptor less (Cnga3-/-; Rho-/- or Gnat1-/-) mice were subjected to brief red and blue light stimuli of increasing intensity. To describe the initial dynamic response to light, the maximal pupillary constriction amplitudes and the derivative curve of the first 3 seconds were determined. To estimate the postillumination phase, the constriction amplitude at 9.5 seconds after light termination was related to the maximal constriction amplitude.Rho-/- mice showed decreased constriction amplitude but more prolonged pupilloconstriction to all blue and red light stimuli compared to wild type mice. Cnga3-/- mice had constriction amplitudes similar to WT however following maximal constriction, the early and rapid dilation to low intensity blue light was decreased. To high intensity blue light, the Cnga3-/- mice demonstrated marked prolongation of the pupillary constriction. Cnga3-/-; Rho-/- mice had no pupil response to red light of low and medium intensity.From specific gene defective mouse models which selectively voided the rod or cone function, we determined that mouse rod photoreceptors are highly contributing to the pupil response to blue light stimuli but also to low and medium red stimuli. We also observed that cone cells mainly drive the partial rapid dilation of the initial response to low blue light stimuli. Thus photoreceptor dysfunction can be derived from chromatic pupillometry in mouse models.
| S-EPMC4868103 | biostudies-literature
Project description:Key pointsMost vertebrate eyes have rods for dim-light vision and cones for brighter light and higher temporal sensitivity. Rods evolved from cone-like precursors through expression of different transduction genes or the same genes at different expression levels, but we do not know which molecular differences were most important. We approached this problem by analysing rod and cone responses with the same model but with different values for model parameters. We showed that, in addition to outer-segment volume, the most important differences between rods and cones are: (1) decreased transduction gain, reflecting smaller amplification in the G-protein cascade; (2) a faster rate of turnover of the second messenger cGMP in darkness; and (3) an accelerated rate of decay of the effector enzyme phosphodiesterase and perhaps also of activated visual pigment. We believe our analysis has identified the principal alterations during evolution responsible for the duplex retina.AbstractMost vertebrates have rod and cone photoreceptors, which differ in their sensitivity and response kinetics. We know that rods evolved from cone-like precursors through the expression of different transduction genes or the same genes at different levels, but we do not know which molecular differences were most important. We have approached this problem in mouse retina by analysing the kinetic differences between rod flash responses and recent voltage-clamp recordings of cone flash responses, using a model incorporating the principal features of photoreceptor transduction. We apply a novel method of analysis using the log-transform of the current, and we ask which of the model's dynamic parameters need be changed to transform the flash response of a rod into that of a cone. The most important changes are a decrease in the gain of the response, reflecting a reduction in amplification of the transduction cascade; an increase in the rate of turnover of cGMP in darkness; and an increase in the rate of decay of activated phosphodiesterase, with perhaps also an increase in the rate of decay of light-activated visual pigment. Although we cannot exclude other differences, and in particular alterations in the Ca2+ economy of the photoreceptors, we believe that we have identified the kinetic parameters principally responsible for the differences in the flash responses of the two kinds of photoreceptors, which were likely during evolution to have resulted in the duplex retina.
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Project description:The purpose of this study was to evaluate a chromatic pupillometry protocol for specific functional assessment of rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs) in dogs.Chromatic pupillometry was tested and compared in 37 dogs in different stages of primary loss of rod, cone, and combined rod/cone and optic nerve function, and in 5 wild-type (WT) dogs. Eyes were stimulated with 1-s flashes of dim (1 cd/m2) and bright (400 cd/m2) blue light (for scotopic conditions) or bright red (400 cd/m2) light with 25-cd/m2 blue background (for photopic conditions). Canine retinal melanopsin/Opn4 was cloned, and its expression was evaluated using real-time quantitative reverse transcription-PCR and immunohistochemistry.Mean ± SD percentage of pupil constriction amplitudes induced by scotopic dim blue (scDB), scotopic bright blue (scBB), and photopic bright red (phBR) lights in WT dogs were 21.3% ± 10.6%, 50.0% ± 17.5%, and 19.4% ± 7.4%, respectively. Melanopsin-mediated responses to scBB persisted for several minutes (7.7 ± 4.6 min) after stimulus offset. In dogs with inherited retinal degeneration, loss of rod function resulted in absent scDB responses, followed by decreased phBR responses with disease progression and loss of cone function. Primary loss of cone function abolished phBR responses but preserved those responses to blue light (scDB and scBB). Although melanopsin/Opn4 expression was diminished with retinal degeneration, melanopsin-expressing ipRGCs were identified for the first time in both WT and degenerated canine retinas.Pupil responses elicited by light stimuli of different colors and intensities allowed differential functional assessment of canine rods, cones, and ipRGCs. Chromatic pupillometry offers an effective tool for diagnosing retinal and optic nerve diseases.
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Project description:Retinitis pigmentosa (RP) is a generic term for a group of genetic diseases characterized by loss of rod and cone photoreceptor cells. Although the genetic causes of RP frequently only affect the rod photoreceptor cells, cone photoreceptors become stressed in the absence of rods and undergo a secondary degeneration. Changes in the gene expression profile of cone photoreceptor cells are likely to occur prior to observable physiological changes. To this end, we sought to achieve greater understanding of the changes in cone photoreceptor cells early in the degeneration process of the Rho-/- mouse model. To account for gene expression changes attributed to loss of cone photoreceptor cells, we normalized PCR in the remaining number of cones to a cone cell reporter (OPN1-GFP). Gene expression profiles of key components involved in the cone phototransduction cascade were correlated with tests of retinal cone function prior to cell loss. A significant downregulation of the photoreceptor transcription factor Crx was observed, which preceded a significant downregulation in cone opsin transcripts that coincided with declining cone function. Our data add to the growing understanding of molecular changes that occur prior to cone dysfunction in a model of rod-cone dystrophy. It is of interest that gene supplementation of CRX by adeno-associated viral vector delivery prior to cone cell loss did not prevent cone photoreceptor degeneration in this mouse model.
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Project description:Background:Pupillary response by pupillary dilatation reflex (PDR) is a robust reflex, even measurable during general anaesthesia. However, the ability of infrared pupillometry to detect PDR differences obtained by intraoperative opioid administration in anaesthesized patients remains largely unknown. We analyzed the performance of automated infrared pupillometry in detecting differences in pupillary dilatation reflex response by a inbuilt standardized nociceptive stimulation program in patients under general anesthesia with a standardized propofol/fentanyl scheme. Methods:In this single center, interventional cohort study 38 patients (24-74 years) were enrolled. Patients were anesthetized with propofol until loss of consciousness. Two dynamic pupil measurements were performed in each patient (before opioid administration and after opioid steady state). Automated infrared pupillometry was used to determine PDR during nociceptive stimulations (10-60 mA) applied by a inbuilt pupillary pain index protocol (PPI) to the skin area innervated by the median nerve. Increasing stimulations by protocol are device specific and automatically performed until pupil dilation of > 13%. Pupil characteristics, blood pressure, heart rate values were collected. Results:After opioid administration, patients needed a higher stimulation intensity (45.26 mA vs 30.79 mA, p = 0.00001). PPI score showed a reduction after analgesic treatment (5.21 vs 7.68, p = 0.000001), resulting in a 32.16% score reduction. Conclusions:PDR via automated increased tetanic stimulation may reflect opioid effect under general anaesthesia. Further research is required to detect possible confounding factors such as medication interaction and optimization of individualized opioid dosage.
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Project description:Cone rod dystrophies (CRDs) (prevalence 1/40,000) are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP), also called the rod cone dystrophies (RCDs) resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7). Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far). The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs), CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs), and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs). It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, and the visual prognosis is poor. Management aims at slowing down the degenerative process, treating the complications and helping patients to cope with the social and psychological impact of blindness.
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Project description:In 1934, Gordon Walls forwarded his radical theory of retinal photoreceptor 'transmutation'. This proposed that rods and cones used for scotopic and photopic vision, respectively, were not fixed but could evolve into each other via a series of morphologically distinguishable intermediates. Walls' prime evidence came from series of diurnal and nocturnal geckos and snakes that appeared to have pure-cone or pure-rod retinas (in forms that Walls believed evolved from ancestors with the reverse complement) or which possessed intermediate photoreceptor cells. Walls was limited in testing his theory because the precise identity of visual pigments present in photoreceptors was then unknown. Subsequent molecular research has hitherto neglected this topic but presents new opportunities. We identify three visual opsin genes, rh1, sws1 and lws, in retinal mRNA of an ecologically and taxonomically diverse sample of snakes central to Walls' theory. We conclude that photoreceptors with superficially rod- or cone-like morphology are not limited to containing scotopic or photopic opsins, respectively. Walls' theory is essentially correct, and more research is needed to identify the patterns, processes and functional implications of transmutation. Future research will help to clarify the fundamental properties and physiology of photoreceptors adapted to function in different light levels.
| S-EPMC4795032 | biostudies-literature
Project description:To identify the causative mutation in a canine cone-rod dystrophy (crd3) that segregates as an adult onset disorder in the Glen of Imaal Terrier breed of dog.Glen of Imaal Terriers were ascertained for crd3 phenotype by clinical ophthalmoscopic examination, and in selected cases by electroretinography. Blood samples from affected cases and non-affected controls were collected and used, after DNA extraction, to undertake a genome-wide association study using Affymetrix Version 2 Canine single nucleotide polymorphism chips and 250K Sty Assay protocol. Positional candidate gene analysis was undertaken for genes identified within the peak-association signal region. Retinal morphology of selected crd3-affected dogs was evaluated by light and electron microscopy.A peak association signal exceeding genome-wide significance was identified on canine chromosome 16. Evaluation of genes in this region suggested A Disintegrin And Metalloprotease domain, family member 9 (ADAM9), identified concurrently elsewhere as the cause of human cone-rod dystrophy 9 (CORD9), as a strong positional candidate for canine crd3. Sequence analysis identified a large genomic deletion (over 20 kb) that removed exons 15 and 16 from the ADAM9 transcript, introduced a premature stop, and would remove critical domains from the encoded protein. Light and electron microscopy established that, as in ADAM9 knockout mice, the primary lesion in crd3 appears to be a failure of the apical microvilli of the retinal pigment epithelium to appropriately invest photoreceptor outer segments. By electroretinography, retinal function appears normal in very young crd3-affected dogs, but by 15 months of age, cone dysfunction is present. Subsequently, both rod and cone function degenerate.Identification of this ADAM9 deletion in crd3-affected dogs establishes this canine disease as orthologous to CORD9 in humans, and offers opportunities for further characterization of the disease process, and potential for genetic therapeutic intervention.
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Project description:AimTo present the clinical manifestations of 5 autosomal dominant cone-rod dystrophy (adCORD) patients from two Chinese families with cone-rod homeobox (CRX) mutation (p.R41W), and to explore the clinical heterogeneity of adCORD with CRX mutation (p.R41W).MethodsInterrogation and ophthalmological examinations were undertaken in all patients and unaffected members. Analysis of clinical features was performed by visual acuity, slit lamp examination, visual field examination, fundoscopy, autofluorescence and spectral domain optical coherence tomography. Targeted next-generation sequencing was applied as a useful tool to identify the causative mutation of CORD genes.ResultsA CRX missense mutation c.121C>T was identified in all patients, resulting in an amino acid change from arginine acid to tryptophan (p.R41W). The patients presented with early onset, progressive and different severities with CORD.ConclusionThis is the first report of the clinical phenotype of CRX mutation (p.R41W) in Chinese families, and the mutation can lead to a wide range of various retinal phenotypes.
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Project description:Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.
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