Millions of people worldwide suffer vision loss from progressed stages of age-related macular degeneration and retinitis pigmentosa. Through the disease, much of the retinal pigment epithelium (RPE) and many photoreceptors are irreversibly lost and new cutting edge treatments using trophic factors or gene therapy are ineffective because the tissues are no longer present to be rescued. Our goal is to remediate vision loss through transplantation of retinal progenitor tissue sheets into the degenerated retina. In rodent models of retinal degeneration (RD), several studies have demonstrated that retinal progenitor sheets successfully integrate into the host retina, through synaptic connectivity between the transplant retina and host, and evoke responses to flashes of light in the superior colliculus (SC, a midbrain visual nucleus and direct target of retinal ganglion cells). However, in order to determine the complexity and quality of visual information provided by the transplant visual responsivity must be determined at a greater level of detail and in structures such as higher visual cortex where more complex visual processing occurs. Our main hypothesis is that transplants of fetal- and hESC-derived retinal progenitor sheets will drive complex and specialized visual responses in visual cortex (Aims 1 and 2), as well as visually guided behavior, and, that feedforward and feedback cortical circuitry at the level of specific neuronal cell types will be more similar to normal rats than RD rats without transplants (Aim 3). These studies will be performed using two rat models that are effectively blind by 3 months of age - through a collaboration combining visual neurophysiology expertise and cutting edge neural circuit tracing using genetically modified rabies viruses from the PI with the unrivaled surgical skills for retinal sheet transplantation and expert breeding knowledge of transgenic RD rats by the CO-PI. This project directly addresses the NEI Audacious Goals Initiative to regenerate the eye and visual system.

PROJECT NARRATIVE Retinal progenitor sheet transplants into rodents with retinal degeneration (RD) have been shown to make nerve connections to the recipient RD retina, and to generate basic visual responses to light in the superior colliculus (SC, a primary target of retinal ganglion cells). However, we still do not know whether and to what degree complex, higher-level visual processing is restored in visual cortex. The objectives of this study are to investigate to what extent rat fetal- and hESC-derived retinal sheet transplants restore higher level visual function and connectivity in the visual cortex in rat models of severe RD.