Detailed Visual Cortical Responses Generated by Retinal Sheet Transplants in Rats with Severe Retinal Degeneration

Abstract

To combat retinal degeneration, healthy fetal retinal sheets have been successfully transplanted into both rodent models and humans, with synaptic connectivity between transplant and degenerated host retina having been confirmed. In rodent studies, transplants have been shown to restore responses to flashes of light in a region of the superior colliculus corresponding to the location of the transplant in the host retina. To determine the quality and detail of visual information provided by the transplant, visual responsivity was studied here at the level of visual cortex where higher visual perception is processed. For our model, we used the transgenic Rho-S334ter line-3 rat (both sexes), which loses photoreceptors at an early age and is effectively blind at postnatal day 30. These rats received fetal retinal sheet transplants in one eye between 24 and 40 d of age. Three to 10 months following surgery, visually responsive neurons were found in regions of primary visual cortex matching the transplanted region of the retina that were as highly selective as normal rat to stimulus orientation, size, contrast, and spatial and temporal frequencies. Conversely, we found that selective response properties were largely absent in nontransplanted line-3 rats. Our data show that fetal retinal sheet transplants can result in remarkably normal visual function in visual cortex of rats with a degenerated host retina and represents a critical step toward developing an effective remedy for the visually impaired human population.

Visual response characteristics in lateral and medial subdivisions of the rat pulvinar

“…In LPrm in particular, which receives no collicular input but does receive cortical projections from V1 and V2 (Takahashi, 1985;Masterson et al, 2009), the additional delay versus V1 likely arises from the addition of synapses from cortex to LP. Similar latency to what we found has been previously reported in V1 of rat (Wang et al, 2006;Foik et al, 2018) and mouse (Durand et al, 2016), but response latencies in some areas of higher visual cortex in mouse are much longer than in V1 on average (Polack and Contreras, 2012), which could account for longer response delays in LP cells.…”

“…We found V1 receptive field sizes of about 20° on average, similar to previously reported values in rat (Girman et al, 1999;Foik et al, 2018), and LP receptive field sizes averaging 70°.…”

Projections between visual cortex and pulvinar nucleus in the rat

“…Injections of modified rabies virus were carried out in nine adult female Long-Evans rats in order to retrogradely label connected cells (Foik et al, 2018). All procedures were approved by the University of California, Irvine Institutional Animal Care and Use Committee and the Institutional Biosafety Committee, and followed the guidelines of the National Institutes of Health.…”

Novel rabies virus variant for bi-directional optical control reveals modulatory influence of the pulvinar on visual cortex in rat

“…To package the effector genes we used glycoprotein-deleted rabies virus (RVdG), which offers several advantages over other methods of gene delivery (Figure 1c; Wickersham et al 2007a;Osakada et al 2011). When enveloped with rabies glycoprotein or optimized glycoprotein (oG; Kim et al 2016), RVdG is able to retrogradely trace and deliver genes to the cell body of all pre-synaptically connected neurons, revealing the projections of one brain area to another (e.g., Connolly et al 2012;Negwer et al 2017;Foik et al 2018). In addition, a major benefit of using rabies virus to package channelrhodopsin genes is the ability to pseudotype the virus (Wickersham et al 2007b) to target specific protein receptors delivered transgenically, via helper viruses, and through single cell electroporation (Marshel et al 2010;Wall et al 2010;Miyamichi et al 2011;Rancz et al 2011;Kim et al 2015;Callaway and Luo, 2015;Wertz et al 2015;Wall et al, 2016).…”