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Journal of Neural Engineering Mar 2023Retinal prostheses use electric current to activate inner retinal neurons, providing artificial vision for blind people. Epiretinal stimulation primarily targets retinal...
Retinal prostheses use electric current to activate inner retinal neurons, providing artificial vision for blind people. Epiretinal stimulation primarily targets retinal ganglion cells (RGCs), which can be modeled with cable equations. Computational models provide a tool to investigate the mechanisms of retinal activation, and improve stimulation paradigms. However, documentation of RGC model structure and parameters is limited, and model implementation can influence model predictions.We created a functional guide for building a mammalian RGC multi-compartment cable model and applying extracellular stimuli. Next, we investigated how the neuron's three-dimensional shape will influence model predictions. Finally, we tested several strategies to maximize computational efficiency.We conducted sensitivity analyses to examine how dendrite representation, axon trajectory, and axon diameter influence membrane dynamics and corresponding activation thresholds. We optimized the spatial and temporal discretization of our multi-compartment cable model. We also implemented several simplified threshold prediction theories based on activating function, but these did not match the prediction accuracy achieved by the cable equations.Through this work, we provide practical guidance for modeling the extracellular stimulation of RGCs to produce reliable and meaningful predictions. Robust computational models lay the groundwork for improving the performance of retinal prostheses.
Topics: Humans; Animals; Retinal Ganglion Cells; Electric Stimulation; Retina; Visual Prosthesis; Axons; Action Potentials; Mammals
PubMed: 36848677
DOI: 10.1088/1741-2552/acbf79 -
Open Biology Apr 2023Individual retinal cell types exhibit semi-regular spatial patterns called retinal mosaics. Retinal ganglion cells (RGCs) and starburst amacrine cells (SACs) are known...
Individual retinal cell types exhibit semi-regular spatial patterns called retinal mosaics. Retinal ganglion cells (RGCs) and starburst amacrine cells (SACs) are known to exhibit such layouts. Mechanisms responsible for the formation of mosaics are not well understood but follow three main principles: (i) homotypic cells prevent nearby cells from adopting the same type, (ii) cell tangential migration and (iii) cell death. Alongside experiments in mouse, we use BioDynaMo, an agent-based simulation framework, to build a detailed and mechanistic model of mosaic formation. We investigate the implications of the three theories for RGC's mosaic formation. We report that the cell migration mechanism yields the most regular mosaics. In addition, we propose that low-density RGC type mosaics exhibit on average low regularities, and thus we question the relevance of regular spacing as a criterion for a group of RGCs to form a RGC type. We investigate SAC mosaics formation and interactions between the ganglion cell layer (GCL) and inner nuclear layer (INL) populations. We propose that homotypic interactions between the GCL and INL populations during mosaics creation are required to reproduce the observed SAC mosaics' characteristics. This suggests that the GCL and INL populations of SACs might not be independent during retinal development.
Topics: Mice; Animals; Retinal Ganglion Cells; Amacrine Cells; Retina; Software; Computer Simulation
PubMed: 37015288
DOI: 10.1098/rsob.220217 -
Biomedicine & Pharmacotherapy =... Dec 2020Diabetic retinopathy(DR) is an expanding global health problem, the exact mechanism of which has not yet been clarified clearly, new insights into retinal physiology... (Review)
Review
Diabetic retinopathy(DR) is an expanding global health problem, the exact mechanism of which has not yet been clarified clearly, new insights into retinal physiology indicate that diabetes-induced retinal dysfunction may be viewed as an impairment of the retinal neurovascular unit, including retinal ganglion cells, glial cells, endothelial cells, pericytes, and retinal pigment epithelium. Different retinal cells have unique structure and functions, while the interactions among which are less known. Cells are the basic unit of organism structure and function, their impairment could lead to abnormal physiological functions and even organ disorder. Considering the body is multi-dimension and the complexity of DR, one point or a single type of cell can't be used to illustrate the mechanism of occurrence and development of DR. In this review, we provided a systematic and comprehensive elaboration of the cells that are involved in the process of DR. We underlined the importance of considering the neurovascular unit, not just retinal vascular and neural cells, in understanding the pathophysiology of DR. Our studies provided a better understanding of the pathological process in DR and provide a theoretical basis for further research.
Topics: Animals; Diabetic Retinopathy; Endothelial Cells; Humans; Retina; Retinal Ganglion Cells; Retinal Pigment Epithelium; Retinal Vessels
PubMed: 33053509
DOI: 10.1016/j.biopha.2020.110818 -
Neuroscience Jan 2023The development and connectivity of retinal ganglion cells (RGCs), the retina's sole output neurons, are patterned by activity-independent transcriptional programs and...
The development and connectivity of retinal ganglion cells (RGCs), the retina's sole output neurons, are patterned by activity-independent transcriptional programs and activity-dependent remodeling. To inventory the molecular correlates of these influences, we applied high-throughput single-cell RNA sequencing (scRNA-seq) to mouse RGCs at six embryonic and postnatal ages. We identified temporally regulated modules of genes that correlate with, and likely regulate, multiple phases of RGC development, ranging from differentiation and axon guidance to synaptic recognition and refinement. Some of these genes are expressed broadly while others, including key transcription factors and recognition molecules, are selectively expressed by one or a few of the 45 transcriptomically distinct types defined previously in adult mice. Next, we used these results as a foundation to analyze the transcriptomes of RGCs in mice lacking visual experience due to dark rearing from birth or to mutations that ablate either bipolar or photoreceptor cells. 98.5% of visually deprived (VD) RGCs could be unequivocally assigned to a single RGC type based on their transcriptional profiles, demonstrating that visual activity is dispensable for acquisition and maintenance of RGC type identity. However, visual deprivation significantly reduced the transcriptomic distinctions among RGC types, implying that activity is required for complete RGC maturation or maintenance. Consistent with this notion, transcriptomic alternations in VD RGCs significantly overlapped with gene modules found in developing RGCs. Our results provide a resource for mechanistic analyses of RGC differentiation and maturation, and for investigating the role of activity in these processes.
Topics: Mice; Animals; Retinal Ganglion Cells; Vision, Ocular; Transcription Factors; Transcriptome; Gene Expression Profiling; Retina
PubMed: 35870562
DOI: 10.1016/j.neuroscience.2022.07.013 -
Stem Cells Translational Medicine Dec 2022Glaucoma is the most prevalent form of optic neuropathy where a progressive degeneration of retinal ganglion cells (RGCs) leads to irreversible loss of vision. The... (Review)
Review
Glaucoma is the most prevalent form of optic neuropathy where a progressive degeneration of retinal ganglion cells (RGCs) leads to irreversible loss of vision. The mechanism underlying glaucomatous degeneration remains poorly understood. However, evidence suggests that microglia, which regulate RGC numbers and synaptic integrity during development and provide homeostatic support in adults, may contribute to the disease process. Hence, microglia represent a valid cellular target for therapeutic approaches in glaucoma. Here, we provide an overview of the role of microglia in RGC development and degeneration in the backdrop of neurogenesis and neurodegeneration in the central nervous system and discuss how pathological recapitulation of microglia-mediated developmental mechanisms may help initiate or exacerbate glaucomatous degeneration.
Topics: Animals; Humans; Disease Models, Animal; Glaucoma; Intraocular Pressure; Microglia; Retinal Ganglion Cells
PubMed: 36426733
DOI: 10.1093/stcltm/szac077 -
Cells Jun 2021As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible... (Review)
Review
As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible vision loss by damaging RGCs and their axons, which compose the optic nerve. To functionally restore vision, lost RGCs must be replaced. Despite tremendous advancements in experimental models of optic neuropathy that have elucidated pathways to induce RGC neuroprotection and axon regeneration, obstacles to achieving functional visual recovery through RGC transplantation remain. Key challenges include poor graft survival, low donor neuron localization to the host retina, and inadequate dendritogenesis and synaptogenesis with afferent amacrine and bipolar cells. In this review, we summarize the current state of experimental RGC transplantation, and we propose a set of standard approaches to quantifying and reporting experimental outcomes in order to guide a collective effort to advance the field toward functional RGC replacement and optic nerve regeneration.
Topics: Animals; Humans; Nerve Regeneration; Neuroprotection; Regenerative Medicine; Retinal Ganglion Cells; Stem Cell Transplantation
PubMed: 34200991
DOI: 10.3390/cells10061426 -
Neurology Nov 2020The majority of patients with traumatic brain injury (TBI) are classified as having a mild TBI. Despite being categorized as mild, these individuals report ongoing and... (Review)
Review
The majority of patients with traumatic brain injury (TBI) are classified as having a mild TBI. Despite being categorized as mild, these individuals report ongoing and complex symptoms, which negatively affect their ability to complete activities of daily living and overall quality of life. Some of the major symptoms include anxiety, depression, sleep problems, headaches, light sensitivity, and difficulty reading. The root cause for these symptoms is under investigation by many in the field. Of interest, several of these symptoms such as headaches, ocular pain, light sensitivity, and sleep disturbances may overlap and share underlying circuitry influenced by the intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells are light sensing, but non-image forming, and they influence corneal function, pupillary constriction, and circadian rhythm. In this review, we discuss these symptoms and propose a role of the ipRGCs as at least one underlying and unifying cause for such symptoms.
Topics: Animals; Brain Injuries, Traumatic; Humans; Photophobia; Retinal Ganglion Cells
PubMed: 32934170
DOI: 10.1212/WNL.0000000000010830 -
International Journal of Molecular... Mar 2020The retinal ganglion cells (RGCs) are the output cells of the retina into the brain. In mammals, these cells are not able to regenerate their axons after optic nerve... (Review)
Review
The retinal ganglion cells (RGCs) are the output cells of the retina into the brain. In mammals, these cells are not able to regenerate their axons after optic nerve injury, leaving the patients with optic neuropathies with permanent visual loss. An effective RGCs-directed therapy could provide a beneficial effect to prevent the progression of the disease. Axonal injury leads to the functional loss of RGCs and subsequently induces neuronal death, and axonal regeneration would be essential to restore the neuronal connectivity, and to reestablish the function of the visual system. The manipulation of several intrinsic and extrinsic factors has been proposed in order to stimulate axonal regeneration and functional repairing of axonal connections in the visual pathway. However, there is a missing point in the process since, until now, there is no therapeutic strategy directed to promote axonal regeneration of RGCs as a therapeutic approach for optic neuropathies.
Topics: Animals; Cell Differentiation; Cell- and Tissue-Based Therapy; Clinical Trials as Topic; Disease Progression; Humans; Neuroprotective Agents; Retinal Ganglion Cells
PubMed: 32218163
DOI: 10.3390/ijms21072262 -
ELife Feb 2023Spontaneous activity is a hallmark of developing neural systems. In the retina, spontaneous activity comes in the form of retinal waves, comprised of three stages...
Spontaneous activity is a hallmark of developing neural systems. In the retina, spontaneous activity comes in the form of retinal waves, comprised of three stages persisting from embryonic day 16 (E16) to eye opening at postnatal day 14 (P14). Though postnatal retinal waves have been well characterized, little is known about the spatiotemporal properties or the mechanisms mediating embryonic retinal waves, designated stage 1 waves. Using a custom-built macroscope to record spontaneous calcium transients from whole embryonic retinas, we show that stage 1 waves are initiated at several locations across the retina and propagate across a broad range of areas. Blocking gap junctions reduced the frequency and size of stage 1 waves, nearly abolishing them. Global blockade of nAChRs similarly nearly abolished stage 1 waves. Thus, stage 1 waves are mediated by a complex circuitry involving subtypes of nAChRs and gap junctions. Stage 1 waves in mice lacking the β2 subunit of the nAChRs (β2-nAChR-KO) persisted with altered propagation properties and were abolished by a gap junction blocker. To assay the impact of stage 1 waves on retinal development, we compared the spatial distribution of a subtype of retinal ganglion cells, intrinsically photosensitive retinal ganglion cells (ipRGCs), which undergo a significant amount of cell death, in WT and β2-nAChR-KO mice. We found that the developmental decrease in ipRGC density is preserved between WT and β2-nAChR-KO mice, indicating that processes regulating ipRGC numbers and distributions are not influenced by spontaneous activity.
Topics: Animals; Mice; Gap Junctions; Retina; Retinal Ganglion Cells; Synaptic Transmission
PubMed: 36790167
DOI: 10.7554/eLife.81983 -
International Ophthalmology Mar 2023To explore the pathological changes in optic nerve injury models under varying forces.
PURPOSE
To explore the pathological changes in optic nerve injury models under varying forces.
METHODS
The rats were classified into 4 groups: sham operation (SH), 0.1, 0.3, and 0.5 N. Modeling was performed using the lateral optic nerve pulling method. Seven days after modeling, Brn3a immunofluorescence was used to detect retinal ganglion cell (RGC) number, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to detect RGC apoptosis, and flash visual evoked potential (FVEP) was used to detect the optic nerve function on days 1, 3, and 7 after modeling. In addition, LC3 II and P62 expression levels in retinal tissues were detected by western blotting to observe the changes in autophagy levels.
RESULTS
RGC number decreased 7 d after modeling, and it showed a downward trend with increasing damaging force. The number of apoptotic RGCs in ganglion cell layer in the 0.3 and 0.5 N groups was increased and was higher than that in the 0.1 N group. The difference in FVEP of rats in each group was mainly reflected in the P2 peak latency. LC3 II and P62 expression levels in retinal tissue of 0.3 and 0.5 N groups were higher than those of the SH and 0.1 groups; however, the difference between the 0.1 N and SH groups was not statistically significant.
CONCLUSION
Precisely controlling the force of the optic nerve clamping injury model is necessary because different forces acting on the optic nerve will lead to differences in the loss of optic neurons, the conduction function of the optic nerve, and autophagy level in retinal tissues.
Topics: Rats; Animals; Optic Nerve Injuries; Evoked Potentials, Visual; Retina; Retinal Ganglion Cells; Optic Nerve; Disease Models, Animal
PubMed: 36038691
DOI: 10.1007/s10792-022-02476-2