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The authors demonstrate that the short wavelength–Off (S-Off) responses in the mammalian retina are mediated not by a distinct S-Off bipolar cell, but by an inhibitory amacrine cell that resides in the circuit between the S-On bipolar cell and the S-Off ganglion cell. The dynamic range of visual coding is extended by having separate ganglion cell types that respond to light increments and decrements. Although the primordial color vision system in mammals contains a well-characterized ganglion cell that responds to blue light increments (a blue On center cell), less is known about ganglion cells that respond to blue light decrements (blue Off center cells). We identified a regular mosaic of blue Off center ganglion cells in the ground squirrel. Contrary to the standard scheme, blue Off responses came from a blue On bipolar and inverting amacrine cell.

Fixational eye movements alter the number and timing of spikes transmitted from the retina to the brain, but whether these changes enhance or degrade the retinal signal is unclear. To quantify this, we developed a Bayesian method for reconstructing natural images from the recorded spikes of hundreds of retinal ganglion cells (RGCs) in the macaque retina (male), combining a likelihood model for RGC light responses with the natural image prior implicitly embedded in an artificial neural network optimized for denoising. The method matched or surpassed the performance of previous reconstruction algorithms, and provides an interpretable framework for characterizing the retinal signal. Reconstructions were improved with artificial stimulus jitter that emulated fixational eye movements, even when the eye movement trajectory was assumed to be unknown and had to be inferred from retinal spikes. Reconstructions were degraded by small artificial perturbations of spike times, revealing more precise temporal encoding than suggested by previous studies. Finally, reconstructions were substantially degraded when derived from a model that ignored cell-to-cell interactions, indicating the importance of stimulus-evoked correlations. Thus, fixational eye movements enhance the precision of the retinal representation. The visual signals transmitted by the retina to the brain are affected by random drift in eye position, but the impact of this on visual capabilities is not clear. Here, the authors show that the decoding of images from evoked spike trains recorded in the macaque retina improves with fixational eye movements, even when the eye position is unknown.

At least 20 distinct retinal ganglion cell (RGC) types have been identified morphologically in the primate retina, but our understanding of the distinctive visual messages they send to various targets in the brain remains limited, particularly for naturalistic stimuli. Here, we use large-scale multi-electrode recordings to examine how multiple functionally distinct RGC types in the macaque retina respond to flashed natural images. Responses to white noise visual stimulation were used to functionally identify 936 RGCs of 12 types in three recordings. Each cell type was confirmed by the mosaic organization of receptive fields, and seven cell types were cross-identified between recordings. Responses to thousands of natural images were used to examine the average firing rate kinetics in each RGC type as well as the repertoire of distinct firing patterns that each type produced. The average response across images was highly stereotyped for cells of each type and distinct for cells of different types. The responses to natural images more clearly distinguished certain cell types than did the response to white noise stimulation. Moreover, the full repertoires of firing patterns produced by different cell types, assessed by their latency and duration, were largely distinct in most cases and in some cases non-overlapping. Together these data provide an overview of the diversity of RGC signals transmitted from the primate retina to the brain in natural viewing conditions.

To understand a neural circuit requires knowledge of its connectivity. Here we report measurements of functional connectivity between the input and ouput layers of the macaque retina at single-cell resolution and the implications of these for colour vision. Multi-electrode technology was used to record simultaneously from complete populations of the retinal ganglion cell types (midget, parasol and small bistratified) that transmit high-resolution visual signals to the brain. Fine-grained visual stimulation was used to identify the location, type and strength of the functional input of each cone photoreceptor to each ganglion cell. The populations of ON and OFF midget and parasol cells each sampled the complete population of long- and middle-wavelength-sensitive cones. However, only OFF midget cells frequently received strong input from short-wavelength-sensitive cones. ON and OFF midget cells showed a small non-random tendency to selectively sample from either long- or middle-wavelength-sensitive cones to a degree not explained by clumping in the cone mosaic. These measurements reveal computations in a neural circuit at the elementary resolution of individual neurons. Photoreceptor networks mapped Colour vision arises in the retina, and in primates the first stage of processing consists of overlapping lattices of cone cells and ganglion cells, each of which samples visual space uniformly. Colour perception arises from the comparison of signals from different cone types, but how these inputs are combined by the ganglion cells, which transmit the output of the retina, has been an issue of contention over the years. Using large-scale multi-electrode arrays and fine-grained visual stimulation, Field et al . have now mapped out the location and type of single-cone inputs to entire populations of ganglion cells, resulting in input–output maps at an unprecedented resolution and scale. Colour perception arises from the comparison of signals from different cone types, but how these inputs are combined by ganglion cells, which transmit the output of the retina, has been an issue of contention. Using large-scale multi-electrode arrays and fine-grained visual stimulation, these authors map out the locations and types of single-cone inputs to entire populations of ganglion cells, resulting in input–output maps at an unprecedented resolution and scale.

The visual message conveyed by a retinal ganglion cell (RGC) is often summarized by its spatial receptive field, but in principle also depends on the responses of other RGCs and natural image statistics. This possibility was explored by linear reconstruction of natural images from responses of the four numerically-dominant macaque RGC types. Reconstructions were highly consistent across retinas. The optimal reconstruction filter for each RGC – its visual message – reflected natural image statistics, and resembled the receptive field only when nearby, same-type cells were included. ON and OFF cells conveyed largely independent, complementary representations, and parasol and midget cells conveyed distinct features. Correlated activity and nonlinearities had statistically significant but minor effects on reconstruction. Simulated reconstructions, using linear-nonlinear cascade models of RGC light responses that incorporated measured spatial properties and nonlinearities, produced similar results. Spatiotemporal reconstructions exhibited similar spatial properties, suggesting that the results are relevant for natural vision. Vision begins in the retina, the layer of tissue that lines the back of the eye. Light-sensitive cells called rods and cones absorb incoming light and convert it into electrical signals. They pass these signals to neurons called retinal ganglion cells (RGCs), which convert them into electrical signals called spikes. Spikes from RGCs then travel along the optic nerve to the brain. They are the only source of visual information that the brain receives. From this information, the brain constructs our entire visual world. The primate retina contains roughly 20 types of RGCs. Each encodes a different visual feature, such as the presence of bright spots of a certain size, or information about texture and movement. But exactly what input each RGC sends to the brain, and how the brain uses this information, is unclear. Brackbill et al. set out to answer these questions by measuring and analyzing the electrical activity in isolated retinas from macaque monkeys. Studying the macaque retina was important because the primate visual system differs from that of other species in several ways. These include the numbers and types of RGCs present in the retina. These primates are also similar to humans in their high-resolution central vision and trichromatic color vision. Using electrode arrays to monitor hundreds of RGCs at the same time, Brackbill et al. recorded the responses of macaque retinas to real-life images of landscapes, objects, animals or people. Based on these recordings, plus existing knowledge about RGC responses, Brackbill et al. then attempted to reconstruct the original images using just the electrical activity recorded. The resulting reconstructions were similar across all retinas tested. Moreover, they showed a striking resemblance to the original images. These results made it possible to comprehend how the light-response properties of each cell represent visual information that can be used by the brain. Understanding how macaque retinas work in natural conditions is critical to decoding how our own retinas process and convey information. A better knowledge of how the brain uses this input to generate images could ultimately make it possible to design artificial retinas to restore vision in patients with certain forms of blindness.

Responses of sensory neurons are often modeled using a weighted combination of rectified linear subunits. Since these subunits often cannot be measured directly, a flexible method is needed to infer their properties from the responses of downstream neurons. We present a method for maximum likelihood estimation of subunits by soft-clustering spike-triggered stimuli, and demonstrate its effectiveness in visual neurons. For parasol retinal ganglion cells in macaque retina, estimated subunits partitioned the receptive field into compact regions, likely representing aggregated bipolar cell inputs. Joint clustering revealed shared subunits between neighboring cells, producing a parsimonious population model. Closed-loop validation, using stimuli lying in the null space of the linear receptive field, revealed stronger nonlinearities in OFF cells than ON cells. Responses to natural images, jittered to emulate fixational eye movements, were accurately predicted by the subunit model. Finally, the generality of the approach was demonstrated in macaque V1 neurons.

Neural implants have the potential to restore lost sensory function by electrically evoking the complex naturalistic activity patterns of neural populations. However, it can be difficult to predict and control evoked neural responses to simultaneous multi-electrode stimulation due to nonlinearity of the responses. We present a solution to this problem and demonstrate its utility in the context of a bidirectional retinal implant for restoring vision. A dynamically optimized stimulation approach encodes incoming visual stimuli into a rapid, greedily chosen, temporally dithered and spatially multiplexed sequence of simple stimulation patterns. Stimuli are selected to optimize the reconstruction of the visual stimulus from the evoked responses. Temporal dithering exploits the slow time scales of downstream neural processing, and spatial multiplexing exploits the independence of responses generated by distant electrodes. The approach was evaluated using an experimental laboratory prototype of a retinal implant: large-scale, high-resolution multi-electrode stimulation and recording of macaque and rat retinal ganglion cells ex vivo. The dynamically optimized stimulation approach substantially enhanced performance compared to existing approaches based on static mapping between visual stimulus intensity and current amplitude. The modular framework enabled parallel extensions to naturalistic viewing conditions, incorporation of perceptual similarity measures, and efficient implementation for an implantable device. A direct closed-loop test of the approach supported its potential use in vision restoration.

The function of a neural circuit is shaped by the computations performed by its interneurons, which in many cases are not easily accessible to experimental investigation. Here, we elucidate the transformation of visual signals flowing from the input to the output of the primate retina, using a combination of large-scale multi-electrode recordings from an identified ganglion cell type, visual stimulation targeted at individual cone photoreceptors, and a hierarchical computational model. The results reveal nonlinear subunits in the circuity of OFF midget ganglion cells, which subserve high-resolution vision. The model explains light responses to a variety of stimuli more accurately than a linear model, including stimuli targeted to cones within and across subunits. The recovered model components are consistent with known anatomical organization of midget bipolar interneurons. These results reveal the spatial structure of linear and nonlinear encoding, at the resolution of single cells and at the scale of complete circuits. Light that enters the eye begins the process of vision by activating two types of photoreceptors: rods, which support vision under low light levels, and cones, which are responsible for fine detail and color vision. Activation of either type of photoreceptor triggers responses in bipolar cells, which activate the ganglion cells that transmit visual signals to the brain. Bipolar cells therefore belong to a class of cells called interneurons, which relay information from certain cell types to others. Interneurons play an important role in information processing throughout the brain, but directly accessing them or characterizing their role in neural computation is often difficult. To address this problem, Freeman, Field et al. have developed a combined computational and experimental approach to describe the flow of sensory signals through the circuits within the retina of primates. Large arrays of electrodes were used to record the responses of many retinal ganglion cells in response to the activation or de-activation of pairs of cones. These experiments revealed that the responses of ganglion cells are not simply the sum of the inputs that they receive from cones; specifically, the activation of one cone is not cancelled by the deactivation of another. Instead, the data suggest that bipolar cells add cone inputs together and then pass on the total activation (but not deactivation) to ganglion cells. By analyzing the responses of ganglion cells to numerous random patterns of cone activation, Freeman, Field et al. were able to estimate the locations and arrangements of bipolar cells that connect to them. These predicted patterns of connectivity agreed with observations from anatomical studies. This work provides detailed insights into how the primate retina works. It also suggests that similar approaches may be used to characterize how signals flow across other brain networks in which large-scale recordings are now possible.

In the visual system, large ensembles of neurons collectively sample visual space with receptive fields (RFs). A puzzling problem is how neural ensembles provide a uniform, high-resolution visual representation in spite of irregularities in the RFs of individual cells. This problem was approached by simultaneously mapping the RFs of hundreds of primate retinal ganglion cells. As observed in previous studies, RFs exhibited irregular shapes that deviated from standard Gaussian models. Surprisingly, these irregularities were coordinated at a fine spatial scale: RFs interlocked with their neighbors, filling in gaps and avoiding large variations in overlap. RF shapes were coordinated with high spatial precision: the observed uniformity was degraded by angular perturbations as small as 15 degrees, and the observed populations sampled visual space with more than 50% of the theoretical ideal uniformity. These results show that the primate retina encodes light with an exquisitely coordinated array of RF shapes, illustrating a higher degree of functional precision in the neural circuitry than previously appreciated.

It has been thought that blue-yellow color opponent cells in the primate retina receive little input from rods. Here, the authors report that rod and cone signals are multiplexed in blue-yellow cells and that this may be the source of the blue hue bias in night vision. Small bistratified cells (SBCs) in the primate retina carry a major blue-yellow opponent signal to the brain. We found that SBCs also carry signals from rod photoreceptors, with the same sign as S cone input. SBCs exhibited robust responses under low scotopic conditions. Physiological and anatomical experiments indicated that this rod input arose from the AII amacrine cell–mediated rod pathway. Rod and cone signals were both present in SBCs at mesopic light levels. These findings have three implications. First, more retinal circuits may multiplex rod and cone signals than were previously thought to, efficiently exploiting the limited number of optic nerve fibers. Second, signals from AII amacrine cells may diverge to most or all of the ∼20 retinal ganglion cell types in the peripheral primate retina. Third, rod input to SBCs may be the substrate for behavioral biases toward perception of blue at mesopic light levels.