scholarly journals Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes

2019 ◽  
Author(s):  
Nicholas M. Tran ◽  
Karthik Shekhar ◽  
Irene E. Whitney ◽  
Anne Jacobi ◽  
Inbal Benhar ◽  
...  
Keyword(s):  
Single Cell ◽  
Ganglion Cells ◽  
Morphological Changes ◽  
Retinal Ganglion ◽  
Nerve Crush ◽  
Adult Retina ◽  
Neuronal Types ◽  
The Central Nervous System ◽  
Differential Gene

SummaryNeuronal types in the central nervous system differ dramatically in their resilience to injury or insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ~80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC, characterized transcriptomic, physiological, and morphological changes that preceded degeneration, and identified genes selectively expressed by each type. Finally, using loss- and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury, and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.

Effects of different neurotrophic factors on the survival of retinal ganglion cells after a complete intraorbital nerve crush injury: A quantitative in vivo study

2009 ◽  
Vol 89 (1) ◽  
pp. 32-41 ◽  
Author(s):  
Guillermo Parrilla-Reverter ◽  
Marta Agudo ◽  
Paloma Sobrado-Calvo ◽  
Manuel Salinas-Navarro ◽  
María P. Villegas-Pérez ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Neurotrophic Factors ◽  
Ganglion Cells ◽  
Crush Injury ◽  
In Vivo Study ◽  
Retinal Ganglion ◽  
Nerve Crush ◽  
Nerve Crush Injury

scholarly journals The mito-QC Reporter for Quantitative Mitophagy Assessment in Primary Retinal Ganglion Cells and Experimental Glaucoma Models

2020 ◽  
Vol 21 (5) ◽  
pp. 1882
Author(s):  
Ines Rosignol ◽  
Beatriz Villarejo-Zori ◽  
Petra Teresak ◽  
Elena Sierra-Filardi ◽  
Xandra Pereiro ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Ex Vivo ◽  
Iron Chelator ◽  
Stress Factors ◽  
Retinal Ganglion ◽  
Nerve Crush ◽  
Experimental Glaucoma

Mitochondrial damage plays a prominent role in glaucoma. The only way cells can degrade whole mitochondria is via autophagy, in a process called mitophagy. Thus, studying mitophagy in the context of glaucoma is essential to understand the disease. Up to date limited tools are available for analyzing mitophagy in vivo. We have taken advantage of the mito-QC reporter, a recently generated mouse model that allows an accurate mitophagy assessment to fill this gap. We used primary RGCs and retinal explants derived from mito-QC mice to quantify mitophagy activation in vitro and ex vivo. We also analyzed mitophagy in retinal ganglion cells (RGCs), in vivo, using different mitophagy inducers, as well as after optic nerve crush (ONC) in mice, a commonly used surgical procedure to model glaucoma. Using mito-QC reporter we quantified mitophagy induced by several known inducers in primary RGCs in vitro, ex vivo and in vivo. We also found that RGCs were rescued from some glaucoma relevant stress factors by incubation with the iron chelator deferiprone (DFP). Thus, the mito-QC reporter-based model is a valuable tool for accurately analyzing mitophagy in the context of glaucoma.

scholarly journals Rescue of retinal ganglion cells in optic nerve injury using cell-selective AAV mediated delivery of SIRT1

Gene Therapy ◽  
2021 ◽  
Author(s):  
Ahmara G. Ross ◽  
Devin S. McDougald ◽  
Reas S. Khan ◽  
Thu T. Duong ◽  
Kimberly E. Dine ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Ganglion Cell ◽  
Optic Neuropathy ◽  
Visual Function ◽  
Ganglion Cells ◽  
Transduction Efficiency ◽  
Retinal Ganglion ◽  
Optokinetic Response ◽  
Nerve Crush

AbstractSIRT1 prevents retinal ganglion cell (RGC) loss in models of optic neuropathy following pharmacologic activation or genetic overexpression. The exact mechanism of loss is not known, prior evidence suggests this is through oxidative stress to either neighboring cells or RGC specifically. We investigated the neuroprotective potential of RGC-selective SIRT1 gene therapy in the optic nerve crush (ONC) model. We hypothesized that AAV-mediated overexpression of SIRT1 in RGCs reduces RGC loss, thereby preserving visual function. Cohorts of C57Bl/6J mice received intravitreal injection of experimental or control AAVs using either a ganglion cell promoter or a constitutive promoter and ONC was performed. Visual function was examined by optokinetic response (OKR) for 7 days following ONC. Retina and optic nerves were harvested to investigate RGC survival by immunolabeling. The AAV7m8-SNCG.SIRT1 vector showed 44% transduction efficiency for RGCs compared with 25% (P > 0.05) by AAV2-CAG.SIRT1, and AAV7m8-SNCG.SIRT1 drives expression selectively in RGCs in vivo. Animals modeling ONC demonstrated reduced visual acuity compared to controls. Intravitreal delivery of AAV7m8-SNCG.SIRT1 mediated significant preservation of the OKR and RGC survival compared to AAV7m8-SNCG.eGFP controls, an effect not seen with the AAV2 vector. RGC-selective expression of SIRT1 offers a targeted therapy for an animal model with significant ganglion cell loss. Over-expression of SIRT1 through AAV-mediated gene transduction suggests a RGC selective component of neuro-protection using the ONC model. This study expands our understanding of SIRT1 mediated neuroprotection in the context of compressive or traumatic optic neuropathy, making it a strong therapeutic candidate for testing in all optic neuropathies.

Up-regulation of SKIP relates to retinal ganglion cells apoptosis after optic nerve crush in vivo

2014 ◽  
Vol 45 (6) ◽  
pp. 715-721 ◽  
Author(s):  
Yu Wu ◽  
Fan Xu ◽  
Hui Huang ◽  
Lifei Chen ◽  
Meidan Wen ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Optic Nerve Crush ◽  
Retinal Ganglion ◽  
Nerve Crush

scholarly journals Laser capture microdissection-based single-cell RNA sequencing reveals optic nerve crush-related early mRNA alterations in retinal ganglion cells

2020 ◽  
Author(s):  
Dongyan Pan ◽  
Mengqiao Xu ◽  
Xin Chang ◽  
Mao Xia ◽  
Yibin Fang ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Single Cell ◽  
Rna Sequencing ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Optic Nerve Crush ◽  
Retinal Ganglion ◽  
Nerve Crush ◽  
Single Cell Rna Sequencing ◽  
Laser Capture

AbstractRetinal ganglion cells (RGC) are the primary cell type injured in a variety of diseases of the optic nerve, and the early changes of RGC’s RNA profiling may be important to understand the mechanism of optic nerve injury and axon regeneration. Here we employed the optic nerve crush (ONC) model to explore early mRNA alterations in RGCs using laser capture microdissection (LCM) and single-cell RNA sequencing. We successfully established an optimal LCM protocol using 30 μm-thick retinal tissue sections mounted on glass slides and laser pressure catapulting (LPC) to collect RGCs and obtain high-quality RNA for single-cell sequencing. Based on our protocol, we identified 8744 differentially expressed genes that were involved in ONC-related early mRNA alterations in RGCs. Candidate genes included Atf3, Lgals3, LOC102551701, Plaur, Tmem140 and Maml1. The LCM-based single-cell RNA sequencing allowed new insights into the early mRNA changes in RGCs, highlighting new molecules associated with ONC.

scholarly journals Strong and specific connections between retinal axon mosaics and midbrain neurons revealed by large scale paired recordings

2021 ◽  
Author(s):  
Jérémie Sibille ◽  
Carolin Gehr ◽  
Jonathan I. Benichov ◽  
Hymavathy Balasubramanian ◽  
Kai Lun Teh ◽  
...  
Keyword(s):  
Single Cell ◽  
Retinal Ganglion Cells ◽  
Large Scale ◽  
Ganglion Cells ◽  
Brain Regions ◽  
High Density ◽  
List Type ◽  
Retinal Ganglion ◽  
Midbrain Neurons

SUMMARYThe superior colliculus (SC) is a midbrain structure that plays important roles in visually guided behaviors. Neurons in the SC receive afferent inputs from retinal ganglion cells (RGC), the output cells of the retina, but how SC neurons integrate RGC activity in vivo is unknown. SC neurons might be driven by strong but sparse retinal inputs, thereby reliably transmitting specific retinal functional channels. Alternatively, SC neurons could sum numerous but weak inputs, thereby extracting new features by combining a diversity of retinal signals. Here, we discovered that high-density electrodes simultaneously capture the activity and the location of large populations of retinal axons and their postsynaptic SC target neurons, permitting us to investigate the retinocollicular circuit on a structural and functional level in vivo. We show that RGC axons in the mouse are organized in mosaics that provide a single cell precise representation of the retina as input to SC. This isomorphic mapping between retina and SC builds the scaffold for highly specific wiring in the retinocollicular circuit which we show is characterized by strong connections and limited functional convergence, established in log-normally distributed connection strength. Because our novel method of large-scale paired recordings is broadly applicable for investigating functional connectivity across brain regions, we were also able to identify retinal inputs to the avian optic tectum of the zebra finch. We found common wiring rules in mammals and birds that provide a precise and reliable representation of the visual world encoded in RGCs to neurons in retinorecipient areas.HIGHLIGHTSHigh-density electrodes capture the activity of afferent axons and target neurons in vivoRetinal ganglion cells axons are organized in mosaicsSingle cell precise isomorphism between dendritic and axonal RGC mosaicsMidbrain neurons are driven by sparse but strong retinal inputsFunctional wiring of the retinotectal circuit is similar in mammals and birds

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