Although numerous studies have begun to define the role of growth factors on neuron development, survival and communication in the peripheral nervous system, the role of such factors in the central nervous system (CNS) is poorly understood. This is due, in part, to the inaccessibility and complexity of the CNS, particularly in developing animals. We, however, are now in position to examine such developmental regulation in the CNS. We have succeeded in growing brain nuclei in an accessible tissue culture environment for prolonged times and we are able to combine study of these nuclei in vitro with sensitive biochemical and morphological techniques. We propose to use this combination of techniques to examine molecular mechanisms regulating neuron development and the formation of connections in the brain. In particular, we have examined development of the basal forebrain (BF) and hippocampus (HI), two interacting brain systems. These brain regions exhibit specific cholinergic and peptidergic traits, allowing development and interaction to be monitored in detail. In addition, we have found that cholinergic neurons of the BF are regulated by the fully sequenced trophic factor beta-NGF (nerve growth factor). We now propose to delineate the role of this molecule in the formation and maintenance of these interacting brain systems. These studies aim to define molecular regulatory events underlying selective neuronal survival, specific systems formation and genesis of connectivity in the brain. To carry out this work baseline development of neurotransmitter related traits in vivo will first be compared to development of NGF receptors in this system. The BF-HI system will next be examined as it develops in culture and the effects of NGF on this maturing system will be defined. Finally, culture results will be extended to the live animals to examine the role of NGF on development in vivo. We hope to begin identification of the molecular basis for development of neural systems in the brain and to define molecular loci where disease processes may intervene in ontogeny.
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