Examining the effects of retinal cell loss on downstream visual brain areas

Because humans rely heavily on vision to experience the world, diseases of the eye are particularly debilitating in that they have significant adverse effects on patient health and quality of life. Much is known about the mechanisms underlying retinal cell loss in eye diseases like glaucoma. However, significantly less is known

about how retinal cell loss impacts visual brain areas downstream of the retina. Visual brain areas immediately downstream of the retina, especially the lateral geniculate nucleus (LGN) of the thalamus and its main cortical target, primary visual cortex (V1), are likely to undergo substantial structural and functional reorganization

following the removal of their major source of input from the retina. Accordingly, full restoration of visual perception in patients with eye disease will require “brain-level” vision restoration in addition to repair of the damaged retina. The goal of this new research program is to fill a glaring knowledge gap by examining the effects

of retinal cell loss on the structure and function of neurons in the LGN. We have developed a model of retinal ganglion cell (RGC) loss in the ferret through intravitreal injection of kainic acid (KA). Ferrets have a number of visual specializations homologous to primates, including humans, that make them an excellent model in which

to study the downstream effects of RGC loss. Importantly, the early visual pathways in ferrets are organized into parallel processing streams enabling examination of differential effects of RGC loss across functionally distinct neuronal classes in the LGN. As a part of Specific Aim 1, we will characterize the extent, pattern, and possible

RGC-type specificity of cell loss in our ferret model and compare patterns of RGC loss in the ferret with those observed in human eye disease for phenotypic similarities. Also in Specific Aim 1, we will characterize the impact of RGC loss on the structure and physiology of LGN neurons. In Specific Aim 2, we will describe the rate of

changes in LGN neuronal structure and physiology after different survival times following KA-induced RGC loss. We will employ innovative methods such as high-resolution optical coherence tomography imaging, full-field electroretinogram recording, and retinal histology to quantify RGC loss and to guide multi-electrode array

recordings in the LGN to scotoma locations. We will record simultaneously from multiple individual neurons in bilateral LGNs downstream of intact and injected eyes in order to quantify physiological response properties and functional connectivity. Finally, we will utilize brain tissue histological analyses to characterize axonal

degeneration and neuronal morphology in the LGN in order to quantify downstream structural changes. Quantified structural and physiological data will be correlated per animal to control for variability due to injection size. Patterns of structural and physiological changes will then be examined across cohorts of animals with

different survival times post-injection to assess rates of change. The long-term goal of this project is to establish a mechanistic understanding of the impact of RGC loss on the neurons and circuits downstream of the retina in order to inform potential therapeutic treatments and enact a brain-level approach toward vision restoration.