Photoreceptor Adaptation Research Articles

Regional tuning of photoreceptor adaptation in the primate retina

Adaptation in cone photoreceptors allows our visual system to effectively operate over an enormous range of light intensities. However, little is known about the properties of cone adaptation in the specialized region of the primate central retina called the fovea, which is densely packed with cones and mediates high-acuity central vision. Here we show that macaque foveal cones exhibit weaker and slower luminance adaptation compared to cones in the peripheral retina. We find that this difference in adaptive properties between foveal and peripheral cones is due to differences in the magnitude of a hyperpolarization-activated current, Ih. This Ih current regulates the strength and time course of luminance adaptation in peripheral cones where it is more prominent than in foveal cones. A weaker and slower adaptation in foveal cones helps maintain a higher sensitivity for a longer duration which may be well-suited for maximizing the collection of high-acuity information at the fovea during gaze fixation between rapid eye movements.

Biophysical neural adaptation mechanisms enable artificial neural networks to capture dynamic retinal computation

Adaptation is a universal aspect of neural systems that changes circuit computations to match prevailing inputs. These changes facilitate efficient encoding of sensory inputs while avoiding saturation. Conventional artificial neural networks (ANNs) have limited adaptive capabilities, hindering their ability to reliably predict neural output under dynamic input conditions. Can embedding neural adaptive mechanisms in ANNs improve their performance? To answer this question, we develop a new deep learning model of the retina that incorporates the biophysics of photoreceptor adaptation at the front-end of conventional convolutional neural networks (CNNs). These conventional CNNs build on ’Deep Retina,’ a previously developed model of retinal ganglion cell (RGC) activity. CNNs that include this new photoreceptor layer outperform conventional CNN models at predicting male and female primate and rat RGC responses to naturalistic stimuli that include dynamic local intensity changes and large changes in the ambient illumination. These improved predictions result directly from adaptation within the phototransduction cascade. This research underscores the potential of embedding models of neural adaptation in ANNs and using them to determine how neural circuits manage the complexities of encoding natural inputs that are dynamic and span a large range of light levels.

Horizontal-cell like Dm9 neurons in Drosophila modulate photoreceptor output to supply multiple functions in early visual processing.

Dm9 neurons in Drosophila have been proposed as functional homologs of horizontal cells in the outer retina of vertebrates. Here we combine genetic dissection of neuronal circuit function, two-photon calcium imaging in Dm9 and inner photoreceptors, and immunohistochemical analysis to reveal novel insights into the functional role of Dm9 in early visual processing. Our experiments show that Dm9 receive input from all four types of inner photoreceptor R7p, R7y, R8p, and R8y. Histamine released from all types R7/R8 directly inhibits Dm9 via the histamine receptor Ort, and outweighs simultaneous histamine-independent excitation of Dm9 by UV-sensitive R7. Dm9 in turn provides inhibitory feedback to all R7/R8, which is sufficient for color-opponent processing in R7 but not R8. Color opponent processing in R8 requires additional synaptic inhibition by R7 of the same ommatidium via axo-axonal synapses and the second Drosophila histamine receptor HisCl1. Notably, optogenetic inhibition of Dm9 prohibits color opponent processing in all types of R7/R8 and decreases intracellular calcium in photoreceptor terminals. The latter likely results from reduced release of excitatory glutamate from Dm9 and shifts overall photoreceptor sensitivity toward higher light intensities. In summary, our results underscore a key role of Dm9 in color opponent processing in Drosophila and suggest a second role of Dm9 in regulating light adaptation in inner photoreceptors. These novel findings on Dm9 are indeed reminiscent of the versatile functions of horizontal cells in the vertebrate retina.

Genetic manipulation of rod-cone differences in mouse retina.

Though rod and cone photoreceptors use similar phototransduction mechanisms, previous model calculations have indicated that the most important differences in their light responses are likely to be differences in amplification of the G-protein cascade, different decay rates of phosphodiesterase (PDE) and pigment phosphorylation, and different rates of turnover of cGMP in darkness. To test this hypothesis, we constructed TrUx;GapOx rods by crossing mice with decreased transduction gain from decreased transducin expression, with mice displaying an increased rate of PDE decay from increased expression of GTPase-activating proteins (GAPs). These two manipulations brought the sensitivity of TrUx;GapOx rods to within a factor of 2 of WT cone sensitivity, after correcting for outer-segment dimensions. These alterations did not, however, change photoreceptor adaptation: rods continued to show increment saturation though at a higher background intensity. These experiments confirm model calculations that rod responses can mimic some (though not all) of the features of cone responses after only a few changes in the properties of transduction proteins.

Poster Session II: Light-adaptation clamp: A tool to predictably manipulate photoreceptor light responses.

Computation in neural circuits relies on judicious use of nonlinear circuit components. In many cases, multiple nonlinear components work collectively to control circuit outputs. Separating the contributions of these different components is difficult, and this hampers our understanding of the mechanistic basis of many important computations. Here, we introduce a tool that permits the design of light stimuli that predictably alter rod and cone phototransduction currents - including the compensation for nonlinear properties such as light adaptation. This tool, based on well-established models for the rod and cone phototransduction cascade, permits the separation of nonlinearities in phototransduction from those in downstream circuits. This will allow, for example, direct tests of the role of photoreceptor adaptation in downstream visual signals or in perception.

Dynamical adaptation in photoreceptors with gain control

The retina hosts all processes needed to convert external visual stimuli into a neural code. Light phototransduction and its conversion into an electrical signal involve biochemical cascades, ionic regulations, and different kinds of coupling, among other relevant processes. These create a nonlinear processing scheme and light-dependent adaptive responses. The dynamical adaptation model formulated in recent years is an excellent phenomenological candidate to resume all these phenomena into a single feedforward processing scheme. In this work, we analyze this description in highly nonlinear conditions and find that responses do not match those resulting from a very detailed microscopic model, developed to reproduce electrophysiological recordings on horizontal cells. When a delayed light-dependent gain factor incorporates into the description, responses are in excellent agreement, even when spanning several orders of magnitude in light intensity, contrast, and duration, for simple and complex stimuli. This extended model may be instrumental for studies of the retinal function, enabling the linking of the microscopic domain to the understanding of signal processing properties, and further incorporated in spatially extended retinal networks.

Adaptation in cone photoreceptors contributes to an unexpected insensitivity of primate On parasol retinal ganglion cells to spatial structure in natural images.

Neural circuits are constructed from nonlinear building blocks, and not surprisingly overall circuit behavior is often strongly nonlinear. But neural circuits can also behave near linearly, and some circuits shift from linear to nonlinear behavior depending on stimulus conditions. Such control of nonlinear circuit behavior is fundamental to neural computation. Here, we study a surprising stimulus dependence of the responses of macaque On (but not Off) parasol retinal ganglion cells: these cells respond nonlinearly to spatial structure in some stimuli but near linearly to spatial structure in others, including natural inputs. We show that these differences in the linearity of the integration of spatial inputs can be explained by a shift in the balance of excitatory and inhibitory synaptic inputs that originates at least partially from adaptation in the cone photoreceptors. More generally, this highlights how subtle asymmetries in signaling - here in the cone signals - can qualitatively alter circuit computation.

First-order visual interneurons distribute distinct contrast and luminance information across ON and OFF pathways to achieve stable behavior.

The accurate processing of contrast is the basis for all visually guided behaviors. Visual scenes with rapidly changing illumination challenge contrast computation because photoreceptor adaptation is not fast enough to compensate for such changes. Yet, human perception of contrast is stable even when the visual environment is quickly changing, suggesting rapid post receptor luminance gain control. Similarly, in the fruit fly Drosophila, such gain control leads to luminance invariant behavior for moving OFF stimuli. Here, we show that behavioral responses to moving ON stimuli also utilize a luminance gain, and that ON-motion guided behavior depends on inputs from three first-order interneurons L1, L2, and L3. Each of these neurons encodes contrast and luminance differently and distributes information asymmetrically across both ON and OFF contrast-selective pathways. Behavioral responses to both ON and OFF stimuli rely on a luminance-based correction provided by L1 and L3, wherein L1 supports contrast computation linearly, and L3 non-linearly amplifies dim stimuli. Therefore, L1, L2, and L3 are not specific inputs to ON and OFF pathways but the lamina serves as a separate processing layer that distributes distinct luminance and contrast information across ON and OFF pathways to support behavior in varying conditions.

EML1 is essential for retinal photoreceptor migration and survival

Calcium regulates the response sensitivity, kinetics and adaptation in photoreceptors. In striped bass cones, this calcium feedback includes direct modulation of the transduction cyclic nucleotide-gated (CNG) channels by the calcium-binding protein CNG-modulin. However, the possible role of EML1, the mammalian homolog of CNG-modulin, in modulating phototransduction in mammalian photoreceptors has not been examined. Here, we used mice expressing mutant Eml1 to investigate its role in the development and function of mouse photoreceptors using immunostaining, in-vivo and ex-vivo retinal recordings, and single-cell suction recordings. We found that the mutation of Eml1 causes significant changes in the mouse retinal structure characterized by mislocalization of rods and cones in the inner retina. Consistent with the fraction of mislocalized photoreceptors, rod and cone-driven retina responses were reduced in the mutants. However, the Eml1 mutation had no effect on the dark-adapted responses of rods in the outer nuclear layer. Notably, we observed no changes in the cone sensitivity in the Eml1 mutant animals, either in darkness or during light adaptation, ruling out a role for EML1 in modulating cone CNG channels. Together, our results suggest that EML1 plays an important role in retina development but does not modulate phototransduction in mammalian rods and cones.

An Efficient Digital Realization of Retinal Light Adaptation in Cone Photoreceptors

In recent years, hardware modeling for various parts of the body’s sensitive organs, including the brain and nervous system, heart and eyes, has been considered for the treatment of diseases and rehabilitation, as well as for moving towards the construction of artificial prostheses. The retina is a thin layer that is the innermost layer of the human eye. In this paper, low-cost hardware implementation for retinal cone cells is performed. Existing mathematical models for implementing the behavior of these cells include a series of nonlinear functions that, if implemented directly, would require a large amount of hardware and, in addition, would not have the desired speed. The proposed model uses multi-linear functions to approximate the nonlinear terms and eliminate the multiplication expressions. The simulation results show that the proposed model tracks the behavior of the original model with high precision. There is also a good match between the main model and the proposed model in terms of dynamic behaviors. The results of hardware implementation using the virtex5 XC5VLX20T (2FF323) reconfigurable board (FPGA) show that the proposed model is fully valid and has a lower hardware volume as well as a 4 times higher frequency, and 22% less power consumption than the original model.

Adaptive light: a lighting control method aligned with dark adaptation of human vision

Light exposure before sleep causes a reduction in the quality and duration of sleep. In order to reduce these detrimental effects of light exposure, it is important to dim the light. However, dimming the light often causes inconvenience and can lower the quality of life (QOL). We therefore aimed to develop a lighting control method for use before going to bed, in which the illuminance of lights can be ramped down with less of a subjective feeling of changes in illuminance. We performed seven experiments in a double-blind, randomized crossover design. In each experiment, we compared two lighting conditions. We examined constant illuminance, linear dimming, and three monophasic and three biphasic exponential dimming, to explore the fast and slow increases in visibility that reflect the dark adaptation of cone and rod photoreceptors in the retina, respectively. Finally, we developed a biphasic exponential dimming method termed Adaptive Light 1.0. Adaptive Light 1.0 significantly prevented the misidentification seen in constant light and effectively suppressed perceptions of the illuminance change. This novel lighting method will help to develop new intelligent lighting instruments that reduce the negative effect of light on sleep and also lower energy consumption.

Mislocalization of cone nuclei impairs cone function in mice.

The nuclei of cone photoreceptors are located on the apical side of the outer nuclear layer (ONL) in vertebrate retinas. However, the functional role of this evolutionarily conserved localization of cone nuclei is unknown. We previously showed that Linkers of the Nucleoskeleton to the Cytoskeleton (LINC complexes) are essential for the apical migration of cone nuclei during development. Here, we developed an efficient genetic strategy to disrupt cone LINC complexes in mice. Experiments with animals from both sexes revealed that disrupting cone LINC complexes resulted in mislocalization of cone nuclei to the basal side of ONL in mouse retina. This, in turn, disrupted cone pedicle morphology, and appeared to reduce the efficiency of synaptic transmission from cones to bipolar cells. Although we did not observe other developmental or phototransduction defects in cones with mislocalized nuclei, their dark adaptation was impaired, consistent with a deficiency in chromophore recycling. These findings demonstrate that the apical localization of cone nuclei in the ONL is required for the timely dark adaptation and efficient synaptic transmission in cone photoreceptors.

High-Throughput Ca2+ Flux Assay To Monitor Cyclic Nucleotide-Gated Channel Activity and Characterize Achromatopsia Mutant Channel Function.

Cone photoreceptor cyclic-nucleotide gated channels (CNG) are tetrameric proteins composed of subunits from CNGA3 and CNGB3. These channels transduce light information into electrical signals carried by both Na+ and Ca2+ ions. More than 100 mutations in the CNGA3 gene are associated with the inherited retinal disorder, achromatopsia 2 (ACHM2), which results in attenuation or loss of color vision, daylight blindness, and reduced visual acuity. Classical techniques to measure CNG channel function utilize patch clamp electrophysiology measuring Na currents in the absence of divalent cations, yet intracellular Ca2+ regulates both light and dark adaptation in photoreceptors. We developed a fluorescence-based, high-throughput Ca2+ flux assay using yellow fluorescent protein (YFP) tagged CNGA3 channels expressed in HEK293 cells which allow monitoring for folding defects in mutant channels. The cell permeant cGMP analog, 8-(4-chlorophenylthio)-cGMP (CPT-cGMP), was used to activate Ca2+ flux. The assay was validated using wild-type CNGA3 homomeric and heteromeric channels and ACHM2-associated homomeric mutant CNG channels, CNGA3-R427C, CNGA3-E590K, and CNGA3-L633P. Additionally, we examined two naturally occurring canine mutations causing day-blindness previously studied by patch clamp. We compared the CPT-cGMP K0.5 values of the channels with patch clamp values from previous studies. The assay provides a screen for modulation of gating and/or rescue of trafficking and/or misfolding defects in ACHM2-associated CNG channels. Importantly, the calcium flux assay is advantageous compared to patch clamp as it allows the ability to monitor CNG channel activity in the presence of calcium.

The Role of the Voltage-Gated Potassium Channel Proteins Kv8.2 and Kv2.1 in Vision and Retinal Disease: Insights from the Study of Mouse Gene Knock-Out Mutations.

Mutations in the KCNV2 gene, which encodes the voltage-gated K+ channel protein Kv8.2, cause a distinctive form of cone dystrophy with a supernormal rod response (CDSRR). Kv8.2 channel subunits only form functional channels when combined in a heterotetramer with Kv2.1 subunits encoded by the KCNB1 gene. The CDSRR disease phenotype indicates that photoreceptor adaptation is disrupted. The electroretinogram (ERG) response of affected individuals shows depressed rod and cone activity, but what distinguishes this disease is the supernormal rod response to a bright flash of light. Here, we have utilized knock-out mutations of both genes in the mouse to study the pathophysiology of CDSRR. The Kv8.2 knock-out (KO) mice show many similarities to the human disorder, including a depressed a-wave and an elevated b-wave response with bright light stimulation. Optical coherence tomography (OCT) imaging and immunohistochemistry indicate that the changes in six-month-old Kv8.2 KO retinae are largely limited to the outer nuclear layer (ONL), while outer segments appear intact. In addition, there is a significant increase in TUNEL-positive cells throughout the retina. The Kv2.1 KO and double KO mice also show a severely depressed a-wave, but the elevated b-wave response is absent. Interestingly, in all three KO genotypes, the c-wave is totally absent. The differential response shown here of these KO lines, that either possess homomeric channels or lack channels completely, has provided further insights into the role of K+ channels in the generation of the a-, b-, and c-wave components of the ERG.

Apo-Opsin Exists in Equilibrium Between a Predominant Inactive and a Rare Highly Active State.

Bleaching adaptation in rod photoreceptors is mediated by apo-opsin, which activates phototransduction with effective activity 105- to 106-fold lower than that of photoactivated rhodopsin (meta II). However, the mechanism that produces such low opsin activity is unknown. To address this question, we sought to record single opsin responses in mouse rods. We used mutant mice lacking efficient calcium feedback to boosts rod responses and generated a small fraction of opsin by photobleaching ∼1% of rhodopsin. The bleach produced a dramatic increase in the frequency of discrete photoresponse-like events. This activity persisted for hours, was quenched by 11-cis-retinal, and was blocked by uncoupling opsin from phototransduction, all indicating opsin as its source. Opsin-driven discrete activity was also observed in rods containing non-activatable rhodopsin, ruling out transactivation of rhodopsin by opsin. We conclude that bleaching adaptation is mediated by opsin that exists in equilibrium between a predominant inactive and a rare meta II-like state.SIGNIFICANCE STATEMENT Electrophysiological analysis is used to show that the G-protein-coupled receptor opsin exists in equilibrium between a predominant inactive and a rare highly active state that mediates bleaching adaptation in photoreceptors.

Dephosphorylation by protein phosphatase 2A regulates visual pigment regeneration and the dark adaptation of mammalian photoreceptors

Resetting of G-protein-coupled receptors (GPCRs) from their active state back to their biologically inert ground state is an integral part of GPCR signaling. This "on-off" GPCR cycle is regulated by reversible phosphorylation. Retinal rod and cone photoreceptors arguably represent the best-understood example of such GPCR signaling. Their visual pigments (opsins) are activated by light, transduce the signal, and are then inactivated by a GPCR kinase and arrestin. Although pigment inactivation by phosphorylation is well understood, the enzyme(s) responsible for pigment dephosphorylation and the functional significance of this reaction remain unknown. Here, we show that protein phosphatase 2A (PP2A) acts as opsin phosphatase in both rods and cones. Elimination of PP2A substantially slows pigment dephosphorylation, visual chromophore recycling, and ultimately photoreceptor dark adaptation. These findings demonstrate that visual pigment dephosphorylation regulates the dark adaptation of photoreceptors and provide insights into the role of this reaction in GPCR signaling.

LED Lights With Hidden Intensity-Modulated Blue Channels Aiming for Enhanced Subconscious Visual Responses.

A new form of light-emitting diode (LED) light suitable for general illumination is proposed to enhance subconscious, nonimage-forming visual responses, which are essential to our well-being. Pulsing light has been shown to reduce photoreceptor adaptation and elicit stronger subconscious visual responses at an indoor illumination level. Using the silent substitution technique, a melanopsin-selective flicker can be added into white light. A linear optimization algorithm was developed to suppress any perceivable fluctuation of light intensity and colors of illuminated objects. Two examples of lights are given to illustrate the potential applications of the proposed multi-LED light for general illumination and therapeutic purposes.

A novel mechanism of cone photoreceptor adaptation.

An animal’s ability to survive depends on its sensory systems being able to adapt to a wide range of environmental conditions, by maximizing the information extracted and reducing the noise transmitted. The visual system does this by adapting to luminance and contrast. While luminance adaptation can begin at the retinal photoreceptors, contrast adaptation has been shown to start at later stages in the retina. Photoreceptors adapt to changes in luminance over multiple time scales ranging from tens of milliseconds to minutes, with the adaptive changes arising from processes within the phototransduction cascade. Here we show a new form of adaptation in cones that is independent of the phototransduction process. Rather, it is mediated by voltage-gated ion channels in the cone membrane and acts by changing the frequency response of cones such that their responses speed up as the membrane potential modulation depth increases and slow down as the membrane potential modulation depth decreases. This mechanism is effectively activated by high-contrast stimuli dominated by low frequencies such as natural stimuli. However, the more generally used Gaussian white noise stimuli were not effective since they did not modulate the cone membrane potential to the same extent. This new adaptive process had a time constant of less than a second. A critical component of the underlying mechanism is the hyperpolarization-activated current, Ih, as pharmacologically blocking it prevented the long- and mid- wavelength sensitive cone photoreceptors (L- and M-cones) from adapting. Consistent with this, short- wavelength sensitive cone photoreceptors (S-cones) did not show the adaptive response, and we found they also lacked a prominent Ih. The adaptive filtering mechanism identified here improves the information flow by removing higher-frequency noise during lower signal-to-noise ratio conditions, as occurs when contrast levels are low. Although this new adaptive mechanism can be driven by contrast, it is not a contrast adaptation mechanism in its strictest sense, as will be argued in the Discussion.

Ontogenetic adaptations in the visual systems of deep-sea crustaceans.

For all visually competent organisms, the driving force behind the adaptation of photoreceptors involves obtaining the best balance of resolution to sensitivity in the prevailing light regime, as an increase in sensitivity often results in a decrease in resolution. A number of marine species have an additional problem to deal with, in that the juvenile stages live in relatively brightly lit shallow (100-200 m depth) waters, whereas the adult stages have daytime depths of more than 600 m, where little downwelling light remains. Here, I present the results of electrophysiological analyses of the temporal resolution and irradiance sensitivity of juvenile and adult stages of two species of ontogenetically migrating crustaceans (Gnathophausia ingens and Systellaspis debilis) that must deal with dramatically different light environments and temperatures during their life histories. The results demonstrate that there are significant effects of temperature on temporal resolution, which help to optimize the visual systems of the two life-history stages for their respective light environments.This article is part of the themed issue 'Vision in dim light'.

The outer and inner halves of photoreceptor adaptation.

A major problem confronting anyone who attempts to construct a model of a light receptor is to account for the changes in sensitivity which enable photoreceptors to deal with a wide range of light intensities (Hodgkin, 1972). Such changes in sensitivity are remarkable. Rods signal the absorption of single photons to support vision in starlight, yet tune themselves to work even when illumination is brighter by orders of magnitude (Luo et al. 2008). Furthermore, this tuning follows the Weber–Fechner law – a change in the overall light level is matched by an equal and opposite change in sensitivity – and therefore favours the encoding of contrast. Adaptation by both rods and cones is a large part of how one sees over the ∼10 log-unit breadth of environmental irradiances, and of how objects appear similar under different lighting conditions (Rieke & Rudd, 2009). Much has been learned about mechanisms of negative feedback in the phototransduction cascade that generate adaptation (Arshavsky & Burns, 2012). Less attention has been paid to the voltage-gated currents that shape the output of this cascade and ultimately govern signal transmission. In this issue of The Journal of Physiology, Pahlberg and colleagues demonstrate a potent role of these currents in rod adaptation (Pahlberg et al. 2017). To appreciate the sophistication of their experiments, a summary of rod photoreception is helpful. Rods capture photons using a molecule called rhodopsin, which activates a G-protein cascade to close non-selective cation channels. These steps occur in a compartment called the outer segment. The resulting hyperpolarization propagates through the inner segment, which contains voltage-gated ion channels, to influence the synaptic output. Rhodopsin has a purple hue, but its colour is fleeting. Following photon absorption, the activated pigment splits into its constituent opsin protein and chromophore, both of which are transparent to the human eye at physiological concentrations. In other words, the pigment bleaches. Photoreceptor sensitivity is reduced as fewer rhodopsins remain available for photon catch. Sensitivity falls further because of bleaching adaptation, whereby opsin weakly but constitutively activates phototransduction, including elements of negative feedback that reduce gain in the cascade (Cornwall & Fain, 1994). Gain also declines with the number of transduction channels that remain to be closed, due to response compression. Rods express a palette of voltage-gated currents, two of which are especially well-positioned to drive negative feedback during phototransduction. These are a hyperpolarization-activated, non-selective cation current (Ih) and an inwardly rectifying potassium current (IKx). As phototransduction produces hyperpolarization, IKx deactivates and Ih activates to promote depolarization (Barnes, 1994). Thus, these currents produce a smaller, faster, and more tightly regulated response to light. The question taken up by Pahlberg and colleagues is how voltage-gated currents might influence adaptation. Their central experiments took advantage of the rod's compartmentalization. Drawing the outer segment into a suction electrode caused phototransduction current to be isolated, while viewing the cell through a patch electrode allowed other currents to be included. They found that phototransduction current displayed a steeper decline in sensitivity with light history than did the overall voltage response. Furthermore, this difference was eliminated by blocking voltage-gated currents. The exquisite quality of the data and the precision of the analysis make the message clear: voltage-gated currents support the dynamic range of rod photoreception. Additional evidence for this conclusion was recently provided by in vivo studies of animals lacking the channel that produces Ih in rods (Sothilingam et al. 2016). Many questions are open for future investigation. For example, how do individual currents flow during the light response to generate its particular waveform? To what degree are their voltage dependencies and kinetics matched to the parameters of phototransduction and synaptic release, especially with changes in adaptation state? How different is the situation in cones and other sensory cells? Each human retina is estimated to contain ∼120 million rods, which exceeds the number of cones by ∼20-fold. A common view is that rods are inoperative in daylight because their extreme sensitivity comes at the cost of dynamic range; in this scenario, ∼95% of the photoreceptors consume resources without contributing to vision. In providing an especially sharp view of how voltage-gated currents extend rod function over high irradiances, Pahlberg and colleagues highlight the possibility that these cells influence perception in ways that have yet to be found. None declared. Support was provided by the National Institutes of Health (R01 EY023648, R01 EY025555 and R21 EY025840 to M.T.H.D.; 1U54HD090255 to the Boston Children's Hospital IDDRC; and P30 EY012196 to Harvard Medical School). S. Barnes, V. Kefalov and K.-W. Yau provided valuable critiques of the manuscript.