Rapid and protracted phases of retinal ganglion cell loss follow axotomy in the optic nerve of adult rats (original) (raw)
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International Journal of Molecular Sciences
Background: To analyze the course of microglial and macroglial activation in injured and contralateral retinas after unilateral optic nerve crush (ONC). Methods: The left optic nerve of adult pigmented C57Bl/6 female mice was intraorbitally crushed and injured, and contralateral retinas were analyzed from 1 to 45 days post-lesion (dpl) in cross-sections and flat mounts. As controls, intact retinas were studied. Iba1+ microglial cells (MCs), activated phagocytic CD68+MCs and M2 CD206+MCs were quantified. Macroglial cell changes were analyzed by GFAP and vimentin signal intensity. Results: After ONC, MC density increased significantly from 5 to 21 dpl in the inner layers of injured retinas, remaining within intact values in the contralateral ones. However, in both retinas there was a significant and long-lasting increase of CD68+MCs. Constitutive CD206+MCs were rare and mostly found in the ciliary body and around the optic-nerve head. While in the injured retinas their number increase...
Annals of the New York Academy of Sciences, 1991
Trauma or disease that interrupts axons in the central nervous system (CNS) of adult mammals usually leads to persistent functional deficits. Although numerous factors contribute to these deficits, attempts to understand or ameliorate this situation must address two main injury-related effects that contribute to the impairment of neural connectivity in the CNS of adult mammals: (1) the retrograde loss of neurons that follows axotomy and (2) the failure of axons to regrow the distances necessary to reconnect widely separated parts of the nervous system.
Investigative Ophthalmology & Visual Science, 2003
To use a rat model of optic nerve injury to differentiate primary and secondary retinal ganglion cell (RGC) injury. METHODS. Under general anesthesia, a modified diamond knife was used to transect the superior one third of the orbital optic nerve in albino Wistar rats. The number of surviving RGC was quantified by counting both the number of cells retrogradely filled with fluorescent gold dye injected into the superior colliculus 1 week before nerve injury and the number of axons in optic nerve cross sections. RGCs were counted in 56 rats, with 24 regions examined in each retinal wholemount. Rats were studied at 4 days, 8 days, 4 weeks, and 9 weeks after transection. The interocular difference in RGCs was also compared in five control rats that underwent no surgery and in five rats who underwent a unilateral sham operation. It was confirmed histologically that only the upper optic nerve had been directly injured. RESULTS. At 4 and 8 days after injury, superior RGCs showed a mean difference from their fellow eyes of Ϫ30.3% and Ϫ62.8%, respectively (P ϭ 0.02 and 0.001, t-test, n ϭ 8 rats/group), whereas sham-operation eyes had no significant loss (mean difference between eyes ϭ 1.7%, P ϭ 0.74, t-test). At 8 days, inferior RGCs were unchanged from control, fellow eyes (mean interocular difference ϭ Ϫ4.8%, P ϭ 0.16, t-test). Nine weeks after transection, inferior RGC had 34.5% fewer RGCs than their fellow eyes, compared with 41.2% fewer RGCs in the superior zones of the injured eyes compared with fellow eyes. Detailed, serial section studies of the topography of RGC axons in the optic nerve showed an orderly arrangement of fibers that were segregated in relation to the position of their cell bodies in the retina. CONCLUSIONS. A model of partial optic nerve transection in rats showed rapid loss of directly injured RGCs in the superior retina and delayed, but significant secondary loss of RGCs in the inferior retina, whose axons were not severed. The findings confirm similar results in monkey eyes and provide a rodent model in which pharmacologic interventions against secondary degeneration can be tested. (Invest Ophthalmol Vis Sci.
Experimental Eye Research, 2011
The fate of retinal ganglion cells after optic nerve injury has been thoroughly described in rat, but not in mice, despite the fact that this species is amply used as a model to study different experimental paradigms that affect retinal ganglion cell population. Here we have analyzed, quantitatively and topographically, the course of mice retinal ganglion cells loss induced by intraorbital nerve transection. To do this, we have doubly identified retinal ganglion cells in all retinas by tracing them from their main retinorecipient area, the superior colliculi, and by their expression of BRN3A (product of Pou4f1 gene). In rat, this transcription factor is expressed by a majority of retinal ganglion cells; however in mice it is not known how many out of the whole population of these neurons express it. Thus, in this work we have assessed, as well, the total population of BRN3A positive retinal ganglion cells. These were automatically quantified in all whole-mounted retinas using a newly developed routine. In control retinas, tracedretinal ganglion cells were automatically quantified, using the previously reported method . After optic nerve injury, though, traced-retinal ganglion cells had to be manually quantified by retinal sampling and their total population was afterwards inferred. In naïve whole-mounts, the mean (AEstandard deviation) total number of traced-retinal ganglion cells was 40,437 (AE3196) and of BRN3A positive ones was 34,697(AE1821). Retinal ganglion cell loss was first significant for both markers 5 days post-axotomy and by day 21, the last time point analyzed, only 15% or 12% of traced or BRN3A positive retinal ganglion cells respectively, survived. Isodensity maps showed that, in control retinas, BRN3A and traced-retinal ganglion cells were distributed similarly, being densest in the dorsal retina along the naso-temporal axis. After axotomy the progressive loss of BRN3A positive retinal ganglion cells was diffuse and affected the entire retina. In conclusion, this is the first study assessing the values, in terms of total number and density, of the retinal ganglion cells surviving axotomy from 2 till 21 days post-lesion. Besides, we have demonstrated that BRN3A is expressed by 85.6% of the total retinal ganglion cell population, and because BRN3A positive retinal ganglion cells show the same spatial distribution and temporal course of degeneration than traced ones, BRN3A is a reliable marker to identify, quantify and assess, ex-vivo, retinal ganglion cell loss in this species.
Experimental Brain Research, 1991
A lesion to the optic nerve of adult mammals leads to the retrograde degeneration and finally to the death of injured retinal ganglion cells. In this study, we have evaluated the effects induced by different sites of axotomy on the functional changes occurring in the retinal ganglion cells after optic nerve section. We have investigated the functional properties of retinal ganglion cells of adult rats by recording the retinal responses to patterned stimuli (pattern eleetroretinogram) after unilateral section of the optic nerve at two different levels: intraorbital and intracranial. The results show that the site of lesion of the optic nerve affects the time of disappearance of the pattern electroretinogram. The pattern electroretinogram takes longer to be degraded after an intracranial section than an intraorbital section.
Molecular plasticity of retinal ganglion cells after partial optic nerve injury
Restorative neurology and neuroscience
In the past few years we established the partial crush of the optic nerve as an in vivo model system for the study of signaling pathways involved in molecular plasticity after axonal injury. The simplicity of this model at the cellular level allows decisive questions to be answered whilst functional aspects of visual information processing can be studied in parallel. A major advantage of a partial optic nerve crush model is the opportunity to directly compare different cell populations: (i) the rapidly degenerating retinal ganglion cells (RGC), (ii) the axotomized RGC population that eventually dies over the period of the next few weeks, (iii) the axotomized RGC population surviving for a long time in the retina without an axon and (iv) the surviving RGC population that maintains axonal connections to their brain targets. Thus, differential aspects of post-lesion plasticity between axotomized and non-axotomized cells can be studied and gene transcription leading either to cell death or survival can be analyzed. Using this axonal injury model we investigated the expression of immediate early genes, glutamate receptors, and other differentially expressed genes that we identified with a combined subtractive hybridization and suppression polymerase chain reaction (PCR) screen. Moreover, we characterized time course of cell death, the astroglia response of the retina and optic nerve as well as the topography of anterograde and retrograde axonal transport.
Retinal Ganglion Cells Lose Trophic Responsiveness after Axotomy
Neuron, 1999
Franke et al., 1998). Rapid recruitment of trophic recep-Department of Neurobiology tors is a mechanism likely to account for the ability of Stanford, California 94305 depolarization and cAMP to rapidly increase the trophic † Wistar Institute responsiveness of CNS neurons in culture (Meyer-Philadelphia, Pennsylvania 19104 Franke et al., 1998).