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Nature Communications Sep 2022Retina ganglion cells extract specific features from natural scenes and send this information to the brain. In particular, they respond to local light increase (ON...
Retina ganglion cells extract specific features from natural scenes and send this information to the brain. In particular, they respond to local light increase (ON responses), and/or decrease (OFF). However, it is unclear if this ON-OFF selectivity, characterized with synthetic stimuli, is maintained under natural scene stimulation. Here we recorded ganglion cell responses to natural images slightly perturbed by random noise patterns to determine their selectivity during natural stimulation. The ON-OFF selectivity strongly depended on the specific image. A single ganglion cell can signal luminance increase for one image, and luminance decrease for another. Modeling and experiments showed that this resulted from the non-linear combination of different retinal pathways. Despite the versatility of the ON-OFF selectivity, a systematic analysis demonstrated that contrast was reliably encoded in these responses. Our perturbative approach uncovered the selectivity of retinal ganglion cells to more complex features than initially thought.
Topics: Photic Stimulation; Retina; Retinal Ganglion Cells
PubMed: 36138007
DOI: 10.1038/s41467-022-33242-8 -
Molecular Neurobiology Mar 2022The BCL-2 (B-cell lymphoma-2) family of proteins contributes to mitochondrial-based apoptosis in models of neurodegeneration, including glaucomatous optic neuropathy...
The BCL-2 (B-cell lymphoma-2) family of proteins contributes to mitochondrial-based apoptosis in models of neurodegeneration, including glaucomatous optic neuropathy (glaucoma), which degrades the retinal ganglion cell (RGC) axonal projection to the visual brain. Glaucoma is commonly associated with increased sensitivity to intraocular pressure (IOP) and involves a proximal program that leads to RGC dendritic pruning and a distal program that underlies axonopathy in the optic projection. While genetic deletion of the Bcl2-associated X protein (Bax) prolongs RGC body survival in models of glaucoma and optic nerve trauma, axonopathy persists, thus raising the question of whether dendrites and the RGC light response are protected. Here, we used an inducible model of glaucoma in Bax mice to determine if Bax contributes to RGC dendritic degeneration. We performed whole-cell recordings and dye filling in RGCs signaling light onset (αON-Sustained) and offset (αOFF-Sustained). We recovered RGC dendritic morphologies by confocal microscopy and analyzed dendritic arbor complexity and size. Additionally, we assessed RGC axon function by measuring anterograde axon transport of cholera toxin subunit B to the superior colliculus and behavioral spatial frequency threshold (i.e., spatial acuity). We found 1 month of IOP elevation did not cause significant RGC death in either WT or Bax retinas. However, IOP elevation reduced dendritic arbor complexity of WT αON-Sustained and αOFF-Sustained RGCs. In the absence of Bax, αON- and αOFF-Sustained RGC dendritic arbors remained intact following IOP elevation. In addition to dendrites, neuroprotection by Bax generalized to αON-and αOFF-Sustained RGC light- and current-evoked responses. Both anterograde axon transport and spatial acuity declined during IOP elevation in WT and Bax mice. Collectively, our results indicate Bax contributes to RGC dendritic degeneration and distinguishes the proximal and distal neurodegenerative programs involved during the progression of glaucoma.
Topics: Animals; Disease Models, Animal; Glaucoma; Intraocular Pressure; Mice; Retinal Ganglion Cells; bcl-2-Associated X Protein
PubMed: 34984584
DOI: 10.1007/s12035-021-02675-5 -
Journal of Translational Medicine May 2024Retinal ischemia/reperfusion (RIR) is implicated in various forms of optic neuropathies, yet effective treatments are lacking. RIR leads to the death of retinal ganglion...
BACKGROUND
Retinal ischemia/reperfusion (RIR) is implicated in various forms of optic neuropathies, yet effective treatments are lacking. RIR leads to the death of retinal ganglion cells (RGCs) and subsequent vision loss, posing detrimental effects on both physical and mental health. Apigenin (API), derived from a wide range of sources, has been reported to exert protective effects against ischemia/reperfusion injuries in various organs, such as the brain, kidney, myocardium, and liver. In this study, we investigated the protective effect of API and its underlying mechanisms on RGC degeneration induced by retinal ischemia/reperfusion (RIR).
METHODS
An in vivo model was induced by anterior chamber perfusion following intravitreal injection of API one day prior to the procedure. Meanwhile, an in vitro model was established through 1% oxygen and glucose deprivation. The neuroprotective effects of API were evaluated using H&E staining, spectral-domain optical coherence tomography (SD-OCT), Fluoro-Gold retrograde labeling, and Photopic negative response (PhNR). Furthermore, transmission electron microscopy (TEM) was employed to observe mitochondrial crista morphology and integrity. To elucidate the underlying mechanisms of API, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry assay, western blot, cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, JC-1 kit assay, dichlorofluorescein-diacetate (DCFH-DA) assay, as well as TMRE and Mito-tracker staining were conducted.
RESULTS
API treatment protected retinal inner plexiform layer (IPL) and ganglion cell complex (GCC), and improved the function of retinal ganglion cells (RGCs). Additionally, API reduced RGC apoptosis and decreased lactate dehydrogenase (LDH) release by upregulating Bcl-2 and Bcl-xL expression, while downregulating Bax and cleaved caspase-3 expression. Furthermore, API increased mitochondrial membrane potential (MMP) and decreased extracellular reactive oxygen species (ROS) production. These effects were achieved by enhancing mitochondrial function, restoring mitochondrial cristae morphology and integrity, and regulating the expression of OPA1, MFN2, and DRP1, thereby regulating mitochondrial dynamics involving fusion and fission.
CONCLUSION
API protects RGCs against RIR injury by modulating mitochondrial dynamics, promoting mitochondrial fusion and fission.
Topics: Retinal Ganglion Cells; Apigenin; Animals; Reperfusion Injury; Neuroprotective Agents; Mitochondrial Dynamics; Male; Apoptosis; Mitochondria; Reactive Oxygen Species; Models, Biological; Mice, Inbred C57BL
PubMed: 38741132
DOI: 10.1186/s12967-024-05260-1 -
Journal of Vision Aug 2019The size of the pupil depends on light level. Watson and Yellott (2012) developed a unified formula to predict pupil size from luminance, field diameter, age, and number...
The size of the pupil depends on light level. Watson and Yellott (2012) developed a unified formula to predict pupil size from luminance, field diameter, age, and number of eyes. Luminance reflects input from the L and M cones in the retina but ignores the contribution of intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin, which are known to control the size of the pupil. We discuss the role of melanopsin in controlling pupil size by reanalyzing an extant data set (Bouma, 1962). We confirm that melanopsin-weighted quantities, in conjunction with Watson and Yellott's formula, adequately model intensity-dependent pupil size. We discuss the contributions of other photoreceptors into pupil control.
Topics: Animals; Humans; Photic Stimulation; Pupil; Retinal Cone Photoreceptor Cells; Retinal Ganglion Cells; Rod Opsins
PubMed: 31415056
DOI: 10.1167/19.9.5 -
Journal of Glaucoma Nov 2019It is often said that substantial retinal ganglion cells are lost before glaucomatous damage is detected by standard automated perimetry. There are 4 key articles... (Review)
Review
It is often said that substantial retinal ganglion cells are lost before glaucomatous damage is detected by standard automated perimetry. There are 4 key articles referenced to support this belief. To test the hypothesis that the 4 key articles are incorrectly cited, the publications in the first 6 months of 2019 that reference 1 or more of these 4 articles were examined. In particular, the degree to which the quotes from these 2019 publications accurately reflected the evidence in the 4 key articles was assessed. These quotes are inadequately supported by the data, and in some cases even by the conclusions found in the abstracts of the key articles. This is despite several review articles that have questioned the evidence in these key articles. Further, a case can be made that the evidence in the key articles better supports the opposite conclusion. That is, the data suggest that sensitivity loss can be seen on standard automated perimetry before retinal ganglion cells are missing.
Topics: Glaucoma, Open-Angle; Humans; Intraocular Pressure; Retinal Diseases; Retinal Ganglion Cells; Vision Disorders; Visual Field Tests; Visual Fields
PubMed: 31688445
DOI: 10.1097/IJG.0000000000001380 -
International Journal of Molecular... Sep 2022The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), the neurons that... (Review)
Review
The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), the neurons that extend axons through the optic nerve, begin to die. Thus, there are few clinical options to improve vision after traumatic or ischemic optic nerve injury or in neurodegenerative diseases such as glaucoma, dominant optic neuropathy, or optic pathway gliomas. Research over the past two decades has identified several strategies to enable RGCs to regenerate axons the entire length of the optic nerve, in some cases leading to modest reinnervation of di- and mesencephalic visual relay centers. This review primarily focuses on the role of the innate immune system in improving RGC survival and axon regeneration, and its synergy with manipulations of signal transduction pathways, transcription factors, and cell-extrinsic suppressors of axon growth. Research in this field provides hope that clinically effective strategies to improve vision in patients with currently untreatable losses could become a reality in 5-10 years.
Topics: Axons; Cell Survival; Humans; Inflammation; Nerve Regeneration; Optic Nerve Injuries; Retinal Ganglion Cells
PubMed: 36077577
DOI: 10.3390/ijms231710179 -
Genes Mar 2021Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the retinal ganglion cells (RGCs). There has been little progress in developing...
Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the retinal ganglion cells (RGCs). There has been little progress in developing efficient strategies for neuroprotection in glaucoma. We profiled the retina transcriptome of Lister Hooded rats at 2 weeks after optic nerve crush (ONC) and analyzed the data from the genomic fabric paradigm (GFP) to bring additional insights into the molecular mechanisms of the retinal remodeling after induction of RGC degeneration. GFP considers three independent characteristics for the expression of each gene: level, variability, and correlation with each other gene. Thus, the 17,657 quantified genes in our study generated a total of 155,911,310 values to analyze. This represents 8830x more data per condition than a traditional transcriptomic analysis. ONC led to a 57% reduction in RGC numbers as detected by retrograde labeling with 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanine perchlorate (DiI). We observed a higher relative expression variability after ONC. Gene expression stability was used as a measure of transcription control and disclosed a robust reduction in the number of very stably expressed genes. Predicted protein-protein interaction (PPI) analysis with STRING revealed axon and neuron projection as mostly decreased processes, consistent with RGC degeneration. Conversely, immune response PPIs were found among upregulated genes. Enrichment analysis showed that complement cascade and Notch signaling pathway, as well as oxidative stress and kit receptor pathway were affected after ONC. To expand our studies of altered molecular pathways, we examined the pairwise coordination of gene expressions within each pathway and within the entire transcriptome using Pearson correlations. ONC increased the number of synergistically coordinated pairs of genes and the number of similar profiles mainly in complement cascade and Notch signaling pathway. This deep bioinformatic study provided novel insights beyond the regulation of individual gene expression and disclosed changes in the control of expression of complement cascade and Notch signaling functional pathways that may be relevant for both RGC degeneration and remodeling of the retinal tissue after ONC.
Topics: Animals; Female; Glaucoma; Optic Nerve; Optic Nerve Injuries; Rats; Retinal Ganglion Cells; Transcriptome
PubMed: 33799827
DOI: 10.3390/genes12030403 -
BMC Ophthalmology Jun 2022The ganglion cell layer (GCL) measurements with Optical Coherence Tomography (OCT) are important for both ophthalmologists and neurologists because of their association...
BACKGROUND
The ganglion cell layer (GCL) measurements with Optical Coherence Tomography (OCT) are important for both ophthalmologists and neurologists because of their association with many ophthalmic and neurological diseases. Different factors can affect these measurements, such as brain pathologies, ocular axial length (AL) as well as age and sex. Studies conducted to measure the GCL have overlooked many of these factors. The purpose of this study is to examine the effect of age, sex, and AL on normal retinal GCL thickness and volume in a healthy population without any neurological diseases.
METHODS
A prospective cross-sectional study was designed to measure GCL thickness and total volume with OCT with automated segmentation and manual correction where needed. Visual acuity, AL, and autorefraction were also measured. A mixed linear model was used to determine the association of the effect of the various parameters on the GCL thickness and volume.
RESULTS
One hundred and sixteen eyes of 60 subjects (12-76 years of age, 55% female) were examined of which 77% had 0 ± 2 D of spherical equivalent, and mean axial length was 23.86 mm. About 25% of the OCT-automated GCL measurements required manual correction. GCL thickness did not differ in similar anatomic regions in right and left eyes (P > 0.05). GCL volume was greater in males relative to females after adjustment for age and axial length (1.13 ± 0.07 mm for males vs 1.09 ± 0.09 mm for females; P = 0.031). GCL thickness differed between males and females in the inner retinal ring (P = 0.025) but not in the outer ring (P = 0.66). GCL volume declined with age (P = 0.031) but not after adjustment for sex and axial length (P = 0.138). GCL volume declined with longer axial length after adjustment for age and sex (P = 0.048).
CONCLUSION
Age, sex and axial length should be taken into consideration when measuring the GCL thickness and volume with OCT. Automated OCT segmentation should be reviewed for manual adjustments.
Topics: Cross-Sectional Studies; Female; Humans; Male; Nerve Fibers; Prospective Studies; Retinal Ganglion Cells; Tomography, Optical Coherence
PubMed: 35751115
DOI: 10.1186/s12886-022-02488-7 -
Scientific Reports May 2021Administration of the mitochondrial complex I inhibitor rotenone provides an excellent model to study the pathomechanism of oxidative stress-related neural degeneration...
Administration of the mitochondrial complex I inhibitor rotenone provides an excellent model to study the pathomechanism of oxidative stress-related neural degeneration diseases. In this study, we examined the glial roles in retinal cell survival and degeneration under the rotenone-induced oxidative stress condition. Mouse-derived Müller, microglial (BV-2), and dissociated retinal cells were used for in vitro experiments. Gene expression levels and cell viability were determined using quantitative reverse transcription-polymerase chain reaction and the alamarBlue assay, respectively. Conditioned media were prepared by stimulating glial cells with rotenone. Retinal ganglion cells (RGCs) and inner nuclear layer (INL) were visualized on rat retinal sections by immunohistochemistry and eosin/hematoxylin, respectively. Rotenone dose-dependently induced glial cell death. Treatment with rotenone or rotenone-stimulated glial cell-conditioned media altered gene expression of growth factors and inflammatory cytokines in glial cells. The viability of dissociated retinal cells significantly increased upon culturing in media conditioned with rotenone-stimulated or Müller cell-conditioned media-stimulated BV-2 cells. Furthermore, intravitreal neurotrophin-5 administration prevented the rotenone-induced reduction of RGC number and INL thickness in rats. Thus, glial cells exerted both positive and negative effects on retinal cell survival in rotenone-induced neural degeneration via altered expression of growth factors, especially upregulation of microglia-derived Ntf5, and proinflammatory cytokines.
Topics: Animals; Cell Survival; Culture Media, Conditioned; Cytokines; Ependymoglial Cells; Intercellular Signaling Peptides and Proteins; Microglia; Nerve Degeneration; Oxidative Stress; Rats; Retinal Ganglion Cells; Rotenone
PubMed: 34045544
DOI: 10.1038/s41598-021-90604-w -
Nano Letters Dec 2023Bacteriorhodopsin, isolated from a halophilic bacterium, is a photosynthetic protein with a structure and function similar to those of the visual pigment rhodopsin. A...
Bacteriorhodopsin, isolated from a halophilic bacterium, is a photosynthetic protein with a structure and function similar to those of the visual pigment rhodopsin. A voltaic cell with bacteriorhodopsin sandwiched between two transparent electrodes exhibits a time-differential response akin to that observed in retinal ganglion cells. It is intriguing as a means to emulate excitation and inhibition in the neural response. Here, we present a neuromorphic device emulating the retinal ganglion cell receptive field fabricated by patterning bacteriorhodopsin onto two transparent electrodes and encapsulating them with an electrolyte solution. This protein-based artificial ganglion cell receptive field is characterized as a bandpass filter that simultaneously replicates excitatory and inhibitory responses within a single element, successfully detecting image edges and phenomena of brightness illusions. The device naturally emulates the highly interacting ganglion cell receptive fields by exploiting the inherent properties of proteins without the need for electronic components, bias power supply, or an external operating circuit.
Topics: Humans; Retinal Ganglion Cells; Bacteriorhodopsins; Illusions; Retina
PubMed: 38048176
DOI: 10.1021/acs.nanolett.3c03257