Abstract
During development, neurons extend axons to different brain areas and produce stereotypical patterns of connections. The mechanisms underlying this process have been intensively studied in the visual system, where retinal neurons form retinotopic maps in the thalamus and superior colliculus. The mechanisms active in map formation include molecular guidance cues, trophic factor release, spontaneous neural activity, spike-timing dependent plasticity (STDP), synapse creation and retraction, and axon growth, branching and retraction. To investigate how these mechanisms interact, a multi-component model of the developing retinocollicular pathway was produced based on phenomenological approximations of each of these mechanisms. Core assumptions of the model were that the probabilities of axonal branching and synaptic growth are highest where the combined influences of chemoaffinity and trophic factor cues are highest, and that activity-dependent release of trophic factors acts to stabilize synapses. Based on these behaviors, model axons produced morphologically realistic growth patterns and projected to retinotopically correct locations in the colliculus. Findings of the model include that STDP, gradient detection by axonal growth cones and lateral connectivity among collicular neurons were not necessary for refinement, and that the instructive cues for axonal growth appear to be mediated first by molecular guidance and then by neural activity. Although complex, the model appears to be insensitive to variations in how the component developmental mechanisms are implemented. Activity, molecular guidance and the growth and retraction of axons and synapses are common features of neural development, and the findings of this study may have relevance beyond organization in the retinocollicular pathway.
Highlights
During neural system development, groups of neurons project to various areas of the brain and produce stereotypical patterns of innervation
While molecular guidance cues and retinal waves are both present throughout this age, modeled development occurred in two stages, each lasting 60 hours
Eliminating the activity-dependent mechanism underlying trophic factor release and having trophic factor released on every postsynaptic spike completely prevented refinement, with too much release resulting in very little synapse turnover, as most synapses became stabilized by the trophic factor received, and too little release preventing synapse stabilization and causing very high rates of turnover. These results indicate that activity-dependent trophic factor release, or an equivalent mechanism providing performance feedback to individual synapses, guides the removal of inappropriately targeted synapses and refines the retinotopic projection
Summary
Groups of neurons project to various areas of the brain and produce stereotypical patterns of innervation. These organization patterns are an emergent property of the physiological mechanisms regulating neural behavior. Similar phenomena are observed in many other brain areas during development [9,10,11,12,13]. An important question is how these underlying phenomena combine to produce the emergent patterns of connections seen throughout the brain. A well studied example of such organization is the retinotopically ordered projection from the retina to the thalamus and superior colliculus
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