ROLES OF NEUROTROPHINS IN OCULAR DOMINANCE PLASTICITY

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DESCRIPTION (Adapted from applicant's abstract): Neurotrophins (NTs) comprise a family of macromolecules that play a trophic support role in the developing cortex. They are also involved in activity-dependent processes in the adult cortex. In the proposed physiological experiments, we will determine whether NT's play a role in the regulation of ocular dominance plasticity in developing visual cortex. There are basically two possible outcomes of cortically infused NTs on developing binocular interactions: one is the suppression of binocular competition and the other its promotion. The two predictions come from two opposing views on the in vivo cellular action of endogenous NTs in the brain. In model 1, NTs are generally necessary for competing, especially immature, axon terminals to survive (survival factor" in Maffei's proposal). In model 2, NTs have a more specific role as a stabilizer of active synapses and whose release in controlled by afferent activity itself ("specific retrograde messenger" in Thoenen's hypothesis). In the proposed study, 6 physiological experiments are designed to maximally distinguish between the two models. Exp 1: Either nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) will be directly infused into the kitten visual cortex for a week, concurrently with monocular lid suture. Changes in the ocular dominance distribution, in favor of model 1 or 2 or neither, will be compared between different concentrations of the two NTs. Exp 2: Each of the two NTs will be infused as Exp 1, but the eyes will be untouched to study effects of the competition on a natural level. This will allow examination of the direct chemical action of NTs on cortical activity. Exp 3: As a control for Exp 2, NT-infused, otherwise normal kittens will be kept in the dark during the week of the NT infusion. Exp 4: The effects of NT infusion will be studied in relation to an unusual level of binocular interactions between the tetrodotoxin-injected eye and the lid-sutured fellow eye. Exp 5: NTs will be infused into visual cortex of binocularly deprived kittens. The last two preparations are included because the discrimination between the above-mentioned two models is strong or moderated, if the specific effects of NTs are detectable. Exp 6: We will study whether rapid physiological effects of NTs shown in other in vivo systems also work to induce changes in ocular dominance under general anesthesia and paralysis. Exp 7: We will examine the intracortical spread of directly infused BDNF for a week or less. Using the "in vivo dilution curve" thus obtained, we will titrate the lowest-yet-effective concentrations of BDNF for its physiological effects.