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Experimental Eye Research Sep 2023The etiology of myopia remains unclear. This study investigated whether retinal ganglion cells (RGCs) in the myopic retina encode visual information differently from the...
The etiology of myopia remains unclear. This study investigated whether retinal ganglion cells (RGCs) in the myopic retina encode visual information differently from the normal retina and to determine the role of Connexin (Cx) 36 in this process. Generalized linear models (GLMs), which can capture stimulus-dependent changes in real neurons with spike timing precision and reliability, were used to predict RGCs responses to focused and defocused images in the retinas of wild-type (normal) and Lens-Induced Myopia (LIM) mice. As the predominant subunit of gap junctions in the mouse retina and a plausible modulator in myopia development, Cx36 knockout (KO) mice were used as a control for an intact retinal circuit. The kinetics of excitatory postsynaptic currents (EPSCs) of a single αRGC could reflect projection of both focused and defocused images in the retinas of normal and LIM, but not in the Cx36 knockout mice. Poisson GLMs revealed that RGC encoding of visual stimuli in the LIM retina was similar to that of the normal retina. In the LIM retinas, the linear-Gaussian GLM model with offset was a better fit for predicting the spike count under a focused image than the defocused image. Akaike information criterion (AIC) indicated that nonparametric GLM (np-GLM) model predicted focused/defocused images better in both LIM and normal retinas. However, the spike counts in 33% of αRGCs in LIM retinas were better fitted by exponential GLM (exp-GLM) under defocus, compared to only 13% αRGCs in normal retinas. The differences in encoding performance between LIM and normal retinas indicated the possible amendment and plasticity of the retinal circuit in myopic retinas. The absence of a similar response between Cx36 KO mice and normal/LIM mice might suggest that Cx36, which is associated with myopia development, plays a role in encoding focused and defocused images.
Topics: Animals; Mice; Retinal Ganglion Cells; Reproducibility of Results; Retina; Myopia; Mice, Knockout
PubMed: 37580002
DOI: 10.1016/j.exer.2023.109616 -
International Review of Cytology 2007The retinas of teleost fish have long been of interest to developmental neurobiologists for their persistent plasticity during growth, life history changes, and response... (Review)
Review
The retinas of teleost fish have long been of interest to developmental neurobiologists for their persistent plasticity during growth, life history changes, and response to injury. Because the vertebrate retina is a highly conserved tissue, the study of persistent plasticity in teleosts has provided insights into mechanisms for postembryonic retinal neurogenesis in mammals. In addition, in the past 10 years there has been an explosion in the use of teleost fish-zebrafish (Danio rerio) in particular-to understand the mechanisms of embryonic retinal neurogenesis in a model vertebrate with genetic resources. This review summarizes the key features of teleost retinal neurogenesis that make it a productive and interesting experimental system, and focuses on the contributions to our knowledge of retinal neurogenesis that uniquely required or significantly benefited from the use of a fish model system.
Topics: Animals; Nerve Regeneration; Organogenesis; Photoreceptor Cells, Vertebrate; Retina; Signal Transduction; Stem Cells; Visual Pathways; Zebrafish
PubMed: 17425942
DOI: 10.1016/S0074-7696(06)59005-9 -
Experimental Eye Research Feb 2023Photoreceptor synaptic terminals are responsible for transmitting visual information to downstream neurons. In vertebrate retinas, photoreceptor synaptic terminals are...
Photoreceptor synaptic terminals are responsible for transmitting visual information to downstream neurons. In vertebrate retinas, photoreceptor synaptic terminals are of different sizes and structures. The molecular mechanisms that underlie photoreceptor synaptic development are not clearly understood. Here, we have systematically examined the size variations in the synaptic terminals of cone and rod photoreceptors in the adult zebrafish retina. We reveal that the average cone pedicle sizes expand in the order of UV, blue, green, and red cones, echoing the increasing maximally sensitive wavelengths of the opsins expressed in the corresponding cone types. In addition, rod spherules are smaller than all cone pedicles. The terminals of each photoreceptor type also display distinct regional variations across the retina and between males and females. These findings establish the basis for using the zebrafish retina to study the molecular mechanisms that regulate the sizes and structures of photoreceptor terminals for proper visual functions.
Topics: Animals; Male; Female; Zebrafish; Presynaptic Terminals; Synapses; Retina; Retinal Cone Photoreceptor Cells
PubMed: 36587757
DOI: 10.1016/j.exer.2022.109377 -
Neuron Jan 2010We rely on our visual system to cope with the vast barrage of incoming light patterns and to extract features from the scene that are relevant to our well-being. The... (Review)
Review
We rely on our visual system to cope with the vast barrage of incoming light patterns and to extract features from the scene that are relevant to our well-being. The necessary reduction of visual information already begins in the eye. In this review, we summarize recent progress in understanding the computations performed in the vertebrate retina and how they are implemented by the neural circuitry. A new picture emerges from these findings that helps resolve a vexing paradox between the retina's structure and function. Whereas the conventional wisdom treats the eye as a simple prefilter for visual images, it now appears that the retina solves a diverse set of specific tasks and provides the results explicitly to downstream brain areas.
Topics: Animals; Computational Biology; Humans; Nerve Net; Neurology; Retina; Visual Pathways; Visual Perception; Workforce
PubMed: 20152123
DOI: 10.1016/j.neuron.2009.12.009 -
ELife Sep 2021Enhancers and silencers often depend on the same transcription factors (TFs) and are conflated in genomic assays of TF binding or chromatin state. To identify sequence...
Enhancers and silencers often depend on the same transcription factors (TFs) and are conflated in genomic assays of TF binding or chromatin state. To identify sequence features that distinguish enhancers and silencers, we assayed massively parallel reporter libraries of genomic sequences targeted by the photoreceptor TF cone-rod homeobox (CRX) in mouse retinas. Both enhancers and silencers contain more TF motifs than inactive sequences, but relative to silencers, enhancers contain motifs from a more diverse collection of TFs. We developed a measure of information content that describes the number and diversity of motifs in a sequence and found that, while both enhancers and silencers depend on CRX motifs, enhancers have higher information content. The ability of information content to distinguish enhancers and silencers targeted by the same TF illustrates how motif context determines the activity of -regulatory sequences.
Topics: Animals; Binding Sites; Female; Male; Mice; Photoreceptor Cells; Protein Binding; Retina; Transcription Factors
PubMed: 34486522
DOI: 10.7554/eLife.67403 -
Cells Sep 2021Ischemia/reperfusion (I/R) events are involved in the pathophysiology of numerous ocular diseases. The purpose of this study was to test the hypothesis that betulinic...
Ischemia/reperfusion (I/R) events are involved in the pathophysiology of numerous ocular diseases. The purpose of this study was to test the hypothesis that betulinic acid protects from I/R injury in the mouse retina. Ocular ischemia was induced in mice by increasing intraocular pressure (IOP) to 110 mm Hg for 45 min, while the fellow eye served as a control. One group of mice received betulinic acid (50 mg/kg/day p.o. once daily) and the other group received the vehicle solution only. Eight days after the I/R event, the animals were killed and the retinal wholemounts and optic nerve cross-sections were prepared and stained with cresyl blue or toluidine blue, respectively, to count cells in the ganglion cell layer (GCL) of the retina and axons in the optic nerve. Retinal arteriole responses were measured in isolated retinas by video microscopy. The levels of reactive oxygen species (ROS) were assessed in retinal cryosections and redox gene expression was determined in isolated retinas by quantitative PCR. I/R markedly reduced cell number in the GCL and axon number in the optic nerve of the vehicle-treated mice. In contrast, only a negligible reduction in cell and axon number was observed following I/R in the betulinic acid-treated mice. Endothelial function was markedly reduced and ROS levels were increased in retinal arterioles of vehicle-exposed eyes following I/R, whereas betulinic acid partially prevented vascular endothelial dysfunction and ROS formation. Moreover, betulinic acid boosted mRNA expression for the antioxidant enzymes SOD3 and HO-1 following I/R. Our data provide evidence that betulinic acid protects from I/R injury in the mouse retina. Improvement of vascular endothelial function and the reduction in ROS levels appear to contribute to the neuroprotective effect.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Male; Mice; Mice, Inbred C57BL; Pentacyclic Triterpenes; Protective Agents; Reactive Oxygen Species; Reperfusion Injury; Retina; Betulinic Acid
PubMed: 34572088
DOI: 10.3390/cells10092440 -
Cell Death & Disease Jul 2018Retinitis pigmentosa (RP) is an inherited retinopathy that leads to photoreceptor loss. RP has been related to oxidative stress, autophagy, and inflammation. This study...
Retinitis pigmentosa (RP) is an inherited retinopathy that leads to photoreceptor loss. RP has been related to oxidative stress, autophagy, and inflammation. This study aimed to identify changes in the levels of oxidative stress and autophagy markers in the retina of control and rd10 mice during different phases of retinal development. Changes in the retinal oxidation system were investigated by measuring the levels of oxidized and reduced glutathione (GSH/GSSG), retinal avidin-positive cells, and 4-hydroxynonenal (4-HNE) staining intensity. Autophagy characterization was explored by measuring the levels of microtubule-associated protein 1 light chain 3 (LC3), beclin, autophagy-related proteins 5 and 7 (Atg5 and Atg7), and lysosomal associated membrane protein-2A (LAMP-2A). At P28 retinal GSH concentrations decreased in rd10 mice compared to the controls. No differences were found in retinal GSSG concentrations between the control and rd10 mice. There was an increase in retinal GSSG concentrations and a decrease in the GSH/GSSG ratio in the control and rd10 mice at P21 and P28 compared to P13. We observed an increase in avidin-positive cells in rd10 retinas. 4-HNE was increased in rd10 retinas at P13, and it also increased in control mice with age. We did not observe any differences in the retinal levels of LC3II/I ratio, Beclin, Atg5, or Atg7 in the rd10 mice compared to the controls. There was an increase in the LAMP-2A concentrations in the control and rd10 mice with development age (P28 concentrations vs. P13). Although only slight differences were found in the oxidative stress and autophagy markers between the control and rd10 mice, there were increases in the GSSG, 4-HNE, and LAMP-2A with age. This increase in the oxidative stress and chaperone-mediated autophagy has not been described before and occurred just after the mice opened their eyes, potentially indicating a retinal response to light exposure.
Topics: Animals; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Disease Models, Animal; Glutathione; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Oxidative Stress; Retina; Retinal Degeneration; Sulfhydryl Compounds
PubMed: 30042417
DOI: 10.1038/s41419-018-0855-8 -
Journal of the American Chemical Society Feb 2021The development of fluorescent dyes that emit and absorb light at wavelengths greater than 700 nm and that respond to biochemical and biophysical events in living...
The development of fluorescent dyes that emit and absorb light at wavelengths greater than 700 nm and that respond to biochemical and biophysical events in living systems remains an outstanding challenge for noninvasive optical imaging. Here, we report the design, synthesis, and application of near-infrared (NIR)-absorbing and -emitting optical voltmeter based on a sulfonated, phosphine-oxide (po) rhodamine for voltage imaging in intact retinas. We find that po-rhodamine based voltage reporters, or poRhoVRs, display NIR excitation and emission profiles at greater than 700 nm, show a range of voltage sensitivities (13 to 43% ΔF/F per 100 mV in HEK cells), and can be combined with existing optical sensors, like Ca-sensitive fluorescent proteins (GCaMP), and actuators, like light-activated opsins ChannelRhodopsin-2 (ChR2). Simultaneous voltage and Ca imaging reveals differences in activity dynamics in rat hippocampal neurons, and pairing poRhoVR with blue-light based ChR2 affords all-optical electrophysiology. In retinas isolated from a mouse model of retinal degeneration, poRhoVR, together with GCaMP-based Ca imaging and traditional multielectrode array (MEA) recording, can provide a comprehensive physiological activity profile of neuronal activity, revealing differences in voltage and Ca dynamics within hyperactive networks of the mouse retina. Taken together, these experiments establish that poRhoVR will open new horizons in optical interrogation of cellular and neuronal physiology in intact systems.
Topics: Animals; Calcium; Fluorescent Dyes; Infrared Rays; Mice; Neurons; Optical Imaging; Oxides; Phosphines; Retina; Rhodamines
PubMed: 33501825
DOI: 10.1021/jacs.0c11382 -
Translational Vision Science &... Mar 2020Photobiomodulation (PBM) refers to therapeutic irradiation of tissue with low-energy, 630- to 1000-nm wavelength light. An increasing body of evidence supports a...
PURPOSE
Photobiomodulation (PBM) refers to therapeutic irradiation of tissue with low-energy, 630- to 1000-nm wavelength light. An increasing body of evidence supports a beneficial effect of PBM in retinal disorders. To date, most studies have utilized light-emitting diode irradiation sources. Slit-lamp-mounted retinal lasers produce a coherent beam that can be delivered with precisely defined dosages and predetermined target area; however, the use of retinal lasers raises safety concerns that warrant investigation prior to clinical application. In this study, we determined safe dosages of laser-delivered PBM to the retina.
METHODS
A custom-designed, slit-lamp-delivered, 670-nm, red/near-infrared laser was used to administer a range of irradiances to healthy pigmented and non-pigmented rat retinas. The effects of PBM on various functional and structural parameters of the retina were evaluated utilizing a combination of electroretinography, Spectral Domain Optical Coherence (SD-OCT), fluorescein angiography, histology and immunohistochemistry.
RESULTS
In non-pigmented rats, no adverse events were identified at any irradiances up to 500 mW/cm. In pigmented rats, no adverse events were identified at irradiances of 25 or 100 mW/cm; however, approximately one-third of rats that received 500 mW/cm displayed very localized photoreceptor damage in the peripapillary region, typically adjacent to the optic nerve head.
CONCLUSIONS
A safety threshold exists for laser-delivered PBM in pigmented retinas and was identified as 500 mW/cm irradiance; therefore, caution should be exercised in the dosage of laser-delivered PBM administered to pigmented retinas.
TRANSLATIONAL RELEVANCE
This study provides important data necessary for clinical translation of laser-delivered PBM for retinal diseases.
Topics: Animals; Electroretinography; Lasers; Light; Low-Level Light Therapy; Rats; Retina
PubMed: 32818109
DOI: 10.1167/tvst.9.4.22 -
International Journal of Molecular... Aug 2021The cytoprotective versus cytotoxic role of macroautophagy in ocular ischemia/reperfusion injuries remains controversial and its effects under hyperglycemia are unclear....
The cytoprotective versus cytotoxic role of macroautophagy in ocular ischemia/reperfusion injuries remains controversial and its effects under hyperglycemia are unclear. We investigated the involvement of autophagy in in vitro and in vivo normoglycemic and hyperglycemic models of retinal ischemia/reperfusion injury. Retinal ischemia (2 h) and reperfusion (2 or 22 h) was induced in wild-type and type I diabetic Ins2 mice using a middle cerebral artery occlusion model. R28 retinal precursor cells were subjected to CoCl-induced hypoxia with or without autophagic inhibitor NHCl. Autophagic regulation during ischemia/reperfusion was assessed through immunohistochemical detection and Western blotting of microtubule-associated protein 1A/1B-light chain 3 (LC3) and lysosomal associated membrane protein 1 (LAMP1). Effect of autophagic inhibition on cell viability and morphology under hypoxic conditions was also evaluated. Upregulation of autophagic markers in the inner retinae was seen after two hours reperfusion, with tapering of the response following 22 h of reperfusion in vivo. LC3-II turnover assays confirmed an increase in autophagic flux in our hypoxic in vitro model. Pharmacological autophagic inhibition under hypoxic conditions decreased cell survival and induced structural changes not demonstrated with autophagic inhibition alone. Yet no statistically significant different autophagic responses in ischemia/reperfusion injuries were seen between the two glycemic states.
Topics: Animals; Autophagy; Cell Survival; Female; Male; Mice, Inbred C57BL; Reperfusion Injury; Retina; Stem Cells; Mice
PubMed: 34445152
DOI: 10.3390/ijms22168446