Competition for neurotrophic factor in the development of nerve connections

Abstract

The development of nerve connections is thought to involve competition among axons for survival promoting factors, or neurotrophins, which are released by the cells that are innervated by the axons. Although the notion of competition is widely used within neurobiology, there is little understanding of the nature of the competitive process and the underlying mechanisms. We present a new theoretical model to analyse competition in the development of nerve connections. According to the model, the precise manner in which neurotrophins regulate the growth of axons, in particular the growth of the amount of neurotrophin receptor, determines what patterns of target innervation can develop. The regulation of neurotrophin receptors is also involved in the degeneration and regeneration of connections. Competition in our model can be influenced by factors dependent on and independent of neuronal electrical activity. Our results point to the need to measure directly the specific form of the regulation by neurotrophins of their receptors.

On the dynamics of cortical development: synchrony and synaptic self-organization

“…Secondly, embryonic neurons developing in vitro develop synchronous firing, and as their growth proceeds, show self-organization into “small world” networks (Downes et al, 2012). We propose that the synchronous firing and protection from apoptosis are directly causally related, because during cortical embryogenesis there is competition among developing neurons and synapses, which, although mediated by trophic factors (Harris et al, 1997; van Ooyen and Willshaw, 1999; van Ooyen, 2001) is ultimately a competition for available metabolic energy and/or some other scarce resource needed to promote metabolism (Montague, 1996; Thomaidou et al, 1997). We suppose that pre-synaptic pulse synchrony increases uptake of critical metabolic resources by some action not presently specified, and we argue that the assembly of cells that maximizes synchronous firing, and thus energy uptake, is also that which has the minimum metabolic cost per neuron in the length of axonal connections—the combination optimum for their survival.…”

Integrative Utilization of Microenvironments, Biomaterials and Computational Techniques for Advanced Tissue Engineering

“…Developing appropriate tunable biomaterials for a systematic study of neuronal cell growth and differentiation is another important aspect that is considered by many groups [135,[250][251][252], and has resulted in functional materials for improving axonal development [253]. Moreover, computational studies have been employed for predicting the mechanism of neurotrophic factor gradient generation, polarization of growth cone receptors, and cytoskeleton organization [254][255][256][257][258].…”

Neural Fields

“…Fragmented nuclear DNA markers suggest that the bulk of differentiating neurons die soon after they are generated, and the majority of the cells that die are in the fastest proliferating regions [12]. We propose that synchronous firing and protection from apoptosis are related because competition among developing neurons and synapses, although mediated by trophic factors [39,94,97,98], is ultimately a competition for available metabolic energy, and that pulse synchrony increases uptake of critical metabolic resources, perhaps by some collective pumping action. Yet, although the generation of action potentials must greatly increase metabolic demands, synchronous action potential generation appears to protect against apoptosis, since neurons in neonatal cerebral cortical slices show increased apoptosis when their capacity to enter into synchronous firing is disrupted by pharmacological means [43].…”