DESCRIPTION (provided by applicant): Our long-term goal is to uncover the fundamental circuit design rules that govern retinal visual processing. We focus in this proposal upon a recently discovered but ubiquitous form of circuitry that utilizes push-pull interactions. This circuit motif exists throughout the visual pathway from ganglion cells to cells in the LGN and visual cortex but has never been fully investigated. Push-pull interactions occur when inhibition decreases while excitation increases at a given neuron, or vice versa. We have recently discovered that push pull interactions represent a dominant form of circuitry in bipolar, amacrine and ganglion cells. In all cases, push pull interactions utilize the convergence of complementary, activity from the ON and OFF pathways. When excitation from the ON pathway increases, there is concomitant decrease in inhibition from the OFF pathway and vice versa. Push pull crossover inhibition is manifest in many different circuitries: It is expressed as feedback inhibition between ON and OFF bipolar cells, as feedforward inhibition to ON and OFF retinal ganglion cells, and recursive inhibition between ON and OFF amacrine cells. These crossover inhibitory interactions underlie a form of parallel processing where the integration of ON and OFF visual signals compensate for signal degradation and enhance signal processing functions such as common mode rejection, drift reduction, and noise reduction and non-linearity corrections. Similar circuitry is known to be used extensively in modern electronic circuit design. The overall goal of the studies is to extract principles of functional organization in the circuitry of the retina that will set precedents for processing of visual information in the retina and at higher visual centers as well as in other sensory systems. Crossover pathways will be studied using isolated retina and retinal slices, using patch clamp recording. Synaptic pathways will be dissected and evaluated using pharmacological agonists and antagonists. Correlation with previously established cell types will be implemented through morphological analysis using confocal microscopy of intracellularly-stained and patch-recorded neurons. The push-pull, crossover pathways constitute a fundamental paradigm for signal transmission and processing throughout the visual system. A thorough understanding of these circuitries will help us decipher the strategies used by the retina and higher visual centers to process the visual message. This understanding will enhance our ability to diagnose visual signal processing anomalies in the retina and higher visual centers, to treat disorders of the visual system, and to design devises for enhancing vision with prosthetic devices.