The role of nerve growth factor in the regulation of collateral axon sprouting

A fundamental question in neurobiology is to what extent the mammalian brain retains the ability to remodel neuronal connections throughout maturity. Although the mature brain is normally not permissive to extensive axonal growth, there are situations where the environment does become permissive to axonal remodeling. A current hypothesis to explain axonal remodeling suggests that the postsynaptic target and trophic signals derived therefrom contribute most to changes in axonal connectivity. Several authors have provided evidence that the signal eliciting such changes is the accumulation of trophic molecules, such as nerve growth factor (NGF), produced by a denervated target. One example of axonal remodeling within the mature mammalian brain is the collateral sprouting of uninjured sympathetic axons into the septal-denervated rat hippocampal formation. Considerable evidence supports the hypothesis that the accumulation of NGF within the hippocampal formation elicits sympathetic ingrowth. In this paper, I will review the evidence that trophic molecules are responsible for the initiation and maintenance of collateral sprouting phenomena in general, and the sympathohippocampal sprouting response in particular. I will then present two research reports that demonstrate that although intraventricular infusion of NGF fails to elicit sympathetic sprouting into the hippocampal formation, it dramatically increases the sympathetic innervation of the extracerebral vasculature. Furthermore, when NGF is infused at various times after sympathetic axons have been induced to grow into the brain by a medial septal lesion, intraventricular NGF infusion not only fails to enhance the sprouted projection but reduces the amount and delays the onset of such sprouting. I will then propose that changes in NGF levels, in the absence of injury, are sufficient to produce extensive remodeling of mature, sympathetic arbors; and that such remodeling may be based on competition between branches of the same neuron.