Dark adaptation and the retinoid cycle of vision

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Abstract

Following exposure of our eye to very intense illumination, we experience a greatly elevated visual threshold, that takes tens of minutes to return completely to normal. The slowness of this phenomenon of “dark adaptation” has been studied for many decades, yet is still not fully understood. Here we review the biochemical and physical processes involved in eliminating the products of light absorption from the photoreceptor outer segment, in recycling the released retinoid to its original isomeric form as 11-cis retinal, and in regenerating the visual pigment rhodopsin. Then we analyse the time-course of three aspects of human dark adaptation: the recovery of psychophysical threshold, the recovery of rod photoreceptor circulating current, and the regeneration of rhodopsin. We begin with normal human subjects, and then analyse the recovery in several retinal disorders, including Oguchi disease, vitamin A deficiency, fundus albipunctatus, Bothnia dystrophy and Stargardt disease. We review a large body of evidence showing that the time-course of human dark adaptation and pigment regeneration is determined by the local concentration of 11-cis retinal, and that after a large bleach the recovery is limited by the rate at which 11-cis retinal is delivered to opsin in the bleached rod outer segments. We present a mathematical model that successfully describes a wide range of results in human and other mammals. The theoretical analysis provides a simple means of estimating the relative concentration of free 11-cis retinal in the retina/RPE, in disorders exhibiting slowed dark adaptation, from analysis of psychophysical measurements of threshold recovery or from analysis of pigment regeneration kinetics.

Introduction

Our visual system is able to function over an enormously wide range of light intensities, from starlight to a bright sunny day—a range that encompasses more than 10 log10 units. Under most conditions this ability to “light adapt” to different levels of illumination is an extremely rapid phenomenon, and we adjust to the new level within seconds. Furthermore, it does not actually matter whether the light intensity is rising or falling: adaptation occurs rapidly in both cases, so that the term light adaptation is equally applicable to decreases and increases in the ambient level of illumination. However, this adaptational ability breaks down under one situation. When we return to darkness after exposure of the eye to lights so intense or prolonged that an appreciable proportion of the visual pigment in the photoreceptors has been “bleached” (activated by light to its colourless form), then it can take tens of minutes for our full visual sensitivity to return to normal. This very slow recovery of visual sensitivity is termed “dark adaptation” or “bleaching adaptation”, to distinguish it from the more rapid adjustment known as light adaptation.

A classic result from the dark adaptation literature is plotted in Fig. 1, reproduced from Hecht et al. (1937). The threshold intensity required for an observer to detect a visual stimulus is plotted vertically on a logarithmic scale, against time after the extinction of a bleaching exposure, for five different levels of bleach. After the most intense exposure, which produced a near-total bleach of pigment, the observer's visual threshold was elevated by at least 5 orders of magnitude initially and then recovered with a characteristic biphasic form. Over the first several minutes there was rapid recovery to a plateau level ∼3 log units above the dark-adapted value, and this rapid phase is known to be mediated by the cone photoreceptor system. After about 11 min, the threshold began dropping again as the rod system became more sensitive than the cone system, and recovery proceeded steadily at first but then later more slowly, so that it took more than 40 min to attain the original fully dark-adapted sensitivity.

The primary purpose of this review is to examine a wide range of experimental evidence that can provide clues about the molecular processes underlying this very slow recovery of the rod (scotopic) visual system. From the outset a number of important points can be made about dark adaptation.

Firstly, the term “adaptation” is something of a misnomer, suggesting as it does that the phenomenon is useful. Instead, we stress that the elevation of visual threshold that occurs during dark adaptation can never be considered advantageous to the owner of the eye (Barlow, 1972; Lamb, 1990). The situation is analogous to buying a camcorder and then discovering that, after the camera has been used outside in sunshine, it takes more than half-an-hour to obtain a picture under dimly lit conditions—one would be inclined to take such a camera back for a refund.

Secondly, though, it is worth emphasizing that the very slowest recovery in Fig. 1 (where the eye's sensitivity takes more than 40 min to return to baseline after a total bleach) represents an extreme phenomenon that is seldom encountered in everyday life. Even though post-bleach recovery is very slow, it is nevertheless adequate to cope with (and perhaps is even matched to) the time-course of the fading of light at dusk.

Thirdly, the recoveries plotted in Fig. 1 do not contain any contribution from changes in pupil size, because in this experiment the incident light entered the subject's pupil through an aperture smaller than the most constricted size of the pupil; instead the cause of the threshold elevation in Fig. 1 is entirely internal to the retina. Furthermore, as we shall investigate in this review, it is now abundantly clear that the underlying mechanism resides in the photoreceptor cells.

Fourthly, the magnitude of the threshold elevation is out of all proportion to the reduction in the amount of pigment capable of capturing light (Hecht et al., 1937; Granit et al., 1938). For example, a bleach of just 20% of the pigment (second set of symbols) initially caused an elevation of visual threshold of more than 1000-fold (>3 log units), and even after a couple of minutes in darkness the threshold elevation remained at least 100-fold, even though at least 80% of the pigment was always present. The work of Granit et al. (1938) showed that dark adaptation was not due primarily to the disappearance of visual pigment, and suggested instead that it was somehow related to the presence of one or more of the products of light absorption. Over the years it has been proposed that the threshold-elevating species might be one (or more) of the following: a metarhodopsin photoproduct, “free opsin”, or all-trans retinal (the latter two of which are formed when metarhodopsin is hydrolysed). In this review we will attempt to determine which of those products are involved in human psychophysical dark adaptation.

Fifthly, it has been known for many decades that the recovery of visual sensitivity is somehow associated with the “retinoid cycle” of visual pigment regeneration that occurs after the bleach. One of the earliest pieces of evidence for this proposition was the finding that dark adaptation becomes even slower when retinoid levels are low, as occurs in vitamin A deficiency (see Section 5.2). Subsequently it was shown that exogenous application of 11-cis retinal rapidly restores sensitivity to a bleached retina, and that it also restores circulating current and sensitivity to bleached photoreceptors (see references in Section 1.2). Accordingly we shall need to consider the anatomy and chemistry of the retinoid cycle (Sections 2), and to examine dark adaptation and pigment regeneration kinetics not only in normal subjects (Section 3), but also in vitamin A deficient patients (Section 5).

A final important feature, discovered in 1932 by Stiles and Crawford, is that during dark adaptation the visual system behaves as if it is experiencing a phenomenon equivalent to light, and the intensity of this “equivalent background light” gradually fades away as time progresses. In the early 1980s it became clear that this equivalent light is internal to the photoreceptors, as if some long-lasting product of light absorption acts as a very weak imitator of the activated rhodopsin (Rh*) initially produced by light. Then in the 1990s it was shown that both free opsin and metarhodopsin products exhibit a very weak ability to activate the photoreceptors and/or to desensitize them (See Section 1.2). However, it has seldom been possible to perform such experiments under in vivo conditions, and this complicates the analysis.

Goals: The overriding aim of our analysis is to provide a comprehensive description of dark adaptation and pigment regeneration in the living human eye. Specific goals that we wish to achieve are: to identify the products of light-absorption that underlie the dynamic recovery of visual threshold under real-life conditions, and to account for the kinetics of inactivation or removal of these substances.

Sequence: We will begin with a brief historical overview of the progress that has been made in understanding dark adaptation and its relationship to pigment regeneration and retinoid metabolism (Section 1.2).

Next we will examine the anatomical relationship between the photoreceptors and the retinal pigment epithelium, where retinoid recycling occurs, and we will consider the biochemical pathways involved in the retinoid cycle (Section 2). Then we will analyse post-bleach recovery in normal human subjects (Section 3). We will present quantitative measurements of three aspects of human dark adaptation: the recovery of psychophysical visual threshold (Section 3.1); the recovery of human rod circulating current (Section 3.2); and the regeneration of visual pigment in the living human eye (3.3 Interpretation of the similarity of dark adaptation and a-wave recoveries, 3.4 Extraction of human rhodopsin regeneration from psychophysical and a-wave recoveries). We will also briefly examine the recovery of the human cone system (Section 3.5).

From these analyses we will be able to draw a number of important conclusions about the mechanisms underlying dark adaptation and pigment regeneration, enabling us to put forward a mathematical model and molecular description of the overall phenomenon (Section 4). That model will allow us to make a number of predictions about the behaviour that would be expected if certain parameters (such as retinoid levels) were altered (Section 4.3).

We will then test those predictions against results in the literature. In Section 5, we will examine a variety of retinal diseases that affect human dark adaptation and/or retinoid kinetics, and show how the observations can be explained. And in Section 6 we will examine post-bleach recovery in a number of other mammalian species, again showing how our model can account for the findings.

Finally, in Section 7 we will draw together our conclusions from these different approaches.

In this section we briefly review experiments and concepts that have been important in the development of knowledge of dark adaptation but that, because of limitations of space, cannot be treated in detail in subsequent sections.

The concept of equivalent light: In 1932, Stiles and Crawford proposed a method for characterizing the adaptational state of any region of retina, based on the concept of an “equivalent background brightness.” Thus, the state of adaptation caused by any experimental manipulation was quantified by the intensity of a steady background light that would produce an equal desensitization. Stiles and Crawford applied this method to characterize the recovery of an observer from a 5 min exposure to a stimulus of luminance 1.5 ft cd (which would have produced a bleach of ∼1%), and they determined the time course of decay of the equivalent intensity, which they related to the time course of decay of a hypothetical photoproduct.

Rejection of the pigment depletion hypothesis: During the 1930s other investigators, including Hecht and colleagues (Fig. 1), focused on the time course of dark adaptation after a wide range of initial exposure intensities. These investigators clearly understood that light exposure bleached rhodopsin, and they proposed that recovery of sensitivity involved “the accumulation of [light-]sensitive material”; i.e. the regeneration of visual pigment (Hecht et al., 1937). Many discussions in the 1930s and 1940s presented the problem as if the loss of sensitivity were directly due to depletion of pigment (for a review, see Hecht, 1937). However, that view was shown to be incompatible with experimental data by Granit et al. (1938), though regrettably this study was over-looked subsequently. Further experimental work using the equivalent light concept to quantify dark adaptation was undertaken by Crawford (1937), Crawford (1947). His papers introduced the idea that exposure of the eye to strong illumination led to the creation of a substance that acted like light and that slowly decayed or was removed. Although it had long been known that “visual purple” (rhodopsin) provided the photochemical substrate for night vision, little was known at the time about the processes governing rhodopsin's post-bleach regeneration in the living eye.

Rise of the Dowling–Rushton relation: The disproportionate nature of the relationship between the amount of rhodopsin bleached and the loss of sensitivity became clearer, once it was possible to measure the level of rhodopsin in the living eye. In their discussion of the first reflection densitometry measurements, Rushton et al. (1955) comment that, 7 min after an intense bleaching exposure to the human eye, rhodopsin is half-regenerated but “the rods, if functional at all, have a threshold many hundreds of times greater than the final value”. Thus, they confirmed the rejection by Granit et al. (1938) of pigment depletion as the primary explanation of the elevated threshold after a bleaching exposure. Rushton et al. (1955) nevertheless suggested that there might still be a causal relationship between scotopic threshold and “the instantaneous rhodopsin level”.

In the early 1960s a quantitative relationship of this kind emerged. Dowling (1960), working with albino rats, and Rushton (1961), studying a rod monochromat, reported that the elevation of threshold (or reduction in sensitivity) was proportional to the antilogarithm of the amount of pigment remaining bleached. Explicitly, they proposed that ΔIID=10aB, where ΔI is the threshold intensity, ΔID is its dark-adapted value, B is the fraction of pigment remaining bleached, and a is a constant, with a magnitude of a≈12–20. Evidence in support of this “Dowling–Rushton relation” was put forward in a number of studies (e.g. Blakemore and Rushton, 1965; Rushton, 1965), though in retrospect one can see that it only ever provided a reasonable description for recovery following a near-total bleach.

Dependence of pigment regeneration on level of 11-cis retinal: By the late 1960s it was clearly understood that the rate of regeneration of visual pigment was directly proportional to both the concentration of “free opsin” and the concentration of 11-cis retinal; see, for example, Rushton and Henry (1968, p. 629). However, what was much less clearly understood was the role of this opsin in contributing to the elevation of visual threshold.

Confirmation of the “equivalent light” hypothesis: At around the same time, considerable evidence emerged from a wide range of psychophysical experiments supporting the proposal of Stiles and Crawford (1932) that pigment bleaching generated an after-effect equivalent to light (reviewed in Barlow, 1972).

Role of metarhodopsin: In the 1960s and 1970s, it was shown that (at least in the amphibian retina) much of the transient elevation of threshold after bleaching could be attributed to the presence and decay of metarhodopsin products (e.g. Donner and Reuter (1967), Donner and Reuter (1968)). During those decades, a great deal of research was devoted by many labs to quantifying the kinetics of the decay of the thermal intermediates in vitro and in isolated retina (reviewed in Langer, 1973). We will examine some of those results in detail in Section 2.4.

Restoration of sensitivity to the bleached retina by application of 11-cis retinal: A notable advance in the understanding of the molecular mechanism of post-bleach desensitization was made by Pepperberg et al. (1978), who measured aspartate-isolated responses from the isolated skate retina. After a 40% bleach, for example, the threshold (reciprocal sensitivity) was initially greatly elevated but then recovered within about 20 min to a stable level more than 2 log10 units above the dark-adapted level, and thereafter the threshold remained unchanged for a further 40 min. At that stage, 11-cis retinal was delivered to the retina, and threshold rapidly recovered, almost to the pre-bleach level. These finding made a very strong case that in those experiments the species elevating threshold in the steady state was opsin itself, which required only delivery of the 11-cis aldehyde to return to its inactive native state, rhodopsin. However, it was still not possible to determine whether the normal time-course of recovery of threshold in the living eye was mediated by the decay of metarhodopsin or by the removal of opsin.

Activation by different species of photoproduct: Evidence has accumulated over many years that different “photoproducts” of bleaching can activate phototransduction, and that the resulting state of activation may underlie the phenomenon of dark adaptation. However, the relative importance of the contributions of the different species of rhodopsin, metarhodopsin, and opsin has not been clear. We will now briefly consider evidence for activation of phototransduction by transient intermediates and by opsin, which (in isolated cell preparations) remains present after the transient products have decayed.

Photon-like noise caused by metarhodopsin products: Following the development of the suction pipette method for recording the current from individual photoreceptors, Lamb (1980) reported that small bleaches (∼1%) elicited at least three effects on the photoreceptor current, which gradually recovered with the progression of time. Not only were the sensitivity and circulating current both reduced (as if the cell were light adapted), but in addition the current exhibited pronounced fluctuations that were indistinguishable from the random occurrence of single-photon responses, as would occur in the presence of dim light. This result supported the view that bleaching left in its wake some kind of product(s) that could exactly mimic light. Subsequent experiments showed, though, that the situation was more complicated, and that product(s) of pigment bleaching could cause two slightly different after-effects: one identical to light, and another that mimicked light's steady effects of desensitization and current suppression, but that lacked the photon-like events (Leibrock et al., 1994). In addition, experiments with hydroxylamine (which has the effect of removing the metarhodopsins) demonstrated that at least some of these post-bleach phenomena were caused by the presence of metarhodopsin products (Leibrock and Lamb, 1997; reviewed in Leibrock et al., 1998).

Enzymatic activity of opsin: In addition to the effect of metarhodopsin(s) in generating an equivalent light, an additional component with much lower activity was present, which could be eliminated by the exogenous application of 11-cis chromophore (Corson et al., 1990), indicating its origin to be unregenerated (“free”) opsin. The effectiveness of opsin in activating phototransduction has been measured with two approaches: single-cell electrophysiology (Cornwall and Fain, 1994), and biochemistry (Melia et al., 1997), as we now discuss.

Cornwall and Fain (1994) exposed isolated amphibian photoreceptors to a strong bleach, in the absence of exogenous 11-cis retinal, and then allowed a long period for the attainment of a steady state, by which time all the bleached rhodopsin would have decayed to “opsin”. Under these conditions, they found that 106 opsin molecules were equivalent to a steady-state illumination producing 1Rh*s−1, so that each opsin molecule would be equivalent to ∼10−6Rh*s−1. The precise biochemical status of this “opsin” is not entirely clear, though. Thus, although it seems reasonable to think that arrestin would have unbound from opsin after hydrolysis of the Schiff-base bond, it is not known whether the opsin molecule remains phosphorylated. Nor is it clear whether the “exit site” on opsin (Section 2.3.2) would still be occupied by chromophore.

Melia et al. (1997) created opsin in vitro by bleaching bovine rod disc membranes that had been stripped of peripheral proteins and of retinoid with hydroxylamine. These experiments yielded the estimate that at, room temperature (23°C), 106 molecules of opsin were equivalent in activity to ∼1 molecule of unphosphorylated metarhodopsin II (i.e. equivalent to the presence of ∼1Rh* that could not be inactivated). If we take into consideration the lifetime of Rh*, which at body temperature is probably about 0.1 s, then their results would indicate that each bovine opsin molecule would be equivalent to ∼10−5Rh*s−1.

In considering these estimates of opsin activity, we would mention that there are difficulties in accurately quantifying the activity of the various intermediates of bleaching in vivo. One difficulty is that during its inactivation Rh* is modified by phosphorylation and arrestin binding (Section 2.5.1), so that it is difficult if not impossible to specify the phosphorylation and arrestin-binding status of the bleached molecules during the time course of their decay. Quantification in vivo is further complicated by the fact that two major determinants of cascade activity, transducin and arrestin, have in some species been shown to migrate between the inner and the outer segment after strong bleaching. Caveats also apply to the in vitro measurements, in part because of the difficulty in establishing the biochemical activity of a fully activated Rh* molecule.

Most of the figures that we present in Section 3 come from studies in which we participated ourselves, and we therefore had available the original data for re-plotting. However, the great majority of the results that we present in 5 Abnormalities of human dark adaptation and pigment regeneration, 6 Pigment regeneration in other mammalian species, as well as Fig. 5 in Section 2, and Fig. 10, Fig. 11 in Section 3, are taken from the published studies of other groups. In one case, the numerical data were tabulated in the paper (Fig. 22). But in most cases we extracted the data points from the previous work ourselves, by digitally scanning the published figures, and then measuring the individual points using a custom Matlab script (“UnGraph.m”); the accuracy of this approach is probably around ±1% of the span of the original figures.

Section snippets

Anatomy and biochemistry of the retinoid cycle

Vision is initiated when a photon is captured by the 11-cis retinal chromophore of a photopigment molecule, and the chromophore is thereby isomerized to its all-trans form. This photoisomerization reaction initiates the conversion of the rhodopsin (or cone pigment) molecule into a species termed metarhodopsin II (M2) that activates a heterotrimeric G-protein (transducin) which in turn triggers the subsequent events of the phototransduction cascade (reviewed recently by Pugh and Lamb, 2000;

Human scotopic dark adaptation: normal psychophysics

More extensive human psychophysical dark adaptation data than those illustrated in Fig. 1 have been obtained by Pugh (1975), and the results he collected over a wide range of bleaching levels are shown in Fig. 6. The elevation of threshold (in log10 units) for the detection of a visual stimulus is plotted against time in darkness, after exposures of nine different levels, that were estimated to bleach from 0.5% to 98% of the rhodopsin.

The recoveries plotted in Fig. 6 are broadly similar to the

A molecular model of dark adaptation and pigment regeneration

In Section 3 we presented evidence supporting the notion that following large bleaches the removal from the photoreceptor outer segment of a product of light absorption becomes rate-limited, and that it is the removal of this substance that underlies three phenomena in the human eye: the recovery of scotopic dark adaptation at late times, the recovery of rod circulating current, and the regeneration of rhodopsin (and indeed the recovery of cone pigment as well). In Section 5 we will present

Abnormalities of human dark adaptation and pigment regeneration

In this section we discuss a number of human diseases involving abnormalities of dark adaptation and pigment regeneration—all such cases are characterized by slowed dark adaptation, and we know of no disorders that lead to accelerated dark adaptation. For each of the diseases we review, at least some of the patients have rod thresholds that are within normal limits under fully dark-adapted conditions. This strongly suggests the existence of a full complement of rhodopsin, i.e. it implies that

Pigment regeneration in other mammalian species

Reflection densitometry has been applied in a number of species, and it has generally been found that rhodopsin regeneration is slower than in human, and sometimes more clearly rate-limited (albino rabbit: Hagins and Rushton, 1953; Rushton et al., 1955; cat: Bonds and MacLeod, 1974; Ripps et al., 1981; Kemp et al. (1988a), Kemp et al. (1988b), Kemp et al. (1989); owl monkey: Kemp and Jacobson, 1991; mouse: Wenzel et al., 2001). Indeed, Hagins and Rushton (1953) explicitly commented on the

Summary, conclusions and future directions

Summary of our model

1. In the MLP model, we postulate that the presence of “opsin” generates an “equivalent background light” that leads to the elevation of visual threshold during component S2 of psychophysical threshold recovery. Furthermore, we postulate that the rate of “removal” of this opsin is determined by the rate at which 11-cis retinal can be delivered to the outer segment. The 11-cis retinal is assumed to be present at concentration C, and to diffuse to opsin from that location via a

Acknowledgements

We are most grateful to Jan van de Kraats and Dirk van Norren for providing the unpublished data for Fig. 10C, to Jack Saari for providing the original data for Fig. 23, and to David Jeffrey for advice on the Lambert W function solution in the Theory section. We are also grateful to Steve Fisher for supplying the image for Fig. 2A, and Marie Burstedt for supplying the data for Fig. 19. We thank Dean Bok, Victor Govardovskii, Robert Rando and Jack Saari both for helpful discussions and for

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