Explore the vast range of titles available.

In the vertebrate visual system, all output of the retina is carried by retinal ganglion cells. Each type encodes distinct visual features in parallel for transmission to the brain. How many such ‘output channels’ exist and what each encodes are areas of intense debate. In the mouse, anatomical estimates range from 15 to 20 channels, and only a handful are functionally understood. By combining two-photon calcium imaging to obtain dense retinal recordings and unsupervised clustering of the resulting sample of more than 11,000 cells, here we show that the mouse retina harbours substantially more than 30 functional output channels. These include all known and several new ganglion cell types, as verified by genetic and anatomical criteria. Therefore, information channels from the mouse eye to the mouse brain are considerably more diverse than shown thus far by anatomical studies, suggesting an encoding strategy resembling that used in state-of-the-art artificial vision systems. Two-photon calcium imaging reveals that the mouse retina contains more than 30 functionally distinct retinal ganglion cells, including some that have not been described before, exceeding current estimates and suggesting that the functional diversity of retinal ganglion cells may be much larger than previously thought. Multiple retinal ganglion cell types Retinal ganglion cells (RGCs) convey visual information from the retina to the brain. How many types of RGC exist and how they should be classified have been long-standing questions. Thomas Euler and colleagues used two-photon calcium imaging to record responses to stimuli in more than 11,000 cells in a patch of the mouse ganglion cell layer, and applied unsupervised clustering of the resulting data. This revealed that the mouse retina harbours more than 30 distinct functional RGC types, including several that have not been described before. This number substantially exceeds current estimates and indicates that the functional diversity of RGCs is greater than previously thought.

Optogenetics may enable mutation-independent, circuit-specific restoration of neuronal function in neurological diseases. Retinitis pigmentosa is a neurodegenerative eye disease where loss of photoreceptors can lead to complete blindness. In a blind patient, we combined intraocular injection of an adeno-associated viral vector encoding ChrimsonR with light stimulation via engineered goggles. The goggles detect local changes in light intensity and project corresponding light pulses onto the retina in real time to activate optogenetically transduced retinal ganglion cells. The patient perceived, located, counted and touched different objects using the vector-treated eye alone while wearing the goggles. During visual perception, multichannel electroencephalographic recordings revealed object-related activity above the visual cortex. The patient could not visually detect any objects before injection with or without the goggles or after injection without the goggles. This is the first reported case of partial functional recovery in a neurodegenerative disease after optogenetic therapy. Combined intraocular injection of an adeno-associated viral vector, encoding an optogenetic sensor, with light stimulation via engineered goggles enables partial recovery of visual function in a blind patient.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are a subset of cells that participate in image-forming and non–image-forming visual responses. Although both functional and morphological subtypes of ipRGCs have been described in rodents, parallel functional subtypes have not been identified in primate or human retinas. In this study, we used a human organ donor preparation method to measure human ipRGCs’ photoresponses. We discovered three functional ipRGC subtypes with distinct sensitivities and responses to light. The response of one ipRGC subtype appeared to depend on exogenous chromophore supply, and this response is conserved in both human and mouse retinas. Rods and cones also provided input to ipRGCs; however, each subtype integrated outer retina light signals in a distinct fashion.

Besides generating vision, light modulates various physiological functions, including mood. While light therapy applied in the daytime is known to have anti-depressive properties, excessive light exposure at night has been reportedly associated with depressive symptoms. The neural mechanisms underlying this day–night difference in the effects of light are unknown. Using a light-at-night (LAN) paradigm in mice, we showed that LAN induced depressive-like behaviors without disturbing the circadian rhythm. This effect was mediated by a neural pathway from retinal melanopsin-expressing ganglion cells to the dorsal perihabenular nucleus (dpHb) to the nucleus accumbens (NAc). Importantly, the dpHb was gated by the circadian rhythm, being more excitable at night than during the day. This indicates that the ipRGC→dpHb→NAc pathway preferentially conducts light signals at night, thereby mediating LAN-induced depressive-like behaviors. These findings may be relevant when considering the mental health effects of the prevalent nighttime illumination in the industrial world.An et al. discovered a new brain pathway in mice that conveys light signals from the retina to mood-relevant subcortical nuclei under circadian gating and thereby mediates depressive-like behaviors induced by abnormal nighttime light exposure.

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.

Electronic retinal prostheses for stimulating retinal neurons are promising for vision restoration. However, the rigid electrodes of conventional retinal implants can inflict damage on the soft retina tissue. They also have limited selectivity due to their poor proximity to target cells in the degenerative retina. Here we present a soft artificial retina (thickness, 10 μm) where flexible ultrathin photosensitive transistors are integrated with three-dimensional stimulation electrodes of eutectic gallium–indium alloy. Platinum nanoclusters locally coated only on the tip of these three-dimensional liquid-metal electrodes show advantages in reducing the impedance of the stimulation electrodes. These microelectrodes can enhance the proximity to the target retinal ganglion cells and provide effective charge injections (72.84 mC cm −2 ) to elicit neural responses in the retina. Their low Young’s modulus (234 kPa), owing to their liquid form, can minimize damage to the retina. Furthermore, we used an unsupervised machine learning approach to effectively identify the evoked spikes to grade neural activities within the retinal ganglion cells. Results from in vivo experiments on a retinal degeneration mouse model reveal that the spatiotemporal distribution of neural responses on their retina can be mapped under selective localized illumination areas of light, suggesting the restoration of their vision. A soft artificial retina with flexible phototransistors and three-dimensional liquid-metal microelectrodes is used to enhance proximity to retinal ganglion cells and minimize damage to soft tissue as well as improve charge injection for vision restoration in retinal degenerative in vivo models.

The restoration of light response with complex spatiotemporal features in retinal degenerative diseases towards retinal prosthesis has proven to be a considerable challenge over the past decades. Herein, inspired by the structure and function of photoreceptors in retinas, we develop artificial photoreceptors based on gold nanoparticle-decorated titania nanowire arrays, for restoration of visual responses in the blind mice with degenerated photoreceptors. Green, blue and near UV light responses in the retinal ganglion cells (RGCs) are restored with a spatial resolution better than 100 µm. ON responses in RGCs are blocked by glutamatergic antagonists, suggesting functional preservation of the remaining retinal circuits. Moreover, neurons in the primary visual cortex respond to light after subretinal implant of nanowire arrays. Improvement in pupillary light reflex suggests the behavioral recovery of light sensitivity. Our study will shed light on the development of a new generation of optoelectronic toolkits for subretinal prosthetic devices. The restoration of light response using retinal prosthesis could be a way to restore vision following retinal degenerative disease. Here the authors develop gold-titania nanowire arrays that restore visual response in blind mice.

Using a combination of viral-tracing and in vivo imaging techniques, the authors show that there are several parallel pathways in the mouse visual system and that directional and orientation selectivity in the cortex may arise from the specialized tuning of retinal circuits. How the eye observes directional change The motion-detecting cells of the retina, called direction-selective ganglion cells (DSGCs), have been known about and studied for more than half a century but their precise role in visual processing has remained unclear. Using a combination of genetic, anatomical and imaging techniques, Andrew Huberman and colleagues investigate the connections made by DSGCs in the mouse brain and find that they link specifically to neurons in the superficial layers of primary visual cortex. Inputs from several different DSGC types are combined to convey both directional and orientation information to the cortex. In addition, non-direction-tuned information from the retina is sent to deeper layers of cortex. This reveals that the mouse visual system contains several functionally distinct parallel pathways and that directional and orientation selectivity in the cortex may arise from the earliest stages of visual processing involving motion-detecting cells in the retina. How specific features in the environment are represented within the brain is an important unanswered question in neuroscience. A subset of retinal neurons, called direction-selective ganglion cells (DSGCs), are specialized for detecting motion along specific axes of the visual field 1 . Despite extensive study of the retinal circuitry that endows DSGCs with their unique tuning properties 2 , 3 , their downstream circuitry in the brain and thus their contribution to visual processing has remained unclear. In mice, several different types of DSGCs connect to the dorsal lateral geniculate nucleus (dLGN) 4 , 5 , 6 , the visual thalamic structure that harbours cortical relay neurons. Whether direction-selective information computed at the level of the retina is routed to cortical circuits and integrated with other visual channels, however, is unknown. Here we show that there is a di-synaptic circuit linking DSGCs with the superficial layers of the primary visual cortex (V1) by using viral trans-synaptic circuit mapping 7 , 8 and functional imaging of visually driven calcium signals in thalamocortical axons. This circuit pools information from several types of DSGCs, converges in a specialized subdivision of the dLGN, and delivers direction-tuned and orientation-tuned signals to superficial V1. Notably, this circuit is anatomically segregated from the retino-geniculo-cortical pathway carrying non-direction-tuned visual information to deeper layers of V1, such as layer 4. Thus, the mouse harbours several functionally specialized, parallel retino-geniculo-cortical pathways, one of which originates with retinal DSGCs and delivers direction- and orientation-tuned information specifically to the superficial layers of the primary visual cortex. These data provide evidence that direction and orientation selectivity of some V1 neurons may be influenced by the activation of DSGCs.

The vertebrate retina first evolved some 500 million years ago in ancestral marine chordates. Since then, the eyes of different species have been tuned to best support their unique visuoecological lifestyles. Visual specializations in eye designs, large-scale inhomogeneities across the retinal surface and local circuit motifs mean that all species’ retinas are unique. Computational theories, such as the efficient coding hypothesis, have come a long way towards an explanation of the basic features of retinal organization and function; however, they cannot explain the full extent of retinal diversity within and across species. To build a truly general understanding of vertebrate vision and the retina’s computational purpose, it is therefore important to more quantitatively relate different species’ retinal functions to their specific natural environments and behavioural requirements. Ultimately, the goal of such efforts should be to build up to a more general theory of vision.

Humans are highly visual. Retinal ganglion cells (RGCs), the neurons that connect the eyes to the brain, fail to regenerate after damage, eventually leading to blindness. Here, we review research on regeneration and repair of the optic system. Intrinsic developmental growth programs can be reactivated in RGCs, neural activity can enhance RGC regeneration, and functional reformation of eye-to-brain connections is possible, even in the adult brain. Transplantation and gene therapy may serve to replace or resurrect dead or injured retinal neurons. Retinal prosthetics that can restore vision in animal models may too have practical power in the clinical setting. Functional restoration of sight in certain forms of blindness is likely to occur in human patients in the near future.