In the mammalian visual system, neuronal activity exerts a powerful influence on the development of circuits required for normal vision. Specific forms of visual experience during early life, such as monocular deprivation, lead to irrevocable changes in the cortex's ability to process visual information. Several theories for the role of activity in cortical development propose that inputs from the lateral geniculate nucleus (LGN) compete, in an activity-dependent manner, for limiting quantities of some factor present in developing cortex. The overall goal of the proposed research is to determine whether neurotrophins fulfill the criteria necessary for them to be these factors. A fundamental requirement for neurotrophins to function in this context is that their release be regulated by neuronal activity. In the first series of experiments, sensitive bioassays will be combined with a new method for extracting neurotrophins from slices to address this issue. The next series of experiments will determine whether local augmentation or depletion of specific neurotrophins rescues or replicates the effects of monocular shifts in ocular dominance, and the preservation of orientation selectivity. To assess these effects, a new method for local delivery of neurotrophins, based on neurotrophin-coated latex microspheres, will be combined with the final group of experiments, a combination of short-term cultures of brain slices, particle-mediated gene transfer, and manipulations of neurotrophin levels will be used to assess the interactions between neurotrophins and neuronal activity in modifying dendritic arbors in layer 4. Taken together, these experiments should provide critical tests of the role of neurotrophins in cortical development. This in turn could lead to the design of rational therapies for amblyopia and other disorders involving congenital or trauma-induced failures in growth of cortical circuits.
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