Our laboratory has identified a neurotrophic factor active in the geniculocortical pathway of rats in vivo, and the studies described in this proposal will utilize this factor to test directly the validity of the trophic factor hypothesis in the CNS. In particular we will test the idea that a target-derived molecule is important for the survival and differentiation of developing neurons of the dorsal lateral geniculate nucleus (dLGN), as well as the survival of these same neurons after they mature. In addition, an intensive effort is proposed to scale up production of this factor (which is already close to purification) for amino acid sequencing and monoclonal antibody production. This factor is retrieved in vitro from co-cultures of embryonic rat cortex and diencephalon; an important finding concerning its role in vivo is that it is maximally effective in supporting the survival of different sub- population of developing dLGN neurons - separated from their targets by cortical lesions -at distinctly different concentrations. In this proposal we will test in normal rats the role of this factor in maintaining these dLGN neurons during their period of natural cell death, as well as determine if the different neuron sub-populations (defined by their time of origin) also have different concentration requirements for this factor during this normal cell death period. Concentration-specific requirements for this factor in order for adult dLGN neurons to survive axotomy will also be tested in vivo, along with the correlated idea that this concentration specificity may reflect different rates of factor depletion in the different sub-populations after axotomy. Finally another important prediction of the trophic factor hypothesis - that developing neurons require specific trophic factors in order to differentiate - will be tested in vitro by determining the effect of different concentrations of the factor on relationship between the optimal outgrowth-promoting concentration and the optimal survival-promoting concentration for each population will be examined.
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