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Far out in the periphery of the retina, receptive-field centers are made up of thousands of receptors and can have diameters ofi degree or more. Thus as we go out along the retina from its center, three items correlate in an impressive way, surely not by coincidence: visual acuity falls, the size of the receptor population contributing to the direct pathway (from receptors to bipolars to ganglion cells) increases, and the sizes of receptive-field centers increase. These three trends are clues that help us understand the meaning of the direct and indirect paths from receptors to ganglion cells. The strong implication is that the center of the receptive field is determined by the direct path and the antagonistic surround by the indirect one, and that the direct path sets limits on our acuity. To obtain more evidence for this conclusion, it was necessary to record from the other cells in the retina, as I will describe in the next section.


                                 THE PHOTORECEPTORS
It was many years before much progress was made in the physiology of the receptors, bipolars, horizontal cells, or amacrine cells. There are many reasons for this: vascular pulsations bedevil our attempts to keep microelectrodes in or close to single cells; receptors, bipolars, and horizontal cells do not fire impulses, so that recording the much smaller graded potentials requires intracellular techniques; and it is hard to be certain which of the cell types our electrode is in or near. We can circumvent some of these problems by choosing just the right animal: retinas of cold-blooded vertebrates survive when taken out of the eye and bathed in oxygenated salt water, and eliminating the blood circulation eliminates arterial pulsations; the mudpuppy (a kind of large salamander) has very large cells, easy to record from; fish, frogs, turtles, rabbits, and cats all have special advantages for one or another kind of study, so that many species have been used in the study of retinal physiology.
The problem with using so many species is that the details of the organization of the retinas can differ markedly from one species to the next. Moreover, our knowledge of the primate retina, one of the most difficult to record from, has until recently had to depend largely on inferences from the results pooled from these other species. But progress in primates is accelerating as the technical difficulties are overcome.
In the past few years, our understanding of the way in which a rod or cone responds to light has dramatically increased, so much so that one has the feeling of at last beginning to understand how they work.
Rods and cones differ in a number of ways. The most important difference is in their relative sensitivity: rods are sensitive to very dim light, cones require much brighter light. I have already described the differences in their distribution throughout the retina, the most notable being the absence of rods in the fovea. They differ in shape: rods are long and slender; cones are short and tapered. Both rods and cones contain light-sensitive pigments. All rods have the same pigment; cones are of three types, each type containing a different visual pigment. The four pigments are sensitive to different wavelengths of light, and in the case of the cones these differences form the basis of our color vision.
The receptors respond to light through a process called bleaching. In this process a molecule of visual pigment absorbs a photon, or single package, of visible light and is thereby chemically changed into another compound that absorbs light less well, or perhaps differs in its wavelength sensitivity. In virtually all animals, from insects to humans and even in some bacteria, this receptor pigment consists of a protein coupled to a small molecule related to vitamin A, which is the part that is chemically transformed by light. Thanks largely to the work in the 1950s of George Wald at Harvard, we now know a lot about the chemistry of bleaching and the subsequent reconstitution of visual pigments.
Most ordinary sensory receptors—chemical, thermal, or mechanical—are depolarized in response to the appropriate stimulus, just as nerves become depolarized in response to an excitatory stimulus; the depolarization leads to release of transmitter at the axon terminals. (Often, as in visual receptors, no impulse occurs, probably because the axon is very short.) Light receptors in invertebrates, from barnacles to insects, behave in this way, and up to 1964 it was assumed that a similar mechanism—depolarization in response to light—
would hold for vertebrate rods and cones.
In that year Japanese neurophysiologist Tsuneo Tomita, working at Keio University in Tokyo, first succeeded in getting a microelectrode inside the cones of a fish, with a result so surprising that many contemporaries at first seriously doubted it. In the dark, the potential across the cone membrane was unexpectedly low for a nerve cell: roughly 50 millivolts rather than the usual 70 millivolts. When the cone was illuminated, this potential increased—the membrane became hyperpoUrized—just the reverse of what everyone had assumed would happen. In the dark, vertebrate light receptors are apparently more depolarized (and have a lower membrane potential) than ordinary resting nerve cells, and the depolarization causes a steady release of transmitter at the axon terminals, just as it would in a conventional receptor during stimulation.
Light, by increasing the potential across the receptor-cell membrane (that is, by hyperpolarizing it), cuts down this transmitter release. Stimulation thus turns the receptors off, strange as that may seem. Tomita's discovery may help us to understand why the optic-nerve fibers of vertebrates are so active in the dark: it is the receptors that are spontaneously active; presumably, many of the bipolar and ganglion cells are simply doing what the receptors tell them to do.
In the ensuing decades, the main problems have been to learn how light leads to hyperpolarization of the receptor, especially how bleaching as little as a single molecule of visual pigment, by a single photon of light, can lead, in the rod, to a measureable change in membrane potential. Both processes are now reasonably well understood. Hyperpolarization by light is caused by the shutting off of a flow of ions. In darkness, part of the receptor membrane is more permeable than the rest of the membrane to sodium ions. Consequently, sodium ions continually flow into the cell there, and potassium ions flow out elsewhere. This flow of ions in the dark, or dark current, was discovered in 1970 by William Hagins, Richard Penn, and Shuko Yoshikami at the National Institute of Arthritis and Metabolic Diseases in Bethesda. It causes depolarization of the receptor at rest, and hence its continual activity. As a result of the bleaching of the visual pigment in response to light, the sodium pores close, the dark current decreases, and the membrane depolarization declines—the cell thus hyperpolarizes. Its rate of activity (that is, transmitter release) decreases.
Today, as a result of the work of Evgeniy Fesenko and co-workers at the Academy of Sciences in Moscow, Denis Baylor at Stanford University, KingWai Yau of the University of Texas, and others, we are much closer to understanding the linkage between the bleaching and the closing of the sodium pores. For example, it had been very hard to imagine how the bleaching of a single molecule could lead to the closing of the millions of pores that the observed potential changes would require. It now appears that the pores of the receptor are kept open by molecules of a chemical called cyclic guanosine monophosphate, or cGMP. When the visual pigment molecule is bleached a cascade of events is let loose. The protein part of the bleached pigment molecule activates a large number of molecules of an enzyme called transducin; each of these in turn inactivates hundreds of cGMP molecules, with consequent closing of the pores. Thus as a result of a single pigment molecule being bleached, millions of pores close off.
All this makes it possible to explain several previously puzzling phenomena.
First, we have long known that a fully dark-adapted human can see a brief flash of light so feeble that no single receptor can have received more than i photon of light. Calculations show that about six closely spaced rods must be stimulated, each by a photon of light, within a short time, to produce a visible flash. It now becomes clear how a single photon can excite a rod enough to make it emit a significant signal.
Second, we can now explain the inability of rods to respond to changes in illumination if the light is already bright. It seems that rods are so sensitive that at high illumination levels—for example, in sunlight—all the sodium pores are closed, and that any further increase in light can have no further effect. We say the rods are saturated.
Perhaps a few years from now students of biology will regard this entire story of the receptors as one more thing to learn—I hope not. To appreciate fully its impact, it helps to have spent the years wondering how the receptors could possibly work; then suddenly, in the space of a decade or less of spectacular research, it all unfolds. The sense of excitement still has not subsided.

   
 
 
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A single cone (left) and two rods and a cone (right) have been teased apart and stained with osmic acid. The slender process at the top of each cell is the outer segment, which contains the visual pigment.
The fibers at the bottom go to the synaptic regions, not shown.


 
 
 
 
 





This electron-micrograph section through the peripheral retina of a monkey passes through the layers of rods and cones. The tiny white circles are rods; the larger black regions with a white dot in the center are cones.
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