The experiments outlined in this proposal focus on the requirements of neurons in the CNS for survival and normal functioning, both during development and following brain injury in adults. One general hypothesis to be tested is that the trophic requirements of developing and mature neurons are similiar. We will continue our investigations of the nature and specificity of trophic interactions in the visual system of developing rats, using both explant culture and intracranial transplantation methods, and begin the search for the specific molecules that underly these interactions. Included in these experiments is a test of the possibility that the same trophic agents are produced in different regions of the developing neocortex, but the timing of their production differs so that the survival of specific subcortical neurons is supported at the appropriate time. We will also follow up on recent results showing a survival-promoting effect of neocortical transplants in adult rats by testing the specificity and mechanisms of this effect (including a test for the operation of the same specific trophic molecules that support developing neurons). Another general hypothesis to be tested relates to a neuron's requirement for a particular pattern of synaptic connections, one in which afferent and target contacts are balanced to fulfill an intrinsic requirement for normal functioning. We propose that cells make adjustments in their connectivity during development in order to achieve this balance. Preliminary studies on locus coeruleus neurons of mutant mouse tottering and retinal ganglion cells of rats monocularly enucleated at birth are consistent with the occurrence of such synaptic adjustments; these results will be confirmed and extended in order to test this hypothesis more directly.
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