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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.

Dendritic and axonal arbors of many neuronal types exhibit self-avoidance, in which branches repel each other. In some cases, these neurites interact with those of neighboring neurons, a phenomenon called self/non-self discrimination. The functional roles of these processes remain unknown. In this study, we used retinal starburst amacrine cells (SACs), critical components of a direction-selective circuit, to address this issue. In SACs, both processes are mediated by the gamma-protocadherins (Pcdhgs), a family of 22 recognition molecules. We manipulated Pcdhg expression in SACs and recorded from them and their targets, direction-selective ganglion cells (DSGCs). SACs form autapses when self-avoidance is disrupted and fail to form connections with other SACs when self/non-self discrimination is perturbed. Pcdhgs are also required to prune connections between closely spaced SACs. These alterations degrade the direction selectivity of DSGCs. Thus, self-avoidance, self/non-self discrimination, and synapse elimination are essential for proper function of a circuit that computes directional motion. Nerve cells (or neurons) connect to one another to form circuits that control the animal's behavior. Typically, each neuron receives signals from other cells via branch-like structures called dendrites. Each specific type of neuron has a characteristic pattern of branched dendrites, which is different from the pattern of other types of neuron. Therefore, it is reasonable to imagine that the shape of these branches can influence how the neuron works; however, this idea has rarely been tested experimentally. Different processes are known to act together to control the pattern of the branched dendrites. For example, dendrites in some neurons avoid other dendrites from the same neuron. This phenomenon is referred to as ‘self-avoidance’. In some of these cases, the same dendrites freely interact with the dendrites of neighboring neurons of the same type; this is called ‘self/non-self discrimination’. It is not clear, however, how these two processes influence the activity of neural circuits. Both self-avoidance and self/non-self discrimination rely on the expression of genes that encode so-called recognition molecules. Kostadinov and Sanes have now altered the expression of these genes in mice to see the effect that disrupting these two phenomena has on a set of neurons called ‘starburst amacrine cells’ that are found at the back the eye. The dendrites of starburst amacrine cells generate signals when objects move across the animal's field of vision. These dendrites then signal to other starburst amacrine cells and to so-called ‘direction-selective ganglion cells’, which in turn send this information to the brain for further processing. The experiments revealed that these disruptions affected the connections between the dendrites. Starburst amacrine cells that lacked self-avoidance mistakenly formed connections with themselves—as if they mistook their own dendrites for those of other starburst cells. In contrast, neurons that lacked self/non-self discrimination made the opposite mistake, and rarely formed connections with each other—as if they mistook the dendrites of other starbursts for their own. Disruptions to either phenomenon interfered with the activity of the direction-selective ganglion cells. Following on from the work of Kostadinov and Sanes, the next challenges include uncovering how the recognition molecules help with self-avoidance and self/non-self discrimination. It will also be important to examine whether the conclusions based on one type of neurons can be generalized to others that also exhibit these two phenomena.

Starburst amacrine cells in the retina detect motion by responding to light going on or off. L. O. Sun et al. ( 10.1126/science.1241974 ) analyzed how the cellular circuits develop in the mouse retina to form the basis of motion detection. Expression patterns of semaphorin 6A and its receptor plexin A2 defined the shape and reactivity of the starburst amacrine cells. Semaphorin 6A expression was restricted to particular cells, generating two classes of starburst amacrine cells with distinct morphologies and opposing functions. Work in mice reveals how motion-detection circuitry is established during visual system development. Direction-selective responses to motion can be to the onset (On) or cessation (Off) of illumination. Here, we show that the transmembrane protein semaphorin 6A and its receptor plexin A2 are critical for achieving radially symmetric arborization of On starburst amacrine cell (SAC) dendrites and normal SAC stratification in the mouse retina. Plexin A2 is expressed in both On and Off SACs; however, semaphorin 6A is expressed in On SACs. Specific On-Off bistratified direction-selective ganglion cells in semaphorin 6A −/− mutants exhibit decreased tuning of On directional motion responses. These results correlate the elaboration of symmetric SAC dendritic morphology and asymmetric responses to motion, shedding light on the development of visual pathways that use the same cell types for divergent outputs.

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.

The proper connectivity between neurons is essential for the implementation of the algorithms used in neural computations, such as the detection of directed motion by the retina. The analysis of neuronal connectivity is possible with electron microscopy, but technological limitations have impeded the acquisition of high-resolution data on a large enough scale. Here we show, using serial block-face electron microscopy and two-photon calcium imaging, that the dendrites of mouse starburst amacrine cells make highly specific synapses with direction-selective ganglion cells depending on the ganglion cell’s preferred direction. Our findings indicate that a structural (wiring) asymmetry contributes to the computation of direction selectivity. The nature of this asymmetry supports some models of direction selectivity and rules out others. It also puts constraints on the developmental mechanisms behind the formation of synaptic connections. Our study demonstrates how otherwise intractable neurobiological questions can be addressed by combining functional imaging with the analysis of neuronal connectivity using large-scale electron microscopy. Untangling neural nets in the visual system Connectivity forms the basis of functional computations performed by neural circuits, but it is notoriously difficult to follow the complex structural wiring between neurons to the function of individual cells. Now, using a combination of functional imaging and three-dimensional serial electron-microscopic reconstruction at an unprecedented scale, two groups present detailed representations of the connectivity of single cells in the mouse visual system. Davi Bock et al . in Clay Reid's lab investigate connectivity in the primary visual cortex, and find that inhibitory neurons receive input from excitatory cells with widely varying functions, consistent with predictions from recent physiological studies of the mouse cortex. Kevin Briggman, Moritz Helmstaedter and Winfried Denk show that direction-selective ganglion cells receive more synapses from a starburst amacrine cell dendrite if their preferred directions are opposites, suggesting that the directional sensitivity of retinal ganglion cells arises from the asymmetry in their wiring with amacrine cells. To date, various aspects of connectivity have been inferred from electron microscopy (EM) of synaptic contacts, light microscopy of axonal and dendritic arbors, and correlations in activity. However, until now it has not been possible to relate the complex structural wiring between neurons to the function of individual cells. Using a combination of functional imaging and three-dimensional serial EM reconstruction at unprecedented scale, two papers now describe the connectivity of single cells in the mouse visual system. This study examines how the selectivity of directionally selective retinal ganglion cells may arise from their asymmetry in the wiring with amacrine cells.

Dopaminergic amacrine cells (DACs) are a subclass of amacrine cells that modulate retinal processing and light adaptation by releasing dopamine. Although the role of dopamine is largely conserved, their retinal distribution across mammals remains incompletely characterized. In mice, rats, thirteen-lined ground squirrels (TLGSs), and macaques, we systematically compared the localization, number, and topography of DACs by their expression of tyrosine hydroxylase (TH), a crucial enzyme in the biosynthesis of dopamine. In all species examined, TH+ cells were primarily located in the inner nuclear layer; however, there was a species-dependent influence on their number and distribution. Mice exhibited the highest density of TH+cells but completely lacked displaced TH+cells (dTH+cells) in the ganglion cell layer. Despite interspecies variation in the total number of TH+cells in the retina, the overall density in rats, TLGSs, and macaques was similar. Most species displayed a higher density of DACs toward central retinal regions. However, rats exhibited a distinctive dorsal concentration, particularly among dTH+cells. Although most species examined exhibited a similar ratio of TH+cells to Brn3a+ retinal ganglion cells, TLGSs showed a marked reduction, indicating a potentially diminished dopaminergic modulatory role. Species-specific DAC topographies aligned with specialized visual regions, such as the visual streak in TLGS and the macula in macaques. These results reveal both conserved and divergent features of retinal dopamine circuitry, reflecting evolutionary adaptations to visual processing demands.

Retinal ischemia-reperfusion (I/R) injury induces oxidative stress, leukocyte infiltration, and neuronal cell death. Sulforaphane (SF), which can be obtained in cruciferous vegetables such as broccoli, exerts protective effects in response to oxidative stress in various tissues. These effects can be initiated through nuclear factor E2-related factor 2 (Nrf2)-mediated induction of heme oxygenase-1 (HO-1). This investigation was designed to elucidate the neural protective mechanisms of SF in the retinal I/R rat model. Animals were intraperitoneally (i.p.) injected with SF (12.5 mg/kg) or vehicle (corn oil) once a day for 7 consecutive days. Then, retinal I/R was made by elevating the intraocular pressure (IOP) to 130 mmHg for 1 h. To determine if HO-1 was involved in the Nrf2 antioxidant pathway, rats were subjected to protoporphyrin IX zinc (II) (ZnPP, 30 mg/kg, i.p.) treatments at 24 h before retinal ischemia. The neuroprotective effects of SF were assessed by determining the morphology of the retina, counting the infiltrating inflammatory cells and the surviving retinal ganglion cells (RGCs) and amacrine cells, and measuring apoptosis in the retinal layers. The expression of Nrf2 and HO-1 was studied by immunofluorescence analysis and western blotting. I/R induced a marked increase of ROS generation, caused pronounced inflammation, increased the apoptosis of RGCs and amacrine cells and caused the thinning of the inner retinal layer (IRL), and these effects were diminished or abolished by SF pretreatment. Meanwhile, SF pretreatment significantly elevated the nuclear accumulation of Nrf2 and the level of HO-1 expression in the I/R retinas; however, ZnPP reversed the protective effects of SF on I/R retinas. Together, we offer direct evidence that SF had protective effects on I/R retinas, which could be attributed, at least in part, to the activation of the Nrf2/HO-1 antioxidant pathway.

Calcium is involved in vision processes in the retina and implicated in various pathologies, including glaucoma. Rod cells rely on store-operated calcium entry (SOCE) to safeguard against the prolonged lowering of intracellular calcium ion concentrations. Zebrafish that lacked the endoplasmic reticulum Ca 2+ sensor Stim2 ( stim2 knockout [KO]) exhibited impaired vision and lower light perception-related gene expression. We sought to understand mechanisms that are responsible for vision impairment in stim2 KO zebrafish. The single-cell RNA (scRNA) sequencing of neuronal cells from brains of 5 days postfertilization larvae distinguished 27 cell clusters, 10 of which exhibited distinct gene expression patterns, including amacrine and γ-aminobutyric acid (GABA)ergic retinal interneurons and GABAergic optic tectum cells. Five clusters exhibited significant changes in cell proportions between stim2 KO and controls, including GABAergic diencephalon and optic tectum cells. Transmission electron microscopy of stim2 KO zebrafish revealed decreases in width of the inner plexiform layer, ganglion cells, and their dendrites numbers (a hallmark of glaucoma). GABAergic neuron densities in the inner nuclear layer, including amacrine cells, as well as photoreceptors significantly decreased in stim2 KO zebrafish. Our study suggests a novel role for Stim2 in the regulation of neuronal insulin expression and GABAergic-dependent vision causing glaucoma-like retinal pathology.

The lamprey, a primitive jawless vertebrate whose ancestors diverged from all other vertebrates over 500 million years ago, offers a unique window into the ancient formation of the retina. Using single-cell RNA-sequencing, we characterize retinal cell types in the lamprey and compare them to those in mouse, chicken, and zebrafish. We find six cell classes and 74 distinct cell types, many shared with other vertebrate species. The conservation of cell types indicates their emergence early in vertebrate evolution, highlighting primordial designs of retinal circuits for the rod pathway, ON-OFF discrimination, and direction selectivity. The diversification of amacrine and some ganglion cell types appears, however, to be distinct in the lamprey. We further infer genetic regulators in specifying retinal cell classes and identify ancestral regulatory elements across species, noting decreased conservation in specifying amacrine cells. Altogether, our characterization of the lamprey retina illuminates the evolutionary origin of visual processing in the retina. Lampreys, an ancient vertebrate lineage, can provide unique insights into early retinal evolution. Using scRNA-seq and computational analysis, this study compared retinal cell types between lamprey and jawed species, illuminating retinal cell origins and diversification.

Retinal circuits detect salient features of the visual world and report them to the brain through spike trains of retinal ganglion cells. The most abundant ganglion cell type in mice, the so-called W3 ganglion cell, selectively responds to movements of small objects. Where and how object motion sensitivity arises in the retina is incompletely understood. In this study, we use 2-photon-guided patch-clamp recordings to characterize responses of vesicular glutamate transporter 3 (VGluT3)-expressing amacrine cells (ACs) to a broad set of visual stimuli. We find that these ACs are object motion sensitive and analyze the synaptic mechanisms underlying this computation. Anatomical circuit reconstructions suggest that VGluT3-expressing ACs form glutamatergic synapses with W3 ganglion cells, and targeted recordings show that the tuning of W3 ganglion cells' excitatory input matches that of VGluT3-expressing ACs' responses. Synaptic excitation of W3 ganglion cells is diminished, and responses to object motion are suppressed in mice lacking VGluT3. Object motion, thus, is first detected by VGluT3-expressing ACs, which provide feature-selective excitatory input to W3 ganglion cells. Animals can use their eyes to detect moving objects, which helps them to avoid predators and other threats, and to spot potential prey or allies. Visual information from the eyes is sent to the brain, which processes the information to form a coherent picture of how the objects are moving. This processing has to be able to account for movements of the head, eyes, and body—which can cause the image of an object on the retina within the eye to move even if the object itself remains stationary. Within the retina, light is converted into electrical signals by cells called rods and cones. A layer of cells called bipolar cells relay these signals to the ‘ganglion’ cells, which in turn pass them on to the brain. In mice, a type of ganglion cell called the W3 ganglion cell has been shown to respond selectively to small moving objects, but exactly how these cells acquire their motion sensitivity remained unclear. Kim et al. now reveal that cells called amacrine cells, which regulate the transfer of signals from the bipolar cells to ganglion cells, supply the information needed for motion detection. The mouse eye contains up to 50 different types of amacrine cells. One of these—called the VG3-amacrine cell—increases its activity whenever an object moves relative to its background, but decreases its activity whenever the object and background move together. The overall effect is that the cells respond selectively to the presence of small moving objects. Most amacrine cells regulate the transfer of signals within the retina by inhibiting the activity of ganglion cells. But, Kim et al. show that VG3-amacrine cells release a molecule called glutamate to activate W3 ganglion cells when a moving object is detected. These unusual and specialized cells are, thus, an essential component of a circuit in the nervous system that supports motion detection. It is possible that some other types of amacrine cells may also play specialized roles in the detection of other features in the visual world.