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Neurite outgrowth: elongation and branching

During development, neurons become assembled into functional networks by growing out axons and dendrites (collectively called neurites) that connect synaptically to other neurons. The outgrowth of neurons proceeds by means of the dynamic behavior of growth cones, specialized hand-shaped structures at the tip of growing neurites. Growth cone migration elongates the trailing neurite, whereas growth cone splitting creates new daughter branches.

Despite the importance of neurite outgrowth for development, only a few computational models exist. In one of the most successful models, elongation and branching are described in a stochastic, phenomenological manner (see Jaap van Pelt). Each growth cone in the growing neuritic tree is given a branching probability and an elongation rate, the values of which depend on the growth cone's position in the tree and the tree's total number of growth cones. The model is able to generate realistic neuronal morphologies, and we use it in our simulation framework NETMORPH (Koene et al., 2009) to study the formation of synaptic connectivity in cortical networks (see network formation).

However, phenomenological models do not clarify how the underlying biological mechanisms involved in neurite outgrowth—the dynamics of the tubulin and actin cytoskeletons—may lead to the generation of neuronal morphologies.

Together with Bruce Graham, we therefore developed biologically realistic models for the generation of axonal and dendritic morphologies. To this end, we also extended the compartmental modeling approach (see Methods in Neuronal Modeling) to growing neurites (Graham and Van Ooyen, 2001).

An interesting experimental observation is that the elongation of neurite branches is often accompanied by the simultaneous retraction of other branches belonging to the same neuritic tree. Using compartmental models of outgrowing neurites, we showed that this phenomenon, which is highly relevant for the formation of synaptic connectivity, can arise from competition for tubulin dimers (Hjorth et al., 2014). Tubulin dimers are produced in the soma and transported to the growth cones, where they are assembled into the cytoskeleton to elongate the neurites.

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