Guyton and Hall Physiology Chapter 51 - The Eye II. PDF

CHAPTER 51 UNIT X The Eye: II. Receptor and Neur...

CHAPTER 51 UNIT X The Eye: II. Receptor and Neural Function of the Retina The retina is the light-sensitive portion of the eye that con- retina, which are arranged in layers or boundaries from tains the following: (1) the cones, which are responsible for the outside to the inside, as follows: (1) pigment layer; (2) color vision; and (2) the rods, which can detect dim light photoreceptor layer containing rods and cones project- and are mainly responsible for black and white vision and ing to the pigment; (3) outer limiting membrane; (4) outer vision in the dark. When either rods or cones are excited, nuclear layer containing the cell bodies of the rods and signals are transmitted first through successive layers of cones; (5) outer plexiform layer; (6) inner nuclear layer; neurons in the retina and, finally, into optic nerve fibers (7) inner plexiform layer; (8) ganglionic layer; (9) layer of and the cerebral cortex. In this chapter, we explain the optic nerve fibers; and (10) inner limiting membrane. mechanisms whereby the rods and cones detect light and After light passes through the lens system of the eye and color and convert the visual image into optic nerve signals. then through the vitreous humor, it enters the retina from the inside of the eye (see Figure 51-1); that is, it passes first ANATOMY AND FUNCTION OF THE through the ganglion cells and then through the plexiform STRUCTURAL ELEMENTS OF THE and nuclear layers before it finally reaches the layer of rods RETINA and cones located all the way on the outer edge of the ret- ina. This distance is a thickness of several hundred microm- The Retina Is Composed of Ten Layers or Boundaries. eters; visual acuity is decreased by this passage through Figure 51-1 shows the functional components of the such nonhomogeneous tissue. However, in the central Pigmented layer Photoreceptor layer Rod Cone Cone Outer limiting membrane Outer nuclear layer Distal Outer plexiform layer Vertical Horizontal cell pathway Bipolar Bipolar Lateral pathway Inner nuclear cell Amacrine cell layer cell Amacrine cell Proximal Inner plexiform layer Ganglion cell Ganglion cell layer To optic nerve Stratum opticum Inner limiting membrane DIRECTION OF LIGHT Figure 51-1. Layers of the retina. 639 UNIT X The Nervous System: B. The Special Senses Path of light Cornea Lens Membrane shelves Outer segment lined with rhodopsin or color pigment Vitreous Mitochondria Inner segment Retina Outer limiting Optic nerve membrane Nucleus Fovea Vitreous Ganglion cell Bipolar cell Synaptic body Figure 51-3. Schematic drawing of the functional parts of the rods and cones. rower and longer than the cones, but this is not always the case. In the peripheral portions of the retina, the rods are 2 Pigmented layer Cone Rod to 5 micrometers in diameter, whereas the cones are 5 to 8 micrometers in diameter; in the central part of the retina, Figure 51-2. Projection of light to the photoreceptors (cones) in the retina. Note that in the foveal region the photoreceptors are entirely in the fovea, there are no rods, and the cones are slender cones and that neuronal cells are all displaced to one side, allowing and have a diameter of only 1.5 micrometers. light to pass unimpeded to the cones. The major functional segments of either a rod or cone are shown in Figure 51-3: (1) the outer segment; (2) the inner segment; (3) the nucleus; and (4) the synaptic body. foveal region of the retina, as discussed subsequently, the The light-sensitive photochemical is found in the outer inside layers are pulled aside to decrease this loss of acuity. segment. In the case of the rods, this photochemical is rhodopsin; in the cones, it is one of three “color” pho- Foveal Region of the Retina and Its Importance in Acute tochemicals, usually called simply color pigments, that Vision. The fovea is a minute area in the center of the retina, function almost exactly the same as rhodopsin except for shown in Figure 51-2; it occupies a total area a little more differences in spectral sensitivity. than 1 square millimeter. It is especially capable of acute and In the outer segments of the rods and cones in Figures detailed vision. The central fovea, only 0.3 millimeter in di- 51-3 and 51-4, note the large numbers of discs. Each disc ameter, is composed almost entirely of cones. These cones is actually an infolded shelf of cell membrane. There are as have a special structure that aids their detection of detail in many as 1000 discs in each rod or cone. the visual image—that is, the foveal cones have especially Both rhodopsin and the color pigments are conjugated long and slender bodies, in contradistinction to the much proteins. They are incorporated into the membranes of fatter cones located more peripherally in the retina. Also, the discs in the form of transmembrane proteins. The in the foveal region, the blood vessels, ganglion cells, inner concentrations of these photosensitive pigments in the nuclear layer of cells, and plexiform layers are all displaced discs are so great that the pigments themselves constitute to one side rather than resting directly on top of the cones, about 40% of the entire mass of the outer segment. which allows light to pass unimpeded to the cones. The inner segment of the rod or cone contains the usual cytoplasm, with cytoplasmic organelles. Especially Rods and Cones Are Essential Components of Photo- important are the mitochondria, which, as explained later, receptors. Figure 51-3 is a diagrammatic representation play the important role of providing energy for function of the essential components of a photoreceptor (either a of the photoreceptors. rod or a cone). As shown in Figure 51-4, the outer segment The synaptic body is the portion of the rod or cone that of the cone is conical in shape. In general, the rods are nar- connects with subsequent neuronal cells, the horizontal 640  CHAPTER 51 The Eye: II. Receptor and Neural Function of the Retina surface. Thus, the inner layers of the retina have their own blood supply, independent of the other structures of the eye. However, the outermost layer of the retina is adherent to the choroid, which is also a highly vascular tissue lying between the retina and the sclera. The outer layers of the retina, especially the outer segments of the rods and cones, UNIT X depend mainly on diffusion from the choroid blood vessels for their nutrition, especially for their oxygen. Retinal Detachment. The neural retina occasionally de- taches from the pigment epithelium. In some cases, the cause of such detachment is injury to the eyeball that allows fluid or blood to collect between the neural retina and the pigment epithelium. Detachment is occasionally caused by contrac- ture of fine collagenous fibrils in the vitreous humor, which pull areas of the retina toward the interior of the globe. Partly because of diffusion across the detachment gap, and partly because of the independent blood supply to the neural retina through the retinal artery, the detached retina can resist degeneration for days and can become functional Figure 51-4. Membranous structures of the outer segments of a rod again if it is surgically replaced in its normal relation with (left) and a cone (right). (Courtesy Dr. Richard Young.) the pigment epithelium. If it is not replaced soon, however, the retina will be destroyed and will be unable to function, even after surgical repair. and bipolar cells, which represent the next stages in the vision chain. PHOTOCHEMISTRY OF VISION Pigment Layer of the Retina. The black pigment mela- nin in the pigment layer prevents light reflection through- Both rods and cones contain chemicals that decompose on out the globe of the eyeball, which is extremely important exposure to light and, in the process, excite the nerve fibers for clear vision. This pigment performs the same function leading from the eye. The light-sensitive chemical in the in the eye as the black coloring inside the bellows of a rods is called rhodopsin; the light-sensitive chemicals in the camera. Without it, light rays would be reflected in all di- cones, called cone pigments or color pigments, have compo- rections in the eyeball and would cause diffuse lighting of sitions only slightly different from that of rhodopsin. the retina rather than the normal contrast between dark In this section, we discuss principally the photochem- and light spots required to form precise images. istry of rhodopsin, but the same principles can be applied The importance of melanin in the pigment layer is well to the cone pigments. illustrated by its absence in people with albinism (congen- ital absence of melanin pigment in all parts of their bod- RHODOPSIN-RETINAL VISUAL CYCLE AND ies). When a person with albinism enters a bright room, EXCITATION OF THE RODS light that impinges on the retina is reflected in all direc- tions inside the eyeball by the unpigmented surfaces of Rhodopsin and Its Decomposition by Light Energy. the retina and by the underlying sclera, so a single discrete The outer segment of the rod that projects into the pigment spot of light that would normally excite only a few rods or layer of the retina has a concentration of about 40% of the cones is reflected everywhere and excites many receptors. light-sensitive pigment called rhodopsin, or visual purple. Therefore, the visual acuity of people with albinism, even This substance is a combination of the protein scotopsin with the best optical correction, is seldom better than and the carotenoid pigment retinal (also called “retinene”). 20/100 to 20/200 rather than the normal 20/20 values. Furthermore, the retinal is a particular type called 11-cis The pigment layer also stores large quantities of retinal. This cis form of retinal is important because only vitamin A. This vitamin A is exchanged back and forth this form can bind with scotopsin to synthesize rhodopsin. through the cell membranes of the outer segments of the When light energy is absorbed by rhodopsin, the rho- rods and cones, which are embedded in the pigment. We dopsin begins to decompose within a very small fraction discuss later that vitamin A is an important precursor of of a second, as shown at the top of Figure 51-5. The cause the photosensitive chemicals of the rods and cones. of this rapid decomposition is photoactivation of elec- trons in the retinal portion of the rhodopsin, which leads Blood Supply of the Retina—The Central Retinal Artery to instantaneous change of the cis form of retinal into an and the Choroid. The nutrient blood supply for the internal all-trans form that has the same chemical structure as the layers of the retina is derived from the central retinal artery, cis form but a different physical structure—it is a straight which enters the eyeball through the center of the optic molecule rather than an angulated molecule. Because the nerve and then divides to supply the entire inside retinal three-dimensional orientation of the reactive sites of the 641 UNIT X The Nervous System: B. The Special Senses Vitamin A is present both in the cytoplasm of the rods Light energy and in the pigment layer of the retina. Therefore, vitamin Rhodopsin Bathorhodopsin A is normally always available to form new retinal when (psec) (nsec) needed. Conversely, when there is excess retinal in the Lumirhodopsin retina, it is converted back into vitamin A, thus reducing (μsec) the amount of light-sensitive pigment in the retina. We shall see later that this interconversion between retinal (minutes) Metarhodopsin I and vitamin A is especially important in long-term adap- (msec) tation of the retina to different light intensities. Night Blindness Due to Vitamin A Deficiency. Night Metarhodopsin II (sec) blindness occurs in persons with severe vitamin A defi- ciency because, without vitamin A, the amounts of retinal Scotopsin and rhodopsin that can be formed are severely depressed. This condition is called night blindness because the amount Isomerase of light available at night is too little to permit adequate vi- 11-cis retinal All-trans retinal sion in vitamin A–deficient persons. For night blindness to occur, a person usually must re- Isomerase 11-cis retinol All-trans retinol main on a vitamin A–deficient diet for months, because (Vitamin A) large quantities of vitamin A are normally stored in the liver and can be made available to the eyes. Once night blindness Figure 51-5. The rhodopsin-retinal visual cycle in the rod, showing develops, it can sometimes be reversed in less than 1 hour decomposition of rhodopsin during exposure to light and subsequent by intravenous injection of vitamin A. slow re-formation of rhodopsin by the chemical processes. all-trans retinal no longer fits with the orientation of the Excitation of the Rod When Rhodopsin Is reactive sites on the protein scotopsin, the all-trans retinal Activated by Light begins to pull away from the scotopsin. The immediate The Rod Receptor Hyperpolarizes in Response to product is bathorhodopsin, which is a partially split com- Light. Exposure of the rod to light causes increased nega- bination of the all-trans retinal and scotopsin. Bathorho- tivity of the intrarod membrane potential, which is a state dopsin is extremely unstable and decays in nanoseconds of hyperpolarization. This is exactly opposite to the de- to lumirhodopsin. This product then decays in microsec- creased negativity (the process of “depolarization”) that onds to metarhodopsin I, then in about a millisecond to occurs in almost all other sensory receptors. metarhodopsin II, and finally, much more slowly (in sec- How does activation of rhodopsin cause hyperpolar- onds), into the completely split products scotopsin and all- ization? The answer is that when rhodopsin decomposes, it trans retinal. decreases the rod membrane conductance for sodium ions It is the metarhodopsin II, also called activated rho- in the outer segment of the rod causing hyperpolarization. dopsin, that excites electrical changes in the rods, and the Figure 51-6 shows movement of sodium and potas- rods then transmit the visual image into the central ner- sium ions in a complete electrical circuit through the vous system in the form of optic nerve action potentials, inner and outer segments of the rod. The inner segment as we discuss later. continually pumps sodium from inside the rod to the out- side, and potassium ions are pumped to the inside of the Re-Formation of Rhodopsin. The first stage in re- cell. Potassium ions leak out of the cell through nongated formation of rhodopsin, as shown in Figure 51-5, is to potassium channels that are confined to the inner segment reconvert the all-trans retinal into 11-cis retinal. This pro- of the rod. As in other cells, this sodium-potassium pump cess requires metabolic energy and is catalyzed by the en- creates a negative potential on the inside of the entire cell. zyme retinal isomerase. Once the 11-cis retinal is formed, However, the outer segment of the rod, where the pho- it automatically recombines with the scotopsin to re-form toreceptor discs are located, is entirely different. Here, rhodopsin, which then remains stable until its decompo- the rod membrane, in the dark state, is leaky to sodium sition is again triggered by absorption of light energy. ions that flow through cyclic guanosine monophosphate Role of Vitamin A for Formation of Rhodopsin. Note (cGMP)–gated channels. In the dark state, cGMP levels in Figure 51-5 that there is a second chemical route are high, permitting positively charged sodium ions to whereby all-trans retinal can be converted into 11-cis continually leak back to the inside of the rod and thereby retinal. This second route is by conversion of the all-trans neutralize much of the negativity on the inside of the retinal first into all-trans retinol, which is one form of vi- entire cell. Thus, under normal dark conditions, when the tamin A. Then, the all-trans retinol is converted into 11- rod is not excited, there is reduced electronegativity inside cis retinol under the influence of the enzyme isomerase. the membrane of the rod, measuring about −40 millivolts Finally, the 11-cis retinol is converted into 11-cis retinal, rather than the usual −70 to −80 millivolts found in most which combines with scotopsin to form new rhodopsin. sensory receptors. 642  CHAPTER 51 The Eye: II. Receptor and Neural Function of the Retina A cGMP-gated channels Outer segment membrane Rhodopsin G-Protein cGMP Transducin Phosphodiesterase UNIT X Current flow Light Na+ 5′-GMP cGMP cGMP gated sodium channel K+ selective Na+ channels ATP K+ Figure 51-7. Phototransduction in the outer segment of the photo- receptor (rod or cone) membrane. When light hits the photoreceptor (e.g., a rod cell), the light-absorbing retinal portion of rhodopsin is ac- tivated. This activation stimulates transducin, a G protein, which then activates cyclic guanosine monophosphate (cGMP) phosphodiester- ase. This enzyme catalyzes the degradation of cGMP into 5′-GMP. The reduction in cGMP then causes closure of the sodium channels, which, in turn, causes hyperpolarization of the photoreceptor. of the inner segment. Thus, more sodium ions now leave B Dark Light the rod than leak back in. Because they are positive ions, their loss from inside the rod creates increased negativity Na+ Na+ inside the membrane, and the greater the amount of light energy striking the rod, the greater the electronegativity becomes—that is, the greater is the degree of hyperpo- larization. At maximum light intensity, the membrane potential approaches −70 to −80 millivolts, which is near High (cGMP), Low (cGMP), the equilibrium potential for potassium ions across the open channels closed channels membrane. Figure 51-6. A, Sodium flows into a photoreceptor (e.g., a rod) through cyclic guanosine monophosphate (cGMP)–gated channels. Duration of the Receptor Potential, and Logarithmic Potassium flows out of the cell through nongated potassium chan- Relation of the Receptor Potential to Light Intensity. nels. A sodium-potassium pump maintains steady levels of sodium When a sudden pulse of light strikes the retina, the tran- and potassium inside the cell. B, In the dark, cGMP levels are high, sient hyperpolarization (receptor potential) that occurs and the sodium channels are open. In the light, cGMP levels are re- in the rods reaches a peak in about 0.3 second and lasts duced and the sodium channels close, causing the cell to hyperpolar- ize. ATP, Adenosine triphosphate. for more than 1 second. In cones, the change occurs four times as fast as in the rods. A visual image impinged on the rods of the retina for only one-millionth of a second When the rhodopsin in the outer segment of the rod can sometimes cause the sensation of seeing the image for is exposed to light, it is activated and begins to decom- longer than 1 second. pose. The cGMP-gated sodium channels are then closed, Another characteristic of the receptor potential is that and the outer segment membrane conductance of sodium it is approximately proportional to the logarithm of the to the interior of the rod is reduced by a three-step pro- light intensity. This characteristic is exceedingly impor- cess (Figure 51-7): (1) light is absorbed by the rhodop- tant because it allows the eye to discriminate light inten- sin, causing photoactivation of the electrons in the retinal sities through a range many thousand times as great as portion, as previously described; (2) the activated rho- would be possible otherwise. dopsin stimulates a G protein called transducin, which then activates cGMP phosphodiesterase, an enzyme that Mechanism Whereby Rhodopsin Decomposition De- catalyzes the breakdown of cGMP to 5′-GMP; and (3) the creases Membrane Sodium Conductance—The Ex- reduction in cGMP closes the cGMP-gated sodium chan- citation “Cascade.” Under optimal conditions, a single nels and reduces the inward sodium current. Sodium ions photon of light, the smallest possible quantal unit of light continue to be pumped outward through the membrane energy, can cause a receptor potential of about 1 millivolt in 643 UNIT X The Nervous System: B. The Special Senses a rod. Only 30 photons of light will cause half-saturation of Blue Green Red the rod. How can such a small amount of light cause such cone Rods cone cone 100 great excitation? The answer is that the photoreceptors (percent of maximum) Light absorption have an extremely sensitive chemical cascade that ampli- 75 fies the stimulatory effects about a millionfold, as follows: 1. The photon activates an electron in the 11-cis retinal 50 portion of the rhodopsin; this activation leads to the formation of metarhodopsin II, which is the active 25 form of rhodopsin, as shown in Figure 51-5. 2. The activated rhodopsin functions as an enzyme to 0 activate many molecules of transducin, a protein 400 500 600 700 present in an inactive form in the membranes of the Wavelength (nanometers) discs and cell membrane of the rod. Violet Blue Green Yellow Orange Red 3. The activated transducin activates many more mol- Figure 51-8. Light absorption by the pigment of the rods and by ecules of phosphodiesterase. the pigments of the three color-receptive cones of the human retina. 4. Activated phosphodiesterase immediately hydrolyzes (Data from Marks WB, Dobelle WH, MacNichol EF Jr: Visual pig- ments of single primate cones. Science 143:1181, 1964; and Brown many molecules of cGMP, thus destroying it. Before PK, Wald G: Visual pigments in single rods and cones of the human being destroyed, the cGMP had been bound with the retina: direct measurements reveal mechanisms of human night and sodium channel protein of the rod’s outer membrane color vision. Science 144:45, 1964.) in a way that “splints” it in the open state. However, in light, hydrolyzation of the cGMP by phosphodies- terase removes the splinting and allows the sodium pigment, green-sensitive pigment, and red-sensitive pig- channels to close. Several hundred channels close for ment. The absorption characteristics of the pigments in each originally activated molecule of rhodopsin. Be- the three types of cones show peak absorbencies at light cause the sodium flux through each of these channels wavelengths of 445, 535, and 570 nanometers, respectively. has been extremely rapid, flow of more than 1 million These wavelengths are also the wavelengths for peak light sodium ions is blocked by the channel closure before sensitivity for each type of cone, which begins to explain the channel opens again. This diminution of sodium how the retina differentiates the colors. The approximate ion flow is what excites the rod, as already discussed. absorption curves for these three pigments are shown in 5. Within about 1 second, another enzyme, rhodopsin Figure 51-8. Also shown is the absorption curve for the kinase, which is always present in the rod, inacti- rhodopsin of the rods, with a peak at 505 nanometers. vates the activated rhodopsin (metarhodopsin II), AUTOMATIC REGULATION OF RETINAL and the entire cascade reverses back to the normal SENSITIVITY—LIGHT AND DARK state with open sodium channels. ADAPTATION Thus, the rods have developed an important chemi- cal cascade that amplifies the effect of a single photon of If a person has been in bright light for hours, large por- light to cause movement of millions of sodium ions. This tions of the photochemicals in both the rods and the cones mechanism explains the extreme sensitivity of the rods will have been reduced to retinal and opsins. Furthermore, under dark conditions. much of the retinal of both the rods and the cones will The cones are about 30 to 300 times less sensitive than the have been converted into vitamin A. Because of these two rods, but even this degree of sensitivity allows color vision effects, the concentrations of the photosensitive chemicals at any intensity of light greater than extremely dim twilight. remaining in the rods and cones are considerably reduced, and the sensitivity of the eye to light is correspondingly Photochemistry of Color Vision by the reduced. This process is called light adaptation. Cones Conversely, if a person remains in darkness for a long We previously pointed out that the photochemicals in the time, the retinal and opsins in the rods and cones are con- cones have almost exactly the same chemical composition verted back into the light-sensitive pigments. Furthermore, as that of rhodopsin in the rods. The only difference is that vitamin A is converted back into retinal to increase light- the protein portions, or the opsins—called photopsins in the sensitive pigments, the final limit being determined by the cones—are slightly different from the scotopsin of the rods. amount of opsins in the rods and cones to combine with the The retinal portion of all the visual pigments is exactly the retinal. This process is called dark adaptation. same in the cones and rods. The color-sensitive pigments of the Figure 51-9 shows the course of dark adaptation when cones, therefore, are combinations of retinal and photopsins. a person is exposed to total darkness after having been Only one of three types of color pigments is present in exposed to bright light for several hours. Note that the each of the different cones, thus making the cones selec- sensitivity of the retina is very low on first entering the tively sensitive to different colors—blue, green, or red. darkness, but within 1 minute, the sensitivity has already These color pigments are called, respectively, blue-sensitive increased 10-fold—that is, the retina can respond to light 644  CHAPTER 51 The Eye: II. Receptor and Neural Function of the Retina 100,000 Value of Light and Dark Adaptation in Vision. Be- tween the limits of maximal dark adaptation and maximal light adaptation, the eye can change its sensitivity to light 10,000 Retinal sensitivity as much as 500,000 to 1 million times, with the sensitivity automatically adjusting to changes in illumination. 1000 Because registration of images by the retina requires UNIT X Rod adaptation detection of both dark and light spots in the image, it is essential that the sensitivity of the retina always be 100 adjusted so that the receptors respond to the lighter areas but not to the darker areas. An example of maladjust- 10 ment of retinal adaptation occurs when a person leaves a Cone adaptation movie theater and enters the bright sunlight. Then, even the dark spots in the images seem exceedingly bright, and 1 as a consequence, the entire visual image is bleached, with 0 10 20 30 40 50 Minutes in dark little contrast among its different parts. This poor vision remains until the retina has adapted sufficiently so that Figure 51-9. Dark adaptation demonstrating the relation of cone adaptation to rod adaptation. the darker areas of the image no longer stimulate the receptors excessively. Conversely, when a person first enters darkness, the of one-tenth that of the previously required intensity. At sensitivity of the retina is usually so slight that even the the end of 20 minutes, the sensitivity has increased about light spots in the image cannot excite the retina. After 6000-fold and, at the end of 40 minutes, it has increased dark adaptation, the light spots begin to register. As an about 25,000-fold. example of the extremes of light and dark adaptation, the The resulting curve of Figure 51-9 is called the dark intensity of sunlight is about 10 billion times that of star- adaptation curve. Note the inflection in the curve. The light, yet the eye can function both in bright sunlight after early portion of the curve is caused by adaptation of the light adaptation and in starlight after dark adaptation. cones because all the chemical events of vision, includ- ing adaptation, occur about four times as rapidly in cones as in rods. However, the cones do not achieve anywhere COLOR VISION near the same degree of sensitivity change in darkness as From the preceding sections, we learned that different the rods. Therefore, despite rapid adaptation, the cones cones are sensitive to different colors of light. This sec- cease adapting after only a few minutes, whereas the tion is a discussion of the mechanisms whereby the ret- slowly adapting rods continue to adapt for many minutes ina detects the different gradations of color in the visual and even hours, with their sensitivity increasing tremen- spectrum. dously. Additional sensitivity of the rods is caused by neu- ronal signal convergence of 100 or more rods onto a single TRICOLOR MECHANISM OF COLOR ganglion cell in the retina; these rods summate to increase DETECTION their sensitivity, as discussed later in the chapter. All theories of color vision are based on the well-known Other Mechanisms of Light and Dark Adaptation. In observation that the human eye can detect almost all gra- addition to adaptation caused by changes in concentra- dations of colors when only red, green, and blue mono- tions of rhodopsin or color photochemicals, the eye has chromatic lights are appropriately mixed in different two other mechanisms for light and dark adaptation. The combinations. first is a change in pupillary size, as discussed in Chapter 50. This change can cause adaptation of approximately 30- Spectral Sensitivities of the Three Types of Cones. On fold within a fraction of a second because of changes in the the basis of color vision tests, the spectral sensitivities of amount of light allowed through the pupillary opening. the three types of cones in humans have proved to be es- The other mechanism is neural adaptation, involving sentially the same as the light absorption curves for the the neurons in the successive stages of the visual chain in three types of pigment found in the cones. These curves the retina and in the brain. That is, when light intensity are shown in Figure 51-8 and slightly differently in Fig- first increases, the signals transmitted by the bipolar cells, horizontal cells, amacrine cells, and ganglion cells are all ure 51-10. They can explain most of the phenomena of intense. However, most of these signals decrease rapidly color vision. at different stages of transmission in the neural circuit. Al- Interpretation of Color in the Nervous System. In Fig- though the degree of adaptation is only a fewfold rather ure 51-10, one can see that an orange monochromatic than the many thousandfold that occurs during adaptation light with a wavelength of 580 nanometers stimulates the of the photochemical system, neural adaptation occurs in a fraction of a second, in contrast to the many minutes to red cones to a value of about 99 (99% of the peak stimu- hours required for full adaptation by the photochemicals. lation at optimum wavelength); it stimulates the green cones to a value of about 42, but the blue cones are not 645 UNIT X The Nervous System: B. The Special Senses Blue Green Red Red-green color blindness is a genetic disorder that oc- cone cone cone curs almost exclusively in males. That is, genes in the fe- 100 97 99 Green (percent of maximum) male X chromosome code for the respective cones. Yet, 83 83 color blindness almost never occurs in females because at Light absorption 75 least one of the two X chromosomes almost always has a 67 normal gene for each type of cone. Because the male has Yellow Blue 50 42 only one X chromosome, a missing gene can lead to color 36 Orange blindness. 31 25 Because the X chromosome in the male is always inher- ited from the mother, never from the father, color blindness 0 is passed from mother to son, and the mother is said to be 0 400 500 600 700 a color blindness carrier. About 8% of all women are color Wavelength (nanometers) blindness carriers. Violet Blue Green Yellow Orange Red Blue Weakness. Only rarely are blue cones missing, al- though sometimes they are underrepresented in a geneti- Figure 51-10. Demonstration of the degree of stimulation of the dif- ferent color-sensitive cones by monochromatic lights of four colors— cally inherited condition called blue weakness. blue, green, yellow, and orange. Color Test Charts. A rapid method for determining color blindness is based on the use of spot charts such as those shown in Figure 51-11. These charts are arranged stimulated at all. Thus, the ratios of stimulation of the with a mixture of spots of several different colors. In the three types of cones in this case are 99:42:0. The nerv- top chart, a person with normal color vision reads “74,” ous system interprets this set of ratios as the sensation whereas a red-green color-blind person reads “21.” In the of orange. Conversely, a monochromatic blue light with a bottom chart, a person with normal color vision reads wavelength of 450 nanometers stimulates the red cones to “42,” whereas a red-blind person reads “2,” and a green- a stimulus value of 0, the green cones to a value of 0, and blind person reads “4.” the blue cones to a value of 97. This set of ratios—0:0:97— is interpreted by the nervous system as blue. Likewise, NEURAL FUNCTION OF THE RETINA ratios of 83:83:0 are interpreted as yellow, and ratios of Figure 51-12 presents the essentials of the retina’s 31:67:36 are interpreted as green. neural connections, showing the circuit in the periph- Perception of White Light. About equal stimulation of eral retina at the left and the circuit in the foveal retina all the red, green, and blue cones gives one the sensation at the right. The different neuronal cell types are as of seeing white. Yet, there is no single wavelength of light follows: corresponding to white; instead, white is a combination of 1. The photoreceptors—the rods and cones—which all the wavelengths of the spectrum. Furthermore, the per- transmit signals to the outer plexiform layer, where ception of white can be achieved by stimulating the retina they synapse with bipolar cells and horizontal cells with a proper combination of only three chosen colors 2. The horizontal cells, which transmit signals hori- that stimulate the respective types of cones about equally. zontally in the outer plexiform layer from the rods and cones to bipolar cells Color Blindness 3. The bipolar cells, which transmit signals vertically from the rods, cones, and horizontal cells to the in- Red-Green Color Blindness. When a single group of color-receptive cones is missing from the eye, the per- ner plexiform layer, where they synapse with gan- son is unable to distinguish some colors from others. For glion cells and amacrine cells example, one can see in Figure 51-10 that green, yellow, 4. The amacrine cells, which transmit signals in two orange, and red colors, which are the colors between the directions, either directly from bipolar cells to gan- wavelengths of 525 and 675 nanometers, are normally dis- glion cells or horizontally within the inner plexiform tinguished from one another by the red and green cones. layer from axons of the bipolar cells to dendrites of If either of these two cones is missing, the person cannot the ganglion cells or to other amacrine cells use this mechanism for distinguishing these four colors; the 5. The ganglion cells, which transmit output signals person is especially unable to distinguish red from green from the retina through the optic nerve into the brain and is therefore said to have red-green color blindness. A sixth type of neuronal cell in the retina, which is A person with loss of red cones is called a protanope; the not very prominent and is not shown in the figure, is the overall visual spectrum is noticeably shortened at the long wavelength end because of a lack of the red cones. A color- interplexiform cell. This type of cell transmits signals in blind person who lacks green cones is called a deuteranope; the retrograde direction from the inner plexiform layer this person has a perfectly normal visual spectral width be- to the outer plexiform layer. These signals are inhibitory cause red cones are available to detect the long wavelength and are believed to control lateral spread of visual signals red color. However, a deuteranope can only distinguish 2 by the horizontal cells in the outer plexiform layer. Their or 3 different hues, whereas somebody with normal vision role may be to help control the degree of contrast in the sees 7 unique hues. visual image. 646  CHAPTER 51 The Eye: II. Receptor and Neural Function of the Retina Pigment layer Cones Rods UNIT X Rod nuclei Horizontal Bipolar cells cells Amacrine cells Ganglion cells Figure 51-12. Neural organization of the retina, with the peripheral area to the left and the foveal area to the right. brain two to five times as rapidly. Also, the circuitry for the two systems is slightly different. To the right in Figure 51-12 is the visual pathway from the foveal portion of the retina, representing the new, fast cone system. This illustration shows three neurons in the direct pathway: (1) cones; (2) bipolar cells; and (3) gan- glion cells. In addition, horizontal cells transmit inhibitory signals laterally in the outer plexiform layer, and amacrine cells transmit signals laterally in the inner plexiform layer. To the left in Figure 51-12 are the neural connections for the peripheral retina, where both rods and cones are present. Three bipolar cells are shown; the middle of these connects only to rods, representing the type of visual sys- tem present in many lower animals. The output from the bipolar cell passes only to amacrine cells, which relay the signals to the ganglion cells. Thus, for pure rod vision, there are four neurons in the direct visual pathway: (1) rods; (2) bipolar cells; (3) amacrine cells; and (4) ganglion cells. In addition, horizontal and amacrine cells provide Figure 51-11. Two Ishihara charts. In this chart (upper panel), a lateral connectivity. person with normal vision reads “74,” but a red-green color-blind The other two bipolar cells shown in the peripheral person reads “21.” In this chart (lower panel), a red-blind person retinal circuitry of Figure 51-12 connect with both rods (protanope) reads “2,” but a green-blind person (deuteranope) reads “4.” A person with normal vision reads “42.” (From Ishihara S. Tests and cones; the outputs of these bipolar cells pass both for color-blindness. Handaya, Tokyo: Hongo Harukicho, 1917. Note directly to ganglion cells and by way of amacrine cells. that tests for color blindness cannot be conducted with this material. For accurate testing, the original plates should be used.) Neurotransmitters Released by Retinal Neurons. Not all the neurotransmitter chemical substances used for synaptic transmission in the retina have been entirely The Visual Pathway From the Cones to the Ganglion delineated. However, both the rods and the cones release Cells Functions Differently From the Rod Pathway. As glutamate at their synapses with the bipolar cells. is true for many of our other sensory systems, the retina Histological and pharmacological studies have proven has both an old type of vision based on rod vision and a the existence of many types of amacrine cells that secrete new type of vision based on cone vision. The neurons and at least eight types of transmitter substances, including nerve fibers that conduct the visual signals for cone vision gamma-aminobutyric acid (GABA), glycine, dopamine, are considerably larger than those that conduct the visual acetylcholine, and indolamine, all of which normally func- signals for rod vision, and the signals are conducted to the tion as inhibitory transmitters. The transmitters of the 647 UNIT X The Nervous System: B. The Special Senses bipolar, horizontal, and interplexiform cells are unclear, but at least some of the horizontal cells release inhibitory transmitters. Transmission of Most Signals Occurs in the Retinal Neurons by Electrotonic Conduction, Not by Action Light beam Potentials. The only retinal neurons that always transmit visual signals via action potentials are the ganglion cells, and they send their signals all the way to the brain through the optic nerve. Occasionally, action potentials have also Excited area been recorded in amacrine cells, although the importance of these action potentials is questionable. Otherwise, all Neither excited the retinal neurons conduct their visual signals by electro- nor inhibited tonic conduction, not by action potentials. Electrotonic conduction means direct flow of electric Inhibited area current, not action potentials, in the neuronal cytoplasm and nerve axons from the point of excitation all the way to the output synapses. Even in the rods and cones, con- Figure 51-13. Excitation and inhibition of a retinal area caused by a duction from their outer segments to the synaptic bodies small beam of light, demonstrating the principle of lateral inhibition. is by electrotonic conduction. That is, when hyperpolar- ization occurs in response to light in the outer segment of a rod or a cone, almost the same degree of hyperpo- Some of the amacrine cells probably provide additional larization is conducted by direct electric current flow in lateral inhibition and further enhancement of visual con- the cytoplasm all the way to the synaptic body, and no trast in the inner plexiform layer of the retina as well. action potential is required. Then, when the transmitter from a rod or cone stimulates a bipolar cell or horizontal Depolarizing and Hyperpolarizing Bipolar cell, once again the signal is transmitted from the input to Cells the output by direct electric current flow, not by action Two types of bipolar cells provide opposing excitatory potentials. and inhibitory signals in the visual pathway: (1) the depo- The importance of electrotonic conduction is that it larizing bipolar cell; and (2) the hyperpolarizing bipolar allows graded conduction of signal strength. Thus, for the cell. That is, some bipolar cells depolarize when the rods rods and cones, the strength of the hyperpolarizing out- and cones are excited, and others hyperpolarize. put signal is directly related to the intensity of illumina- There are two possible explanations for this difference. tion; the signal is not all or none, as would be the case for One explanation is that the two bipolar cells are of entirely each action potential. different types, with one responding by depolarizing in response to the glutamate neurotransmitter released by Lateral Inhibition to Enhance Visual the rods and cones and the other responding by hyper- Contrast—Function of the Horizontal Cells polarizing. The other possibility is that one of the bipolar The horizontal cells, shown in Figure 51-12, connect lat- cells receives direct excitation from the rods and cones, erally between the synaptic bodies of the rods and cones whereas the other receives its signal indirectly through a and with the dendrites of the bipolar cells. The outputs horizontal cell. Because the horizontal cell is an inhibi- of the horizontal cells are always inhibitory. Therefore, tory cell, this would reverse the polarity of the electrical this lateral connection provides the same phenomenon of response. lateral inhibition that is important in other sensory sys- Regardless of the mechanism for the two types of bipo- tems—that is, helping to ensure transmission of visual lar responses, the importance of this phenomenon is that patterns with proper visual contrast. This phenomenon it allows half the bipolar cells to transmit positive signals is demonstrated in Figure 51-13, which shows a min- and the other half to transmit negative signals. We shall ute spot of light focused on the retina. The visual path- see later that both positive and negative signals are used way from the central most area where the light strikes is in transmitting visual information to the brain. excited, whereas an area to the side is inhibited. In other Another important aspect of this reciprocal relation words, instead of the excitatory signal spreading widely in between depolarizing and hyperpolarizing bipolar cells the retina because of spreading dendritic and axonal trees is that it provides a second mechanism for lateral inhi- in the plexiform layers, transmission through the hori- bition, in addition to the horizontal cell mechanism. zontal cells puts a stop to this spread by providing lateral Because depolarizing and hyperpolarizing bipolar cells inhibition in the surrounding areas. This process is essen- lie immediately against each other, this provides a mecha- tial to allow high visual accuracy in transmitting contrast nism for separating contrast borders in the visual image, borders in the visual image. even when the border lies exactly between two adjacent 648  CHAPTER 51 The Eye: II. Receptor and Neural Function of the Retina photoreceptors. In contrast, the horizontal cell mecha- give even more intense stimulation of the peripheral gan- nism for lateral inhibition operates over a much greater glion cells and their optic nerve fibers. distance. Retinal Ganglion Cells and Their Amacrine Cells and Their Functions Respective Fields About 30 types of amacrine cells have been identified by W, X, and Y Cells. Early studies in cats described three UNIT X morphological or histochemical means. The functions of distinct types of retinal ganglion cells, designated W, X, about half a dozen types of amacrine cells have been char- and Y cells, based on their differences in structure and acterized, and all of them are different: function.
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The Y cells respond to rapid the retina. changes in visual images and apprise the central nervous system almost instantaneously when a new visual event GANGLION CELLS AND OPTIC NERVE occurs anywhere in the visual field, but they do not spec- FIBERS ify the location of the event with great accuracy, other than to give clues that make the eyes move toward the Each retina contains about 100 million rods and 3 million exciting vision. cones, yet the number of ganglion cells is only about 1.6 million. Thus, an average of 60 rods and 2 cones converge P and M Cells. In primates, a different classification of on each ganglion cell and the optic nerve fiber leading retinal ganglion cells is used, and as many as 20 types from the ganglion cell to the brain. of retinal ganglion cells have been described, each re- However, major differences exist between the periph- sponding to a different feature of the visual scene. Some eral retina and the central retina. As one approaches the cells respond best to specific directions of motion or fovea, fewer rods and cones converge on each optic fiber, orientations, whereas others respond to fine details, in- and the rods and cones also become more slender. These creases or decreases in light, or particular colors. The effects progressively increase the acuity of vision in the two general classes of retinal ganglion cells that have central retina. In the central fovea, there are only slen- been studied most extensively in primates, including der cones—about 35,000 of them—and no rods. Also, humans, are designated as magnocellular (M) and par- the number of optic nerve fibers leading from this part vocellular (P) cells. of the retina is almost exactly equal to the number of The P cells (also known as beta cells or, in the central cones, as shown at the right in Figure 51-12. This phe- retina, as midget ganglion cells) project to the parvocel- nomenon explains the high degree of visual acuity in the lular (small cells) layer of the lateral geniculate nucleus of central retina in comparison with the much poorer acuity the thalamus. The M cells (also called alpha or parasol peripherally. cells) project to the magnocellular (large cells) layer of the Another difference between the peripheral and central lateral geniculate nucleus, which, in turn, relays informa- portions of the retina is the much greater sensitivity of tion from the optic tract to the visual cortex, as discussed the peripheral retina to weak light, which occurs partly in Chapter 52. The main differences between P and M because rods are 30 to 300 times more sensitive to light cells are as follows: than cones. However, this greater sensitivity is further 1. The receptive fields for P cells are much smaller magnified by the fact that as many as 200 rods converge than for M cells. on a single optic nerve fiber in the more peripheral por- 2. P-cell axons conduct impulses much more slowly tions of the retina, so signals from the rods summate to than do M cells. 649 UNIT X The Nervous System: B. The Special Senses 3. The responses of P cells to stimuli, especially color on off stimuli, can be sustained, whereas the responses of M cells are much more transient. 1 4. The P cells are generally sensitive to the color of a Excitation stimulus, whereas M cells are not sensitive to color stimuli. 2 5. The M cells are much more sensitive than are P cells Lateral inhibition to low-contrast, black and white stimuli. Figure 51-14. Responses of a ganglion cell to light in (1) an area The main functions of M and P cells are obvious from excited by a spot of light and (2) an area adjacent to the excited their differences: The P cells are highly sensitive to visual spot. The ganglion cell in this area is inhibited by the mechanism signals that relate to fine details and to different colors but of lateral inhibition. (Modified from Granit R: Receptors and Sensory are relatively insensitive to low-contrast signals, whereas Perception: A Discussion of Aims, Means, and Results of Electrophysi- ological Research into the Process of Reception. New Haven, CT: Yale the M cells are highly sensitive to low-contrast stimuli and University Press, 1955.) to rapid movement visual signals. A third type of photosensitive retinal ganglion cell has been described that contains its own photopigment, Conversely, the same gnat sitting quietly remains below melanopsin. Much less is known about this cell type, but the threshold of visual detection. these cells appear to send signals mainly to nonvisual areas of the brain, particularly the suprachiasmatic nucleus of Transmission of Signals Depicting the hypothalamus, the master circadian pacemaker. Pre- Contrasts in the Visual Scene—The Role sumably, these signals help control circadian rhythms that of Lateral Inhibition synchronize physiological changes with night and day. Many ganglion cells respond mainly to contrast borders in the scene, which seems to be the major means whereby the pattern of a scene is transmitted to the brain. When EXCITATION OF THE GANGLION CELLS flat light is applied to the entire retina, and all the photo- receptors are stimulated equally by the incident light, the Spontaneous, Continuous Action Potentials in the contrast type of ganglion cell is neither stimulated nor Ganglion Cells. It is from the ganglion cells that the long inhibited. The reason for this is that signals transmitted fibers of the optic nerve lead into the brain. Because of the directly from the photoreceptors through depolarizing distance involved, the electrotonic method of conduction bipolar cells are excitatory, whereas the signals transmitted employed in the rods, cones, and bipolar cells in the retina laterally through hyperpolarizing bipolar cells, as well as is no longer appropriate; therefore, ganglion cells trans- through horizontal cells, are mainly inhibitory. Thus, the mit their signals by means of repetitive action potentials direct excitatory signal through one pathway is likely to instead. Furthermore, even when unstimulated, they still be neutralized by inhibitory signals through lateral path- transmit continuous impulses at rates varying between 5 ways. One circuit for this process is demonstrated in Fig- and 40 per second. The visual signals, in turn, are super- ure 51-15, which shows three photoreceptors at the top of imposed onto this background ganglion cell firing. the illustration. The central receptor excites a depolarizing Transmission of Changes in Light Intensity—The On- bipolar cell. The two receptors on each side are connected Off Response. As noted previously, many ganglion cells to the same bipolar cell through inhibitory horizontal cells are specifically excited by changes in light intensity, dem- that neutralize the direct excitatory signal if all three recep- onstrated by the records of nerve impulses in Figure 51- tors are stimulated simultaneously by light. 14. The upper panel shows rapid impulses for a fraction of Now, let us examine what happens when a contrast a second when a light is first turned on, but these impulses border occurs in the visual scene. Referring again to decrease rapidly in the next fraction of a second. The low- Figure 51-15, assume that the central photoreceptor is er tracing is from a ganglion cell located laterally to the stimulated by a bright spot of light while one of the two spot of light; this cell is markedly inhibited when the light lateral receptors is in the dark. The bright spot of light is turned on because of lateral inhibition. Then, when the excites the direct pathway through the bipolar cell. The light is turned off, opposite effects occur. The opposite fact that one of the lateral photoreceptors is in the dark directions of these responses to light are caused, respec- causes one of the horizontal cells to remain unstimulated. tively, by the depolarizing and hyperpolarizing bipolar Therefore, this cell does not inhibit the bipolar cell, which cells, and the transient nature of the responses is probably allows extra excitation of the bipolar cell. Thus, where at least partly generated by the amacrine cells, many of visual contrasts occur, the signals through the direct and which have similar transient responses themselves. lateral pathways accentuate one another. This capability of the eyes to detect changes in light In summary, the mechanism of lateral inhibition func- intensity is strongly developed in the peripheral retina tions in the eye in the same way that it functions in most and the central retina. For example, a minute gnat fly- other sensory systems—to provide contrast detection and ing across the field of vision is instantaneously detected. enhancement. 650  CHAPTER 51 The Eye: II. Receptor and Neural Function of the Retina the direct excitatory route through a depolarizing bipolar cell, whereas the other color type inhibits the ganglion cell by the indirect inhibitory route through a hyperpolarizing bipolar cell. The importance of these color contrast mechanisms is that they represent a means whereby the retina begins UNIT X to differentiate colors. Thus, each color contrast type of ganglion cell is excited by one color but inhibited by the Excitation “opponent” color. Therefore, color analysis begins in the retina and is not entirely a function of the brain. Bibliography Bringmann A, Syrbe S, Görner K, et al: The primate fovea: structure, H function and development. Prog Retin Eye Res 66:49, 2018. H Inhibition Do MT, Yau KW: Intrinsically photosensitive retinal ganglion cells. B Physiol Rev 90:1547, 2010. Douglas RH: The pupillary light responses of animals; a review of their distribution, dynamics, mechanisms and functions. Prog Retin Eye Res 66:17, 2018. Fain GL, Matthews HR, Cornwall MC, Koutalos Y: Adaptation in ver- tebrate photoreceptors. Physiol Rev 81:117, 2001. Gill JS, Georgiou M, Kalitzeos A, Moore AT, Michaelides M: Progres- sive cone and cone-rod dystrophies: clinical features, molecular ge- netics and prospects for therapy. Br J Ophthalmol 2019 Jan 24. pii: bjophthalmol-2018-313278. http://doi.org/10.1136/bjophthalmol- G 2018-313278. Laha B, Stafford BK, Huberman AD: Regenerating optic pathways from the eye to the brain. Science 356:1031, 2017. Luo DG, Xue T, Yau KW: How vision begins: an odyssey. Proc Natl Figure 51-15. Typical arrangement of rods, horizontal cells (H), a bi- Acad Sci U S A 105:9855, 2008. polar cell (B), and a ganglion cell (G) in the retina, showing excitation Ingram NT, Sampath AP, Fain GL: Why are rods more sensitive than at the synapses between the rods and the bipolar cell and horizontal cones? J Physiol 594:5415, 2016. cells but inhibition from the horizontal cells to the bipolar cell. Masland RH: The neuronal organization of the retina. Neuron 76:266, 2012. Transmission of Color Signals by the Masland RH: The tasks of amacrine cells. Vis Neurosci 29:3, 2012. Ganglion Cells Roska B, Sahel JA: Restoring vision. Nature 557:359, 2018. Sahel JA, Bennett J, Roska B: Depicting brighter possibilities for treat- A single ganglion cell may be stimulated by several or only ing blindness. Sci Transl Med 2019 May 29;11(494). pii: eaax2324. a few cones. When all three types of cones—the red, blue, http://doi.org/10.1126/scitranslmed.aax2324 and green types—stimulate the same ganglion cell, the Schmidt TM, Do MT, Dacey D, et al: Melanopsin-positive intrinsically photosensitive retinal ganglion cells: from form to function. J Neu- signal transmitted through the ganglion cell is the same rosci 31:16094, 2011. for any color of the spectrum. Therefore, the signal from Solomon SG, Lennie P: The machinery of colour vision. Nat Rev Neu- the ganglion cell plays no role in the detection of different rosci 8:276, 2007. colors. Instead, it is a “white” signal. Vaney DI, Sivyer B, Taylor WR: Direction selectivity in the retina: sym- Conversely, some of the ganglion cells are excited by metry and asymmetry in structure and function. Nat Rev Neurosci 13:194, 2012. only one color type of cone but are inhibited by a second Varadarajan SG, Huberman AD: Assembly and repair of eye-to-brain type. For example, this mechanism frequently occurs for connections. Curr Opin Neurobiol 53:198, 2018. the red and green cones, with red causing excitation and Vinberg F, Chen J, Kefalov VJ: Regulation of calcium homeostasis in green causing inhibition, or vice versa. the outer segments of rod and cone photoreceptors. Prog Retin The same type of reciprocal effect occurs between Eye Res 67:87, 2018. Wienbar S, Schwartz GW: The dynamic receptive fields of retinal gan- blue cones on the one hand and a combination of red and glion cells. Prog Retin Eye Res 67:102, 2018. green cones (both of which are excited by yellow) on the Wubben TJ, Zacks DN, Besirli CG: Retinal neuroprotection: current other hand, giving a reciprocal excitation-inhibition rela- strategies and future directions. Curr Opin Ophthalmol 30:199, tion between the blue and yellow colors. 2019. The mechanism of this opposing effect of colors is as follows. One color type of cone excites the ganglion cell by 651