STRUCTURAL BASIS OF AMBLYOPIA

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Amblyopia causes visual loss in 2% of the American population, despite improved standards for detection and treatment. The broad objective of this proposal is to elucidate the structural basis of amblyopia in humans. Little direct information is available about the pathological changes induced by amblyopia in human visual cortex, in part because most of the invasive experimental techniques developed for animal studies cannot be used in humans. The cytochrome oxidase (CO) method of Wong-Riley has the special advantage that it is suitable for mapping patterns of metabolic activity in human autopsy tissues. In this proposal, CO histochemistry will be applied to specimens of visual cortex obtained post-mortem from patients with a history of early visual loss. The specific aim is to define the timing and duration of the critical period for the plasticity of ocular dominance columns, by examining cases involving loss of visual function (or actual loss of one eye, e.g., retinoblastoma, trauma) at various ages during childhood. In addition, the patterns of CO activity in striate cortex associated with different forms of amblyopia will be tested by examining specimens from patients with well-documented histories of early unilateral cataract, strabismus, or anisometropia. CO will also be used to determine if patches are present in human newborns. To interpret the CO data from human tissues, and to further explore the structural and physiological alterations in visual cortex responsible for amblyopia, a series of correlative experiments will be performed in macaque monkeys. The specific aims are: 1) To determine whether a gradient exists across the cortical representation of the visual field, from fovea to periphery, in the susceptibility of ocular dominance columns to shrinkage induced by visual deprivation. This will be achieved by reconstructing the entire mosaic of ocular dominance columns, labelled with CO histochemistry and proline autoradiography, in monkeys deprived at different ages by unilateral eyelid suture. 2) To determine whether ocular dominance columns in macaques are segregated at birth. This will be achieved by intraocular injection of [3H]-proline in monkeys delivered by Caesarean section 1 week before the end of normal gestation. 3) To characterize the receptive field properties and ocular dominance of cells within the foveal representation of amblyopic monkeys. This will be achieved by using quantitative electrophysiological recording techniques. 4) To determine whether visual deprivation reduces thalamic input to CO patches in V1 serving the amblyopic eye. This will be achieved by making large injections of [3H]-proline into the thalamus of visually deprived monkeys to label the patches in V1. 5) To determine whether visual deprivation causes a selective loss of projections from V1 -> V2 which serve the deprived eye. This will be achieved by injecting horseradish peroxidase into V2, and correlating the position of retrogradely labelled cells in V1 with the ocular dominance columns labelled by CO histochemistry.