We review and comment on the recent model of Grimbert and Cang of the development of topographically ordered maps from the retina to the superior colliculus. This model posits a phase in which arbors are created in zones permitted by Eph and ephrin signaling, followed by a phase in which activity-dependent synaptic plasticity refines the map. We show that it is not possible to generate the arborization probability functions used in the simulations of Grimbert and Cang using gradients of Ephs and ephrins and the interaction mechanism that Grimbert and Cang propose in their results. Furthermore, the arborization probabilities we do generate are far less sharp than we imagine truly “permissive” ones would be. It remains to be seen if maps can be generated from the nonpermissive arborization probabilities generated from gradients.

Cathepsin-D (Cat-D) is a major proteolytic enzyme in phagocytic cells. In the retinal pigment epithelium (RPE), it is responsible for the daily degradation of photoreceptor outer segments (POSs) to maintain retinal homeostasis. Melanoregulin (MREG)-mediated loss of phagocytic capacity has been linked to diminished intracellular Cat-D activity. Here, we demonstrate that loss of MREG enhances the secretion of intermediate Cat-D (48 kDa), resulting in a net enhancement of extracellular Cat-D activity. These results suggest that MREG is required to maintain Cat-D homeostasis in the RPE and likely plays a protective role in retinal health. In this regard, in the Mregdsu/dsu mouse, we observe increased basal laminin. Loss of the Mregdsu allele is not lethal and therefore leads to slow age-dependent changes in the RPE. Thus, we propose that this model will allow us to study potential dysregulatory functions of Cat-D in retinal disease.

Dynamin proteins are involved in vesicle generation, providing mechanical force to excise newly formed vesicles from membranes of cellular compartments. In the brain, dynamin-1, dynamin-2, and dynamin-3 have been well studied; however, their function in the retina remains elusive. A retina-specific splice variant of dynamin-1 interacts with the photoreceptor-specific protein Tubby-like protein 1 (Tulp1), which when mutated causes an early onset form of autosomal recessive retinitis pigmentosa. Here, we investigated the role of the dynamins in the retina, using immunohistochemistry to localize dynamin-1, dynamin-2, and dynamin-3 and immunoprecipitation followed by mass spectrometry to explore dynamin-1 interacting proteins in mouse retina. Dynamin-2 is primarily confined to the inner segment compartment of photoreceptors, suggesting a role in outer segment protein transport. Dynamin-3 is present in the terminals of photoreceptors and dendrites of second-order neurons but is most pronounced in the inner plexiform layer where second-order neurons relay signals from photoreceptors. Dynamin-1 appears to be the dominant isoform in the retina and is present throughout the retina and in multiple compartments of the photoreceptor cell. This suggests that it may function in multiple cellular pathways. Surprisingly, dynamin-1 expression and localization did not appear to be disrupted in tulp1−/− mice. Immunoprecipitation experiments reveal that dynamin-1 associates primarily with proteins involved in cytoskeletal-based membrane dynamics. This finding is confirmed by western blot analysis. Results further implicate dynamin-1 in vesicular protein transport processes relevant to synaptic and post-Golgi pathways and indicate a possible role in photoreceptor stability.

Eye evolution is driven by the evolution of visually guided behavior. Accumulation of gradually more demanding behaviors have continuously increased the performance requirements on the photoreceptor organs. Starting with nondirectional photoreception, I argue for an evolutionary sequence continuing with directional photoreception, low-resolution vision, and finally, high-resolution vision. Calculations of the physical requirements for these four sensory tasks show that they correlate with major innovations in eye evolution and thus work as a relevant classification for a functional analysis of eye evolution. Together with existing molecular and morphological data, the functional analysis suggests that urbilateria had a simple set of rhabdomeric and ciliary receptors used for directional photoreception, and that organ duplications, positional shifts and functional shifts account for the diverse patterns of eyes and photoreceptors seen in extant animals. The analysis also suggests that directional photoreception evolved independently at least twice before the last common ancestor of bilateria and proceeded several times independently to true vision in different bilaterian and cnidarian groups. This scenario is compatible with Pax-gene expression in eye development in the different animal groups. The whole process from the first opsin to high-resolution vision took about 170 million years and was largely completed by the onset of the Cambrian, about 530 million years ago. Evolution from shadow detectors to multiple directional photoreceptors has further led to secondary cases of eye evolution in bivalves, fan worms, and chitons.

We discuss hypotheses that link the measurements we can make with infants to inferences about their developing neural mechanisms. First, we examine evidence from the sensitivity to visual stimulus properties seen in infants’ responses, using both electrophysiological measures (transient and steady-state recordings of visual evoked potentials/visual event-related potentials) and behavioral measures and compare this with the sensitivity of brain processes, known from data on mammalian neurophysiology and human neuroimaging. The evidence for multiple behavioral systems with different patterns of visual sensitivity is discussed. Second, we consider the analogies which can be made between infants’ behavior and that of adults with identified brain damage, and extend these links to hypothesize about the brain basis of visual deficits in infants and children with developmental disorders. Last, we consider how these lines of data might allow us to form “inverse linking hypotheses” about infants’ visual experience.

The proline-23-histidine line 3 (P23H-3) transgenic rat carries a human opsin gene mutation leading to progressive photoreceptor loss characteristic of human autosomal dominant retinitis pigmentosa. The aim of the present study was to evaluate neurochemical modifications in the P23H-3 retina as a function of development and degeneration. Specifically, we investigated the ion channel permeability of photoreceptors by tracking an organic cation, agmatine (1-amino-4-guanidobutane, AGB), which permeates through nonspecific cation channels. We also investigated the activity of ionotropic glutamate receptors in distinct populations of bipolar, amacrine, and ganglion cells using AGB tracking in combination with macromolecular markers. We found elevated cation channel permeation in photoreceptors as early as postnatal day 12 (P12) suggesting that AGB labeling is an early indicator of impending photoreceptor degeneration. However, bipolar, amacrine, or ganglion cells displayed normal responses secondary to ionotropic glutamate receptor activation even at P138 when about one half of the photoreceptor layer was lost and apoptosis and gliosis were observed. These results suggest that possible therapeutic windows as downstream neurons in inner retina appear to retain normal function with regard to AGB permeation when photoreceptors are significantly reduced but not lost.

Acetylcholine is present in and released from starburst amacrine cells in the inner plexiform layer (IPL), but its role in retinal function except, perhaps, in early development, is unclear. Nicotinic acetylcholine receptors are thought to be present on ganglion, amacrine, and bipolar cell processes in the IPL, and it is known that acetylcholine increases the spontaneous and light-evoked responses of retinal ganglion cells. The effects of acetylcholine on bipolar cells are not known, and here we report the effects of nicotine on the b-wave of the electroretinogram in larval zebrafish. The b-wave originates mainly from ON-bipolar cells, and the larval zebrafish retina is cone-dominated. Only small rod responses can be elicited with dim lights in wild-type larval zebrafish retinas, but rod responses can be recorded over a range of intensities in a mutant (no optokinetic response f) fish that has no cone function. We find that nicotine strongly enhances cone-driven b-wave response amplitudes but depresses rod driven b-wave response amplitudes without, however, affecting rod- or cone-driven b-wave light sensitivity.

The P23H-1 transgenic rat carries a mutated mouse opsin gene, in addition to endogenous opsin genes, and undergoes progressive photoreceptor loss that is generally characteristic of human autosomal dominant retinitis pigmentosa (RP). Here, we examined morphological changes correlated with visual function that is comparable to clinical application in the pigmented P23H-1 rat retina as photoreceptor degeneration progressed. We found that rod function was compromised as early as postnatal day 28 and was a good indicator for tracking retinal degeneration. Cone function was normal and did not change until the thickness of the photoreceptor layer was reduced by 75%. Similar to the threshold versus intensity curves used to evaluate vision of RP patients, light-adaptation curves showed that cone thresholds depended on the number of remaining functioning cones, but not on its length of outer segments (OS). By 1 year of age, both rod and cone functions were significantly compromised. Correlating with early abnormal rod function, rods and related secondary neurons also underwent progressive degeneration, including shortening of inner and OS of photoreceptors, loss of rod bipolar and horizontal cell dendrites, thickening of the outer Müller cell processes, and reduced density of pre- and postsynaptic markers. Similar early morphological modifications were also observed in cones and their related secondary neurons. However, cone function was maintained at nearly normal level for a long period. The dramatic loss of rods at late stage of degeneration may contribute to the dysfunction of cones. Attention has to be focused on preserving cone function and identifying factors that damage cones when therapeutic regimes are applied to treat retinal degeneration. As such, these findings provide a foundation for future studies involving treatments to counter photoreceptor loss.

Eyes have evolved many times, and arthropods and vertebrates share transcription factors for early development. Moreover, the photochemistry of vision in all eyes employs an opsin and the isomerization of a retinoid from the 11-cis to the all-trans configuration. The opsins, however, have associated with several different G proteins, initiating hyperpolarizing and depolarizing conductance changes at the photoreceptor membrane. Beyond these obvious instances of homology, much of the evolutionary story is one of tinkering, producing a great variety of morphological forms and variation within functional themes. This outcome poses a central issue in the convergence of evolutionary and developmental biology: what are the heritable features in the later stages of development that give natural selection traction in altering phenotypic outcomes? This paper discusses some results of evolutionary tinkering where this question arises and, in some cases, where the reasons for particular outcomes and the role of adaptation may not be understood. Phenotypic features include: the exploitation of microvilli in rhabdomeric photoreceptors for detecting the plane of polarized light; different instances of retinoid in the visual pigment; examples of the many uses of accessory pigments in tuning the spectral sensitivity of photoreceptors; selection of opsins in tuning sensitivity in aquatic environments; employing either reflection or refraction in the optics of compound eyes; the multiple ways of constructing images in compound eyes; and the various ways of regenerating 11-cis retinals to maintain visual sensitivity. Evolution is an irreversible process, but tinkering may recover some lost functions, albeit by new mutational routes. There is both elegance and intellectual coherence to the natural processes that produce such variety and functional complexity. But marginalizing the teaching of evolution in public education is a continuing social and political problem that contributes to the reckless capacity of humans to alter the planet without trying to understand how nature works.

Class A psychophysical observations are based on the linking hypothesis that perceptually distinguishable stimuli must correspond to different brain events. Class B observations are related to the appearance of stimuli not their discriminability. There is no clear linking hypothesis underlying Class B observations, but they are necessary for studying the effects of context on appearance, including a large class of phenomena known as “illusions.” Class B observations are necessarily measures of observer bias (Fechner’s “constant error”) as opposed to Class A measures of sensitivity (Fechner’s “variable error”). It is therefore important that Class B observations distinguish between response biases, decisional biases, and perceptual biases. This review argues that the commonly used method of single stimuli fails to do this, and that multiple-alternative forced choice (mAFC) methods can do a better job, particularly if combined with a roving pedestal.

Nitric oxide (NO) is known to exert multiple effects on the function of many retinal neurons and their synapses. Therefore, it is equally important to understand the potential sources of NO within the retina. To explore this, we employ a combination of 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate (DAF-FM) based NO detection and immunohistochemistry for the NO synthetic enzymes, neuronal and endothelial nitric oxide synthase (nNOS and eNOS). We find DAF signals in photoreceptors, horizontal cells, amacrine cells, efferent synapses, Müller cells, and cells in the ganglion cell layer (GCL). nNOS immunoreactivity was consistent with the DAF signal with the exception that horizontal cells and Müller cells were not clearly labeled. eNOS-like immunoreactivity (eNOS-LI) was more widespread with photoreceptors, horizontal cells, occasional bipolar cells, amacrine cells, Müller cells, and cells in the GCL all showing labeling. Double labeling with antibodies raised against calretinin, syntaxin, and glutamine synthetase confirmed that horizontal cells, amacrine cells, and Müller cells (respectively) were expressing eNOS-LI. Although little or no nNOS labeling is observed in horizontal cells or Müller cells, the expression of eNOS-LI is consistent with the ability of these cells to produce NO. Together these results suggest that the capability to produce NO is widespread in the chicken retina. We propose that multiple forms of regulation for nNOS and eNOS play a role in the patterning of NO production in the chicken retina.

When I first came across William James’ dictum that “ … this sense of sameness is the very keel and backbone of our thinking,” I thought he had foreseen the importance of cross-correlation in the brain, and told myself to find out how he had reached this conclusion. When I finally did this a year or two ago, I slowly came to realize that I had completely misunderstood him; from the full quote it is absolutely clear that his dictum cannot be referring to the process by which a cortical simple cell responds selectively to the orientation of features in a visual image, as I had originally supposed. If one translates the original dictum into two more prosaic modern versions, his version would say: “Our minds could not think at all without neural circuits in our brains that compute auto-correlations,” but in my mistaken interpretation the last word would be “cross-correlations.” Others may have made the same mistake, but the difference is profound, and finding what he really meant has been a revelation to me. This essay explains the revelation, describes how to determine experimentally whether the brain does auto- or cross-correlation, and gives the result of preliminary experiments showing clearly that it does both. A revised view of the visual cortex as autocorrelator as well as cross-correlator claims to tell us what complex cells in the visual cortex do, and it assigns a role to its columnar structure that is as important to fulfilling that role as the concept of the receptive field has been to understanding the simple cells’ fulfillment of theirs. The new view has compelling features, broad implications, and suggests a plausible model of how neural circuits in the cortex achieve thought, but it needs further testing.

All mammalian cone photopigments are derived from the operation of representatives from two opsin gene families (SWS1 and LWS in marsupial and eutherian mammals; SWS2 and LWS in monotremes), a process that produces cone pigments with respective peak sensitivities in the short and middle-to-long wavelengths. With the exception of a number of primate taxa, the modal pattern for mammals is to have two types of cone photopigment, one drawn from each of the gene families. In recent years, it has been discovered that the SWS1 opsin genes of a widely divergent collection of eutherian mammals have accumulated mutational changes that render them nonfunctional. This alteration reduces the retinal complements of these species to a single cone type, thus rendering ordinary color vision impossible. At present, several dozen species from five mammalian orders have been identified as falling into this category, but the total number of mammalian species that have lost short-wavelength cones in this way is certain to be much larger, perhaps reaching as high as 10% of all species. A number of circumstances that might be used to explain this widespread cone loss can be identified. Among these, the single consistent fact is that the species so affected are nocturnal or, if they are not technically nocturnal, they at least feature retinal organizations that are typically associated with that lifestyle. At the same time, however, there are many nocturnal mammals that retain functional short-wavelength cones. Nocturnality thus appears to set the stage for loss of functional SWS1 opsin genes in mammals, but it cannot be the sole circumstance.

At certain temporal frequencies, the human cone flicker electroretinogram (ERG) contains multiple additional responses following the termination of a flicker train. The purpose of this study was to determine whether these poststimulus responses are a continuing response to the terminated flicker train or represent the oscillation of a resonant system. ERGs were recorded from 10 visually normal adults in response to full-field sinusoidally modulated flicker trains presented against a short-wavelength rod-saturating adapting field. The amplitude and timing properties of the poststimulus responses were evaluated within the context of a model of a second-order resonant system. At stimulus frequencies between 41.7 and 71.4 Hz, the majority of subjects showed at least three additional ERG responses following the termination of the flicker train. The interval between the poststimulus responses was approximately constant across stimulus frequency, with a mean of 14.4 ms, corresponding to a frequency of 69.4 Hz. The amplitude and timing characteristics of the poststimulus ERG responses were well described by an underdamped second-order system with a resonance frequency of 70.3 Hz. The observed poststimulus ERG responses may represent resonant oscillations of retinal ON bipolar cells, as has been proposed for electrophysiological recordings of poststimulus responses from retinal ganglion cells. However, further investigation is required to determine the types of retinal neurons involved in the generation of the poststimulus responses of the human flicker ERG.

Contrast-modulated (CM) stimuli are processed by spatial mechanisms that operate at larger spatial scales than those processing luminance-modulated (LM) stimuli and may be more prone to deficits in developing, amblyopic, and aging visual systems. Understanding neural mechanisms of contour interaction or crowding will help in detecting disorders of spatial vision. In this study, contour interaction effects on visual acuity for LM and CM C and bar stimuli are assessed in normal foveal vision. In Experiment 1, visual acuity is measured for all-LM and all-CM stimuli, at ∼3.5× above their respective modulation thresholds. In Experiment 2, visual acuity is measured for Cs and bars of different type (LM C with CM bars and vice versa). Visual acuity is degraded for CM compared with LM Cs (0.46 ± 0.04 logMAR vs. 0.18 ± 0.04 logMAR). With nearby bars, CM acuity is degraded further (0.23 ± 0.01 logMAR or ∼2 lines on an acuity chart), significantly more than LM acuity (0.11 ± 0.01 logMAR, ∼1 line). Contour interaction for CM stimuli extends over greater distances (arcmin) than it does for LM stimuli, but extents are similar with respect to acuities (∼3.5× the C gap width). Contour interaction is evident when the Cs and bars are defined differently: it is stronger when an LM C is flanked by CM bars (0.17 ± 0.03 logMAR) than when a CM C is flanked by LM bars (0.08 ± 0.02 logMAR). Our results suggest that contour interaction for foveally viewed acuity stimuli involves feature integration, such that the outputs of receptive fields representing Cs and bars are combined. Contour interaction operates at LM and CM representational stages, it can occur across stage, and it is enhanced at the CM stage. Greater contour interaction for CM Cs and bars could hold value for visual acuity testing and earlier diagnosis of conditions for which crowding is important, such as in amblyopia.

The notion of a set of neurons that form a “bridge locus” serving as the immediate substrate of visual perception is examined in the light of evidence on the architecture of the visual pathway, of current thinking about perceptual representations, and of the basis of perceptual awareness. The bridge locus is likely to be part of a tangled web of representations, and this complexity raises the question of whether another scheme that relies less on geography might offer a better framework. The bridge locus bears a close relationship to the neural correlate of consciousness (NCC), and like the NCC may be a concept which is no longer precise enough to provide a useful basis for reasoning about the relationship between brain activity and perceptual experience.

Responses of cells in the lateral geniculate nucleus (LGN) of the macaque monkey have been measured for different sizes of chromatic and achromatic stimuli, with relative luminance spanning a range of 3–6 log units. Homogeneous illuminated test fields, centered on the receptive field, were used. Responses to these stimuli deviated from what is expected for the grating stimuli used to study the contrast-sensitive mechanisms in the visual pathway. For test fields smaller than the center of the receptive field, both the excitatory and the inhibitory cone-opponent components were present in the response, and the sensitivity to both components increased with the same factor when the test field increased in size (area summation). For test field areas extending into the suppressive surround of the extraclassical receptive field, the excitatory and the inhibitory cone opponents were both suppressed, again by the same factor. This suppression of the cell’s responsiveness, as a function of test spot area, was described by a logarithmic function, and the spatial sensitivity of attenuation could therefore be described by a power function of radius. The logarithmic suppression was clear for parvocellular and koniocellular cells but was more prominent for magnocellular cells. The surround field suppression was also found for the prepotential inputs to LGN cells, indicating a retinal origin. The difference of Gaussian (DOG) model has been used successfully to describe the cells’ contrast behavior for grating stimuli. However, this model fails to describe the constant excitatory/inhibitory response balance needed to obtain color (hue) stability for light stimuli of different sizes but with the same Commission Internationale de l’Eclairage (CIE) chromaticity and luminance factor. Neither the constant responsiveness found in the center of the receptive field nor the suppressive response in the surround can be described by the DOG model.