This proposal is for studies on normal myelinated and pathological (demyelinated and remyelinated, dysmyelinated) axons. Recent evidence indicates that, in normal myelinated fibers, the nodal membrane exhibits different properties from the internodal axon membrane. This differentiation is especially important in the context of the demyelinating and dysmyelinating diseases, and in some peripheral neuropathies, because in these disorders current may be shunted through non-myelinated (previously internodal) axolemma. Conduction properties may also be changed following remyelination, since nodal spacing is altered so that nodes of Ranvier are formed at previous internodal sites. Our studies indicate that it is possible to cytochemically mark normal nodal membrane. We now plan to use our cytochemical techniques, and morphometric methods, to study normal and pathological myelinated axons, with particular emphasis on the question of structural-functional alterations in the axolemma of de- and remyelinated fibers. In particular, we plan to study the following inter-related problems: What is the temporal relation of differentiation of the nodal axolemma to myelinogenesis; does the specialization of the nodal membrane precede, coincide with, or follow myelination? What are the properties of the axolemma in de- and remyelinated fibers; does the axolemma exhibit any structural alterations following chronic demyelination; how is the formation of new nodes during remyelination related to the differentiation of the original nodes? What are the properties of the dysmyelinated axolemma, and what is the response of the dysmyelinated axon to subsequent demyelination? What are the morphological correlates, in terms of axon membrane structure and myelin morphometrics, of metabolic neuropathies? In what ways is the extracelllar nodal gap substance altered in various axonal pathologies?