The long term goal of these experiments is to understand the functions of axons projecting from the brain to the retina, or retinopetal axons. During the last grant period, axons originating from neurons in the hypothalamus and containing histamine were identified in rat and monkey retinas. To determine the functions of these inputs, exogenous histamine was applied to these retinas in vitro while receding from retinal ganglion cells. One of the most striking effects of histamine was the reduction of the light responses in a subset of ganglion cells in monkeys. The proposed experiments will determine whether these are the parasol cells, which contribute to many aspects of vision, particularly the perception of motion. Histamine receptors (HR) were also localized in these retinas by light and electron microscopy. HR1 were localized to large puncta in the inner plexiform layer, a subset of ganglion cells and retinal blood vessels in monkeys. The cells expressing those receptors will be identified in the proposed anatomical experiments. In rat retinas, HR1 receptors were localized to dopaminergic amacrine cells, and the proposed experiments will test the hypothesis that they are inhibitory. This would greatly amplify the effects of histamine because dopamine influences so many types of neurons in the retina. HR1 were also localized to dendrites of rod bipolar cells, and histamine raised intracellular calcium levels in these cells. The proposed physiological experiments will investigate the underlying mechanism and look for other effects of histamine on rod bipolar cells. There is evidence for HR2 in retinas of both species, and these will be localized in the proposed anatomical experiments. HR3 were found at the apex of ON bipolar cell dendrites in cone pedicles and rod spherules of monkeys, at the first synapse in the pathway detecting increments in light intensity. The proposed physiological experiments will study the effects of histamine on macaque bipolar cells. Taken together, these experiments will provide the first comprehensive description of the mechanism by which axons from the brain act on retinal neurons in mammals and provide insight into their roles in primate vision. The experiments dealing with histamine receptors on macaque retinal blood vessels are particularly important because histamine is known to affect retinal blood flow and capillary permeability. Because retinal blood vessels function abnormally in many eye diseases, the results may also be clinically significant.
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