The goal of this proposal is to define the role of oligodendrocytes, the traditional myelinating cells of the central nervous system, as producers of trophic molecules during development. In this capacity, it is hypothesized that oligodendrocytes produce NGF, BDNF, and NT3, molecules that affect survival and function of oligodendrocytes, as well as local neurons. Local neurons, in turn, regulate oligodendrocyte function. It is suggested that critical autocrine and paracrine interactions may exist to optimize survival and function of oligodendrocytes and related neurons in specific brain regions. This issue will be addressed in oligodendrocyte populations associated with the basal forebrain, a region well-known to be sensitive to neurotrophins. Preliminary studies suggest that this oligodendrocyte population expresses and responds to neurotrophins and is regulated by neural signals. To investigate the role of oligodendrocytes as trophin producers the study will 1) examine the maturation of oligodendrocytes as trophin producers and trophin responders during development in culture, 2) investigate the effects of neurotrophin molecules on oligodendrocyte maturation, 3) define regulation of basal forebrain neurons by oligodendrocytes, 4) define the role of neural signaling on oligodendrocyte development, and 5) determine whether effects in culture are relevant in vivo. These studies are designed to explore the role of oligodendrocyte as providers of the trophic molecules, NGF, BDNF, and NT3. It is proposed that these neurotrophins provide trophic support for oligodendrocytes as well as local neuronal populations. The studies will identify factors that support oligodendrocyte function. As such, they promise to provide new insights into deficits that may occur in demyelinating diseases.
