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The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs 1 . Retinal cell types may have evolved to accommodate these varied needs, but this has not been systematically studied. Here we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a bird, a reptile, a teleost fish and a lamprey. We found high molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells (RGCs) and Müller glia), with transcriptomic variation across species related to evolutionary distance. Major subclasses were also conserved, whereas variation among cell types within classes or subclasses was more pronounced. However, an integrative analysis revealed that numerous cell types are shared across species, based on conserved gene expression programmes that are likely to trace back to an early ancestral vertebrate. The degree of variation among cell types increased from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified rodent orthologues of midget RGCs, which comprise more than 80% of RGCs in the human retina, subserve high-acuity vision, and were previously believed to be restricted to primates 2 . By contrast, the mouse orthologues have large receptive fields and comprise around 2% of mouse RGCs. Projections of both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but are descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information. Single-cell and single-nucleus transcriptomic analysis of retina from 17 vertebrate species shows high conservation of retinal cell types and suggests that midget retinal ganglion cells in primates evolved from orthologous cells in ancestral mammals.

How does the mammalian retina detect motion? This classic problem in visual neuroscience has remained unsolved for 50 years. In search of clues, here we reconstruct Off-type starburst amacrine cells (SACs) and bipolar cells (BCs) in serial electron microscopic images with help from EyeWire, an online community of ‘citizen neuroscientists’. On the basis of quantitative analyses of contact area and branch depth in the retina, we find evidence that one BC type prefers to wire with a SAC dendrite near the SAC soma, whereas another BC type prefers to wire far from the soma. The near type is known to lag the far type in time of visual response. A mathematical model shows how such ‘space–time wiring specificity’ could endow SAC dendrites with receptive fields that are oriented in space–time and therefore respond selectively to stimuli that move in the outward direction from the soma. Motion detection by the retina is thought to rely largely on the biophysics of starburst amacrine cell dendrites; here machine learning is used with gamified crowdsourcing to draw the wiring diagram involving amacrine and bipolar cells to identify a plausible circuit mechanism for direction selectivity; the model suggests similarities between mammalian and insect vision. The retina's sense of direction Motion detection by the mammalian retina has been thought to rely largely on the intrinsic biophysics of the dendrites of starburst amacrine cells (SACs). Now Sebastian Seung and colleagues have combined new machine-learning techniques with crowd sourcing via the EyeWire brain-mapping game to redraw the wiring diagram for amacrine cells and bipolar cells. Their results show that direction selectivity is established at the presynaptic level — in the spatiotemporal inputs to the amacrine cells — identifying neural circuits rather than intrinsic properties of SACs as the key to direction selectivity. This new model brings the mouse retina closer in certain respects to the Reichardt motion detector characteristic of insect vision.

Key Points Bipolar cells are the only neurons that connect the outer retina to the inner retina. They implement an 'extra' layer of processing that is not typically found in other sensory organs. The different types (typically more than ten) of bipolar cells systematically transform the photoreceptor signal in different ways, most notably, but not exclusively, in terms of chromatic preference, polarity (ON versus OFF) and kinetics (transient versus sustained responses). Bipolar cells first shape their specific response properties at their dendrites through a plethora of mechanisms involving different contact morphologies, receptor types and secondary messenger systems, as well as lateral inputs from horizontal cells. Additional scope for signal modification exists in the axonal terminal system, in which local ionic currents and lateral inputs from amacrine cells contribute to shaping a bipolar cell's final output to its postsynaptic partners. Individual bipolar cells may, in principle, provide differential input to different postsynaptic circuits. Postsynaptic circuits may combine inputs from different types of bipolar cells to inherit different, highly specific signalling properties. Retinal bipolar cells provide the link between photoreceptors and retinal ganglion cells, the output neurons of the eye. In this Review, Euler and colleagues explore the features of retinal bipolar cells and examine how they shape the visual signal. Retinal bipolar cells are the first 'projection neurons' of the vertebrate visual system — all of the information needed for vision is relayed by this intraretinal connection. Each of the at least 13 distinct types of bipolar cells systematically transforms the photoreceptor input in a different way, thereby generating specific channels that encode stimulus properties, such as polarity, contrast, temporal profile and chromatic composition. As a result, bipolar cell output signals represent elementary 'building blocks' from which the microcircuits of the inner retina derive a feature-oriented description of the visual world.

In the mouse retina, three different types of photoreceptors provide input to 14 bipolar cell (BC) types. Classically, most BC types are thought to contact all cones within their dendritic field; ON-BCs would contact cones exclusively via so-called invaginating synapses, while OFF-BCs would form basal synapses. By mining publically available electron microscopy data, we discovered interesting violations of these rules of outer retinal connectivity: ON-BC type X contacted only ~20% of the cones in its dendritic field and made mostly atypical non-invaginating contacts. Types 5T, 5O and 8 also contacted fewer cones than expected. In addition, we found that rod BCs received input from cones, providing anatomical evidence that rod and cone pathways are interconnected in both directions. This suggests that the organization of the outer plexiform layer is more complex than classically thought.

Color, an important visual cue for survival, is encoded by comparing signals from photoreceptors with different spectral sensitivities. The mouse retina expresses a short wavelength-sensitive and a middle/long wavelength-sensitive opsin (S- and M-opsin), forming opposing, overlapping gradients along the dorsal-ventral axis. Here, we analyzed the distribution of all cone types across the entire retina for two commonly used mouse strains. We found, unexpectedly, that ‘true S-cones’ (S-opsin only) are highly concentrated (up to 30% of cones) in ventral retina. Moreover, S-cone bipolar cells (SCBCs) are also skewed towards ventral retina, with wiring patterns matching the distribution of true S-cones. In addition, true S-cones in the ventral retina form clusters, which may augment synaptic input to SCBCs. Such a unique true S-cone and SCBC connecting pattern forms a basis for mouse color vision, likely reflecting evolutionary adaptation to enhance color coding for the upper visual field suitable for mice’s habitat and behavior. Many primates, including humans, can see color better than most other mammals. This difference is due to the variety of light-detecting proteins – called opsins – that are produced in the eye by cells known as cones. While humans have three, mice only have two different opsins, known as S and M, which detect blue/UV and green light, respectively. Mouse cones produce either S-opsins, M-opsins or both. Fewer than 10 percent of cone cells in mice produce just the S-opsin, and these cells are essential for color vision. Mice are commonly used in scientific research, and so their vision has been well studied. However, previous research has produced conflicting results. Some studies report that cone cells that contain only S-opsin are evenly spread out across the retina. Other evidence suggests that color vision in mice exists only for the upper field of their vision, in other words, that mice can only distinguish colors that appeared above them. Nadal-Nicolás et al. set out to understand how to reconcile these contrasting findings. Molecular tools were used to detect S- and M-opsin in the retina of mice and revealed large differences between the lower part, known as the ventral retina, and the upper part, known as the dorsal retina. The ventral retina detects light coming from above the animal, and about a third of cone cells in this region produced exclusively S-opsin, compared to only 1 percent of cones in the dorsal retina. These S-opsin cone cells in the ventral retina group into clusters, where they connect with a special type of nerve cells that transmit this signal. To better understand these findings, Nadal-Nicolás et al. also studied albino mice. Although albino mice have a different distribution of S-opsin protein in the retina, the cone cells producing only S-opsin are similarly clustered in the ventral retina. This suggests that the concentration of S-opsin cone cells in the ventral retina is an important feature in mouse sight. This new finding corrects the misconception that S-opsin-only cone cells are evenly spread throughout the retina and supports the previous evidence that mouse color vision is greatest in the upper part of their field of vision. Nadal-Nicolás et al. suggest this arrangement could help the mice to detect predators that may attack them from above during the daytime. Together, these new findings could help to improve the design of future studies involving vision in mice and potentially other similar species.

Rapid and high local calcium (Ca ) signals are essential for triggering neurotransmitter release from presynaptic terminals. In specialized bipolar ribbon synapses of the retina, these local Ca signals control multiple processes, including the priming, docking, and translocation of vesicles on the ribbon before exocytosis, endocytosis, and the replenishment of release-ready vesicles to the fusion sites for sustained neurotransmission. However, our knowledge about Ca signals along the axis of the ribbon active zone is limited. Here, we used fast confocal quantitative dual-color ratiometric line-scan imaging of a fluorescently labeled ribbon binding peptide and Ca indicators to monitor the spatial and temporal aspects of Ca transients of individual ribbon active zones in zebrafish retinal rod bipolar cells (RBCs). We observed that a Ca transient elicited a much greater fluorescence amplitude when the Ca indicator was conjugated to a ribeye-binding peptide than when using a soluble Ca indicator, and the estimated Ca levels at the ribbon active zone exceeded 26 μM in response to a 10 millisecond stimulus, as measured by a ribbon-bound low-affinity Ca indicator. Our quantitative modeling of Ca diffusion and buffering is consistent with this estimate and provides a detailed view of the spatiotemporal [Ca ] dynamics near the ribbon. Importantly, our data demonstrates that the local Ca levels may vary between ribbons of different RBCs and within the same cells. The variation in local Ca signals is found to correlate with ribbon size and active zone extent. Our serial electron microscopy results provide new information about the heterogeneity in ribbon size, shape, and area of the ribbon in contact with the plasma membrane.

Most inherited retinal dystrophies display progressive photoreceptor cell degeneration leading to severe visual impairment. Optogenetic reactivation of retinal neurons mediated by adeno-associated virus (AAV) gene therapy has the potential to restore vision regardless of patient-specific mutations. The challenge for clinical translatability is to restore a vision as close to natural vision as possible, while using a surgically safe delivery route for the fragile degenerated retina. To preserve the visual processing of the inner retina, we targeted ON bipolar cells, which are still present at late stages of disease. For safe gene delivery, we used a recently engineered AAV variant that can transduce the bipolar cells after injection into the eye's easily accessible vitreous humor. We show that AAV encoding channelrhodopsin under the ON bipolar cell–specific promoter mediates long-term gene delivery restricted to ON-bipolar cells after intravitreal administration. Channelrhodopsin expression in ON bipolar cells leads to restoration of ON and OFF responses at the retinal and cortical levels. Moreover, light-induced locomotory behavior is restored in treated blind mice. Our results support the clinical relevance of a minimally invasive AAV-mediated optogenetic therapy for visual restoration.

Parallel ON and OFF (positive- and negative-contrast) pathways fundamental to vision arise at the complex synapse of cone photoreceptors. Cone pedicles form spatially segregated functionally opposite connections with ON and OFF bipolar cells. Here, we discover that mammalian cones express LRFN2, a cell-adhesion molecule, which localizes to the pedicle base. LRFN2 stabilizes basal contacts between cone pedicles and OFF bipolar cell dendrites to guide pathway-specific partner choices, encompassing multiple cell types. In addition, LRFN2 trans-synaptically organizes glutamate receptor clusters, determining the contrast preferences of the OFF pathway. ON and OFF pathways converge in the inner retina to regulate bipolar cell outputs. We analyze LRFN2’s contributions to ON-OFF interactions, pathway asymmetries, and neural and behavioral responses to approaching predators. Our results reveal that LRFN2 controls the formation of the OFF pathway in vision, supports parallel processing in a single synapse, and shapes contrast coding and the detection of visual threats. LRFN2 in cone photoreceptors is vital for building the OFF pathway. Here authors report this cell-adhesion molecule stabilizes contacts with OFF bipolar cells, clusters their ionotropic receptors, and is required for negative-contrast vision and predator-detection behaviors.

Mature mammalian neurons have a limited ability to extend neurites and make new synaptic connections, but the mechanisms that inhibit such plasticity remain poorly understood. Here, we report that OFF-type retinal bipolar cells in mice are an exception to this rule, as they form new anatomical connections within their tiled dendritic fields well after retinal maturity. The Down syndrome cell-adhesion molecule (Dscam) confines these anatomical rearrangements within the normal tiled fields, as conditional deletion of the gene permits extension of dendrite and axon arbors beyond these borders. Dscam deletion in the mature retina results in expanded dendritic fields and increased cone photoreceptor contacts, demonstrating that DSCAM actively inhibits circuit-level plasticity. Electrophysiological recordings from Dscam−/− OFF bipolar cells showed enlarged visual receptive fields, demonstrating that expanded dendritic territories comprise functional synapses. Our results identify cell-adhesion molecule-mediated inhibition as a regulator of circuit-level neuronal plasticity in the adult retina.

The ON pathway of the visual system, which detects increases in light intensity, is established at the first retinal synapse between photoreceptors and ON-bipolar cells. Photoreceptors hyperpolarize in response to light and reduce the rate of glutamate release, which in turn causes the depolarization of ON-bipolar cells. This ON-bipolar cell response is mediated by the metabotropic glutamate receptor, mGluR6, which controls the activity of a depolarizing current. Despite intensive research over the past two decades, the molecular identity of the channel that generates this depolarizing current has remained elusive. Here, we present evidence indicating that TRPM1 is necessary for the depolarizing light response of ON-bipolar cells, and further that TRPM1 is a component of the channel that generates this light response. Gene expression profiling revealed that TRPM1 is highly enriched in ON-bipolar cells. In situ hybridization experiments confirmed that TRPM1 mRNA is found in cells of the retinal inner nuclear layer, and immunofluorescent confocal microscopy showed that TRPM1 is localized in the dendrites of ON-bipolar cells in both mouse and macaque retina. The electroretinogram (ERG) of TRPM1-deficient (TRPM1⁻/⁻) mice had a normal a-wave, but no b-wave, indicating a loss of bipolar cell response. Finally, whole-cell patch-clamp recording from ON-bipolar cells in mouse retinal slices demonstrated that genetic deletion of TRPM1 abolished chemically simulated light responses from rod bipolar cells and dramatically altered the responses of cone ON-bipolar cells. Identification of TRPM1 as a mGluR6-coupled cation channel reveals a key step in vision, expands the role of the TRP channel family in sensory perception, and presents insights into the evolution of vertebrate vision.