26  Sensitivity regulation due to rod-cone interaction

Perhaps the most profound change in our conception of the sensitivity regulation mechanisms, however, came when it was realized that the rod and cone activities were not mutually independent, but that rod activity could influence cone sensitivity and vice versa. Anatomical, electrophysiological and psychophysical studies all contributed to this change in view.

Well-founded histological evidence in favour of the rod-cone interaction hypothesis was provided by Polyak’s investigations of primates, summarized in Polyak (1941/1948). He discovered that, with the exception of the midget cone system, rods and cones were connected to the same pathways in the retina. Furthermore, he showed that the retina of primates was an extremely complex structure composed of a variety of different types of neural networks strongly indicating that the retina, and not just the brain, was involved in analyzing and synthesizing visual information.

More direct evidence in favour of rod-cone interaction was provided by Granit’s ERG measurements. These results were interpreted to mean that rods and cones competed for ‘a final common path’ when excited simultaneously, and that the more active receptor types tended to exclude the other (see Granit, 1938, pp. 65–66).

Later on, Gouras and Link (1966) came to a similar conclusion. They investigated rod-cone interaction in Rhesus monkeys by analyzing the discharge pattern of ganglion cells connected to both rod and cone receptors. Their results showed that impulses from rods or cones arriving first at the ganglion cell would tend to block impulses from the other receptor type when these arrived shortly thereafter. When, for instance, rods and cones were activated simulta­ neously by a light stimulus, the faster cone signals would antagonize

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the rod signals and cut them off completely. Gouras and Link (1966) pointed out that the transitory inhibition they had found would tend to prevent rods and cones from acting in the same place simultaneously and, therefore, might play an important role in the apparent independence of the two receptor systems obtained when tested at threshold levels (see Stiles, 1978).

Yet, the investigation of Gouras and Link (1966) was followed by a long series of psychophysical investigations that established beyond doubt that the two receptor systems also interacted at absolute threshold level. A pioneer study was performed by Frumkes et al. (1972). After dark adapting the eye for 25 min, they presented an adapting flash and a test flash concentrically at 7º in the extrafoveal retina against a continuously exposed scotopic background. The wavelength of the adapting and test flash could both be fixed at either 420 nm (to stimulate rods) or 680 nm (to stimulate cones). In a different experimental series, the time interval between the adapting and test flash was varied.

In opposition to the generally held idea of rod-cone independence at threshold level, they found that there was a marked reciprocal antagonistic interaction between the two systems in that the threshold level of cones was markedly raised by rod activity and vice versa. Indeed, in accord with the relatively long latency of the rod system, they found that the rod adapting flash increased the cone-threshold test-flash intensity level later in time than the cone adapting flash increased the rod-threshold test-flash level.

A series of psychophysical studies on cone-rod and rod-cone interactions with regard to sensitivity followed shortly. Inhibition, facilitation, sustained and transient effects were found and explored (see Frumkes et al., 1973; Makous & Booth, 1974; Ingling et al., 1977; Latch & Lennie, 1977; Temme & Frumkes, 1977; Frumkes & Temme, 1977; Blick & MacLeod, 1978; Buck et al., 1979; Buck & Makous, 1981; Buck et al., 1984; Buck, 1985). Surely, the 1970s and early 1980s witnessed the final blow to the long-held idea of independence between the rod and cone sensitivity regulation mechanisms.

27  Modern conceptions of sensitivity regulation

During the last two decades the presumption that sensitivity regulation is basically controlled by photochemical processes located in the outer segment of the receptors has been replaced by much more complex theoretical conceptions. A recent review paper on gain controls in the retina by Dunn and Rieke (2006) gives an excellent illustration of this development. The authors argue that there aremultiple retinal gain controls (i.e. adaptation mechanisms) that adjust sensitivity to different aspects of the light stimulus such as changes in mean intensity, variability about the mean (i.e. contrast variability) and spectral composition, and that the gain controls have diverse temporal and spatial properties, serve different functional roles and are located at different sites in the retina. Indeed, an additional dimension of complexity is introduced in that the gain controls are assumed to interact with other computations carried out in the retinal pathways.

In support of their suggestion that gain controls of the cone system may operate at different sites in the retina, they present evidence that both small and large steps in mean intensity and contrast may alter the gain adaptation level of ganglion cells, while only large steps change the gain of the receptors. Strong support in favour of the suggestion that gain controls may operate at different sites had previously been provided by Ahn and MacLeod (1993) and Yeh et al. (1996).

Dunn and Rieke (2006) argued that gain controls of the cone and rod systems must be fundamentally different, since the intrinsic noise of rods is several log units less than that of cones. This, of course, gives the rods the advantage of being able to operate at extremely low light levels, but the scarcity of photons absorbed by the rods

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makes rapid control of gain on the basis of signals from single rods impossible in night vision. Thus, the authors point out that less than 0.1 photon is absorbed per second per rod under so-called low to moderate scotopic light intensity levels and that, therefore, the rod system has to exploit spatially averaging of impulses from many rods in order to adapt rapidly to a change in light intensity at these levels.

The authors found behaviour measurements supporting the suggestion that at least one adaptation mechanism that may control the gain of rod-mediated signals operated in the rod bipolar pathways. In accordance with this suggestion, they could conclude from their own physiological recordings that the synapses between rod bipolar and AII amacrine cells were key gain-control sites at low light levels. These sites, they argued, would provide a unique opportunity for specialized processing operating exclusively on rod signals.

Yet, the review article of Dunn and Rieke (2006) leaves us with the impression that research on visual sensitivity regulation is still at a rather undeveloped stage. Obviously, much remains to be clarified. Thus, the different roles in sensitivity regulation played by the different types of receptor, horizontal, bipolar, amacrine and ganglion cells, and also by cells central to the retina, are still largely unknown. Indeed, in spite of the great effort to reveal the gain-control mechanisms of light and dark adaptation at the very first ion channels in the visual pathway (the cGMP gated channels in the plasma membrane of the outer segment of the receptors), there is at present no general agreement about these sensitivity-regulation mechanisms. A deeper understanding would require more knowledge about how dark and light adaptation change the amount of cGMP that gates the outer segment channels and how these changes are related to sensitivity measured psychophysically. The picture appears extremely complicated, since evidence indicates that retinoids (all-trans retinal, all-trans retinol and 11-cis retinal), phosphorylation enzymes andCa2+-binding proteins all may modulate the sensitivity (Dean et al., 2002; McCabe et al., 2004). Knowledge of such influences are, of

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course, essential for an understanding of the adaptation mechanisms of the rod and cone outer segment channels.

The long developmental history described here is obviously at odds with the common conception that the duplicity theory is a static, well-defined theory formulated by Schultze (1866). Instead, it shows that profound changes in the basic presumptions have been made and that the duplicity theory still is rapidly developing 140 years after Schultze’s publication. Actually, we are short of a satisfactory understanding of how rods and cones are involved in any of the major visual functions. This clearly reveals the developmental potential of the theory: since all visual processes are triggered by phototransduction in rods and cones, there will be no end to the developmental history of the duplicity theory until we know, with regard to all major visual functions, the differences and similarities between the rod and cone processing, and also when and how the rod and cone systems interact.