Streptozotocin (STZ)-induced diabetes is associated with reductions in the electrical response of the outer retina and retinal pigment epithelium (RPE) to light. Aldose reductase (AR) is the first enzyme required in the polyol-mediated metabolism of glucose, and AR inhibitors have been shown to improve diabetes-induced electroretinogram (ERG) defects. Here, we used control and AR−/− mice to determine if genetic inactivation of this enzyme likewise inhibits retinal electrophysiological defects observed in a mouse model of type 1 diabetes. STZ was used to induce hyperglycemia and type 1 diabetes. Diabetic and age-matched nondiabetic controls of each genotype were maintained for 22 weeks, after which ERGs were used to measure the light-evoked components of the RPE (dc-ERG) and the neural retina (a-wave, b-wave). In comparison to their nondiabetic controls, wildtype (WT) and AR−/− diabetic mice displayed significant decreases in the c-wave, fast oscillation, and off response components of the dc-ERG but not in the light peak response. Nondiabetic AR−/− mice displayed larger ERG component amplitudes than did nondiabetic WT mice; however, the amplitude of dc-ERG components in diabetic AR−/− animals were similar to WT diabetics. ERG a-wave amplitudes were not reduced in either diabetic group, but b-wave amplitudes were lower in WT and AR−/−diabetic mice. These findings demonstrate that the light-induced responses of the RPE and outer retina are disrupted in diabetic mice, but these defects are not due to photoreceptor dysfunction, nor are they ameliorated by deletion of AR. This latter finding suggests that benefits observed in other studies utilizing pharmacological inhibitors of AR might have been secondary to off-target effects of the drugs.

Replacement of retinal pigment epithelium (RPE) cells by transplantation is a potential treatment for some retinal degenerations. Here, we used a combination of invasive and noninvasive methods to characterize the structural and functional consequences of subretinal injection of RPE cells. Pigmented cells from primary cultures were injected into albino mice. Recovery was monitored over 8 weeks by fundus imaging, spectral domain optical coherence tomography (sdOCT), histology, and electroretinography (ERG). sdOCT showed that retinal reattachment was nearly complete by 1 week. ERG response amplitudes were reduced after injection, with cone-mediated function then recovering better than rod function. Photoreceptor cell loss was evident by sdOCT and histology, near the site of injection, and is likely to have been the main cause of incomplete recovery. With microscopy, injected cells were identified by the presence of apical melanosomes. They either established contact with Bruch’s membrane, and thus became part of the RPE monolayer, or were located on the apical surface of the host’s cells, resulting in apposition of the basal surface of the injected cell with the apical surface of the host cell and the formation of a series of desmosomal junctions. RPE cell density was not increased, indicating that the incorporation of an injected cell into the RPE monolayer was concomitant with the loss of a host cell. The transplanted and remaining host cells contained large vacuoles of ingested debris as well as lipofuscin-like granules, suggesting that they had scavenged the excess injected and host cells, and were stressed by the high digestive load. Therefore, although significant functional and structural recovery was observed, the consequences of this digestive stress may be a concern for longer-term health, especially where RPE cell transplantation is used to treat diseases that include lipofuscin accumulation as part of their pathology.

Monotremes are the most basal egg-laying mammals comprised of two extant genera, which are largely nocturnal. Visual pigments, the first step in the sensory transduction cascade in photoreceptors of the eye, have been examined in a variety of vertebrates, but little work has been done to study the rhodopsin of monotremes. We isolated the rhodopsin gene of the nocturnal short-beaked echidna (Tachyglossus aculeatus) and expressed and functionally characterized the protein in vitro. Three mutants were also expressed and characterized: N83D, an important site for spectral tuning and metarhodopsin kinetics, and two sites with amino acids unique to the echidna (T158A and F169A). The λmax of echidna rhodopsin (497.9 ± 1.1 nm) did not vary significantly in either T158A (498.0 ± 1.3 nm) or F169A (499.4 ± 0.1 nm) but was redshifted in N83D (503.8 ± 1.5 nm). Unlike other mammalian rhodopsins, echidna rhodopsin did react when exposed to hydroxylamine, although not as fast as cone opsins. The retinal release rate of light-activated echidna rhodopsin, as measured by fluorescence spectroscopy, had a half-life of 9.5 ± 2.6 min−1, which is significantly shorter than that of bovine rhodopsin. The half-life of the N83D mutant was 5.1 ± 0.1 min−1, even shorter than wild type. Our results show that with respect to hydroxylamine sensitivity and retinal release, the wild-type echidna rhodopsin displays major differences to all previously characterized mammalian rhodopsins and appears more similar to other nonmammalian vertebrate rhodopsins such as chicken and anole. However, our N83D mutagenesis results suggest that this site may mediate adaptation in the echidna to dim light environments, possibly via increased stability of light-activated intermediates. This study is the first characterization of a rhodopsin from a most basal mammal and indicates that there might be more functional variation in mammalian rhodopsins than previously assumed.

Glycosylphosphatidylinositol (GPI) anchors are critical for the membrane attachment of a wide variety of essential signaling and cell adhesion proteins. The GPI anchor is a complex glycolipid structure that utilizes glycosylphosphatidylinositol-mannosyltransferases (GPI-MTs) for the addition of three core mannose residues during its biosynthesis. Here, we demonstrate that Drosophila GPI-MT2 is required for the GPI-mediated membrane attachment of several GPI-anchored proteins, including the photoreceptor-specific cell adhesion molecule, chaoptin. Mutations in gpi-mt2 lead to defects in chaoptin trafficking to the plasma membrane in Drosophila photoreceptor cells. In gpi-mt2 mutants, loss of sufficient chaoptin in the membrane leads to microvillar instability, photoreceptor cell pathology, and retinal degeneration. Finally, using site-directed mutagenesis, we have identified key amino acids that are essential for GPI-MT2 function and cell viability in Drosophila. Our findings on GPI-MT2 provide a mechanistic link between GPI anchor biosynthesis and protein trafficking in Drosophila and shed light on a novel mechanism for inherited retinal degeneration.

Retinal ganglion cells receive excitatory synapses from bipolar cells and inhibitory synapses from amacrine cells. Previous studies in primate suggest that the strength of inhibitory amacrine input is greater to cells in peripheral retina than to foveal (central) cells. A comprehensive study of a large number of ganglion cells at different eccentricities, however, is still lacking. Here, we compared the amacrine and bipolar input to midget and parasol ganglion cells in central and peripheral retina of marmosets (Callithrix jacchus). Ganglion cells were labeled by retrograde filling from the lateral geniculate nucleus or by intracellular injection. Presumed amacrine input was identified with antibodies against gephyrin; presumed bipolar input was identified with antibodies against the GluR4 subunit of the AMPA receptor. In vertical sections, about 40% of gephyrin immunoreactive (IR) puncta were colocalized with GABAA receptor subunits, whereas immunoreactivity for gephyrin and GluR4 was found at distinct sets of puncta. The density of gephyrin IR puncta associated with ganglion cell dendrites was comparable for midget and parasol cells at all eccentricities studied (up to 2 mm or about 16 degrees of visual angle for midget cells and up to 10 mm or >80 degrees of visual angle for parasol cells). In central retina, the densities of gephyrin IR and GluR4 IR puncta associated with the dendrites of midget and parasol cells are comparable, but the average density of GluR4 IR puncta decreased slightly in peripheral parasol cells. These anatomical results indicate that the ratio of amacrine to bipolar input does not account for the distinct functional properties of parasol and midget cells or for functional differences between cells of the same type in central and peripheral retina.

Their unique patterns of size, numbers, and stratification indicate that amacrine cells have diverse functions. These are mostly unknown, as studies using imaging and electrophysiological methods have only recently begun. However, some of the events that occur within the amacrine cell population—and some important unresolved puzzles—can be stated purely from structural reasoning.

Vitamin A deficiency causes impaired vision and blindness in millions of children around the world. Previous studies in zebrafish have demonstrated that retinoic acid (RA), the acid form of vitamin A, plays a vital role in early eye development. The objective of this study was to describe the effects of early RA deficiency by treating zebrafish with diethylaminobenzaldehyde (DEAB), a potent inhibitor of the enzyme retinaldehyde dehydrogenase (RALDH) that converts retinal to RA. Zebrafish embryos were treated for 2 h beginning at 9 h postfertilization. Gross morphology and retinal development were examined at regular intervals for 5 days after treatment. The optokinetic reflex (OKR) test, visual background adaptation (VBA) test, and the electroretinogram (ERG) were performed to assess visual function and behavior. Early treatment of zebrafish embryos with 100 μM DEAB (9 h) resulted in reduced eye size, and this microphthalmia persisted through larval development. Retinal histology revealed that DEAB eyes had significant developmental abnormalities but had relatively normal retinal lamination by 5.5 days postfertilization. However, the fish showed neither an OKR nor a VBA response. Further, the retina did not respond to light as measured by the ERG. We conclude that early deficiency of RA during eye development causes microphthalmia as well as other visual defects, and that timing of the RA deficiency is critical to the developmental outcome.

Our current understanding of the spectral sensitivities of the mysticete whale rod-based visual pigments is based on two species, the gray whale (Eschrichtius robustus) and the humpback whale (Megaptera novaeangliae) possessing absorbance maxima determined from difference spectra to be 492 and 497 nm, respectively. These absorbance maxima values are blueshifted relative to those from typical terrestrial mammals (≈500 nm) but are redshifted when compared to those identified in the odontocetes (479–484 nm). Although these mysticete species represent two of the four mysticete families, they do not fully represent the mysticete whales in terms of foraging strategy and underwater photic environments where foraging occurs. In order to better understand the spectral sensitivities of the mysticete whale rod visual pigments, we have examined the rod opsin genes from 11 mysticete species and their associated amino acid substitutions. Based on the amino acids occurring at positions 83, 292, and 299 along with the directly determined dark spectra from expressed odontocete and mysticete rod visual pigments, we have determined that the majority of mysticete whales possess deep-sea and pelagic like rod visual pigments with absorbance maxima between 479 and 484 nm. Finally, we have defined the five amino acid substitution events that determine the resulting absorbance spectra and associated absorbance maxima for the mysticete whale rod visual pigments examined here.

Retinal ganglion cell line (RGC-5) has been widely used as a valuable model for studying pathophysiology and physiology of retinal ganglion cells in vitro. However, the electrophysiological characteristics, especially a thorough classification of ionic currents in the cell line, remain to be elucidated in details. In the present study, we determined the resting membrane potential (RMP) in RGC-5 cell line and then identified different types of ionic currents by using the whole-cell patch-clamp technique. The RMP recorded in the cell line was between −30 and −6 mV (−17.6 ± 2.6 mV, n = 10). We observed the following voltage-gated ion channel currents: (1) inwardly rectifying Cl− current (ICl,ir), which could be blocked by Zn2+; (2) Ca2+-activated Cl− current (ICl,Ca), which was sensitive to extracellular Ca2+ and could be inhibited by disodium 4,4’-diisothiocyanatostilbene-2,2’-disulfonate; (3) inwardly rectifying K+ currents (IK1), which could be blocked by Ba2+; (4) a small amount of delayed rectifier K+ current (IK). On the other hand, the voltage-gated sodium channels current (INa) and transient outward potassium channels current (IA) were not observed in this cell line. These results further characterize the ionic currents in the RGC-5 cell line and are beneficial for future studies especially on ion channel (patho)physiology and pharmacology in the RGC-5 cell line.

The receptive fields of on- and off-center parasol cell mosaics independently tile the retina to ensure efficient sampling of visual space. A recent theoretical model represented the on- and off-center mosaics by noisy hexagonal lattices of slightly different density. When the two lattices are overlaid, long-range Moiré interference patterns are generated. These Moiré interference patterns have been suggested to drive the formation of highly structured orientation maps in visual cortex. Here, we show that noisy hexagonal lattices do not capture the spatial statistics of parasol cell mosaics. An alternative model based upon local exclusion zones, termed as the pairwise interaction point process (PIPP) model, generates patterns that are statistically indistinguishable from parasol cell mosaics. A key difference between the PIPP model and the hexagonal lattice model is that the PIPP model does not generate Moiré interference patterns, and hence stimulated orientation maps do not show any hexagonal structure. Finally, we estimate the spatial extent of spatial correlations in parasol cell mosaics to be only 200–350 μm, far less than that required to generate Moiré interference. We conclude that parasol cell mosaics are too disordered to drive the formation of highly structured orientation maps in visual cortex.

The validity of the Barten theoretical model for describing the vertebrate spatial contrast sensitivity function (CSF) and acuity at scotopic light levels has been examined. Although this model (which has its basis in signal modulation transfer theory) can successfully describe vertebrate CSF, and its relation to underlying visual neurophysiology at photopic light levels, significant discrepancies between theory and experimental data have been found at scotopic levels. It is shown that in order to describe scotopic CSF, the theory must be modified to account for important mechanistic changes, which occur as cone vision switches to rod vision. These changes are divided into photon management factors [changes in optical performance (for a dilated pupil), quantum efficiency, receptor sampling] and neural factors (changes in spatial integration area, neural noise, and lateral inhibition in the retina). Predictions of both scotopic CSF and acuity obtained from the modified theory were found to be in good agreement with experimental values obtained from the human, macaque, cat, and owl monkey. The last two species have rod densities particularly suited for scotopic conditions.

The retina of the zebrafish (Danio rerio) provides an unusually favorable preparation for genetic and developmental studies of the retina. Although the retina has been studied extensively for two decades, the neuronal response of the inner retina is largely unknown. This report describes a prominent local field potential of the inner retina, the Proximal Negative Response (PNR). It is best evoked by small (100 μm) precisely positioned spots of light and is exceedingly sensitive to negative luminance contrast. The polarity, waveform, and other properties of the PNR suggest that it arises primarily from ON-OFF neurons of the proximal retina. The dominant response to negative contrast and its enhancement by light adaptation is believed due to a dominant presynaptic input from OFF bipolar cells. Color contrast was investigated by analyzing responses to a green bar moving on green versus red backgrounds. Over an intermediate range of irradiance, the response to green on red was larger than the response to green on green, thereby providing evidence for the encoding of color contrast. The present findings complement the classic principle of color contrast for human vision known as Kirschmann’s third law and bring to mind the view of Walls that color contrast may have been the driving force for the evolution of color vision in lower vertebrates. In sum, the PNR of zebrafish provides clear evidence for the encoding of color and luminance contrast in the inner retina. It exhibits the defining properties common to many other vertebrates, reinforcing the view that the zebrafish may further serve as a model for retinal function and that the PNR may provide a new approach for studies of development, genetics, and retinal degeneration in zebrafish.

Comparisons of S- or prepotential activity, thought to derive from a retinal ganglion cell afferent, with the activity of relay cells of the lateral geniculate nucleus (LGN) have sometimes implied a loss, or leak, of visual information. The idea of the “leaky” relay cell is reconsidered in the present analysis of prepotential firing and LGN responses of color-opponent cells of the macaque LGN to stimuli varying in size, relative luminance, and spectral distribution. Above a threshold prepotential spike frequency, called the signal transfer threshold (STT), there is a range of more than 2 log units of test field luminance that has a 1:1 relationship between prepotential- and LGN-cell firing rates. Consequently, above this threshold, the LGN cell response can be viewed as an extension of prepotential firing (a “nonleaky relay cell”). The STT level decreased when the size of the stimulus increased beyond the classical receptive field center, indicating that the LGN cell is influenced by factors other than the prepotential input. For opponent ON cells, both the excitatory and the inhibitory response decreased similarly when the test field size increased beyond the center of the receptive field. These findings have consequences for the modeling of LGN cell responses and transmission of visual information, particularly for small fields. For instance, for LGN ON cells, information in the prepotential intensity–response curve for firing rates below the STT is left to be discriminated by OFF cells. Consequently, for a given light adaptation, the STT improves the separation of the response range of retinal ganglion cells into “complementary” ON and OFF pathways.

Amacrine cells are a morphologically and functionally diverse group of inhibitory interneurons. Morphologically, they have been divided into approximately 30 types. Although this diversity is probably important to the fine structure and function of the retinal circuit, the amacrine cells have been more generally divided into two subclasses. Glycinergic narrow-field amacrine cells have dendrites that ramify close to their somas, cross the sublaminae of the inner plexiform layer, and create cross talk between its parallel ON and OFF pathways. GABAergic wide-field amacrine cells have dendrites that stretch long distances from their soma but ramify narrowly within an inner plexiform layer sublamina. These wide-field cells are thought to mediate inhibition within a sublamina and thus within the ON or OFF pathway. The postsynaptic targets of all amacrine cell types include bipolar, ganglion, and other amacrine cells. Almost all amacrine cells use GABA or glycine as their primary neurotransmitter, and their postsynaptic receptor targets include the most common GABAA, GABAC, and glycine subunit receptor configurations. This review addresses the diversity of amacrine cells, the postsynaptic receptors on their target cells in the inner plexiform layer of the retina, and some of the inhibitory mechanisms that arise as a result. When possible, the effects of GABAergic and glycinergic inputs on the visually evoked responses of their postsynaptic targets are discussed.

Metabotropic glutamate receptors (mGluRs) have been shown to be involved in the modulation of retinocollicular neurotransmission. In glaucoma, retinal ganglion cells (RGCs) degenerate, which may have an implication on this transmission as the superior colliculus is their major central target in the much-used rodent models of the disease. We have investigated this using an in vitro slice preparation of the superior colliculus by eliciting field excitatory postsynaptic potentials (fEPSPs) through optic tract stimulation in a rat ocular hypertension model of glaucoma. Application of the group III mGluR agonist L-AP4 reduced the peak amplitude of the fEPSP in superior colliculus slices through presynaptic mechanisms as previously shown in our lab. At 3 and 16 weeks after surgery, there were no significant differences in the effect of L-AP4 on fEPSP peak amplitude in the superior colliculus slices receiving input from the glaucomatous eyes [elevated intraocular pressure (IOP)] compared to those with input from the unoperated eyes (normal IOP). However, at 32 weeks, the fEPSP peak amplitude was reduced to a significantly greater degree during L-AP4 application in the elevated IOP slices compared to normal IOP slices. At all time points, there were no significant changes in the baseline amplitudes of fEPSPs or the stimulus intensities required to evoke fEPSPs. These results suggest that the modulation of synaptic transmission through group III mGluRs on RGC terminals to the superior colliculus is changed at later stages due to RGC degeneration through IOP elevation. These changes may be compensatory changes possibly through plasticity in the RGC terminals of surviving cells, which may be due to increases in the numbers of group III mGluRs. This result may have implications on further treatment studies carried out using these models of glaucoma as changes in the central visual system may need to be considered along with the retinal changes that occur.

Amacrine cells receive glutamatergic input from bipolar cells and GABAergic, glycinergic, cholinergic, and dopaminergic input from other amacrine cells. Glutamate, GABA, glycine, and acetylcholine (ACh) interact with ionotropic receptors and it is these interactions that form much of the functional circuitry in the inner retina. However, glutamate, GABA, ACh, and dopamine also activate metabotropic receptors linked to second messenger pathways that have the potential to modify the function of individual cells as well as retinal circuitry. Here, the physiological effects of activating dopamine receptors, metabotropic glutamate receptors, GABAB receptors, and muscarinic ACh receptors on amacrine cells will be discussed. The retina also expresses metabotropic receptors and the biochemical machinery associated with the synthesis and degradation of endocannabinoids and sphingosine-1-phosphate (S1P). The effects of activating cannabinoid receptors and S1P receptors on amacrine cell function will also be addressed.

The goal of this study was an administration of the navigation task in a three-dimensional virtual environment to localize the electroencephalogram (EEG) features responsible for egocentric and allocentric reference frame processing in a horizontal and also in a vertical plane. We recorded the EEG signal of a traverse through a virtual tunnel to search for the best signal features that discriminate between specific strategies in particular plane. We identified intrahemispheric coherences in occipital–parietal and temporal–parietal areas as the most discriminative features. They have 10% lower error rate compared to single electrode features adopted in previous studies. The behavioral analysis revealed that 11% of participants switched from egocentric to allocentric strategy in a vertical plane, while 24% of participants consistently adopted egocentric strategy in both planes.

This study aims to create a prediction model for state-space estimation and to elucidate the required information processing for identifying an external space in prism adaptation. Subjects were 57 healthy students. The subjects were instructed to rapidly perform reaching movements to one of the randomly illuminating light-emitting diode lights. Their movements were measured while wearing prism glasses and after removing that. We provided the following four conditions and control. In target condition, reaching error distance was visually fed back to the subject. In trajectory condition, the trajectory of fingertip movement could be seen, and the final reaching error was not fed back. Two restricted visual feedback conditions were prepared based on a different presentation timing (on-time and late-time conditions). We set up a linear parametric model and an estimation model using Kalman filtering. The goodness of fit between the estimated and observed values in each model was examined using Akaike information criterion (AIC). AIC would be one way to evaluate two models with different number of parameters. In the control, the value of AIC was 179.0 and 154.0 for the linear model and Kalman filtering, respectively, while these values were 173.6 and 161.1 for the target condition, 202.8 and 159.7 for the trajectory condition, 192.7 and 180.8 for the on-time condition, and 206.9 and 174.0 for the late-time condition. Kalman gain in the control was 0.07–0.26. Kalman gain relies on the prior estimation distribution when its value is below 0.5. Kalman gain in the trajectory and late-time conditions was 0.03–0.60 and 0.08–0.95, respectively. The Kalman filter, a state estimation model based on Bayesian theory, expressed the dynamics of the internal model under uncertain feedback information better than the linear parametric model. The probabilistic estimation model can clearly simulate state estimation according to the reliability of the visual feedback.

The aim was to investigate the temporal response properties of magnocellular, parvocellular, and koniocellular visual pathways using increment/decrement changes in contrast to elicit visual evoked potentials (VEPs). Static achromatic and isoluminant chromatic gratings were generated on a monitor. Chromatic gratings were modulated along red/green (R/G) or subject-specific tritanopic confusion axes, established using a minimum distinct border criterion. Isoluminance was determined using minimum flicker photometry. Achromatic and chromatic VEPs were recorded to contrast increments and decrements of 0.1 or 0.2 superimposed on the static gratings (masking contrast 0–0.6). Achromatic increment/decrement changes in contrast evoked a percept of apparent motion when the spatial frequency was low; VEPs to such stimuli were positive in polarity and largely unaffected by high levels of static contrast, consistent with transient response mechanisms. VEPs to finer achromatic gratings showed marked attenuation as static contrast was increased. Chromatic VEPs to R/G or tritan chromatic contrast increments were of negative polarity and showed progressive attenuation as static contrast was increased, in keeping with increasing desensitization of the sustained responses of the color-opponent visual pathways. Chromatic contrast decrement VEPs were of positive polarity and less sensitive to pattern adaptation. The relative contribution of sustained/transient mechanisms to achromatic processing is spatial frequency dependent. Chromatic contrast increment VEPs reflect the sustained temporal response properties of parvocellular and koniocellular pathways. Cortical VEPs can provide an objective measure of pattern adaptation and can be used to probe the temporal response characteristics of different visual pathways.