Annual Review of Vision Science - Volume 1, 2015

The human eye is a relatively simple optical instrument that imposes the first performance limits on the visual system. This review describes the main optical properties of the eye: geometric image formation, aberrations, and intraocular scattering. The article also discusses the sources of optical degradations and their impact on visual performance.

This review starts with a brief history and description of adaptive optics (AO) technology, followed by a showcase of the latest capabilities of AO systems for imaging the human retina and by an extensive review of the literature on clinical uses of AO. It then concludes with a discussion on future directions and guidance on usage and interpretation of images from AO systems for the eye.

Optical coherence tomography (OCT) is changing the way glaucoma is studied and diagnosed. Glaucoma damages retinal ganglion cell (RGC) axons at the optic disc, and the resulting retrograde degeneration destroys the RGC bodies. OCT allows for a noninvasive measurement of both retinal nerve fiber (RNF) and RGC layer thickness. In this article, OCT techniques are described for studying the thinning of these layers due to glaucoma. We have learned that there is more damage to the macula (central ±8 deg) than previously thought, and a simple anatomical model provides an explanation for this finding. Further, OCT technology has led to improved understanding of the relationship between RGC and RNF layer loss and behavioral data. Finally, another imaging technique, adaptive optics, has allowed a better visualization and understanding of details that are often difficult or impossible to see with current OCT technology.

Age-related macular degeneration (AMD) is a chronic degenerative disease of the central retina and a major cause of vision impairment and blindness with millions of people affected in the elderly population. In recent years, considerable efforts have been made to understand disease pathology with the long-term goal of designing novel and effective treatment options for this devastating disease. Although striking advances in treating the neovascular stage of late AMD have occurred, no therapy is available for almost half of all AMD patients, specifically those who are affected by the atrophic form of the disease. This review highlights current knowledge on the genetic factors associated with early- and late-stage forms of the disease. It also summarizes the findings regarding the extent to which these factors may play a role in the transition from one disease stage to another, and it emphasizes the need to explore further the underlying mechanisms for both development and progression of this disease as a starting point for designing innovative therapies for it.

Mitochondrial dysfunction underlies many human disorders, including those that affect the visual system. The retinal ganglion cells, whose axons form the optic nerve, are often damaged by mitochondrial-related diseases which result in blindness. Both mitochondrial DNA (mtDNA) and nuclear gene mutations impacting many different mitochondrial processes can result in optic nerve disease. Of particular importance are mutations that impair mitochondrial network dynamics (fusion and fission), oxidative phosphorylation (OXPHOS), and formation of iron–sulfur complexes. Current genetic knowledge can inform genetic counseling and suggest strategies for novel gene-based therapies. Identifying new optic neuropathy–causing genes and defining the role of current and novel genes in disease will be important steps toward the development of effective and potentially neuroprotective therapies.

Visual defects affect a large proportion of humanity, have a significant negative impact on quality of life, and cause significant economic burden. The wide variety of visual disorders and the large number of gene mutations responsible require a flexible animal model system to carry out research for possible causes and cures for the blinding conditions. With eyes similar to humans in structure and function, zebrafish are an important vertebrate model organism that is being used to study genetic and environmental eye diseases, including myopia, glaucoma, retinitis pigmentosa, ciliopathies, albinism, and diabetes. This review details the use of zebrafish in modeling human ocular diseases.

The retina consists of organized layers of photoreceptors, interneurons, glia, epithelial cells, and endothelial cells. The economic model of supply and demand used to appropriately determine cost is highly applicable to the retina, in which the extreme metabolic demands of phototransduction are met by precisely localized and designed vascular networks. Proper development and maintenance of these networks is critical to normal visual function; dysregulation is characteristic of several devastating human diseases, including but not limited to age-related macular degeneration and diabetic retinopathy. In this article, we focus on the lessons learned from the study of retinal vascular development and how these lessons can be used to better maintain adult vascular networks and prevent retinal diseases. We then outline the vasculotrophic contributions from neurons, retinal pigment epithelium (RPE) cells, and glia (specifically microglia) before we shift our focus to pathology to provide molecular contexts for neovascular retinal diseases. Finally, we conclude with a discussion that applies what we have learned about how retinal cells interact with the vasculature to identify and validate therapeutic approaches for neurovascular disease of the retina.

Severe loss of photoreceptor cells in inherited or acquired retinal degenerative diseases can result in partial loss of sight or complete blindness. The optogenetic strategy for restoration of vision utilizes optogenetic tools to convert surviving inner retinal neurons into photosensitive cells; thus, light sensitivity is imparted to the retina after the death of photoreceptor cells. Proof-of-concept studies, especially those using microbial rhodopsins, have demonstrated restoration of light responses in surviving retinal neurons and visually guided behaviors in animal models. Significant progress has also been made in improving microbial rhodopsin-based optogenetic tools, developing virus-mediated gene delivery, and targeting specific retinal neurons and subcellular compartments of retinal ganglion cells. In this article, we review the current status of the field and outline further directions and challenges to the advancement of this strategy toward clinical application and improvement in the outcomes of restored vision.

Photoreceptors have been the most intensively studied retinal cell type. Early lineage studies showed that photoreceptors are produced by retinal progenitor cells (RPCs) that produce only photoreceptor cells and by RPCs that produce both photoreceptor cells and other retinal cell types. More recent lineage studies have shown that there are intrinsic, molecular differences among these RPCs and that these molecular differences operate in gene regulatory networks (GRNs) that lead to the choice of the rod versus the cone fate. In addition, there are GRNs that lead to the choice of a photoreceptor fate and that of another retinal cell type. An example of such a GRN is one that drives the binary fate choice between a rod photoreceptor and bipolar cell. This GRN has many elements, including both feedforward and feedback regulatory loops, highlighting the complexity of such networks. This and other examples of retinal cell fate determination are reviewed here, focusing on the events that direct the choice of rod and cone photoreceptor fate.

The first synapses transmitting visual information contain an unusual organelle, the ribbon, which is involved in the transport and priming of vesicles to be released at the active zone. The ribbon is one of many design features that allow efficient refilling of the active zone, which in turn enables graded changes in membrane potential to be transmitted using a continuous mode of neurotransmitter release. The ribbon also plays a key role in supplying vesicles for rapid and transient bursts of release that signal fast changes, such as the onset of light. We increasingly understand how the physiological properties of ribbon synapses determine basic transformations of the visual signal and, in particular, how the process of refilling the active zone regulates the gain and adaptive properties of the retinal circuit. The molecular basis of ribbon function is, however, far from clear.

The mammalian retina is an important model system for studying neural circuitry: Its role in sensation is clear, its cell types are relatively well defined, and its responses to natural stimuli—light patterns—can be studied in vitro. To solve the retina, we need to understand how the circuits presynaptic to its output neurons, ganglion cells, divide the visual scene into parallel representations to be assembled and interpreted by the brain. This requires identifying the component interneurons and understanding how their intrinsic properties and synapses generate circuit behaviors. Because the cellular composition and fundamental properties of the retina are shared across species, basic mechanisms studied in the genetically modifiable mouse retina apply to primate vision. We propose that the apparent complexity of retinal computation derives from a straightforward mechanism—a dynamic balance of synaptic excitation and inhibition regulated by use-dependent synaptic depression—applied differentially to the parallel pathways that feed ganglion cells.

Every aspect of visual perception and behavior is built from the neural activity of retinal ganglion cells (RGCs), the output neurons of the eye. Here, we review progress toward understanding the many types of RGCs that communicate visual signals to the brain, along with the subcortical brain regions that use those signals to build and respond to representations of the outside world. We emphasize recent progress in the use of mouse genetics, viral circuit tracing, and behavioral psychophysics to define and map the various RGCs and their associated networks. We also address questions about the homology of RGC types in mice and other species including nonhuman primates and humans. Finally, we propose a framework for understanding RGC typology and for highlighting the relationship between RGC type-specific circuitry and the processing stations in the brain that support and give rise to the perception of sight.

Visual field defects that arise from eye disease are increasing as human life spans lengthen. The consequences of visual field defects on the central visual pathways are important to assess, particularly in light of potential treatments of eye disease that restore function to the retina. For individuals with field defects arising from congenital eye disease, primary visual cortex (V1) appears to remap, whereas this form of reorganization is not present in individuals with field defects that arise later in life as a result of inherited or acquired eye disease. However, research has revealed that the areas of V1 that normally map the visual field defect are active under specific circumstances. This review attempts to resolve whether or not this activity reflects reorganization of the central visual pathways. Alongside the measures of function are measures of anatomical properties of the human visual pathway, which demonstrate transneuronal degeneration in individuals with eye disease. These results are concerning because degeneration of the central visual pathways may ultimately limit the success of sight-restoring treatments of eye disease.

The thalamus is the heavily interconnected partner of the neocortex. All areas of the neocortex receive afferent input from and send efferent projections to specific thalamic nuclei. Through these connections, the thalamus serves to provide the cortex with sensory input, and to facilitate interareal cortical communication and motor and cognitive functions. In the visual system, the lateral geniculate nucleus (LGN) of the dorsal thalamus is the gateway through which visual information reaches the cerebral cortex. Visual processing in the LGN includes spatial and temporal influences on visual signals that serve to adjust response gain, transform the temporal structure of retinal activity patterns, and increase the signal-to-noise ratio of the retinal signal while preserving its basic content. This review examines recent advances in our understanding of LGN function and circuit organization and places these findings in a historical context.

Advances on several fronts have refined our understanding of the neuronal mechanisms of attention. This review focuses on recent progress in understanding visual attention through single-neuron recordings made in behaving subjects. Simultaneous recordings from populations of individual cells have shown that attention is associated with changes in the correlated firing of neurons that can enhance the quality of sensory representations. Other work has shown that sensory normalization mechanisms are important for explaining many aspects of how visual representations change with attention, and these mechanisms must be taken into account when evaluating attention-related neuronal modulations. Studies comparing different brain structures suggest that attention is composed of several cognitive processes, which might be controlled by different brain regions. Collectively, these and other recent findings provide a clearer picture of how representations in the visual system change when attention shifts from one target to another.

Face perception relies on computations carried out in face-selective cortical areas. These areas have been intensively investigated for two decades, and this work has been guided by an influential neural model suggested by Haxby and colleagues in 2000. Here, we review new findings about face-selective areas that suggest the need for modifications and additions to the Haxby model. We suggest a revised framework based on (a) evidence for multiple routes from early visual areas into the face-processing system, (b) information about the temporal characteristics of these areas, (c) indications that the fusiform face area contributes to the perception of changeable aspects of faces, (d) the greatly elevated responses to dynamic compared with static faces in dorsal face-selective brain areas, and (e) the identification of three new anterior face-selective areas. Together, these findings lead us to suggest that face perception depends on two separate pathways: a ventral stream that represents form information and a dorsal stream driven by motion and form information.

Recent advances in neural network modeling have enabled major strides in computer vision and other artificial intelligence applications. Human-level visual recognition abilities are coming within reach of artificial systems. Artificial neural networks are inspired by the brain, and their computations could be implemented in biological neurons. Convolutional feedforward networks, which now dominate computer vision, take further inspiration from the architecture of the primate visual hierarchy. However, the current models are designed with engineering goals, not to model brain computations. Nevertheless, initial studies comparing internal representations between these models and primate brains find surprisingly similar representational spaces. With human-level performance no longer out of reach, we are entering an exciting new era, in which we will be able to build biologically faithful feedforward and recurrent computational models of how biological brains perform high-level feats of intelligence, including vision.

Smooth pursuit eye movements provide a model system for studying how visual inputs are transformed into commands for accurate movement. The neural circuit for pursuit eye movements is largely known and has strong parallels to the circuits for many other movements. Here, we outline progress in defining the conceptual operations that are performed by the pursuit circuit and in aligning those functions with neural circuit mechanisms. We discuss how the visual motion that drives pursuit is represented in the visual cortex, and how the visuomotor circuits decode that representation to estimate target direction and speed and to create motor commands. We outline a modulatory influence called gain control that evaluates the reliability and value of visual inputs and programs appropriate motor activity. Future research on pursuit in nonhuman primates holds the potential to reveal, at an unprecedented level of detail, how visuomotor circuits create coordinated actions.

This review surveys how vision becomes action through the frontal lobe. Signals from extrastriate areas create maps in frontal areas. These maps are shaped by visual features and shaded by goals, values, and experience, and they guide contingent activation of motor circuits to execute coordinated gaze, head, and limb movements. Frontal circuits also support the visual perception of learned objects, events, and actions. Other frontal circuits monitor consequences and exert executive control to improve the effectiveness of visually guided behavior.