In the trichromatic primate retina, the "midget" retinal ganglion cell is the classical substrate for red-green color signaling, with a circuitry that enables antagonistic responses between long (L)- ...and medium (M)-wavelength-sensitive cone inputs. Previous physiological studies showed that some OFF midget ganglion cells may receive sparse input from short (S)-wavelength-sensitive cones, but the effect of S-cone inputs on the chromatic tuning properties of such cells has not been explored. Moreover, anatomical evidence for a synaptic pathway from S cones to OFF midget ganglion cells through OFF midget bipolar cells remains ambiguous. In this study, we address both questions for the macaque monkey retina. First, we used serial block-face electron microscopy to show that every S cone in the parafoveal retina synapses principally with a single OFF midget bipolar cell, which in turn forms a private-line connection with an OFF midget ganglion cell. Second, we used patch electrophysiology to characterize the chromatic tuning of OFF midget ganglion cells in the near peripheral retina that receive combined input from L, M, and S cones. These "S-OFF" midget cells have a characteristic S-cone spatial signature, but demonstrate heterogeneous color properties due to the variable strength of L, M, and S cone input across the receptive field. Together, these findings strongly support the hypothesis that the OFF midget pathway is the major conduit for S-OFF signals in primate retina and redefines the pathway as a chromatically complex substrate that encodes color signals beyond the classically recognized L versus M and S versus L+M cardinal mechanisms.
The first step of color processing in the visual pathway of primates occurs when signals from short (S)-, middle (M)-, and long (L)-wavelength-sensitive cone types interact antagonistically within the retinal circuitry to create color-opponent pathways. The midget (L versus M or "red-green") and small bistratified (S vs L+M, or "blue-yellow") ganglion cell pathways appear to provide the physiological origin of the cardinal axes of human color vision. Here we confirm the presence of an additional S-OFF midget circuit in the macaque monkey fovea with scanning block-face electron microscopy and show physiologically that a subpopulation of S-OFF midget cells combine S, L, and M cone inputs along noncardinal directions of color space, expanding the retinal role in color coding.
Despite the centrality of the retinal pigment epithelium (RPE) in vision and retinopathy our picture of RPE morphology is incomplete. With a volumetric reconstruction of human RPE ultrastructure, we ...aim to characterize major membranous features including apical processes and their interactions with photoreceptor outer segments, basolateral infoldings, and the distribution of intracellular organelles.
A parafoveal retinal sample was acquired from a 21-year-old male organ donor. With serial block-face scanning electron microscopy, a tissue volume from the inner-outer segment junction to basal RPE was captured. Surface membranes and complete internal ultrastructure of an individual RPE cell were achieved with a combination of manual and automated segmentation methods.
In one RPE cell, apical processes constitute 69% of the total cell surface area, through a dense network of over 3000 terminal branches. Single processes contact several photoreceptors. Basolateral infoldings facing the choriocapillaris resemble elongated filopodia and comprise 22% of the cell surface area. Membranous tubules and sacs of endoplasmic reticulum represent 20% of the cell body volume. A dense basal layer of mitochondria extends apically to partly overlap electron-dense pigment granules. Pores in the nuclear envelope form a distinct pattern of rows aligned with chromatin.
Specialized membranes at the apical and basal side of the RPE cell body involved in intercellular uptake and transport represent over 90% of the total surface area. Together with the polarized distribution of organelles within the cell body, these findings are relevant for retinal clinical imaging, therapeutic approaches, and disease pathomechanisms.
From mouse to primate, there is a striking discontinuity in our current understanding of the neural coding of motion direction. In non-primate mammals, directionally selective cell types and circuits ...are a signature feature of the retina, situated at the earliest stage of the visual process. In primates, by contrast, direction selectivity is a hallmark of motion processing areas in visual cortex, but has not been found in the retina, despite significant effort. Here we combined functional recordings of light-evoked responses and connectomic reconstruction to identify diverse direction-selective cell types in the macaque monkey retina with distinctive physiological properties and synaptic motifs. This circuitry includes an ON-OFF ganglion cell type, a spiking, ON-OFF polyaxonal amacrine cell and the starburst amacrine cell, all of which show direction selectivity. Moreover, we discovered that macaque starburst cells possess a strong, non-GABAergic, antagonistic surround mediated by input from excitatory bipolar cells that is critical for the generation of radial motion sensitivity in these cells. Our findings open a door to investigation of a precortical circuitry that computes motion direction in the primate visual system.
In primate retina, "red-green" color coding is initiated when signals originating in long (L) and middle (M) wavelength-sensitive cone photoreceptors interact antagonistically. The center-surround ...receptive field of "midget" ganglion cells provides the neural substrate for L versus M cone-opponent interaction, but the underlying circuitry remains unsettled, centering around the longstanding question of whether specialized cone wiring is present. To address this question, we measured the strength, sign, and spatial tuning of L- and M-cone input to midget receptive fields in the peripheral retina of macaque primates of either sex. Consistent with previous work, cone opponency arose when one of the cone types showed a stronger connection to the receptive field center than to the surround. We implemented a difference-of-Gaussians spatial receptive field model, incorporating known biology of the midget circuit, to test whether physiological responses we observed in real cells could be captured entirely by anatomical nonselectivity. When this model sampled nonselectively from a realistic cone mosaic, it accurately reproduced key features of a cone-opponent receptive field structure, and predicted both the variability and strength of cone opponency across the retina. The model introduced here is consistent with abundant anatomical evidence for nonselective wiring, explains both local and global properties of the midget population, and supports a role in their multiplexing of spatial and color information. It provides a neural basis for human chromatic sensitivity across the visual field, as well as the maintenance of normal color vision despite significant variability in the relative number of L and M cones across individuals.
Red-green color vision is a hallmark of the human and nonhuman primate that starts in the retina with the presence of long (L)- and middle (M)-wavelength sensitive cone photoreceptor types. Understanding the underlying retinal mechanism for color opponency has focused on the broad question of whether this characteristic can emerge from nonselective wiring, or whether complex cone-type-specific wiring must be invoked. We provide experimental and modeling support for the hypothesis that nonselective connectivity is sufficient to produce the range of red-green color opponency observed in midget ganglion cells across the retina. Our nonselective model reproduces the diversity of physiological responses of midget cells while also accounting for systematic changes in color sensitivity across the visual field.
The distinctive red-green dimension of human and nonhuman primate color perception arose relatively recently in the primate lineage with the appearance of separate long (L) and middle (M) ...wavelength-sensitive cone photoreceptor types. "Midget" ganglion cells of the retina use center-surround receptive field structure to combine L and M cone signals antagonistically and thereby establish a "red-green, color-opponent" visual pathway. However, the synaptic origin of red-green opponency is unknown, and conflicting evidence for either random or L versus M cone-selective inhibitory circuits has divergent implications for the developmental and evolutionary origins of trichromatic color vision. Here we directly measure the synaptic conductances evoked by selective L or M cone stimulation in the midget ganglion cell dendritic tree and show that L versus M cone opponency arises presynaptic to the midget cell and is transmitted entirely by modulation of an excitatory conductance. L and M cone synaptic inhibition is feedforward and thus occurs in phase with excitation for both cone types. Block of GABAergic and glycinergic receptors does not attenuate or modify L versus M cone antagonism, discounting both presynaptic and postsynaptic inhibition as sources of cone opponency. In sharp contrast, enrichment of retinal pH-buffering capacity, to attenuate negative feedback from horizontal cells that sum L and M cone inputs linearly and without selectivity, completely abolished both the midget cell surround and all chromatic opponency. Thus, red-green opponency appears to arise via outer retinal horizontal cell feedback that is not cone type selective without recourse to any inner retinal L versus M cone inhibitory pathways.
Anatomical and physiological approaches are beginning to reveal the synaptic origins of parallel ON- and OFF-pathway retinal circuits for the transmission of short (S-) wavelength sensitive cone ...signals in the primate retina. Anatomical data suggest that synaptic output from S-cones is largely segregated; central elements of synaptic triads arise almost exclusively from the "blue-cone" bipolar cell, a presumed ON bipolar, whereas triad-associated contacts derive primarily from the "flat" midget bipolar cell, a hyperpolarizing, OFF bipolar. Similarly, horizontal cell connectivity is also segregated, with only the H2 cell-type receiving numerous contacts from S-cones. Negative feedback from long (L-) and middle (M-) wavelength sensitive cones via the H2 horizontal cells elicits an antagonistic surround in S-cones demonstrating that S versus L + M or "blue-yellow" opponency is first established in the S-cone. However, the S-cone output utilizes distinct synaptic mechanisms to create color opponency at the ganglion cell level. The blue-cone bipolar cell is presynaptic to the small bistratified, "blue-ON" ganglion cell. S versus L + M cone opponency arises postsynaptically by converging S-ON and LM-OFF excitatory bipolar inputs to the ganglion cell's bistratified dendritic tree. The common L + M cone surrounds of the parallel S-ON and LM-OFF cone bipolar inputs appear to cancel resulting in "blue-yellow" antagonism without center-surround spatial opponency. By contrast, in midget ganglion cells, opponency arises by the differential weighting of cone inputs to the receptive field center versus surround. In the macula, the "private-line" connection from a midget ganglion cell to a single cone predicts that S versus L + M opponency is transmitted from the S-cone to the S-OFF midget bipolar and ganglion cell. Beyond the macula, OFF-midget ganglion cell dendritic trees enlarge and collect additional input from multiple L and M cones. Thus S-OFF opponency via the midget pathway would be expected to become more complex in the near retinal periphery as L and/or M and S cone inputs sum to the receptive field center. An important goal for further investigation will be to explore the hypothesis that distinct bistratified S-ON versus midget S-OFF retinal circuits are the substrates for human psychophysical detection mechanisms attributed to S-ON versus S-OFF perceptual channels.
The distinctive parasol ganglion cell of the primate retina transmits a transient, spectrally nonopponent signal to the magnocellular layers of the lateral geniculate nucleus. Parasol cells show ...well-recognized parallels with the alpha-Y cell of other mammals, yet two key alpha-Y cell properties, a collateral projection to the superior colliculus and nonlinear spatial summation, have not been clearly established for parasol cells. Here, we show by retrograde photodynamic staining that parasol cells project to the superior colliculus. Photostained dendritic trees formed characteristic spatial mosaics and afforded unequivocal identification of the parasol cells among diverse collicular-projecting cell types. Loose-patch recordings were used to demonstrate for all parasol cells a distinct Y-cell receptive field "signature" marked by a nonlinear mechanism that responded to contrast-reversing gratings at twice the stimulus temporal frequency second Fourier harmonic (F2) independent of stimulus spatial phase. The F2 component showed high contrast gain and temporal sensitivity and appeared to originate from a region coextensive with that of the linear receptive field center. The F2 spatial frequency response peaked well beyond the resolution limit of the linear receptive field center, showing a Gaussian center radius of approximately 15 microm. Blocking inner retinal inhibition elevated the F2 response, suggesting that amacrine circuitry does not generate this nonlinearity. Our data are consistent with a pooled-subunit model of the parasol Y-cell receptive field in which summation from an array of transient, partially rectifying cone bipolar cells accounts for both linear and nonlinear components of the receptive field.
The fovea of the human retina, a specialization for acute and color vision, features a high concentration of cone photoreceptors. A pit on the inner retinal aspect is created by the centrifugal ...migration of post-receptoral neurons. Foveal cells are specified early in fetal life, but the fovea reaches its final configuration postnatally. Pre-term birth retards migration resulting in a small pit, a small avascular zone, and nearly continuous inner retinal layers. To explore the involvement of Müller glia, we used serial-section electron microscopic reconstructions to examine the morphology and neural contacts of Müller glia contacting a single foveal cone in a 28-year-old male organ donor born at 28 weeks of gestation. A small non-descript foveal avascular zone contained massed glial processes that included a novel class of ‘inner’ Müller glia. Similar to classic ‘outer’ Müller glia that span the retina, inner Müller glia have bodies in the inner nuclear layer (INL). These cells are densely packed with intermediate filaments and insert processes between neurons. Unlike ‘outer’ Müller glia, ‘inner’ Müller glia do not reach the external limiting membrane but instead terminate at the outer plexiform layer. One completely reconstructed inner cell ensheathed cone pedicles and a cone-driven circuit of midget bipolar and ganglion cells. Inner Müller glia outnumber foveal cones by 1.8-fold in the outer nuclear layer (221,448 vs. 123,026 cells/mm 2 ). Cell bodies of inner Müller glia outnumber those of outer Müller glia by 1.7-fold in the INL (41,872 vs. 24,631 cells/ mm 2 ). Müller glia account for 95 and 80% of the volume of the foveal floor and Henle fiber layer, respectively. Determining whether inner cells are anomalies solely resulting from retarded lateral migration of inner retinal neurons in pre-term birth requires further research.
The neural coding of human color vision begins in the retina. The outputs of long (L)-, middle (M)-, and short (S)-wavelength-sensitive cone photoreceptors combine antagonistically to produce ..."red-green" and "blue-yellow" spectrally opponent signals (Hering, 1878; Hurvich and Jameson, 1957). Spectral opponency is well established in primate retinal ganglion cells (Reid and Shapley, 1992; Dacey and Lee, 1994; Dacey et al., 1996), but the retinal circuitry creating the opponency remains uncertain. Here we find, from whole-cell recordings of photoreceptors in macaque monkey, that "blue-yellow" opponency is already present in the center-surround receptive fields of S cones. The inward current evoked by blue light derives from phototransduction within the outer segment of the S cone. The outward current evoked by yellow light is caused by feedback from horizontal cells that are driven by surrounding L and M cones. Stimulation of the surround modulates calcium conductance in the center S cone.
How is the trichromatic cone mosaic of Old World primates sampled by retinal circuits to create wavelength opponency? Red-green (L versus M cone) opponency appears to be mediated largely by the ...segregation of L versus M cone signals to the centre versus the surround of the midget ganglion cell receptive field, implying a complex cone type-specific wiring, the basis of which remains mysterious. Blue-yellow (S versus L+M cone) opponency is mediated by a growing family of low-density ganglion types that receive either excitatory or inhibitory input from S cones. Thus, the retinal circuits that underlie colour signalling in primates may be both more complex and more diverse then previously appreciated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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