Feedback from retinal ganglion cells to the inner retina.
Ontology highlight
ABSTRACT:
SUBMITTER: Vlasiuk A
PROVIDER: S-EPMC8297895 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective.Biomimetic protein-based artificial retinas offer a new paradigm for restoring vision for patients blinded by retinal degeneration. Artificial retinas, comprised of an ion-permeable membrane and alternating layers of bacteriorhodopsin (BR) and a polycation binder, are assembled using layer-by-layer electrostatic adsorption. Upon light absorption, the oriented BR layers generate a unidirectional proton gradient. The main objective of this investigation is to demonstrate the ability of the ion-mediated subretinal artificial retina to activate retinal ganglion cells (RGCs) of degenerated retinal tissue.Approach. Ex vivoextracellular recording experiments with P23H line 1 rats are used to measure the response of RGCs following selective stimulation of our artificial retina using a pulsed light source. Single-unit recording is used to evaluate the efficiency and latency of activation, while a multielectrode array (MEA) is used to assess the spatial sensitivity of the artificial retina films.Main results.The activation efficiency of the artificial retina increases with increased incident light intensity and demonstrates an activation latency of ∼150 ms. The results suggest that the implant is most efficient with 200 BR layers and can stimulate the retina using light intensities comparable to indoor ambient light. Results from using an MEA show that activation is limited to the targeted receptive field.Significance.The results of this study establish potential effectiveness of using an ion-mediated artificial retina to restore vision for those with degenerative retinal diseases, including retinitis pigmentosa.
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Project description:PurposeThe purpose of this study was to investigative the effects of blue light on intrinsically photoreceptive retinal ganglion cells (ipRGCs).MethodsBrown Norway rats were used. Nine rats were continuously exposed to blue light (light emitting diodes [LEDs]: 463 nm; 1000 lx) for 2 days (acute exposure [AE]); 9 rats were exposed to 12 hours of blue light and 12 hours of darkness for 10 days (long-term exposure [LTE]); 6 control rats were exposed to 12 hours of white fluorescent light (1000 lx) and 12 hours of darkness for 10 days. Whole-mount retinas were immunolabelled with melanopsin antibodies; melanopsin-positive (MP) ipRGC somas and processes were counted and measured with Neuron J. To detect apoptosis, retinal cryo-sections were stained with terminal deoxynucleotidyl transferase dUTP nick-end labeling. Ultra-thin sections were visualized with transmission electron microscopy.ResultsThe number of MP ipRGC somas was significantly lower in retinas from AE and LTE rats than in those from control rats (P < 0.001 and = 0.002, respectively). The mean length of MP areas of processes was significantly lower in AE rats (P < 0.001). AE rats had severe retinal damage and massive apoptosis in the outer nuclear layer; their mitochondria were damaged in the axons and dendrites of the nerve fiber layer and the inner plexiform layer. Retinal ganglion cells (RGCs) in AE rats appeared to have reduced amounts of free ribosomes and rough endoplasmic reticulum.ConclusionsAE to blue light reduces melanopsin expression and damages RGCs, likely including ipRGCs. Changes in the axons and dendrites of RGCs suggest possible disruption of intraretinal and extraretinal signal transmission.
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Project description:The retina of lower vertebrates grows continuously by integrating new neurons generated from progenitors in the ciliary margin zone (CMZ). Whether the mammalian CMZ provides the neural retina with retinal cells is controversial. Live imaging of embryonic retina expressing eGFP in the CMZ shows that cells migrate laterally from the CMZ to the neural retina where differentiated retinal ganglion cells (RGCs) reside. Because Cyclin D2, a cell-cycle regulator, is enriched in ventral CMZ, we analyzed Cyclin D2-/- mice to test whether the CMZ is a source of retinal cells. Neurogenesis is diminished in Cyclin D2 mutants, leading to a reduction of RGCs in the ventral retina. In line with these findings, in the albino retina, the decreased production of ipsilateral RGCs is correlated with fewer Cyclin D2+ cells. Together, these results implicate the mammalian CMZ as a neurogenic site that produces RGCs and whose proper generation depends on Cyclin D2 activity.
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Project description:Newborn neurons follow molecular cues to reach their final destination, but whether early life experience influences lamination remains largely unexplored. As light is among the first stimuli to reach the developing nervous system via intrinsically photosensitive retinal ganglion cells (ipRGCs), we asked whether ipRGCs could affect lamination in the developing mouse retina. We show here that ablation of ipRGCs causes cone photoreceptors to mislocalize at different apicobasal positions in the retina. This effect is partly mediated by light-evoked activity in ipRGCs, as dark rearing or silencing of ipRGCs leads a subset of cones to mislocalize. Furthermore, ablation of ipRGCs alters the cone transcriptome and decreases expression of the dopamine receptor D4, while injection of L-DOPA or D4 receptor agonist rescues the displaced cone phenotype observed in dark-reared animals. These results show that early light-mediated activity in ipRGCs influences neuronal lamination and identify ipRGC-elicited dopamine release as a mechanism influencing cone position.
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Project description:Cell replacement therapies may be key in achieving functional recovery in neurodegenerative optic neuropathies diseases such as glaucoma. One strategy that holds promise in this regard is the use of human embryonic stem cell and induced pluripotent stem-derived retinal ganglion cells (hRGCs). Previous hRGC transplantation studies have shown modest success. This is in part due to the low survival and integration of the transplanted cells in the host retina. The field is further challenged by mixed assays and outcome measurements that probe and determine transplantation success. Thefore, we have devised a transplantation assay involving hRGCs and mouse retina explants that bypasses physical barriers imposed by retinal membranes. We show that hRGC neurites and somas are capable of invading mouse explants with a subset of hRGC neurites being guided by mouse RGC axons. Neonatal mouse retina explants, and to a lesser extent, adult explants, promote hRGC integrity and neurite outgrowth. Using this assay, we tested whether suppmenting cultures with brain derived neurotrophic factor (BDNF) and the adenylate cyclase activator, forskolin, enhances hRGC neurite integration, neurite outgrowth, and integrity. We show that supplementing cultures with a combination BDNF and forskolin strongly favors hRGC integrity, increasing neurite outgrowth and complexity as well as the invasion of mouse explants. The transplantation assay presented here is a practical tool for investigating strategies for testing and optimizing the integration of donor cells into host tissues.
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Project description:In mammalian albinism, disrupted melanogenesis in the retinal pigment epithelium (RPE) is associated with fewer retinal ganglion cells (RGCs) projecting ipsilaterally to the brain, resulting in numerous abnormalities in the retina and visual pathway, especially binocular vision. To further understand the molecular link between disrupted RPE and a reduced ipsilateral RGC projection in albinism, we compared gene expression in the embryonic albino and pigmented mouse RPE. We found that the Wnt pathway, which directs peripheral retinal differentiation and, generally, cell proliferation, is dysregulated in the albino RPE. Wnt2b expression is expanded in the albino RPE compared with the pigmented RPE, and the expanded region adjoins the site of ipsilateral RGC neurogenesis and settling. Pharmacological activation of Wnt signaling in pigmented mice by lithium (Li+) treatment in vivo reduces the number of Zic2-positive RGCs, which are normally fated to project ipsilaterally, to numbers observed in the albino retina. These results implicate Wnt signaling from the RPE to neural retina as a potential factor in the regulation of ipsilateral RGC production, and thus the albino phenotype.
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Project description:We have investigated the ontogeny of light-driven responses in mouse retinal ganglion cells (RGCs). Using a large-scale, high-density multielectrode array, we recorded from hundreds to thousands of RGCs simultaneously at pan-retinal level, including dorsal and ventral locations. Responses to different contrasts not only revealed a complex developmental profile for ON, OFF and ON-OFF responses, but also unveiled differences between dorsal and ventral RGC responses. At eye-opening, dorsal RGCs of all types were more responsive to light, perhaps indicating an environmental priority to nest viewing for pre-weaning pups. The developmental profile of ON and OFF responses exhibited antagonistic behaviour, with the strongest ON responses shortly after eye-opening, followed by an increase in the strength of OFF responses later on. Further, we found that with maturation receptive field (RF) center sizes decrease, spike-triggered averaged responses to white noise become stronger, and centers become more circular while maintaining differences between RGC types. We conclude that the maturation of retinal functionality is not spatially homogeneous, likely reflecting ecological requirements that favour earlier maturation of the dorsal retina.
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Project description:Melanopsin-expressing photosensitive retinal ganglion cells (pRGCs) represent a third class of retinal photoreceptor. These cells are intrinsically photosensitive, but also receive inputs from rod and cone photoreceptors, acting as the primary sensory conduit mediating non-image-forming responses to light. Multiple subtypes of pRGC have been described in the mouse retina with characteristic morphologies and functional properties, and which perform distinct physiological roles. Here, we examine the levels of melanopsin expression and distribution of pRGC subtypes across the mouse retina, identifying a previously unreported anatomical and functional specialization of the melanopsin system. Our results show a dorsal-ventral gradient in the expression of melanopsin and the distribution of pRGCs, which, combined with dorsal-ventral gradients in ultraviolet-sensitive and medium-wavelength-sensitive cone opsin expression, produce dramatic variations in the ratio of cone opsins and pRGCs across the retina. Using c-fos expression as a marker of light activation in vivo, we show that the responses of pRGCs are spectrally tuned by gradients in cone opsin expression depending on their location in the retina. These data illustrate the importance of classical photoreceptors in providing spectral tuning of pRGC light responses and have important implications for the complexity of non-image-forming responses to light.
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Project description:Most inherited retinal dystrophies display progressive photoreceptor cell degeneration leading to severe visual impairment. Optogenetic reactivation of inner retinal neurons is a promising avenue to restore vision in retinas having lost their photoreceptors. Expression of optogenetic proteins in surviving ganglion cells, the retinal output, allows them to take on the lost photoreceptive function. Nonetheless, this creates an exclusively ON retina by expression of depolarizing optogenetic proteins in all classes of ganglion cells, whereas a normal retina extracts several features from the visual scene, with different ganglion cells detecting light increase (ON) and light decrease (OFF). Refinement of this therapeutic strategy should thus aim at restoring these computations. Here we used a vector that targets gene expression to a specific interneuron of the retina called the AII amacrine cell. AII amacrine cells simultaneously activate the ON pathway and inhibit the OFF pathway. We show that the optogenetic stimulation of AII amacrine cells allows restoration of both ON and OFF responses in the retina, but also mediates other types of retinal processing such as sustained and transient responses. Targeting amacrine cells with optogenetics is thus a promising avenue to restore better retinal function and visual perception in patients suffering from retinal degeneration.
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Project description:Glaucoma is characterized by the progressive loss of retinal ganglion cells (RGCs), although the pathogenic mechanism remains largely unknown. To study the mechanism and assess RGC degradation, mouse models are often used to simulate human glaucoma and specific markers are used to label and quantify RGCs. However, manually counting RGCs is time-consuming and prone to distortion due to subjective bias. Furthermore, semi-automated counting methods can produce significant differences due to different parameters, thereby failing objective evaluation. Here, to improve counting accuracy and efficiency, we developed an automated algorithm based on the improved YOLOv5 model, which uses five channels instead of one, with a squeeze-and-excitation block added. The complete number of RGCs in an intact mouse retina was obtained by dividing the retina into small overlapping areas and counting, and then merging the divided areas using a non-maximum suppression algorithm. The automated quantification results showed very strong correlation (mean Pearson correlation coefficient of 0.993) with manual counting. Importantly, the model achieved an average precision of 0.981. Furthermore, the graphics processing unit (GPU) calculation time for each retina was less than 1 min. The developed software has been uploaded online as a free and convenient tool for studies using mouse models of glaucoma, which should help elucidate disease pathogenesis and potential therapeutics.
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