My research uses electrophysiological techniques to evaluate normal retinal function, dysfunction caused by blinding retinal diseases and the restoration of function using a variety of therapeutic strategies. We can use our understanding or normal retinal function and disease-related changes to construct optimal therapeutic strategies and evaluate how they ameliorate the effects of disease. Retinitis pigmentosa (RP) is a family of blinding eye diseases caused by photoreceptor degeneration. The absence of the cells that for this primary signal leads to blindness. My interest in RP involves the evaluation of therapies to restore vision: replacing degenerated photoreceptors either with: (1) new stem or other embryonic cells, manipulated to become photoreceptors or (2) prosthetics devices that replace the photoreceptor signal with an electronic signal to light. Glaucoma is caused by increased intraocular pressure and leads to ganglion cell death, which eliminates the link between the retinal output and central visual processing. We are parsing out of the effects of increased intraocular pressure and aging on ganglion cells. Congenital Stationary Night Blindness (CSNB) is a family of diseases in which signaling is eliminated between rod photoreceptors and their postsynaptic targets, rod bipolar cells. This deafferents the retinal circuit that is responsible for vision under dim lighting. My interest in CSNB involves understanding the basic interplay between excitation and inhibition in the retinal circuit and its normal development. Because of the targeted nature of this disease, we are hopeful that a gene therapy approach can be developed to restore night vision. My work utilizes rodent disease models whose mutations mimic those found in human patients. While molecular manipulation of rodents is a fairly common approach, we have recently developed a mutant NIH miniature swine model of a common form of autosomal dominant RP (Pro23His rhodopsin mutation) in collaboration with the National Swine Resource Research Center at University of Missouri. More genetically modified mini-swine models are in the pipeline to examine other retinal diseases.

The vertebrate retina is an important outpost of the central nervous system, responsible for the perception and transmission of visual information. It consists of five different types of neurons that reproducibly laminate into three layers, a process of crucial importance for the organ’s function. Unsurprisingly, impaired fate decisions as well as impaired neuronal migrations and lamination lead to impaired retinal function. However, how processes are coordinated at the cellular and tissue level and how variable or robust retinal formation is, is currently still underexplored. In my lab, we aim to shed light on these questions from different angles, studying on the one hand differentiation phenomena and their variability and on the other hand the downstream migration and lamination phenomena. We use zebrafish as our main model system due to its excellent possibilities for live imaging and quantitative developmental biology. More recently we also started to use human retinal organoids as a comparative system. We further employ cross disciplinary approaches to address these issues combining work of cell and developmental biology, biomechanics, theory and computer science. Together, this allows us to integrate cell with tissue-wide phenomena and generate an appreciation of the reproducibility and variability of events.

Simply put, the goal of my research is to describe the neuronal circuitry of the retina. The organization of the mammalian retina is certainly complex but it is not chaotic. Although there are many cell types, most adhere to a relatively constant morphology and they are distributed in non-random mosaics. Furthermore, each cell type ramifies at a characteristic depth in the retina and makes a stereotyped set of synaptic connections. In other words, these neurons form a series of local circuits across the retina. The next step is to identify the simplest and commonest of these repeating neural circuits. They are the building blocks of retinal function. If we think of it in this way, the retina is a fabulous model for the rest of the CNS. We are interested in identifying specific circuits and cell types that support the different functions of the retina. For example, there appear to be specific pathways for rod and cone mediated vision. Rods are used under low light conditions and rod circuitry is specialized for high sensitivity when photons are scarce (when you’re out camping, starlight). The hallmark of the rod-mediated system is monochromatic vision. In contrast, the cone circuits are specialized for high acuity and color vision under relatively bright or daylight conditions. Individual neurons may be filled with fluorescent dyes under visual control. This is achieved by impaling the cell with a glass microelectrode using a 3D micromanipulator. We are also interested in the diffusion of dye through coupled neuronal networks in the retina. The dye filled cells are also combined with antibody labeling to reveal neuronal connections and circuits. This triple-labeled material may be viewed and reconstructed in 3 dimensions by multi-channel confocal microscopy. We have our own confocal microscope facility in the department and timeslots are available to students in my lab.

Visual processing in the retina has been studied in great detail at all levels such that a comprehensive picture of the retina's cell types and the many neural circuits they form is emerging. However, the currently best performing models of retinal function are black-box CNN models which are agnostic to such biological knowledge. Here, I present two of our recent attempts to develop computational models of processing in the inner retina, which both respect biophysical and anatomical constraints yet provide accurate predictions of retinal activity