From synaptogenesis to map formation - modeling visual system development exploring the contribution of cellular mechanisms to the emergence of retinotopic projections and eye-specific segregation

The brain is composed of many anatomically distinct areas that control different functions. A common feature of these areas is that information is represented in a spatially organized manner. In the visual system, retinal representation is spatially mapped onto visual areas such that neighboring neurons respond to adjacent retinal locations, forming a retinotopic map. When axons from two retinas project to the same target structure, both produce similar retinotopic projections on the large scale but these segregate into eye-specific domains locally. How these spatial representations are formed is not well understood. Experimental studies have shown that many mechanisms are involved. Several modeling studies have addressed how such organization arises, with most representing different varying subsets of the mechanisms known to be present and showing how the particular representation of mechanisms can produce the emergent properties of organization. This results in models producing similar outputs yet coming to different conclusions that often cannot be reconciled. By omitting behaviors that are present and likely to be involved in organization, such as spiking neurons and the dynamics of axon and synapse growth and retraction, the models are poorly constrained. This limits their explanatory and predictive scope regarding how organization develops, and further limits their ability to examine how the different mechanisms interact. To more accurately analyze both how such organization develops and the interactions between underlying mechanisms, a model of the developing retinocollicular pathway was produced that represented a wide range of cellular and subcellular phenomena, including spike-timing dependent plasticity (STDP), chemoaffinity, spontaneous retinal activity, trophic factors, and growth and retraction of synapses and axons. The model demonstrated retinotopic refinement and eye-specific segregation across a wide range of parameters and variations in implementation. Results indicated that the mechanisms necessary for organization were chemoaffinity, retinal waves, trophic factors and homeostatic controls. Analysis of the relative roles of activity and chemoaffinity suggested that these mechanisms play distinct and complementary roles. Among the predictions of the model are that smaller synapses produce more refined projections and, surprisingly, that STDP does not play a significant role in organization.Medicine, Faculty ofGraduat