To restore vision, we must understand how information is processed in the mature retina and how structural and functional organization are affected during degeneration. The divergence of signals at the first synapse in the visual system, where a single cone provides input to 10-12 types of cone bipolar cells, provides a unique opportunity to study the origin of parallel pathways. This synapse also exhibits convergence, where each type of cone bipolar cell receives inputs from a stereotyped number of cones.
Our recent work demonstrates that three types of cone bipolar cells establish their unique patterns of structural contact with presynaptic cone photoreceptors according to different strategies and segregated timelines. However, we know little about how these differences translate into functional properties in the mature circuit. Moreover, how cone bipolar cell types respond to progressive loss of photoreceptors during disease is unclear.
The overall goal of our lab is to understand how visual information is parsed and processed in the retina at the cone-to-cone bipolar synapse, and to determine how this information is perturbed in disease. We aim to determine the functional properties of 12 morphologically characterized bipolar cell types and to uncover how these bipolar cells change their structure and function in a degenerating retina. In pursuit of our goals, we will reveal how a bipolar cell's functional properties are determined by its anatomical connections with cones and will provide an understanding of how bipolar cells respond to photoreceptor degeneration as a model of potential circuit rearrangements in retinal disease.
Goal 1: To determine how cone convergence and divergence shape the functional properties of different bipolar cell types
Based on the structural connectivity between cones and bipolar cells, we hypothesize that the degree of convergence is directly correlated with the receptive field size and confers distinct signaling capabilities to different bipolar cell types. Our past work demonstrates that each bipolar cell type has a unique amount of glutamate receptors and dendritic overlap with cones, suggesting that differences in synapse structure could confer distinct properties on each synapse. We will directly measure spatial receptive fields of specific bipolar cell types in the mature retina. We will determine how signals are shaped when diverging from a single cone to multiple postsynaptic bipolar cells.
Goal 2: To identify the effects of cone degeneration on bipolar cell structure, connectivity, and function
Many retinal diseases leading to blindness originate with the death of photoreceptors. How disease progresses to affect postsynaptic neurons remains unknown. We will determine how different bipolar cells react to the loss of cone photoreceptors. We hypothesize that bipolar cells degenerate or remodel to different extents, depending on the timing of the degeneration and recovery, and the type of bipolar cell. We will use laser ablation and transgenic approaches to control the extent and timing of cone death. Imaging and electrophysiology will allow us to determine the structural connectivity patterns, glutamate receptor distributions, and responses to light stimuli of bipolar cells following controlled cone death.