DEVELOPMENTAL STUDIES OF THE VISUAL SYSTEM

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The rapid retrograde degeneration of neurons in the lateral geniculate nucleus (LGN) following damage to visual cortex in adult mammals precludes subsequent axonal regeneration. In young animals of many species, e.g., cats and primates, LGN neurons also degenerate after damage to the visual cortex but, in contrast to adults, some neurons in the LGN of these species are spared. In cats, these spared LGN neurons establish a new pathway to a major visual cortical area, the lateral suprasylvian visual cortex. This pathway may be involved in the behavioral compensation after cortical damage that is displayed by infant-operated kittens, but not by adults. Recent experimental evidence suggests that certain neurotrophic factors, such as basic fibroblast growth factor (bFGF), ciliary neurotrophic factor (CNTF), and brain-derived neurotrophic factor (BDNF) may, in some circumstances, lessen or prevent the death of neurons that often follows damage to the brain. The specific purpose of the proposed investigation is to determine whether the neurotrophic factors bFGF, CNTF, and BDNF are effective in protecting LGN neurons from the retrograde degeneration that normally occurs after damage to visual cortex. To explore the neuroprotective effectiveness of these three trophic factors, two independent approaches will be taken. In one series of experiments, the factors themselves (proteins) will be injected into the visual cortex for subsequent retrograde transport to the LGN, one to three days prior to making a lesion of visual cortex. In a separate series of experiments, the gene for bFGF, CNTF, or BDNF will be inserted into a replication-deficient, whole-genome, herpes virus (HSV- l) vector. The HSV-1 vector carrying the neurotrophic factor gene of interest then will be injected into visual cortex prior to making a lesion of the cortex. The vector will be transported retrogradely to the LGN, and will allow us to determine whether the production of neurotrophic factors directly by LGN neurons will prevent or mitigate their retrograde degeneration after damage to visual cortex. The long-term goal of the proposed work is to develop an effective therapeutic tool for protecting neurons in the brain from the damaging consequences of trauma, stroke or disease.