Frank L. Rice - US grants

Regeneration of transected nerves results in a loss of sensitivity, loss of sensory discrimination, and/or a variety of bizarre of inappropriate sensations. Little is known about the peripheral or central interactions that occur between different types of sensory afferents or between different fascicles within a transected nerve. The sensory innervation of the mystacial pad in the rat is systematically organized in such a way that subsets of sensory terminals are compartmentalized and are supplied by separate nerve branches from the infraorbital nerve. This organization permits surgical approaches to gain access to specific, repeatable superficial and deep vibrissal nerves that supply separate compartments within vibrissal follicle-simus complexes (f-SC's). These nerves can be selectively labeled with HRP to determine their brainstem projection sites via transganglionic transport. A partially completed study has demonstrated that the superficial and deep vibrissal nerves are separate and predictable projects sites. The first aim of this proposal is to complete the analysis of the topographical organization of these projects. Deep vibrissal nerves can also be rerouted such that the regeneration (as seen in Winkelmann reduced silver preparations) can invade peripheral territories that normally belong to the superficial nerves. The second aim of this proposal is to refine the surgical rerouting technique and to determine the conditions that result in no misguided regeneration. The final aim of the proposed study is to combine the nerve rerouting experiments with the HRP transganglionic labeling experiments to determine the central connections of the misguided deep vibrissal nerves. The status of the peripheral regeneration will be assessed in Winkelmann preparations of the tampered F-SC's. In the same animals, the organization of the afferent projects to the brainstem will be assessed by transganglionic transport of HRP from the regeneration nerves. The experiments will determine if afferents that have regenerated to the incorrect local targets in the periphery can sprout into appropriate central target or it the central projects remain unchanged. Finding the first result brainstem nuclei would remain subject to inappropriate inputs.

DESCRIPTION (Adapted from Applicant's Abstract): Neurotrophins play an essential role in the production, survival and maintenance of neurons in peripheral nerve ganglia. However, little is known about the impact of neurotrophins on the actual innervation of the skin where the full range of neuronal phenotypes and target selection are expressed. The wide variety of organized sensory and autonomic endings in the mystacial pad will be used in an assay to test several hypotheses about neurotrophin signaling mechanisms. These hypotheses are based on several important and surprising observations about the impact of null mutations and overexpression of neurotrophins in skin. The PI now plans to determine neurotrophin receptor expressions for each of the developing sets of innervation to the normal mouse and rat mystacial pad. Neurotrophin receptor expression will also be studied in mice with null mutations for neurotrophins and their receptors and in transgenic mice overexpressing neurotrophins in the skin. The impact of NGF and NT-3 overexpression on sensory and sympathetic endings will be assessed. Finally, the role of p75 in mediating the dramatic suppression of terminal arborization mediated by BDNF will be assessed. These studies should enhance our understanding of the role of neurotrophins and their receptors in regulating the development of specific types cutaneous innervation.