This program is focused on the role of cellular responses and cell-cell interactions subsequent to neurotoxic insult. Different models will be used to address different questions. Toxicant-induced peripheral neuropathy will be examined to determine how neural cells are injured, how they respond to this insult, and how they recover. One of the important models to be used is the primary demyelination of the PNS caused by tellurium. Demyelination is coincident with a block in cholesterol synthesis, and involves degradation of the blood-nerve barrier. We shall study how this toxicity affects metabolism and gene expression by examining regulation of mRNAs specific for differentiated functions of the Schwann cell (primary demyelination), and whether the alteration in Schwann cell function eventually causes changes related to differentiated functions of neurons (axonopathy). Another major direction is to study the influences of blood-nerve barrier alterations on toxic neuropathies. It is believed that barrier breakdown contributes to the demyelinating process. After determining the extent and mechanism by which inhibition of cholesterol biosynthesis occur, we shall ascertain how damage to the blood-nerve- barrier is related to Schwann cell degeneration and demyelination. The role of non-neural cells in peripheral nerve repair after such injury is another focus. Macrophage-derived apolipoprotein E (ApoE) is hypothesized to be important for scavenging cholesterol from degraded myelin, and for being a source of cholesterol needed for remyelination. Transgenic mice will be prepared in which Schwann cells can be specifically ablated during axonal regeneration following nerve injury, thus determining if Schwann cells are necessary for axon regeneration. Transgenic mice deficient in macrophages or macrophage expression of apoE will help elucidate the role of macrophages in recovery. Such cellular interactions will also be studied in the CNS. Glial cell reactions to neuronal injury will be studied using genetic as well as chemical models. The brindled mouse (used during the past project period as a model of neuronal degeneration) will be used to examine both the spatiotemporal relationship and mechanisms of how neuronal degeneration leads to non-neuronal cell reactions. The finding of microglial activation in well-defined regions where neuronal degeneration occurred has led to the hypothesis that degenerating neurons release some factor(s) which stimulate regional glial cell proliferation and attract migration of glial cells from the adjacent area by chemotaxis. These studies, consistent with the overall theme of the program, are of clear relevance to all central neurotoxicants, and addresses a very important area that has received little systematic study. Finally, the mechanisms involved in toxicant-induced "receptor supersensitivity" of dopamine systems will be examined. The studies will test the general hypothesis that direct receptor changes are less important than changes in intracellular transduction mechanisms or in cellular interactions in target fields. This will be pursued using models with specific types of lesions caused by model cytotoxicants (e.g., 6-OHDA). Using autoradiographic, in situ hybridization, as well as in vitro and in vivo functional studies, various hypotheses concerning the mechanisms responsible for the supersensitivity will be tested.