Parallel Information Processing Channels Created in the Retina

Home , Midget cell, Night vision, Parasol cell

Parallel information processing channels created in INAUGURAL ARTICLE the retina

Peter H. Schiller1

Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139

This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2007.

Contributed by Peter H. Schiller, August 13, 2010 (sent for review July 10, 2010) In the retina, several parallel channels originate that extract different individual retinal ganglion cells (3). Doing so, he discovered three attributes from the visual scene. This review describes how these classes of retinal ganglion cells: “ON” cells that discharged vigor- channels arise and what their functions are. Following the introduc- ously when the retina was illuminated, “OFF” cells that discharged tion four sections deal with these channels. The first discusses the when the light was turned off, and ON/OFF cells that responded “ON” and “OFF” channels that have arisen for the purpose of rapidly transiently to both the onset and the termination of light. He also processing images in the visual scene that become visible by virtue of established that each cell is sensitive to only a small area of illu- either light increment or light decrement; the ON channel processes mination on the retinal surface, a region called the receptive field images that become visible by virtue of light increment and the of the cell. Hartline received the Nobel Prize for these discoveries OFF channel processes images that become visible by virtue of light in 1967. Subsequently, Steven Kuffler discovered in the cat, as did decrement. The second section examines the midget and parasol Horace Barlow in the frog, that the receptive field of each ganglion fi channels. The midget channel processes ne detail, wavelength in- cell is actually composed of two regions that are concentrically formation, and stereoscopic depth cues; the parasol channel plays fl arranged: an excitatory center area and an antagonistic surround a central role in processing motion and icker as well as motion region (4, 5). Stimulating the center with a small spot elicited parallax cues for depth perception. Both these channels have ON a vigorous response, whereas a larger spot that impinged also on and OFF subdivisions. The third section describes the accessory optic the surround produced an attenuated response. Stimulation of the

system that receives input from the retinal ganglion cells of Dogiel; NEUROSCIENCE these cells play a central role, in concert with the vestibular system, in surround alone with an annulus produced a weak response of the stabilizing images on the retina to prevent the blurring of images opposite polarity. The ON/OFF cells gave vigorous transient that would otherwise occur when an organism is in motion. The responses to both the onset and the termination of light when fi fi last section provides a brief overview of several additional con ned to the center of their receptive elds; in these cells, the channels that originate in the retina. responses were also attenuated when the size of the stimulus was increased. Similar results were obtained subsequently in many midget channels | ON/OFF channels | parasol channels species suggesting that the ON, OFF, and ON/OFF cells of the retina and their antagonistic center-surround organization form – n the past 120 years, great strides have been made in uncovering a basic ground plan for the visual systems of all vertebrates (6 9). Ihow the brain processes visual information. Several of the dis- ON and OFF Channels coveries were quite surprising and unexpected. It was found that, in Origins of the ON and OFF Channels in the Retina. In the 1960s, it the retina, the photoreceptors faced away from the incoming light became possible to place finely drawn micropipettes inside the and were closest to the pigment epithelium. All the other cell types various cell types of the retina (10, 11). Such intracellular record- in the retina were positioned between the photoreceptors and the ings provided accurate measurements of the graded potentials vitreous humor. This meant that, except for the central foveal re- produced by the neurons and made possible their subsequent an- gion, the incoming photons had to pass through all these cells and atomic identification by minute dye injections. Studies using these their processes before impinging on the photoreceptors. It was also procedures, beginning with the pioneering work in John Dowling’s discovered that there are two distinct photoreceptor types, the rods laboratory, revealed that the basic organization of the retina in and the cones. When Schultze established this in the 1860s with vertebrate species is quite similar (12–16). The photoreceptors in fi anatomical methods he had developed (1), his ndings were met all cases hyperpolarize to light and use the neurotransmitter glu- with considerable skepticism. Undaunted, he went on to ask what tamate, which acts differently on the two major classes of bipolar the reason might be for having two different kinds of photo- cells: OFF bipolars, which have sign-conserving ionotropic recep- receptors. He noted that the rods are absent in the fovea and that tors (iGluRs), and ON bipolars, which have sign-inverting meta- night vision is poor when incoming light is confined to this region. botropic receptors (mGluR6). Thus, the OFF cells polarize in the So he proposed that the rods are for night vision, a fact now fully same manner as do the photoreceptors whereas the ON bipolars accepted. Further studies have identified several distinct classes of polarize in the direction opposite to the photoreceptors. Fig. 1A cells in the retina that included the horizontal cells, the bipolar shows this arrangement schematically. The majority of cones in cells, the amacrine cells, and the ganglion cells that send their axons central retina connect with at least two bipolar cells, one of which to the central nervous system exiting the eye at the optic disk. is ON and the other OFF. The ON and OFF bipolars in turn Studies have yielded yet another unexpected discovery, showing connect with ON and OFF retinal ganglion cells, respectively. that there are several distinct classes of retinal ganglion cells. The Further complexities in this arrangement will be described later. use of the Golgi stain by its inventor, Camillo Golgi, and by San- tiago Ramon y Cajal, was central in establishing these facts (2). For the numerous remarkable findings they made about the organiza- Author contributions: P.H.S. designed research, performed research, and wrote the paper. tion of the brain, Golgi and Cajal received the Nobel Prize in 1906. The author declares no conflict of interest. The subsequent emergence of physiological methods has made Freely available online through the PNAS open access option. it possible to examine the functions of the neurons in the retina. 1E-mail: [email protected]. fi The rst to do so was Haldan Keffer Hartline, who developed This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. procedures that enabled him to record the electrical activity of 1073/pnas.1011782107/-/DCSupplemental.

www.pnas.org/cgi/doi/10.1073/pnas.1011782107 PNAS Early Edition | 1of8 Downloaded by guest on September 29, 2021 The intracellular recording studies have also revealed that A photoreceptors, horizontal cells, and bipolar cells produce only graded potentials. Center-surround organization appears at the level of the bipolar cell (11). Action potentials are first seen in some amacrine cells and are produced by all ganglion cells. The axons of the ganglion cells project to a number of different nuclei in the brain, the largest of which, in primates, is the lateral geniculate nucleus (LGN) of the thalamus. This is a structure with several lamina in which the left and right eye inputs are segregated. In addition, there is a propensity for the various retinal ganglion cell types to terminate in different layers (6, 8, 9, 17). In a few species, there is a clear or partial segregation of the ON and OFF cells in the LGN (8, 9, 18, 19). Neurons from the LGN project to the visual cortex. Although the receptive field characteristics of LGN neurons are similar to those of retinal ganglion cells, in the cortex several new properties are found (6, 20); the majority of cells in primary visual cortex show selectivity for the orientation of edges, and many cells respond selectively to the direction of motion of these edges. B Anatomical studies have revealed that the ON and OFF bipolar cells are distinct structurally and make connections in the inner retina in different subregions of the inner plexiform layer (IPL), as depicted in Fig. 1B; the OFF bipolars make contact with OFF retinal ganglion cell arbors in sublamina a of the IPL and ON bipolars make contact with ON ganglion cells in sublamina b of the IPL (7, 16, 21). The layout of the ON and OFF retinal ganglion cells has been effectively examined in retinal whole mounts, in which the retina is viewed as a flattened preparation. The dendritic arbors of the ON and OFF ganglion cells, once properly labeled, can readily be identified because they come into focus at different depths within the specimen. Using such methods, Heinz Wässle and collaborators discovered that the spacing of the arbors within each of the ON and OFF cell classes, but not between them, is highly orderly (22). This systematic arrangement suggests that the ON and OFF systems provide separate, and probably independent, coverage of the visual field. The synapses bipolar cells make C in the inner retina are glutamatergic. Horizontal and amacrine cells come in many different subtypes and use a variety of neurotransmitters that include gamma-aminobutyric acid (GABA), gly- cine, and acetylcholine. The diversity of horizontal and amacrine cell types appears to decrease in higher mammals in which more complex visual analysis is increasingly relegated to neocortex. That nature has gone to such complexities to create the ON and OFF systems suggests that great benefits must be reaped for the analysis of visual information. The initial ideas were that the ON system signals the onset of light and the OFF system the termination of light. As first suggested by Jung (23), another idea that has gained some degree of acceptance was that the ON system gives rise to the perception of brightness and the OFF system to the perception of darkness. A third consideration was advanced by more physiologically minded investigators, who suggested that the ON and OFF systems have evolved to provide for the antagonistic center-surround organization of receptive fields in retinal ganglion cells and in the cortex (24). Two major schemes have been proposed as to how the preganglionic neural elements of the retina connect to the ganglion cells to yield their antagonistic center/ surround organization. According to the first, the surround mechanism is supplied by the lateral connections of the horizontal and amacrine cells of the retina. According to the second, the center-surround arrangement of the retinal ganglion cells is produced by convergent connections from ON and OFF bipolars (8, 9, 25). The data gathered during the past few years in primates favor the idea that those cells of the retina that can be unequivocally identified as being ON-center or OFF-center types form separate Fig. 1. (A) The basic connections a cone makes with ON and OFF ganglion cells pathways and do not interact extensively. The surround mecha- via ON and OFF bipolar cells. The ON bipolar cells have sign inverting synapses as described in the text. (B) The basic connections rods, cones, bipolar cells, horizontal cells, and amacrine cells make in the retina. [Reprinted from Prog- ress in Retinal and Eye Research, Vol 15, Schiller PH, The ON and OFF channels during, and after the infusion of APB into the eye. APB blocks the ON cell re- of the mammalian visual system, 173–195, Copyright (1995), with permission sponse and has no significant effect on the OFF cell (25). (Reprinted by per- from Elsevier]. (C) The responses of an ON and OFF monkey LGN cell before, mission from Macmillan Publishers Ltd: Nature, 297:580–583, copyright 1982.)

2of8 | www.pnas.org/cgi/doi/10.1073/pnas.1011782107 Schiller Downloaded by guest on September 29, 2021 nism of these cells is a product of the lateral connections in the Except for a transient initial excitatory response, the OFF

retina rather than a product of an interactive connection between bipolars are largely unaffected by APB. As there is no ready uptake INAUGURAL ARTICLE the ON and OFF bipolar cells. In the following sections, three lines mechanism for this artificial substance, it is effective in small of evidence will be considered in support of this view, which come quantities and is broken down slowly. It seems to have little or no from anatomical, physiological, and behavioral studies. direct effect on the synaptic networks of the inner plexiform layer. When Ramon y Cajal et al. (2) examined the organization of the Effect of APB on the responses of single cells in the mammal. To de- retina after the duality of the rod and cone photoreceptors had been termine the effect of APB on the mammalian visual system, several established by Schultze (1), the evidence he gathered suggested to investigators have applied this substance to the retina while re- him that these two systems form separate pathways to the central cording from various visual structures. It became immediately nervous system. Subsequent studies have established, however, evident that the effects of APB noted in the mudpuppy are similar that, for the most part, where the rods and cones coexist in any in the mammalian retina. When APB is administered in appro- region of the retina, their signals converge upon the retinal ganglion priate concentrations to the monkey eye, the ON response in cells (26, 27). Furthermore, current studies have shown that, unlike retinal ganglion cells is abolished whereas the OFF response is for the cones, the rod system in some mammals—including the cat, largely unaffected (9, 24, 25, 37). Fig. 1C shows recordings made monkey, and human—has only ON-type rod bipolars. This has from an ON and OFF cell in the LGN before, during, and after the raised some interesting questions about the manner in which the infusion of APB into the retina. The ON cell stops responding to rods might make their connections with the retinal ganglion cells. the visual stimulus presented in the receptive field of the cell The nature of this connectivity has been worked out in some detail whereas the OFF cell continues to respond. recently. The rod photoreceptor cells form sign-inverting synapses Having established that APB blocks the ON system in the with the rod ON bipolars (28). Examination of the connections of monkey as it does in the mudpuppy, investigators moved on to the rods has also established that each rod ON bipolar cell contacts determine to what extent the ON and OFF bipolar cells make in- many rod photoreceptors; thus the rods have been said to pool their teractive connections with the retinal ganglion cells to produce their fi antagonistic center-surround organization. To do so, the center and signals and, by doing so, form relatively large receptive eld centers fi (29). In the inner retina of the cat and probably the monkey, the rod the surround of receptive elds can be selectively stimulated before bipolars terminate in the inner portions of the inner plexiform layer, and after APB administration. Fig. 2 shows a typical result obtained but do not contact ganglion cells directly. Instead, they terminate on by recording in the parvocellular LGN of a monkey. The cells amacrine cells, most commonly on the AII type. Each of these shown had color-opponent characteristics and were consequently amacrine cells in turn makes two major kinds of contacts: one is stimulated with colored spots that preferentially activated the center and the surround mechanism. The center mechanism was NEUROSCIENCE a gap synaptic junction with ON cone bipolar cells and the other is activated with a small spot of the appropriate wavelength compo- a glycinergic synaptic junction with OFF ganglion cells, as depicted sition; the surround mechanism was activated brieflybothwhenthe in Fig. 1B (28–30). This arrangement appears to accomplish for the center was stimulated and during the off cycle using a large spot of rods in the inner retina what is accomplished for the cones in the a different wavelength composition appropriate for the surround. outer retina: it turns the single-ended photoreceptor system into The inhibitory effect of the surround stimulation is evident for both a double-ended one. As a result of these connections, under dark- the ON and the OFF cell under normal conditions. Following ad- adapted conditions when the cones are unresponsive, the ON ministration of APB, the responses of the ON cell are eliminated ganglion cells are excited by light increment and the OFF ganglion whereas the responses of the OFF cell, including the center-sur- cells by light decrement. round antagonism produced by the stimulus that activated the The organization of the receptive fields under light- and dark- fi fi surround mechanism, are mostly unaffected. These ndings sup- adapted conditions is quite different, as was rst shown by Barlow port the idea that the center-surround organization of retinal et al. (31). This difference, which was subject to considerable in- ganglion cells and LGN cells is not a product of ON and OFF cell credulity at the time, is now readily understandable. The receptive- fi interactions, but rather a product of the lateral networks of the eld center under dark-adapted conditions is driven by the rods retina that involve the horizontal and perhaps the amacrine cells. through the bipolar and amacrine cells. The surround mechanism Thus the model of retinal organization these findings support is that is the product of those portions of bitufted horizontal cells that the ON- and OFF-center ganglion cells, most of which send their make lateral connections only with the rods (16). As a result of this axons to the LGN, form separate pathways (25, 37, 38). Also fa- fi arrangement, several superimposed receptive elds can be created voring this model is an elegant study by Mangel and Miller (39) in for any given patch of retina. which hyperpolarizing current, injected intracellularly into rabbit horizontal cells, produced a decrease in the firing rate of ON Physiological Studies Using 2-Amino-4-Phosphonobutyrate. The use ganglion cells and an increase in OFF ganglion cells. of a glutamate neurotransmitter agonist has provided an important Effects of APB on ON/OFF cells. The ON/OFF cells that respond line of support for the claim that the ON- and OFF-center ganglion transiently to both light increment and light decrement comprise cells form independent pathways to the central nervous system. This the third category of retinal ganglion cells that had been identified substance, 2-amino-4-phosphonobutyrate (APB), was discovered by Hartline (3); these cells are thought to arise as a result of con- by Slaughter and Miller (32) to act differently on the ON and OFF vergent input from the ON and OFF bipolar cells onto individual bipolar cells of the mudpuppy (Necturus maculosus) retina. By de- retinal ganglion cells where the dendritic arbors of the ON/OFF creasing membrane conductance, APB produces prolonged hy- ganglion cell are bistratified. In the primate retina, the ON/OFF perpolarization in the ON bipolar cells, as a result of which they retinal ganglion cells project extensively to the superior colliculus become unresponsive to subsequent light stimulation (32, 33). (40). In many species, such cells also project into the geniculostriate Current evidence shows that ON bipolar cells have a specific system (6, 41). Retinal administration of APB eliminates the re- metabotropic glutamate receptor termed mGluR6 that is coupled sponse to light increment but not to light decrement in collicular to a G protein. The activation of this receptor leads to the closing cells (42). of cGMP-gated cation channels by increasing the rate of cGMP Effects of APB on single cells in area V1. The retinal input through the hydrolysis by a G protein-mediated process (34). The mGluR6 LGN to primary visual cortex, commonly referred to as V1, is receptor responds selectively to L-2-amino-4-phosphonobutyrate transformed in a number of ways, as already noted, yielding neu- (35). In a remarkable recent study, Masu et al. (36) have succeeded rons that are orientation and direction-specific (6, 20). Many of in generating KO mice that lacked mGluR6 expression and hence the neurons receive convergent input from the left and right eyes. lacked the ON system. This work further attests to the unique and V1 neurons are most effectively activated by edges with specific distinct nature of the ON bipolar cells and the ON system in the orientations. The characteristics of V1 neurons were first revealed mammalian retina. by Hubel and Wiesel (20), who received the Nobel Prize in 1981.

Schiller PNAS Early Edition | 3of8 Downloaded by guest on September 29, 2021 001 downward motion. After APB infusion, the leading light edge On-Center LGN Cell -- Normal response is blocked but the directional selectivity of the cell per- 08 sists. In Fig. S1C, orientation tuning curves are shown before and 06 after APB infusion. The orientation tuning function is unaffected fi 04 by the APB block. These ndings indicate that orientation and direction specificities are a product of intracortical circuitry rather 02 than interactions between the ON and OFF channels. That retinal APB infusion does not significantly affect orientation and di- emit 00510001005 sm0002 rection selectivities in area V1 has also been established in the cat by Sherk and Horton (44). 001 On-Center LGN Cell -- APB 08 Behavioral Studies of ON and OFF Channels Using APB. Further

06 insights into the role of the ON and OFF channels in vision come from behavioral studies in which the visual capacities of animals 04 were assessed before and after the ON channel was blocked with 02 APB. In monkeys, the most notable deficit observed under light- adapted conditions was for the detection of stimulus spots made emit 00510001005 sm0002 visible by virtue of increases in light energy; that is, spots that are perceived as brighter than the background (9, 24, 45, 46). There 001 Off-Center LGN Cell -- Normal was little or no deficit in the detection of spots that were darker 08 than the background. Examples of this are shown in Fig. 3, in which Number of spikes 06 both percent correct and reaction-time data are presented. Fol- lowing APB administration the percent correct responses for the 04 detection of light increments decreases dramatically, which is ac- 02 companied by large increases in the response latencies; performance with stimuli seen by virtue of light decrement is unaffected. emit 005 0001 0051 sm0002 These observations fit with the idea that the ON channel is sensitive to light incremental stimuli and signals lightness, whereas the OFF 001 Off-Center LGN Cell -- APB channel is sensitive to light decrement and signals darkness—an 08 idea, as already noted, that had been advanced earlier by Jung (23). Behavioral studies in monkeys have also shown that, under 06 dark-adapted conditions, when only the rods are functional, APB 04 blocks the detection of stimuli seen by virtue of either light in- 02 crement or light decrement; in other words, the rod system is blocked in its entirety and, consequently, the animal becomes emit 005 10000 051 sm0002 night-blind (9, 47). These findings provide additional support for the claim that the rod bipolars in the primate are all ON types.

noitalumitsretnecFR Midget and Parasol Channels noitalumitsdnuorrusFR Anatomy and Physiology of Midget and Parasol Systems. In 1966, fl Fig. 2. The responses of an ON and an OFF cell in the monkey LGN before Enroth-Cugell and Robson (48) published an in uential article and after APB infusion into the eye when the center and the surround of the showing that, in the cat, they distinguished three distinct classes of receptive fields are stimulated with red and green spots of different sizes. retinal ganglion cells, which they called the X, Y, and W. Sub- The surround activated by the large green spot is turned on briefly during sequently, it has been found that similar subclasses of retinal both the on and off cycles of the small red spot. APB application (Lower) ganglion cells exist in most mammalian species (49, 50). In the silences the ON ganglion cell for both center and surround stimulation. The primate, two of these classes were named the midget and parasol response of the OFF ganglion cell is unaffected; the cell retains its center- systems. The ganglion cells of the midget system, as the name surround antagonism (25). (Reprinted by permission from Macmillan Pub- implies, are quite small. The parasol cells, by contrast, are much – lishers Ltd: Nature, 297:580 583, copyright 1982.) larger, with their dendritic arbors and receptive field diameters being approximately three times greater than the midget cells. The Two major classes of cells they have identified in area V1 are the axons of the parasol ganglion cells are larger and have faster simple and complex cells. Simple cells have receptive fields in conduction velocities than do the axons of the midget cells. Fig. 4A which there are spatially distinct ON and OFF regions, whereas provides a cross-sectional view of the midget and parasol cells as in complex cells the ON and OFF regions overlap spatially (6, 20, created by Polyak (51). Fig. 4B shows the dendritic arbor ar- 43). When a properly oriented bar is swept across the receptive rangement of these cells as seen in a whole-mount preparation by field of V1 complex cells, a response is elicited by both the light Watanabe and Rodiek (52). and dark edges of the bar as it sweeps across the receptive field. The midget and parasol cells come in both ON and OFF This is shown in Fig. S1A. When the ON channel is inactivated by subvarieties. The input to the receptive field center of the midget APB infusion into the eye, the light edge response is eliminated but cells of the monkey is composed of a single cone in the central the dark edge response remains. This indicates that the light edge retina. Thus, a single cone will give rise to both an ON and OFF response is caused by the input from the ON system and the dark bipolar cell, as shown in Fig. 1 A and B. By contrast, the receptive edge response to a result of the input from the OFF system. field center of the parasol cells is comprised of several cones that It has been proposed that the direction and orientation speci- are not segregated according to type (16, 50). The receptive field ficity of V1 neurons is a product of the interaction between the ON sizes of these two classes of cells are quite different as are their and OFF systems. An alternative hypothesis proposed was that inputs. The excitatory center of the midget cells in central retina inhibitory intracortical circuitry achieves these attributes in V1 is comprised of a single cone, thereby rendering them color-se- cells (6, 20, 43). Inactivation of the ON channel with APB shows lective. The excitatory center of the parasol ganglion cell re- that direction specificity and orientation selectivity remain un- ceptive fields is comprised of several cones, as is the surround, affected. Fig. S1B shows the responses of a complex cell in monkey indicating that these cells cannot convey information about V1 that under normal conditions responds preferentially to color. The parasol cells, however, are not insensitive to stimu-

4of8 | www.pnas.org/cgi/doi/10.1073/pnas.1011782107 Schiller Downloaded by guest on September 29, 2021 A Mssllectegdi lleclosaraP INAUGURAL ARTICLE Light Increment

noitubirtsidycnetalcidaccaS 001 BPAerofeB 06 08 noitcejni B 05 06 04 04 03 02 02 sm352=naeM 01

001 BPAretfA 06 08 midget cell noitcejni 05 dendritic arbor 06 04 Percent Correct Detection 04 03 02 02 sm604=naeM parasol cell 01 dendritic arbor

005004003002001 007006 sdnocesillimniemiTnoitcaeR Fig. 4. (A) Cross-section of Golgi-stained midget and parasol cells (51). [Reprintedwith permission from Polyak SL (1957) The vertebrate visual system: Its origin, structure, and function and its manifestations in disease with Light an analysis of its role in the life of animals and in the origin of man, pre- Decrement ceded by a historical review of investigations of the eye, and of the visual pathways and centers of the brain (University of Chicago Press, Chicago).] (B) NEUROSCIENCE The dendritic arbors of a midget and parasol cell at comparable eccentricities (52). [Reprinted from Watanabe M, Rodieck RW (1989) Parasol and midget ganglion cells of the primate retina. J Comp Neurol 289:434–454 (Copyright 1989 with permission from Wiley).]

noitubirtsidycnetalcidaccaS 001 BPAerofeB 06 08 noitcejni larger in diameter, as are their dendritic arbors, and they re- 05 spond to visual stimuli in a transient fashion; midget cells, by 06 04 contrast, produce a rather sustained response. 04 03 02 The ability to experience different colors lies within the domain 02 sm942=naeM 01 of the midget system (54–58). Until recently it was believed that the midget system is organized in a pure color-opponent fashion. Thus 001 it was assumed that any given midget cell whose receptive ﬁeld 06 08 BPAretfA center is made up of a long-wavelength cone, has a surround that is

Percent Correct Detection noitcejni 05 06 04 driven by middle-wavelength cones. Serious questions have been raised during the past few years about the validity of this inference. 04 03 02 It has been shown that the horizontal cells of the retina, even for 02 sm152=naeM 01 the midget system, are “promiscuous”: they make contact with all cones within the area they sample (16). If color opponency is the 007006005004003002001 sdnocesillimniemiTnoitcaeR product of interaction between the center and the surround mechanism created by the horizontal cells, it appears that the opponency is not pure; it does not arise by pitting red cones against Fig. 3. Percent correct performance and eye-movement reaction times made to light and dark stimuli presented in various locations of the visual green ones (red/green opponency) and blue cones against red plus field to which a trained rhesus monkey had to make saccadic eye movements green ones (blue/yellow opponency), but by pitting individual to be rewarded. Following APB administration, percent correct performance short-, middle-, and long-wavelength cones forming the center declines and reaction times increase to a bright spot. Percent correct responses mechanism against all cones that feed into the surround mecha- and reaction times to a dark spot are unaffected. nism. That this is a computationally viable alternative has been established by Lennie et al. (59). It must be recognized, however, lation by different wavelengths; they are capable of responding that possible interconnections in the inner retina could provide to chrominance changes as long as the stimuli contain reasonable a clear color-opponent system. The midget and parasol cells of the color contrast. The signals so generated can lead to the per- retina project predominantly to the LGN in the trichromatic pri- ception of stimuli without leading to specific color sensations. mate, where the midget cells make connections within the parvo- One might imagine that, to the parasol system, the world looks cellular layers and the parasol cells within the magnocellular layers. a bit like a black-and-white movie. In turn, the cells in these two sets of layers project to the striate It is generally believed that the midget and parasol systems cortex, where they terminate predominantly in layers 4cα and 4cβ, have their own set of ON and OFF bipolars. This arrangement in respectively. Within the striate cortex, some cells, after a cascade of the midget and parasol cells makes it evident that there is a much connections, receive a convergent input from these two systems higher number of bipolar cells in the primate retina than there (60). Some of the cortical cells, however, are driven exclusively by are cone photoreceptors, yielding a ratio greater than three to one or the other system, although there is commonly a convergence one (16, 53). The receptive fields of the parasol ganglion cells at of the ON and OFF subtypes, as has already been noted. Recent any given retinal eccentricity are approximately three times studies of the connections from the striate cortex to extrastriate

Schiller PNAS Early Edition | 5of8 Downloaded by guest on September 29, 2021 regions have shown that the input to area MT is dominated by the A small region in the stereogram was arranged to appear in depth parasol system, whereas the input to area V4 is mixed (61, 62). by virtue of the disparity introduced. A saccadic eye movement The ratio of the midget and parasol cells changes notably as made to this region was rewarded. The top section of Fig. S3 shows a function of eccentricity. In the center of the fovea (sometimes data obtained using this procedure. Following a midget system called the foveola), there are virtually no parasol cells. Near the block, the monkeys’ ability to perform on this task was devastated. fovea, the midget cells outnumber the parasol cells by approxi- The deficit was complete at the lowest disparity. There was no mately eight to one. This ratio changes gradually until, in the far deficit when the parasol system was blocked. These findings sug- peripheral representation, they become equally represented (63). gest that the midget system plays a central role in stereopsis, es- This arrangement is clearly reflected in the LGN. In central rep- pecially at high spatial frequencies and low disparities. The parasol resentation, out to approximately 18°, the LGN most commonly system, however, seems to be able to contribute to this mechanism has six layers. The dorsal four layers are called parvocellular and at low spatial frequencies and high disparities. contain medium-sized cells. These layers receive input from the To study motion, the display consisted of an array of randomly retinal midget cells (64, 65). The ventral two layers are called placed small dots. On each trial in a small region of the visual field, magnocellular and contain large cells that receive input from the the dots were set in motion. A saccadic eye movement made to that retinal parasol cells. Beyond 18° of the visual field representation location was rewarded. The contrast of the dots was systematically in the LGN, the layers are reduced to four: two parvocellular and varied. The data in the center section of Fig. S3 show that a midget two magnocellular ones. Thus, in central representation, the system block had no effect on motion discrimination whereas the midget cells are far more numerous than the parasol cells, whereas block of the parasol system created a major deficit. In another in peripheral representation, they are equal in number (60). study, depth analysis based on motion parallax was examined, which showed that the parasol system plays a central role in pro- Behavioral Studies Examining Functions of Midget and Parasol cessing this information (68). Systems. A variety of behavioral experiments have been carried The bottom section of Fig. S3 shows data obtained when the out that examined the functions of the midget and parasol systems. task was to discriminate flicker from nonflicker. To do so, an array Some of these experiments have used visual stimulus conditions of light-emitting diodes (LEDs) was used, the flicker rate of which that selectively activated the midget or parasol systems (50, 66–68). could be varied over an extensive range. The data show that, when Another set of experiments blocked the midget or parasol systems the parasol system is blocked, a major deficit arises in flicker per- by making selective lesions in the parvocellular and magnocellular ception. These data establish that the parasol system plays a central portions of the LGN (49, 50, 67). role in temporal processing that includes motion and flicker. To assess the role of these two systems in vision, monkeys had Based on these data, we can conclude that the midget system been trained to perform a variety of visual tasks using detection plays a central role in color, pattern, texture, and stereoscopic and discrimination tasks. Each trial began with a fixation spot depth perception whereas the parasol system plays a central role in appearing in the center of a monitor the monkey faced. Upon motion perception, flicker perception, and depth processing based fixation, as determined by monitoring the monkeys’ eye move- on motion parallax. Both systems contribute to brightness per- ments, either a single stimulus appeared (the detection paradigm) ception. As a result of this work, we believe the midget and parasol or an array of stimuli was presented, one of which, the target, was systems have evolved to extend the range over which visual in- different from the others, called distractors (i.e., oddity task). The formation can be effectively processed. The midget system extends monkey was rewarded for making a saccadic eye movement di- it in the high spatial frequency and wavelength domains whereas rectly to the target. The contrast, size, color, and/or shape of the the parasol system extends it in the temporal domain. target or the distractors was systematically varied. The target was presented in intact regions of the visual field or in regions where Accessory Optic System the midget or the parasol system was blocked (50, 67). Fig. S2 The accessory optic system (AOS) originates in the retina. Its shows data obtained from a monkey that assessed color, texture, ganglion cells project to three target nuclei in the anterior portion and pattern processing. Fig. S2A shows data obtained in a color of the midbrain: the dorsal, medial, and lateral terminal nuclei discrimination task using the oddity task. The target in this case (70–72). The morphology of retinal ganglion cells projecting to the had a different color from that of the isoluminant distractors of terminal nuclei was first studied in the pigeon by Karten and col- a different color. The data show that, after a midget system block, laborators in the 1970s (72–74). They showed that these were the the monkey was no longer able to make color discriminations. displaced ganglion cells of Dogiel whose distribution on the retinal Conversely, the parasol system block did not have much of an ef- surface was remarkably orderly. In the rabbit, which has approxi- fect on color discrimination. These findings establish the fact that mately 350,000 ganglion cells, there are approximately 6,000 to color processing is accomplished by the midget system. Fig. S2B 7,000 directionally selective cells of Dogiel that project to the shows the texture detection task. A single target appeared on nuclei of the AOS (75). a textured background with the target consisting of a small square The responses of direction-specific retinal ganglion cells in the area within which the diagonal lines were reversed relative to the rabbit retina were first studied by Barlow and Levick (76). Based background. Blocking the midget system brought performance to on their work and that of others, it was established that those chance, whereas blocking the parasol system had no effect on direction-selective cells of the rabbit retina that respond best to texture detection. Fig. S2C shows a pattern discrimination task; the very slow velocities of image motion (0.1–1°/s) are all ON types target is different from the distractors by having checkerboards of (75). They have a trilobed spatial distribution of preferred ex- a lower spatial frequency. The data show that a midget system citatory directions (77). Striking about these observations was the block eliminates the ability of the monkey to discriminate fine discovery that the three axes of direction selectivity correspond differences in the perception of patterns whereas a parasol system to the planes of three principal axes of the semicircular canals. block has no significant effect on pattern perception. In contrast The neurons in the terminal nuclei of the rabbit to which the with these dramatic effects, when monkeys were tested for displaced ON-type direction selective cells of Dogiel project brightness discrimination, it was found that this capacity was un- have similar properties but have much larger receptive fields. affected by a midget or parasol block, indicating that both these The preferred direction of cells in the dorsal terminal nucleus systems can process this capacity. was found to be from posterior to anterior in the horizontal Fig. S3 shows data obtained on stereoscopic depth perception, plane. Cells in the medial and lateral terminal nuclei had upward motion detection, and flicker detection. Stereoscopic depth per- or downward excitatory directions, both with a posterior compo- ception has been studied extensively using random-dot stereo- nent. Inhibition plays a prominent role in the AOS as approxi- grams as initially developed by Julesz (68, 69). To study this in mately 50% of the cells have positive glutamic acid decarboxylase monkeys, the monkeys were trained to look through a stereoscope. reactions (78, 79). The terminal nuclei project to the dorsal cap of

6of8 | www.pnas.org/cgi/doi/10.1073/pnas.1011782107 Schiller Downloaded by guest on September 29, 2021 Kooy of the inferior olive (80, 81), which gives rise to climbing to the terminal nuclei, the pupillary system, a small complement of

fibers projecting to the flocculonodular lobe of the cerebellum. cells that project to the hypothalamus, and the so-called konio- INAUGURAL ARTICLE The dorsal cap of the inferior olive also receives a projection from cellular (K) system. the nucleus of the optic tract, which has been studied by Collewijn The W-type cells of the retina, described in the cat and and others (82, 83). This structure, like the terminal nuclei, monkey by a number of investigators, appear to be a “grab-bag” receives input from direction selective cells of the retina, but of category that actually consists of several subtypes and seems to a different class that gives both ON and OFF responses and include the ON/OFF retinal ganglion cells (90). Anatomically, responds best to higher velocities of stimulus motion. Electrical these cells are likely to be of the δ and γ types (16). Many of stimulation of these regions elicits nystagmic eye movements akin these cells come in both ON and OFF subvarieties and, as al- to those obtained during optokinetic nystagmus, and lesions pro- ready noted, project extensively to the superior colliculus and duce deficits in the tracking of moving stimuli. As, in the rabbit, the also to the pretectal nuclei. Prominent among the pretectal nu- retinal direction selective cells projecting to the terminal nuclei are clei is the nucleus of the optic tract that receives input from those all ON types, it is possible to assess the role of these cells in the direction-selective retinal ganglion cells that respond to higher generation of optokinetic nystagmus by applying APB to the retina velocities and come in both ON and OFF subtypes. Another while the animal is exposed to slowly moving vertical stripes. When visually driven structure in the pretectum is the olivary nucleus, this was done by Knapp et al. (84), they found that the optokinetic fl fi which is involved in the generation of the pupillary re ex. As nystagmus was abolished. This nding provided additional support studied in the rat and rabbit (42), it appears that the cells of the for the idea that the ON direction-selective cells of the rabbit olivary pretectal nuclei are all excited, in a tonic fashion, to light retina provide the essential input, via the terminal nuclei, for the increment, suggesting that they are exclusively of the ON type. generation of tracking eye movements for large stimulus con- This is supported by the finding that, in the rabbit, retinal ad- stellations. This curious arrangement of having only ON-type cells ministration of APB eliminates responsiveness to light in the that project into the AOS in the rabbit is not found in all species. olivary pretectal nucleus. However, when the pupillary reflex was Although in the turtle and zebrafish, similar results have been examined in rabbit and monkey following APB blockage of the obtained (85, 86), this was not the case in the cat or monkey. In fl these species, only mild effects of APB were found on OKN, which ON system in the retina, the re ex was only mildly impaired. This was restricted to high spatiotemporal frequencies (84). This sug- suggests that other pathways and the OFF system can make gests that in these species both the ON and OFF channels con- a contribution to light activation of the ciliary muscles (42). tribute to the OKN. In the goldfish, APB also failed to abolish the Yet another class of retinal ganglion cells that has been identified are the K cells that express αCAM kinase/calbindin. OKN (87); it was subsequently discovered, however, that in tele- NEUROSCIENCE osts there are two mechanisms of ON-bipolar generation, one of This system has been extensively studied; several reviews de- scribe it in detail (91–98). Many of the K ganglion cells have which is not sensitive to APB (88). fi On the basis of these observations, a specific function for the bistrati ed dendritic arbors, as a result of which they receive both AOS emerges as proposed by Simpson et al. (89). The AOS signals ON and OFF inputs from bipolar cells. Some of them are driven self-motion as reflected in the slip of the visual world over the by blue cones. A subgroup of these cells project to the intra- retinal surface. The detection of this slip by the direction- and laminar layers of the LGN, from which the projections are pre- velocity-selective cells of the AOS triggers a chain of activity dominantly to the upper layers of area V1 (91–93, 95). through the pathways of the AOS that produces corrective eye On the basis of the foregoing it is evident that, from the single movements, resulting in the stabilization of the retinal image. At layer of photoreceptors, a series of parallel pathways are created higher velocities such stabilization is typically accomplished by the by the stunningly complex and elaborate circuitry of the retina. vestibular system. Hence, the AOS nuclei and the vestibular ap- There are many different retinal ganglion cells that project se- paratus form two complementary systems geared toward the de- lectively to a variety of central nuclei and are involved in dif- tection of self-motion and the appropriate corrective action for ferent aspects of visual information processing. Furthermore, in image stabilization, thereby allowing for the rapid and accurate some of these systems, the same set of retinal ganglion cells can analysis of objects that appear in central vision. carry several kinds of different messages. For example, the midget cells, when excited in the daytime by the cones, can carry Other Parallel Channels Originating in the Retina information about both color and luminance; at night, when they In addition to the systems discussed so far, several others have are driven by the rods, the receptive fields of these same cells been found to originate in the retina. These include the so-called take on a different configuration and convey messages about only W system, directionally selective cells other than those that project luminance. This arrangement renders these cells multifunctional.

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