Structural Neurochemistry of Retinal Circuits

University Of Utah, Salt Lake City UT

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Abstract

The long term goals of this research are to: (1) generate a complete network map for the mammalian retina and (2) define the signaling profiles of all retina cells. Fusions of molecular and computational analysesnow make it possible to perform these tasks in a practical time frame. Specific Aim 1. Realization of a complete network map for the mammalian retina. Retinal networks converge on ganglion cells, creating some 15-20 filtered versions of the visual world. Maps of these filters will be acquired by fusing molecular phenotyping (to visualize all cells), excitation mapping (to visualize function), and large-scale ultrastructural imaging (to visualize all connections). The novelstrategy is the computational propagation of molecular data into the ultrastructural data, producing a combined map of all cell classes and connections. Significance: Understanding any system requires a complete map: a map against which changes triggered by disease or experimental intervention can be gauged. This work has taken on new importance as inherited or acquired retinal degenerations are now known to heavily impact retinal wiring and neuronal survival, showing significant similarities to temporal lobe epilepsy. A complete network map provides the essential guide for any strategy to restore vision. Specific Aim 2. Definition of the basic signaling profiles of all retinal neurons. Each of the60+ retinal neuron classes expresses a profile of molecular mechanisms that precisely tunes it for vision. These profiles will be acquired for all neuronal classes by fusing molecular phenotyping and visualization of function with organic-cation permeation and D-glucosamine metabolic mapping. The glucosamine method is based on the same metabollic principles as fMRI brain imaging, linking cellular and systems visualizations. Permation mapping reports integrated cell currents while metabolic mapping reports integrated cell voltages and each provides a subtly different view of signaling. Significance: A description of any network requires a functional profile for each cell. These profiles shape the visual performances of ranges of each cell. We now know now that these profiles are not static;that they are responsive to developmental experience and are altered by retinal degenerations. Any strategies to restore vision must preserve or restore to the molecular profiles of the key pathways defined in Specific Aim 1.