The goals of this project are to determine the factors that regulate the differentiation neurons comprising the mammalian limbic system and to define the molecular mechanisms that mediate the formation of functional neural circuits during development. Our laboratory is most interested in gaining a basic understanding of these mechanisms in those parts of the mammalian central nervous system that mediate emotional behavior, memory and learning. We will characterize the role of cell surface proteins in the formation of connections, focusing prinicipally on the limbic system associated membrane protein (LAMP), 64,000 dalton glycoprotein isolated in our laboratory that is expressed early in development and may in part regulate the formation of limbic system connections. We propose 3 sets of experiments that will examine different aspects of the development of this system: 1) The role of LAMP and macromolecules carrying the HNK-1 carbohydrate epitope in the regulation of process differentiation and the innervation of targets by limbin neurons will continue to be evaluation in both roller tube explant and monolayer culture systems. 2) LAMP expression will be used as a marker in cortical transplant studies to evaluate the intrinsic and extrinsic factors that may mediate the commitment and differentiation of neurons destined for specific limbic cortical areas. 3) Molecular characterization of LAMP will continue by analyzing metabolic changes in LAMP during axonal growth and by purifying substantial amounts of LAMP to generate new mono- and polyclonal antibodies and in a collaborrative effort, deduce partial sequence information. In a second collaborative arrangement, we will perform expression library screening to isolate and clone the LAMP gene for subsequent sequence analysis and in situ localization of neurons expressing the LAMP gene. These basic developmental studies employ a variety of technical approaches, both anatomical and molecular, to address basic issues of neural circuit formation. Our long-term goal is to utilize this information to determine how developmental defects may result in specific behavioral abnormalities, and ultimately how these may be corrected.
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