Nearsightedness (myopia) is a global health problem of staggering proportions that has driven the... more Nearsightedness (myopia) is a global health problem of staggering proportions that has driven the hunt for environmental and genetic risk factors in hopes of gaining insight into the underlying mechanism and providing new avenues of intervention. Myopia is the dominant risk factor for leading causes of blindness, including myopic maculopathy and retinal detachment. The fundamental defect in myopia—an excessively elongated eyeball—causes blurry distance vision that is correctable with lenses or surgery, but the risk of blindness remains. Haplotypes of the long-wavelength and middle-wavelength cone opsin genes (OPN1LW and OPN1MW, respectively) that exhibit profound exon-3 skipping during pre-messenger RNA splicing are associated with high myopia. Cone photoreceptors expressing these haplotypes are nearly devoid of photopigment. Conversely, cones in the same retina that express non-skipping haplotypes are relatively full of photopigment. We hypothesized that abnormal contrast signals a...
X-linked incomplete achromatopsia (XIA), also called blue-cone monochromacy (BCM), is a rare cone... more X-linked incomplete achromatopsia (XIA), also called blue-cone monochromacy (BCM), is a rare cone disorder that most commonly results either from one of two conditions.. The first condition is a deletion of the locus control region (LCR) which is a critical DNA element that lies upstream of the L and M photopigment gene array on the X-chromosome and is necessary for expression of the photopigment genes. The second condition is an inactivating point mutation within the coding sequence of the remaining photopigment gene in an array from which all but one gene has been deleted. Many previous studies have concluded that affected individuals either have only rods and S-cones (Blackwell & Blackwell, 1957, 1961; Daw & Enoch, 1973; Hess et al., 1989) or have rods, S-cones, and another cone type that contains the rod pigment (Pokorny et al., 1970; Alpern et al., 1971). However, Smith et al. (1983) described individuals with XIA who had residual L-cone function. Here we report results for a s...
Light absorption by photopigment molecules expressed in the photoreceptors in the retina is the f... more Light absorption by photopigment molecules expressed in the photoreceptors in the retina is the first step in seeing. Two types of photoreceptors in the human retina are responsible for image formation: rods, and cones. Except at very low light levels when rods are active, all vision is based on cones. Cones mediate high acuity vision and color vision. Furthermore, they are critically important in the visual feedback mechanism that regulates refractive development of the eye during childhood. The human retina contains a mosaic of three cone types, short-wavelength (S), long-wavelength (L), and middle-wavelength (M) sensitive; however, the vast majority (~94%) are L and M cones. The OPN1LW and OPN1MW genes, located on the X-chromosome at Xq28, encode the protein component of the light-sensitive photopigments expressed in the L and M cones. Diverse haplotypes of exon 3 of the OPN1LW and OPN1MW genes arose thru unequal recombination mechanisms that have intermixed the genes. A subset o...
Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) synchronize o... more Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) synchronize our biological clocks with the external light/dark cycle [1]. In addition to photoentrainment, they mediate the effects of light experience as a central modulator of mood, learning, and health [2]. This makes a complete account of the circuity responsible for ipRGCs' light responses essential to understanding their diverse roles in our well-being. Considerable progress has been made in understanding ipRGCs' melanopsin-mediated responses in rodents [3-5]. However, in primates, ipRGCs also have a rare blue-OFF response mediated by an unknown short-wavelength-sensitive (S)-cone circuit [6]. Identifying this S-cone circuit is particularly important because ipRGCs mediate many of the wide-ranging effects of short-wavelength light on human biology. These effects are often attributed to melanopsin, but there is evidence for an S-cone contribution as well [7, 8]. Here, we tested the hypothesis that the S-OFF response is mediated by the S-ON pathway through inhibitory input from an undiscovered S-cone amacrine cell. Using serial electron microscopy in the macaque retina, we reconstructed the neurons and synapses of the S-cone connectome, revealing a novel inhibitory interneuron, an amacrine cell, receiving excitatory glutamatergic input exclusively from S-ON bipolar cells. This S-cone amacrine cell makes highly selective inhibitory synapses onto ipRGCs, resulting in a blue-OFF response. Identification of the S-cone amacrine cell provides the missing component of an evolutionarily ancient circuit using spectral information for non-image forming visual functions.
Midget retinal ganglion cells (RGCs) are the most common RGC type in the primate retina. Their re... more Midget retinal ganglion cells (RGCs) are the most common RGC type in the primate retina. Their responses mediate both color and spatial vision, yet the specific links between midget RGC responses and visual perception are unclear. Previous research on the dual roles of midget RGCs has focused on those comparing long (L) vs. middle (M) wavelength sensitive cones. However, there is evidence for several other rare midget RGC subtypes receiving S-cone input, but their role in color and spatial vision is uncertain. Here, we confirm the existence of the single S-cone center OFF midget RGC circuit in the central retina of macaque monkey both structurally and functionally, by combining single cell electrophysiology with 3D electron microscopy reconstructions of the upstream circuitry. Like the well-studied L vs. M midget RGCs, the S-OFF midget RGCs have a center-surround receptive field consistent with a role in spatial vision. While spectral opponency in a primate RGC is classically assume...
Nearsightedness (myopia) is a global health problem of staggering proportions that has driven the... more Nearsightedness (myopia) is a global health problem of staggering proportions that has driven the hunt for environmental and genetic risk factors in hopes of gaining insight into the underlying mechanism and providing new avenues of intervention. Myopia is the dominant risk factor for leading causes of blindness, including myopic maculopathy and retinal detachment. The fundamental defect in myopia—an excessively elongated eyeball—causes blurry distance vision that is correctable with lenses or surgery, but the risk of blindness remains. Haplotypes of the long-wavelength and middle-wavelength cone opsin genes (OPN1LW and OPN1MW, respectively) that exhibit profound exon-3 skipping during pre-messenger RNA splicing are associated with high myopia. Cone photoreceptors expressing these haplotypes are nearly devoid of photopigment. Conversely, cones in the same retina that express non-skipping haplotypes are relatively full of photopigment. We hypothesized that abnormal contrast signals a...
X-linked incomplete achromatopsia (XIA), also called blue-cone monochromacy (BCM), is a rare cone... more X-linked incomplete achromatopsia (XIA), also called blue-cone monochromacy (BCM), is a rare cone disorder that most commonly results either from one of two conditions.. The first condition is a deletion of the locus control region (LCR) which is a critical DNA element that lies upstream of the L and M photopigment gene array on the X-chromosome and is necessary for expression of the photopigment genes. The second condition is an inactivating point mutation within the coding sequence of the remaining photopigment gene in an array from which all but one gene has been deleted. Many previous studies have concluded that affected individuals either have only rods and S-cones (Blackwell & Blackwell, 1957, 1961; Daw & Enoch, 1973; Hess et al., 1989) or have rods, S-cones, and another cone type that contains the rod pigment (Pokorny et al., 1970; Alpern et al., 1971). However, Smith et al. (1983) described individuals with XIA who had residual L-cone function. Here we report results for a s...
Light absorption by photopigment molecules expressed in the photoreceptors in the retina is the f... more Light absorption by photopigment molecules expressed in the photoreceptors in the retina is the first step in seeing. Two types of photoreceptors in the human retina are responsible for image formation: rods, and cones. Except at very low light levels when rods are active, all vision is based on cones. Cones mediate high acuity vision and color vision. Furthermore, they are critically important in the visual feedback mechanism that regulates refractive development of the eye during childhood. The human retina contains a mosaic of three cone types, short-wavelength (S), long-wavelength (L), and middle-wavelength (M) sensitive; however, the vast majority (~94%) are L and M cones. The OPN1LW and OPN1MW genes, located on the X-chromosome at Xq28, encode the protein component of the light-sensitive photopigments expressed in the L and M cones. Diverse haplotypes of exon 3 of the OPN1LW and OPN1MW genes arose thru unequal recombination mechanisms that have intermixed the genes. A subset o...
Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) synchronize o... more Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) synchronize our biological clocks with the external light/dark cycle [1]. In addition to photoentrainment, they mediate the effects of light experience as a central modulator of mood, learning, and health [2]. This makes a complete account of the circuity responsible for ipRGCs' light responses essential to understanding their diverse roles in our well-being. Considerable progress has been made in understanding ipRGCs' melanopsin-mediated responses in rodents [3-5]. However, in primates, ipRGCs also have a rare blue-OFF response mediated by an unknown short-wavelength-sensitive (S)-cone circuit [6]. Identifying this S-cone circuit is particularly important because ipRGCs mediate many of the wide-ranging effects of short-wavelength light on human biology. These effects are often attributed to melanopsin, but there is evidence for an S-cone contribution as well [7, 8]. Here, we tested the hypothesis that the S-OFF response is mediated by the S-ON pathway through inhibitory input from an undiscovered S-cone amacrine cell. Using serial electron microscopy in the macaque retina, we reconstructed the neurons and synapses of the S-cone connectome, revealing a novel inhibitory interneuron, an amacrine cell, receiving excitatory glutamatergic input exclusively from S-ON bipolar cells. This S-cone amacrine cell makes highly selective inhibitory synapses onto ipRGCs, resulting in a blue-OFF response. Identification of the S-cone amacrine cell provides the missing component of an evolutionarily ancient circuit using spectral information for non-image forming visual functions.
Midget retinal ganglion cells (RGCs) are the most common RGC type in the primate retina. Their re... more Midget retinal ganglion cells (RGCs) are the most common RGC type in the primate retina. Their responses mediate both color and spatial vision, yet the specific links between midget RGC responses and visual perception are unclear. Previous research on the dual roles of midget RGCs has focused on those comparing long (L) vs. middle (M) wavelength sensitive cones. However, there is evidence for several other rare midget RGC subtypes receiving S-cone input, but their role in color and spatial vision is uncertain. Here, we confirm the existence of the single S-cone center OFF midget RGC circuit in the central retina of macaque monkey both structurally and functionally, by combining single cell electrophysiology with 3D electron microscopy reconstructions of the upstream circuitry. Like the well-studied L vs. M midget RGCs, the S-OFF midget RGCs have a center-surround receptive field consistent with a role in spatial vision. While spectral opponency in a primate RGC is classically assume...
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