This application proposes neurophysiological and neuroanatomical studies to elucidate the mechanisms by which patterns of neural activity guide the development and plasticity of the mammalian visual cortex. Our previous research has shown that spontaneous neural activity in the visual system is required for the development of ocular dominance columns in the primary visual cortex, an event that begins in utero in man and higher primates. These findings suggest that abnormalities in the spontaneous patterns of neural activity may be a hitherto unsuspected cause of birth defects. Our most recent work has demonstrated that some forms of amblyopia, a visual disorder affecting nearly 2% of American children, take place in primates without plasticity of the anatomical ocular dominance columns; while anatomical plasticity of the geniculocortical afferents in response to altered activity can be is remarkably rapid during a critical period in development. In addition to providing insight into the mechanisms of cortical plasticity in development, the studies proposed should aid in the provision of a rational basis to the therapy for amblyopia. The major goal of the proposed studies is to reveal the mechanisms underlying the plasticity of geniculocortical afferents and the formation of ocular dominance columns in cat visual cortex. These afferents lose nearly half of their arbor in as little as 6 days of occlusion of vision in one eye during the critical period. We will first determine the shortest period of monocular occlusion necessary for such anatomical plasticity, and we will relate the new findings, using Phaseolus lectin to reconstruct the arbors of individual geniculocortical afferents, to the findings with bulk labeling of the entire geniculocortical afferent projection serving one eye. We will then investigate the afferent plasticity that underlies the recovery of vision produced by reverse monocular occlusion following brief initial deprivation, and the failure of this recovery when the reverse occlusion follows more prolonged initial deprivation. We will complete our ongoing investigation of the anatomical basis for the reverse plasticity of ocular dominance when cortical cells are pharmacologically inhibited, and will investigate the changes in arbors of the geniculocortical afferents that accompany this plasticity. We will examine the distribution of molecules associated with synaptic function on identified geniculocortical afferent arbors in order to discover the earliest steps in the plasticity of this system. We will finally carry out a series of combined physiological/biochemical studies to evaluate the role of several candidate mediators of synaptic plasticity in the developing ocular dominance columns of the visual cortex, including nitric oxide, carbon monoxide, calcium calmodulin kinase, and metabotropic glutamate receptors.
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