Project Summary To this date, we are still uncovering the exact morphological and functional changes that retina cells undergo throughout retinal degenerative disease timecourse. Furthermore, as common to many neurodegenerative diseases, our knowledge is incomplete when it comes to understanding how these morphological changes to cells affects their role in neural networks, as well as the factors that impact these changes in connectivity. With this proposal, we will take what we have learned from multiscale computational modeling of extracted early data from patho-connectomes, or connectomics volumes constructed from early degeneration stages pathological or neurally degenerating tissues, and pursue large scale network creation and modeling for all four stages of retinal degeneration. For model creation, we will combine the construction of patho-connectomes of photoreceptor to ganglion cell pathways in each stage of degeneration based on TEM images of diseased retina with a genetically-modified, monosynaptic G-deleted rabies viral tracing approach to visualize distinct retinal ganglion cells (RGCs) projection classes and characterize their unique dendritic morphologies. While the first (TEM-based reconstruction) provides unprecedented detail of morphological features of the individual pathways to ganglion cells limited to small areas of tissue and is not viable for mapping long range connections, the second (viral tracing) allows for the reconstruction of the entire retina ganglion cell layer, for all stages of degeneration. Combined, these two strategies will allow us to create a complete mesoscale connectivity atlas of retina and generate its global neural network. This will be the “first of its kind,” large-scale, morphological atlas of the four known phases of retinal degeneration, which will result in unprecedented knowledge of the neuronal changes associated with eye diseases and the development of biomimetic therapeutics. These models will be integrated in our parallel multiscale Admittance Method (AM)-NEURON computational platform, which integrates modeling of exogenous electric field application with neural activity of complex networks to provide insights into the physiological consequences of morphological changes on retinal signaling.