Wednesday, April 2, 2025
4/2/2025
Multi-Cellular Analysis of the Retinal Network - PROJECT SUMMARY/ABSTRACT Retinal circuitry is one of the most promising research platforms in the nervous system where mysteries of neural network function can be unraveled, because individual neuronal circuits therein can be selectively activated by specific natural stimuli, light. Moreover, all vertebrate retinas have similar neuronal and synaptic organizations, and thus knowledge learned from one species can be applied to others, including humans whose neural network dysfunction in disease states manifests. While significant progress has been made in understanding cell types and signal spreading within retinal circuits, we still do not have a comprehensive picture of cell type taxonomy in the retina and their wiring principles, slowing the progress toward a circuit-level mechanistic understanding of how the retina processes visual information. For example, due to the limitation of existing single- or dual- recording techniques, it is difficult to study synaptic connectivity between distinct cell types in the retinal circuit. In addition, as sensitivity and waveform of various cell types change with levels of light adaptation and duration of retinal isolation, single-electrode recordings in different retinas and/or under different adaptation conditions result in response variations and inconsistencies, confounding the functional classification of cell types in the retina. In this application, we will adopt the newly available multi-patch recording system to overcome these issues by recording simultaneous responses and synaptic connectivity of up to 8 retinal neurons. This approach will help to integrate piecemeal experimental results from previous studies into a coherent framework representing the network behavior of the vertebrate retina, which is not feasible with the existing single- or dual- electrode recording techniques. There are 4 Specific Aims. Aim 1 is to study spatiotemporal properties of electric signal spread in the coupled rod photoreceptor network and how HCN channels shape the network behavior. Aim 2 is to compare light response amplitude, waveform, and kinetics of the six types of bipolar cells (BCs) or three functional groups of ganglion cells (GCs) recorded simultaneously in the same dark-adapted retina, and the effects of light adaptation on these responses. Aim 3 is to study profiles of synaptic connectivity between rods at different retinal locations and various types of BCs, and the roles of horizontal cells (HCs) in the rod-HC- cone feedback pathway. Aim 4 is to establish a comprehensive connectivity map between various types of BCs and GCs, and contributions of individual BCs to the light responses of various types of GCs. Results obtained will provide new insights into how coupled photoreceptor networks process visual signals, how adaptation differentially alters light responses of various types of BCs and GCs, and how individual BCs mediate photoreceptor-BC-GC parallel information channels and how multiple retinal neurons function together in processing visual information. A comprehensive connectivity map for lateral synapses in the rod coupled network and radial synapses between various types of BCs and GCs may mark the beginning of establishing a “functional connectome” for the retina.
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