Neuronal response latency usually refers to the time between the presentation of a visual stimulus and the elevation in firing rate that follows. Expanding on this idea, the concept of response offset latency refers to the time between the removal of a stimulus (or its replacement with one that is less effective) and the resulting decline in firing rate. The initial observation that offset latency is usually shorter than onset latency (Bair et al., 2002) has been called into question on the basis of the pulsatile nature of visual stimuli presented on a CRT (Gawne & Woods, 2003). Here, a counter argument is presented in support of the results of Bair et al., 2002.

The mammalian retina contains three classes of photoreceptor. In addition to the rods and cones, a subset of retinal ganglion cells that express the putative sensory photopigment melanopsin are intrinsically photosensitive. Functional and anatomical studies suggest that these inner retinal photoreceptors provide light information for a number of non-image-forming light responses including photoentrainment of the circadian clock and the pupil light reflex. Here, we employ a newly developed mouse model bearing lesions of both rod and cone phototransduction cascades (Rho−/−Cnga3−/−) to further examine the function of these non-rod non-cone photoreceptors. Calcium imaging confirms the presence of inner retinal photoreceptors in Rho−/−Cnga3−/− mice. Moreover, these animals retain a pupil light reflex, photoentrainment, and light induction of the immediate early gene c-fos in the suprachiasmatic nuclei, consistent with previous findings that pupillary and circadian responses can employ inner retinal photoreceptors. Rho−/−Cnga3−/− mice also show a light-dependent increase in the number of FOS-positive cells in both the ganglion cell and (particularly) inner nuclear layers of the retina. The average number of cells affected is several times greater than the number of melanopsin-positive cells in the mouse retina, suggesting functional intercellular connections from these inner retinal photoreceptors within the retina. Finally, however, while we show that wild types exhibit an increase in heart rate upon light exposure, this response is absent in Rho−/−Cnga3−/− mice. Thus, it seems that non-rod non-cone photoreceptors can drive many, but not all, non-image-forming light responses.

Spectral-sensitivity functions for large, long-duration increments presented on a photopic white background indicate that wavelength-opponent mechanisms mediate detection in both normal and dichromatic humans. Normal humans exhibit high color-vision sensitivity as they discriminate the color of spectral flashes at detection-threshold intensities. However, dichromatic humans require stimuli up to about 0.4 log units above detection intensity to see certain colors. This low color-vision sensitivity in human dichromats may be an abnormal condition involving a defect in postreceptoral color processing. To test this hypothesis, we determined color-discrimination thresholds in normally dichromatic species: chipmunk, 13-lined ground squirrel, and tree shrew. For comparison, we also tested humans with normal and abnormal (deutan) color vision with the same apparatus and methods. Animals were trained to perform spatial two-choice discrimination tasks for food reward. Detection thresholds were determined for increments of white, 460 nm, 540 nm, 560 nm, 580 nm, 500 nm/long-pass, and 500 nm/short-pass on white backgrounds of 1.25 cd/m2, 46 cd/m2, and 130 cd/m2. Animals were also trained to respond to the colored increments when paired with the white increment when both were at equally detectable intensities Color-discrimination thresholds were determined by dimming stimulus pairs (colored vs. white) until the subjects could no longer make the discriminations. Results indicated that the normally dichromatic species could discriminate colored stimuli from white at a mean intensity of 0.1 (±0.1) log units above detection threshold. The ability of normally dichromatic species to discriminate color near detection-threshold intensity is consistent with increment spectral-sensitivity functions that indicate detection by wavelength-opponent mechanisms. In keeping with previous studies, normal human trichromats discriminated color near detection-threshold intensities but humans with deutan color vision required suprathreshold intensities to discriminate the color of middle and long wavelengths. This high color-vision sensitivity of normally dichromatic species suggests that the low color-vision sensitivity in dichromatic humans is an abnormal condition and indicates a possible defect in their postreceptoral color-vision processing.

At very low light levels the sensitivity of the visual system is determined by the efficiency with which single photons are captured, and the resulting signal transmitted from the rod photoreceptors through the retinal circuitry to the ganglion cells and on to the brain. Although the tiny electrical signals due to single photons have been observed in rod photoreceptors, little is known about how these signals are preserved during subsequent transmission to the optic nerve. We find that the synaptic currents elicited by single photons in mouse rod bipolar cells have a peak amplitude of 5–6 pA, and that about 20 rod photoreceptors converge upon each rod bipolar cell. The data indicates that the first synapse, between rod photoreceptors and rod bipolar cells, signals a binary event: the detection, or not, of a photon or photons in the connected rod photoreceptors. We present a simple model that demonstrates how a threshold nonlinearity during synaptic transfer allows transmission of the single photon signal, while rejecting the convergent neural noise from the 20 other rod photoreceptors feeding into this first synapse.

In the juvenile trkB knockout (trkB−/−) mouse, retina synaptic communication from rods to bipolar cells is severely compromised as evidenced by a complete absence of electroretinogram (ERG) b-wave, even though the inner retina appears anatomically normal (Rohrer et al., 1999). Since it is well known that the b-wave reflects light-dependent synaptic activation of ON bipolar cells via their metabotropic glutamate receptor, mGluR6, we sought to analyze the anatomical and functional integrity of the glutamatergic synapses at these and other bipolar cells in the trkB−/− mouse. Although rod bipolar cells from wild-type juvenile mice were determined to be immunopositive for trkB, postsynaptic metabotropic and ionotropic glutamate receptor-mediated pathways in ON and OFF bipolar cells were found to be functionally intact, based on patch electrode recordings, using brief applications (“puffs”) of glutamate or its analog, 2-amino-4-phosphonobutyric acid (APB), a selective agonist for mGluR6 receptors. Ionotropic glutamate receptor function was assayed in OFF-cone bipolar and horizontal cells by applying exogenous glutamatergic agonists in the presence of the channel-permeant guanidinium analogue, 1-amino-4-guanidobutane (AGB). Electron-microscopic analysis revealed that the ribbon synapses between rods and postsynaptic rod bipolar and horizontal cells were formed at the appropriate age and appear to be structurally intact, and immunohistochemical analysis did not detect profound defects in the expression of excitatory amino acid transporters involved in glutamate clearance from the synaptic cleft. These data indicate that there does not appear to be evidence for postsynaptic deficits in glutamatergic signaling in the ON and OFF bipolar cells of mice lacking trkB.

The visual arrestins in rhabdomeral photoreceptors are multifunctional phosphoproteins. They are rapidly phosphorylated in response to light, but the functional relevance of this phosphorylation is not yet fully understood. The phosphorylation of Limulus visual arrestin is particularly complex in that it becomes phosphorylated on three sites, and one or more of these site are phosphorylated even in the dark. The purpose of this study was to examine in detail the light-stimulated phosphorylation of each of the three sites in Limulus visual arrestin in intact photoreceptors. We found that light increased the phosphorylation of all three sites (S377, S381, and S396), that S381 is a preferred phosphorylation site, and that S377 and S381 are highly phosphorylated in the dark. The major effect of light was to increase the phosphorylation of S396, the site located closest to the C-terminal and very close to the adaptin binding motif. We speculate that the phosphorylation of this site may be particularly important for regulating the light-driven endocytosis of rhabdomeral membrane.

Early in life, visual experience appears to influence the refinement and maintenance of the orientation-selective responses of neurons in the primary visual cortex. After eye opening, the statistical structure of visually driven neural responses depends not only on the stimulus, but also on how the stimulus is scanned during behavior. Modulations of neural activity due to behavior may thus play a role in the experience-dependent refinement of cell response characteristics. To investigate the possible influences of eye movements on the maturation of thalamocortical connectivity, we have simulated the responses of neuronal populations in the lateral geniculate nucleus (LGN) and V1 of the cat while images of natural scenes were scanned in a way that replicated the cat's oculomotor activity. In the model, fixational eye movements were essential to attenuate neural sensitivity to the broad correlational structure of natural visual input, decorrelate neural responses, and establish a regime of neural activity that was compatible with a Hebbian segregation of geniculate afferents to the cortex. We show that this result is highly robust and does not depend on the precise characteristics of the model.

The mdxCv3 mouse is a model for Duchenne muscular dystrophy (DMD). DMD is an X-linked disorder with defective expression of the protein dystrophin, and which is associated with a reduced b-wave and has other electro- retinogram (ERG) abnormalities. To assess potential causes for the abnormalities, we recorded ERGs from pieces of isolated C57BL/6J and mdxCv3 mouse retinas, including measurements of transretinal and intraretinal potentials. The ERGs from the isolated mdxCv3 retina differ from those of control retinas in that they show reduced b-wave amplitudes and increased b-wave implicit times. Photovoltages obtained by recording across the photoreceptor outer segments of the retinas did not differ from normal, suggesting that the likely causes of the reduced b-wave are localized to the photoreceptor to ON-bipolar synapse. At a concentration of 50 μM, the glutamate analog DL-2-amino-4-phosphonobutyric acid (APB) blocks the b-wave component of the ERG, by binding to sites on the postsynaptic membrane. The On-bipolar cell contribution to the ERG was inferred by extracting the component that was blocked by APB. We found that this component was smaller in amplitude and had longer response latencies in the mdxCv3 mice, but was of similar overall time course. To assess the sensitivity of sites on the postsynaptic membrane to glutamate, the concentration of APB in the media was systematically varied, and the magnitude of blockage of the light response was quantified. We found that the mdxCv3 retina was 5-fold more sensitive to APB than control retinas. The ability of lower concentrations of APB to block the b-wave in mdxCv3 suggests that the ERG abnormalities may reflect alterations in either glutamate release, the glutamate postsynaptic binding sites, or in other proteins that modulate glutamate function in ON-bipolar cells.

Why photoreceptors turn over a portion of their photoreceptive membrane daily is not clear; however, failure to do so properly leads to retinal degeneration in vertebrates and invertebrates. Little is known about the molecular mechanisms that regulate shedding and renewal of photoreceptive membrane. Photoreceptor cells in the lateral eye of the horseshoe crab Limulus turn over their photoreceptive membrane (rhabdom) in a brief, synchronous burst in response to dawn each morning. Transient rhabdom shedding (TRS), the first phase of rhabdom turnover in Limulus, is triggered by dawn, but requires a minimum of 3–5 h of overnight priming from the central circadian clock (Chamberlain & Barlow, 1984). We determined previously that the clock primes the lateral eye for TRS using the neurotransmitter octopamine (OA) (Khadilkar et al., 2002), and report here that OA primes the eye for TRS through a Gs-coupled, adenylate cyclase (AC)/cyclic adenosine 3′,5′-monophosphate (cAMP)/cAMP-dependent protein kinase (PKA) signaling cascade. Long-term intraretinal injections (6–7 h @ 1.4 μl/min) of the AC activator forskolin, or the cAMP analogs Sp-cAMP[S] and 8-Br-cAMP primed the retina for TRS in eyes disconnected from the circadian clock, and/or in intact eyes during the day when the clock is quiescent. This suggests that OA primes the eye for TRS by stimulating an AC-mediated rise in intracellular cAMP concentration ([cAMP]i). Co-injection of SQ 22,536, an AC inhibitor, or the PKA inhibitors H-89 and PKI (14-22) with OA effectively antagonized octopaminergic priming by reducing the number of photoreceptors primed for TRS and the amount of rhabdom shed by those photoreceptors compared with eyes treated with OA alone. Our data suggest that OA primes the lateral eye for TRS in part through long-term phosphorylation of a PKA substrate.

The dorso-laterally located eyes of the southern hemisphere lamprey Mordacia mordax (Agnatha) contain a single morphological type of retinal photoreceptor, which possesses ultrastructural characteristics of both rods and cones. This photoreceptor has a large refractile ellipsosome in the inner segment and a long cylindrical outer segment surrounded by a retinal pigment epithelium that contains two types of tapetal reflectors. The photoreceptors form a hexagonal array and attain their peak density (33,200 receptors/mm2) in the ventro-temporal retina. Using the size and spacing of the photoreceptors and direct measures of aperture size and eye dimensions, the peak spatial resolving power and optical sensitivity are estimated to be 1.7 cycles deg−1 (minimum separable angle of 34′7′′) and 0.64 μm2 steradian (white light) and 1.38 μm2 steradian (preferred wavelength or λmax), respectively. Microspectrophotometry reveals that the visual pigment located within the outer segment is a rhodopsin with a wavelength of maximum absorbance (λmax) at 514 nm. The ellipsosome has very low absorptance (<0.05) across the measured spectrum (350–750 nm) and probably does not act as a spectral filter. In contrast to all other lampreys studied, the optimized receptor packing, the large width of the ellipsosome-bearing inner segment, together with the presence of a retinal tapetum in the photophobic Mordacia, all represent adaptations for low light vision and optimizing photon capture.

Mechanisms underlying the development of the primate area of high acuity (AHA) remain poorly understood. Finite-element models have identified retinal stretch and intraocular pressure (IOP) as possible mechanical forces that can form a pit (Springer & Hendrickson, 2004). A series of Macaca nemestrina monkey retinas between 68 days postconception (dpc) and adult were used to quantify growth and morphological changes. Retinal and pars plana length, optic disc diameter, disc-pit distance, and inner and outer retinal laminar thickness were measured over development to identify when and where IOP or stretch might operate. Horizontal optic disc diameter increased 500 μm between 115 dpc and 2 months after birth when it reached adult diameter. Disc growth mainly influences the immediate surrounding retina, presumably displacing retinal tissue centrifugally. Pars plana elongation also began at 115 dpc and continued steadily to 3–4 years postnatal, so its influence would be relatively constant over retinal development. Unexpectedly, horizontal retinal length showed nonlinear growth, divided into distinct phases. Retinal length increased rapidly until 115 dpc and then remained unchanged (quiescent phase) between 115–180 dpc. After birth, the retina grew rapidly for 3 months and then very slowly into adulthood. The onset of pit development overlapped the late fetal quiescent phase, suggesting that the major mechanical factor initiating pit formation is IOP, not retinal growth-induced stretch. Developmental changes in the thickness of retinal layers were different for inner and outer retina at many, but not all, of the ten eccentricities examined. Peripheral inner and outer retinal layers thinned appreciably with age, consistent with retinal stretch having a larger effect on the retinal periphery. Central inner retina around the area of high acuity (AHA) changed tri-phasically. It increased in thickness prenatally, thinned transiently after birth, and then resumed thickening. Transient postnatal inner retinal thinning around the pit coincided with the resumption of retinal growth and with cone packing providing evidence that a small amount of growth-induced central retinal stretch may account for cone packing as previously hypothesized (Springer, 1999). Central outer retina around the AHA progressively thickened over the fetal period. It reached asymptotic thickness at birth and continued to thicken into adulthood at some temporal, but not nasal, central eccentricities. These data indicate that peripheral outer and inner retina progressively thin with age because of eye growth-induced stretch, while central retina is minimally affected by stretch. Outer and inner retinal laminar thickness at the same locus can change in different directions, suggesting that they shear with respect to one another. This shearing induces the elongation of Henle axons, while their angle reflects the direction of shear.

Gap junctions are commonplace in retina, often between cells of the same morphological type, but sometimes linking different cell types. The strength of coupling between cells derives from the properties of the connexins, but also is regulated by the intracellular environment of each cell. We measured the relative coupling of two different gap junctions made by AII amacrine cells of the rabbit retina. Permeability to the tracer Neurobiotin was measured at different concentrations of the neuromodulators dopamine, nitric oxide, or cyclic adenosine monophosphate (cAMP) analogs. Diffusion coefficients were calculated separately for the gap junctions between pairs of AII amacrine cells and for those connecting AII amacrine cells with ON cone bipolar cells. Increased dopamine caused diffusion rates to decline more rapidly across the AII–AII gap junctions than across the AII–bipolar cell gap junctions. The rate of decline at these sites was well fit by a model proposing that dopamine modulates two independent gates in AII–AII channels, but only a single gate on the AII side of the AII–bipolar channel. However, a membrane-permeant cAMP agonist modulated both types of channel equally. Therefore, the major regulator of channel closure in this network is the local cAMP concentration within each cell, as regulated by dopamine, rather than different cAMP sensitivity of their respective gates. In contrast, nitric oxide preferentially reduced AII–bipolar cell permeabilities. Coupling from AII amacrine cells to the different bipolar cell subtypes was differentially affected by dopamine, indicating that light adaptation acting via dopamine release alters network coupling properties in multiple ways.