Cone Inputs Research Articles

Segregation of short-wavelength sensitive (“blue”) cone signals among neurons in the lateral geniculate nucleus and striate cortex of marmosets

We measured functional input from short-wavelength selective (S) cones to neurons in the dorsal lateral geniculate nucleus (LGN) and striate cortex (area V1) in anaesthetized marmosets. We found that most magnocellular (MC) and parvocellular (PC) cells receive very little (<5%) functional input from S cones, whereas blue-on cells of the koniocellular (KC) pathway receive dominant input from S cones. Cells dominated by S cone input were not encountered in V1, but V1 cells received more S cone input than PC or MC cells. This suggests that S cone inputs are distributed broadly among neurons in V1. No differences in strength of S cone inputs were seen on comparing dichromatic and trichromatic marmosets, suggesting that the addition of a medium-long wavelength selective cone-opponent (“red–green”) channel to a dichromatic visual system does not detectably affect the chromatic properties of the S cone pathways.

Neural models and physiological reality

Neural models of retinal processing provide an important tool for analyzing retinal signals and their functional significance. However, it is here argued that in biological reality, retinal connectivity is unlikely to be as specific as ideal neural models might suggest. The retina is thought to provide functionally specific signals, but this specificity is unlikely to be anatomically complete. This is illustrated by examples of cone connectivity to macaque ganglion cells. For example, cells of the magnocellular pathway appear to avoid short-wavelength cone input, so that such input is negligible under normal conditions. However, there is anatomical, physiological, and psychophysical evidence that under special conditions, weak input may be revealed. Second, ideal models of how retinal information is centrally utilized have to take into account the biological reality of retinal signals. The stochastic nature of impulse trains modifies signal-to-noise ratio in unexpected ways. Also, non-linearities in cell responses make, for example, multiplexing of luminance and chromatic signals in the parvocellular pathway impracticable. The purpose of this analysis is to show than ideal neural models must confront an often more complex and nuanced physiological reality.

Physiology, morphology and spatial densities of identified ganglion cell types in primate retina.

The use of in vitro preparations of primate retina provides new perspectives on the mosaic organization and physiological properties of three ganglion cell types that project to the lateral geniculate nucleus: the parasol, midget and small bistratified cells. Dendritic field sizes and coverage for the three types suggest that their relative densities vary with eccentricity. Of the total ganglion cells in the human fovea, midget cells constitute about 90%, parasol cells about 5%, and small bistratified cells about 1%. In the periphery, midget cells make up about 40-45%, parasol cells about 20% and small bistratified cells about 10% of the total. Thus from peripheral to central retina the number of midget ganglion cells progressively increases relative to the parasol and small bistratified types. Physiological properties of these cells have recently been studied in macaque (Macaca nemestrina) retina by combining intracellular recording and dye injection. As expected, parasol cells, projecting to geniculate magnocellular layers, give phasic, non-opponent light responses. Midget cells, which project to geniculate parvocellular layers, show opponent responses sensitive to only mid and long wavelengths; no evidence of short-wavelength-sensitive cone (S-cone) input to any midget ganglion cell has been found. However, the small bistratified cells, which also project to the parvocellular geniculate layers, give a strong blue-ON response to stimuli designed to modulate S-cones. Thus, S-cone and medium- or long-wavelength-sensitive cone opponent signals arise from morphologically distinct ganglion cell types that project in parallel to the lateral geniculate nucleus.

Responses of Suprachiasmatic Nucleus Neurons to Light and Dark Adaptation: Relative Contributions of Melanopsin and Rod–Cone Inputs

The circadian oscillator in the suprachiasmatic nucleus (SCN) is entrained to the environmental light/dark cycle through photic information conveyed from the retina. The vast majority of projections to the SCN arise from melanopsin-expressing ganglion cells that are intrinsically light sensitive and that receive inputs from both rods and cones. To investigate the relative contributions of the different photoreceptive systems in shaping the photic signal influencing the circadian clock, we analyzed neuronal responses of single SCN neurons using extracellular electrophysiological recordings under different conditions of light adaptation. In the majority of neurons (78%), the spike rate is increased by light stimulation whereas the remainder are light-inhibited. The neuronal response to light is composed of several components distinguished by their temporal dynamics and degree of alteration after previous light exposure. SCN neurons display a sustained response to light followed by persistence of the response after light offset. These responses are sluggish and relatively unaffected by previous light exposures. Neurons also respond with a brisk, excitatory ON response and often an OFF response that is either excitatory or inhibitory. ON-OFF responses are transient and strongly reduced by previous bright white light exposure. Furthermore, two types of neuronal response patterns can be distinguished by the presence or absence of a slow-transient component that follows the transient ON response. The transient ON-OFF components express light adaptation properties characteristic of retinal channels involving cones, whereas the sustained and persistent components are consistent with in vitro response properties reported for melanopsin-expressing ganglion cells.

Intrinsically Photosensitive Retinal Ganglion Cells

The recent discovery of melanopsin-expressing retinal ganglion cells that mediate the pupil light reflex has provided new insights into how the pupil responds to different properties of light. These ganglion cells are unique in their ability to transduce light into electrical energy. There are parallels between the electrophysiologic behavior of these cells in primates and the clinical pupil response to chromatic stimuli. Under photopic conditions, a red light stimulus produces a pupil constriction mediated predominantly by cone input via trans-synaptic activation of melanopsin-expressing retinal ganglion cells, whereas a blue light stimulus at high intensity produces a steady-state pupil constriction mediated primarily by direct intrinsic photoactivation of the melanopsin-expressing ganglion cells. Preliminary data in humans suggest that under photopic conditions, cones primarily drive the transient phase of the pupil light reflex, whereas intrinsic activation of the melanopsin-expressing ganglion cells contributes heavily to sustained pupil constriction. The use of chromatic light stimuli to elicit transient and sustained pupil light reflexes may become a clinical pupil test that allows differentiation between disorders affecting photoreceptors and those affecting retinal ganglion cells.

Interaction between rod and cone inputs in mixed‐input bipolar cells in goldfish retina

One class of goldfish bipolar cells, the mixed-input bipolar cell, contacts both rods and cones. Although the morphology of the different mixed-input bipolar cell subtypes has been described, insight into the interaction between rods and cones at the bipolar cell level is scarce. The aim of this study was to characterize this interaction in the different physiological types of mixed-input bipolar cells. We found mixed-input bipolar cells that depolarized, hyperpolarized, or showed a combination of the two types of response after center stimulation. The relative contributions of rod and cone inputs varied strongly in these cell populations. Depolarizing mixed-input bipolar cells are rod-dominated, having the highest sensitivity and the smallest dynamic range. Hyperpolarizing mixed-input bipolar cells, on the other hand, have a more balanced rod-cone input ratio. This extends their dynamic range and decreases their sensitivity. Finally, opponent mixed-input bipolar cells seem to be mostly cone-dominated, although some rod input is present. The antagonistic photoreceptor inputs form a push-pull system that makes these mixed-input bipolar cells very sensitive to changes in light intensity. Our finding that spectral tuning changes with light intensity conflicts with the idea that the separate non-opponent and opponent channels are related to coding of brightness and color, respectively. The organization of mixed-input bipolar cells into various classes with different dynamic ranges and absolute sensitivities might be a strategy to transmit information about all visual aspects most efficiently, given the sustained nature of bipolar cell responses and their limited voltage range.

Cone Inputs to Simple and Complex Cells in V1 of Awake Macaque

Rules by which V1 neurons combine signals originating in the cone photoreceptors are poorly understood. We measured cone inputs to V1 neurons in awake, fixating monkeys with white-noise analysis techniques that reveal properties of light responses not revealed by purely linear models used in previous studies. Simple cells were studied by spike-triggered averaging that is robust to static nonlinearities in spike generation. This analysis revealed, among heterogeneously tuned neurons, two relatively discrete categories: one with opponent L- and M-cone weights and another with nonopponent cone weights. Complex cells were studied by spike-triggered covariance, which identifies features in the stimulus sequence that trigger spikes in neurons with receptive fields containing multiple linear subunits that combine nonlinearly. All complex cells responded to nonopponent stimulus modulations. Although some complex cells responded to cone-opponent stimulus modulations too, none exhibited the pure opponent sensitivity observed in many simple cells. These results extend the findings on distinctions between simple and complex cell chromatic tuning observed in previous studies in anesthetized monkeys.

Vesicular Glutamate Transport at a Central Synapse Limits the Acuity of Visual Perception in Zebrafish

The neural circuitry that constrains visual acuity in the CNS has not been experimentally identified. We show here that zebrafish blumenkohl (blu) mutants are impaired in resolving rapid movements and fine spatial detail. The blu gene encodes a vesicular glutamate transporter expressed by retinal ganglion cells. Mutant retinotectal synapses release less glutamate, per vesicle and per terminal, and fatigue more quickly than wild-type in response to high-frequency stimulation. In addition, mutant axons arborize more extensively, thus increasing the number of synaptic terminals and effectively normalizing the combined input to postsynaptic cells in the tectum. This presumably homeostatic response results in larger receptive fields of tectal cells and a degradation of the retinotopic map. As predicted, mutants have a selective deficit in the capture of small prey objects, a behavior dependent on the tectum. Our studies successfully link the disruption of a synaptic protein to complex changes in neural circuitry and behavior.

Theory of chromatic noise masking applied to testing linearity of S-cone detection mechanisms

A method for testing the linearity of cone combination of chromatic detection mechanisms is applied to S-cone detection. This approach uses the concept of mechanism noise, the noise as seen by a postreceptoral neural mechanism, to represent the effects of superposing chromatic noise components in elevating thresholds and leads to a parameter-free prediction for a linear mechanism. The method also provides a test for the presence of multiple linear detectors and off-axis looking. No evidence for multiple linear mechanisms was found when using either S-cone increment or decrement tests. The results for both S-cone test polarities demonstrate that these mechanisms combine their cone inputs nonlinearly.

Dopaminergic modulation and rod contribution in the generation of oscillatory potentials in the tiger salamander retina

The roles of rod and cone input and of dopamine in the generation of oscillatory potentials were studied in tiger salamander retina. Under scotopic conditions, oscillations were elicited with a green, but not a red stimulus. With mesopic background illumination, both stimuli caused oscillations. Addition of quinpirole to a mesopic retina eliminated oscillations while SKF-38393 had no effect. Similarly, addition of sulpiride to a light-adapted retina elicited oscillatory activity, but SCH 22390 had no effect. These results suggest that oscillatory potentials are elicited through activation of the rod pathway and are modulated by dopamine through D2-receptors.

Rod and cone input to horizontal cells in the rabbit retina

In the rabbit retina, there are two types of horizontal cell (HC). The A-type HC is axonless and extensively coupled. The B-type HC is axon bearing; the somatic dendrites are radially symmetric and form a second coupled network, while the axon branches expansively to form a complex terminal structure. The B-type axon terminals (ATs) are independently coupled to form a third network in the outer plexiform layer. We have modified our dye-injection methods to obtain detailed fills of the three different horizontal cell networks for analysis via confocal microscopy. We have confirmed that A-type HCs and the somatic dendrites of B-type HCs receive input exclusively from cones, whereas the B-type ATs receive input only from rods. A single B-type AT may receive input from as many as 1,000 rods, but, surprisingly, our data reveal only one end terminal per rod spherule. The somatic dendrites of A- and B-type HCs form clusters at each cone pedicle coincident with GluR2/3 and GluR4 glutamate receptor subunits. The B-type ATs have GluR2/3- or GluR4-labeled glutamate receptors in two locations: small puncta on the end terminals within the rod spherule invagination and large clusters on the terminal stalks, approximately 1.5 microm from the rod synaptic ribbon. We conclude that AMPA receptors of the same or similar composition mediate photoreceptor input to all types of HCs.

Specificity of M and L Cone Inputs to Receptive Fields in the Parvocellular Pathway: Random Wiring with Functional Bias

Many of the parvocellular pathway (PC) cells in primates show red-green spectral selectivity (cone opponency), but PC ganglion cells in the retina show no anatomical signs of cone selectivity. Here we asked whether responses of PC cells are compatible with "random wiring" of cone inputs. We measured long-wavelength-sensitive (L) and medium-wavelength-sensitive (M) cone inputs to PC receptive fields in the dorsal lateral geniculate of marmosets, using discrete stimuli (apertures and annuli) to achieve functional segregation of center and surround. Receptive fields between the fovea and 30 degrees eccentricity were measured. We show that, in opponent PC cells, the center is dominated by one (L or M) cone type, with normally <20% contribution from the other cone type (high "cone purity"), whereas non-opponent cells have mixed L and M cone inputs to the receptive field center. Furthermore, opponent response strength depends on the overall segregation of L and M cone inputs to center and surround rather than exclusive input from one cone type to either region. These data are consistent with random wiring. The majority of PC cells in both foveal (<8 degrees) and peripheral retina nevertheless show opponent responses. This arises because cone purity in the receptive field surround is at least as high as in the center, and the surround in nearly all opponent PC cells is dominated by the opposite cone type to that which dominates the center. These functional biases increase the proportion of opponent PC cells, but their anatomical basis is unclear.

Spatial and Temporal Properties of Cone Signals in Alert Macaque Primary Visual Cortex

Neurons in the lateral geniculate nucleus cannot perform the spatial color calculations necessary for color contrast and color constancy. Under neutral-adapting conditions, we mapped the cone inputs (L, M, and S) to 83 cone-opponent cells representing the central visual field of the next stage of visual processing, primary visual cortex (V1), to determine how the color signals are spatially transformed. Cone-opponent cells, constituting approximately 10% of V1 cells, formed two populations, red-green (L vs M; 66 of 83) and blue-yellow (S vs L+M; 17 of 83). Many cone-opponent cells (48 of 83) were double-opponent, with circular receptive-field centers and crescent-shaped surrounds (0.63 degree offset) that had opposite chromatic tuning to the centers and a time-to-peak 11 ms later than the centers. The remaining cone-opponent cells were either spatially opponent in only one cone system (20 of 83) or lacked spatial opponency (15 of 83). Cells lacking spatial opponency had smaller receptive fields (0.5-0.7 degrees) than spatial-opponent cell centers (approximately 1 degree). We found that red-green cells received S-cone input, which aligned with M input, and, unlike blue-yellow cells, red-green cells gave push-pull responses: receptive-field centers of red-ON cells were excited by both L increments (bright red) and M decrements (dark red) and were suppressed by both L decrements (dark green) and M increments (bright green). Excitatory responses to decrements were slightly larger than to increments, which may account for the lower detection and discrimination thresholds of decrements shown psychophysically. By virtue of their specialized receptive fields, the neurons described here spatially transform the cone signals and represent the first stage in the visual system at which spatially opponent color calculations are made.

Synaptic Plasticity inCNGA3−/−Mice: Cone Bipolar Cells React on the Missing Cone Input and Form Ectopic Synapses with Rods

In the mammalian retina, rods and cones connect to distinct sets of bipolar cells. Rods are presynaptic to a single type of rod bipolar cell, whereas cones connect to different types of cone bipolar cells. Synaptic rewiring between cone photoreceptor terminals and rod bipolar cell dendrites has been described as a general result of photoreceptor degeneration. To investigate whether cone bipolar cells also show synaptic plasticity in the absence of cone input, we studied the connectivity of cone bipolar cell dendrites in CNGA3(-/-) mice, a model with specific loss of cone photoreceptor function. Dendritic connections of ON and OFF cone bipolar cells were visualized using specific cell markers or by intracellular injection with fluorescent dyes. The results show that cone bipolar cells in CNGA3(-/-) mice form ectopic synapses with rods. In contrast, cone bipolar cells do not form ectopic synapses with rods in CNGA3(-/-)Rho(-/-) mice, in which both types of photoreceptors are nonfunctional. In analogy with these results, we found that input-deprived rod bipolar cells form ectopic synapses with functional cones in Rho(-/-) mice but not with inoperable cones in the CNGA3(-/-)Rho(-/-) mouse. Our data indicate that the formation of ectopic bipolar cell synapses in the outer plexiform layer requires a functional presynaptic photoreceptor.

Response of carp (Cyprinus carpio) horizontal cells to heterochromatic flicker photometry

The objective of the present work was to determine the interaction of cone inputs in the response of horizontal cells using heterochromatic flicker photometry (HFP). Intracellular electrophysiological recordings were made in horizontal cells of isolated retinae of carp maintained in physiological solution, with the receptor side up. Sharp glass microelectrodes filled with 3 M KCl solution with resistances between 100 and 120 M Omega were used. Stimuli comprised six cycles of two 6-Hz sinusoidal light waves in counterphase adjusted for the same number of quanta: a green light (550 nm) from a monochromator with a Xenon lamp and an LED red light (628 nm). The stimulation program consisted of 10 steps with the 550-nm wave at constant amplitude, while the 628-nm wave varied in increments of 10% up to 100%, followed by another 10 steps with the 628-nm wave at constant amplitude while the 550-nm wave varied in increments of 10% up to 100%. We recorded responses from four different horizontal cell classes: H1 (monophasic, broadband, n = 37), H2 (biphasic, red-green color-opponent, n = 13), and H3 (biphasic, blue-yellow color-opponent, n = 2) cone horizontal cells; and RH (monophasic, broadband, n = 3) rod horizontal cells. H1 and RH horizontal cells showed a similar cancellation point at a heterochromatic mixture consistent with mixed inputs from 630- and 550-nm cones. No cancellation point was found for the H2 cell class. Fish H1 cells add cone inputs and signal "luminance" in light levels appropriate for cone stimulation. The same occurs with RH cells, which also signal "luminance," but in light levels appropriate for rod work. For both cell classes there is an HFP cancellation point occurring at a combination of 628-nm and 550-nm lights in opposing phase that leads to the cancellation of the cell's response. No cancellation was found for H2 and H3 cells, which are the chromatically opponent horizontal cells in lower vertebrates.

Do magnocellular and parvocellular ganglion cells avoid short-wavelength cone input?

We recently developed a new technique to measure cone inputs to visual neurons and used this technique to seek short-wavelength-sensitive (S) cone inputs to parasol, magnocellular (MC) and midget, parvocellular (PC) ganglion cells. Here, we compare our physiological measurements of S-cone weights to those predicted by a random wiring model that assumes cells' receptive fields receive input from mixed cone types. The random wiring model predicts the average weights of S-cone input to be similar to the total percentage of S-cones but with considerable scatter, and the S-cone input polarity to be consistent with that of PC cells' surround and of MC cells' center. This is not consistent with our physiological measurements. We suggest that the ganglion cells' receptive fields may have a mechanism to avoid S-cone inputs, as is the case in the H1 horizontal cells. Previous reports of S-cone inputs, in particular substantial input to MC cells, are likely to reflect variation in prereceptoral filtering and/or the failure to correct for variation in macular pigment.

Immunohistochemical Evidence of a Melanopsin Cone in Human Retina

Melanopsin, expressed in a subset of intrinsically photosensitive ganglion cells that project to the suprachiasmatic nucleus (SCN), is involved in the photic entrainment of circadian rhythms and other non-image-forming functions (pupil light reflex, masking, acute heart rate response, and alertness). Melanopsin has recently been shown to be a "bireactive" photopigment that functions as a photosensory opsin using 11-cis retinaldehyde as a chromophore and has intrinsic photoisomerase activity. Melanopsin is widely distributed in the retina of vertebrates and, depending on the species, is expressed in ganglion, amacrine, horizontal, and photoreceptor cells. The present study was conducted to determine the distribution of this opsin in the human retina. Human donor eyes were obtained from donors and fixed shortly after death. Immunohistochemistry was used to determine melanopsin expression in the retinas of three donors. The possible coexpression of this photopigment with other opsins was studied by double-labeling immunocytochemistry and confocal analysis. In addition to the expected labeling in ganglion cells of the inner retinal layers, an unexpected finding showed melanopsin-immunopositive label in the outer segments of cones that did not coexpress other known opsins. These melanopsin-expressing cones are extremely sparse (5-25 cones/mm2; 0.1%-0.5% of the entire cone population) and are located in the peripheral retina. The presence of melanopsin in human cones suggests image and non-image-forming roles in visual responses at both the cone input and ganglion cell output stages and their involvement in a broad spectrum of irradiance detection functions in the visual system.

Specificity of Cone Connections in the Retina and Color Vision.Focus on “Specificity of Cone Inputs to Macaque Retinal Ganglion Cells”

The function of a neuron is usually understood to be a consequence of the pattern of its synaptic inputs. The well-studied retinal ganglion cells in the monkey's retina are examples of this principle. Many of the retinal ganglion cells in the monkey's retina will give different signed responses to

Specificity of Cone Inputs to Macaque Retinal Ganglion Cells

The specificity of cone inputs to ganglion cells has implications for the development of retinal connections and the nature of information transmitted to higher areas of the brain. We introduce a rapid and precise method for measuring signs and magnitudes of cone inputs to visual neurons. Colors of stimuli are modulated around circumferences of three color planes in clockwise and counterclockwise directions. For each neuron, the projection of the preferred vector in each plane was estimated by averaging the response phases to clockwise and counterclockwise modulation. The signs and weights of cone inputs were derived directly from the preferred vectors. The efficiency of the method enables us to measure cone inputs at different temporal frequencies and short-wavelength-sensitive (S) cone adaptation levels. The results show that S-cone inputs to the parvocellular and magnocellular ganglion cells are negligible, which implies underlying connectional specificity in the retinal circuitry.

Cone and rod inputs to murine retinal ganglion cells: Evidence of cone opsin specific channels

To identify ultraviolet (UV) and middle- (M) wavelength-sensitive cone and rod signals in murine retinal ganglion cells, single ganglion cell responses were studied in anesthetized, light-adapted C57/BL6 mice with tungsten microelectrodes driven through the sclera and vitreous to the neural retina. One hundred fifty-four ganglion cells were examined in 43 retinas of 34 mice. The retina was stimulated with diffuse flashes and/or pulses of ultraviolet (360 nm) or green (520 nm) light in the presence and absence of a strong steady orange adapting light. Twelve ganglion cells were studied in the dark-adapted retina in order to identify the signals of rods. Three functionally different types of ganglion cells were found: (1) phasic responding cells (31%) with no spontaneous activity and large impulse amplitudes; (2) tonic responding cells (60%) with irregular, low frequency (5-10 Hz) spontaneous activity and smaller impulse amplitudes; and (3) metronome-like cells (9%) with regular, relatively high-frequency (20-40 Hz) spontaneous activity. A few cells (1%) had habituating responses. Every cell encountered was affected by diffuse stimulation. The more common two types were excited at either the ON or OFF or at both the ON and OFF phases of stimulation. Type III cells had weaker responses, sometimes only inhibited by turning off a light. In the light-adapted state, most cells received signals of the same polarity from UV- and M-cones but UV-cone inputs were usually more dominant, especially in ventral retina. A fraction of cells received signals from only UV- (18%) or only M- (3%) cones. In rare cases (2%) these cone inputs had an opposite polarity on the same cell. In the dark-adapted state, all cells were at least four or five logarithmic units more sensitive and more to green than ultraviolet light. The results indicate that co-expression of both UV-and M-cone opsins cannot be ubiquitous in murine retina. Some cones, especially UV cones, exist without the presence of any functional M-cone opsin. This must be the case to explain the presence of ganglion cells that receive inputs only from UV-cones and others that receive inputs of opposite polarity from UV- and M-cones. The results support the hypothesis that murine retina has the physiological capacity to relay signals to the brain that allow the sensing of chromatic contrast and color vision.