The midget ganglion cell and its specialized circuitry in the macular retina are unique to the human and non-human primate visual system and give rise to the primary pathway that initiates the perception of form and color. Loss of cone photoreceptors or ganglion cells in the macula due to degenerative disease is a major cause of vision loss. Despite this fundamental importance in the visual process and as a primary target for the treatment of retinal disease the underlying synaptic mechanisms and circuits that mediate the complex physiological properties of the midget pathway remain poorly understood. Our proposed research plan is to specifically advance understanding of both the synaptic mechanisms and the complete `wiring diagram' that underlie the spatial and color-coding properties of the midget circuit of the macaque monkey as an ideal model for its human counterpart. During the previous budget period we developed methods to characterize the synaptic physiology of the midget ganglion cell. Our preliminary studies provide evidence for several new and unexpected properties of the midget circuit. We have found, surprisingly, that NMDA type glutamate receptors mediate the major fraction of light-evoked excitatory synaptic conductance in midget ganglion cells.
In Aim 1 we therefore propose to determine the role of postsynaptic NMDARs in midget L vs. M cone opponency and achromatic contrast sensitivity. In addition, we have identified a controversial S-cone input to OFF midget ganglion cells and in Aim 2 we will utilize a highly sensitive color-circle stimulus to determine the underlying synaptic mechanisms and role in color-coding for this distinctive circuit. We have also discovered an unexpected high sensitivity rod pathway input to midget ganglion cells and in Aim 3 we propose to determine the synaptic pathways that comprise the midget rod circuit. We will directly test the hypothesis that the primary rod bipolar-AII amacrine pathway mediates the transmission of high sensitivity rod signals to midget ganglion cells and will determine the relative contribution of primary and secondary (rod-cone gap junctions) rod pathways to the midget circuit across the full scotopic range of illuminance. Finally, we have now successfully applied Serial Block-face Electron Microscopy (SBEM) to advance understanding of the foveal connectome and propose to test key hypotheses concerning the foveal midget wiring diagram. First, we will combine physiological identification of L and M cones with reconstruction of midget bipolar cells and directly test the hypothesis that L vs M cone midget circuits can be distinguished morphologically and synaptically. Second, we will directly test the hypothesis that the OFF midget bipolar provides the exclusive OFF pathway for the S cone connectome. Finally, we will make the first reconstruction and identification of narrow field foveal amacrine cell types linked to the midget circuit and test the hypothesis that two distinct narrow field types, the AII cell an the knotty 2 cell, mediate glycinergic inhibition in the foveal midget circuit. These projects will advance knowledge of synaptic mechanisms as well as the `connectome' of the unique and dominant circuit in the primate fovea.

Public Health Relevance

The human macula, a small region near the center of the retina that includes the fovea, is critical for our perception of form and color and it is the regin that is devastated by the blinding degenerative diseases. The proposed project will significantly advance knowledge of the `wiring diagram' and the function of the major visual pathway, the midget circuit, that mediates visual processing of form and color in the fovea and will contribute to the overall goal of restoring vision loss due to macular disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Greenwell, Thomas
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University of Washington
Anatomy/Cell Biology
Schools of Medicine
United States
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Wool, Lauren E; Crook, Joanna D; Troy, John B et al. (2018) Nonselective Wiring Accounts for Red-Green Opponency in Midget Ganglion Cells of the Primate Retina. J Neurosci 38:1520-1540
Liao, Hsi-Wen; Ren, Xiaozhi; Peterson, Beth B et al. (2016) Melanopsin-expressing ganglion cells on macaque and human retinas form two morphologically distinct populations. J Comp Neurol 524:2845-72
Hannibal, J; Kankipati, L; Strang, C E et al. (2014) Central projections of intrinsically photosensitive retinal ganglion cells in the macaque monkey. J Comp Neurol 522:2231-48
Dacey, Dennis M; Crook, Joanna D; Packer, Orin S (2014) Distinct synaptic mechanisms create parallel S-ON and S-OFF color opponent pathways in the primate retina. Vis Neurosci 31:139-51
Joo, Hannah R; Peterson, Beth B; Dacey, Dennis M et al. (2013) Recurrent axon collaterals of intrinsically photosensitive retinal ganglion cells. Vis Neurosci 30:175-82
Schmidt, Tiffany M; Do, Michael Tri H; Dacey, Dennis et al. (2011) Melanopsin-positive intrinsically photosensitive retinal ganglion cells: from form to function. J Neurosci 31:16094-101
Joo, Hannah R; Peterson, Beth B; Haun, Toni J et al. (2011) Characterization of a novel large-field cone bipolar cell type in the primate retina: evidence for selective cone connections. Vis Neurosci 28:29-37
Crook, Joanna D; Manookin, Michael B; Packer, Orin S et al. (2011) Horizontal cell feedback without cone type-selective inhibition mediates ""red-green"" color opponency in midget ganglion cells of the primate retina. J Neurosci 31:1762-72
Packer, Orin S; Verweij, Jan; Li, Peter H et al. (2010) Blue-yellow opponency in primate S cone photoreceptors. J Neurosci 30:568-72
Crook, Joanna D; Davenport, Christopher M; Peterson, Beth B et al. (2009) Parallel ON and OFF cone bipolar inputs establish spatially coextensive receptive field structure of blue-yellow ganglion cells in primate retina. J Neurosci 29:8372-87

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