Ординатура / Офтальмология / Английские материалы / The Retina and its Disorders_Besharse, Bok_2011

acts on autoreceptors on horizontal cells as well as on neighboring horizontal cells, where it would likely be depolarizing as ECl is above Vm; this would provide positive feedback. Overall, these studies indicate multiple targets for GABA in the outer plexiform layer, which could mediate complex actions of GABA in the outer retina.

There are also findings that argue against the role of GABA in mediating horizontal cell feedback onto cones. Principally, GABA agonists and antagonists do not always appear to affect surround-evoked depolarization of cones. However, the presence of GABA receptors on horizontal cells, bipolar cells, as well as on cone photoreceptors complicates the interpretation of experiments using GABA antagonists. Furthermore, it is clear that small changes in the Ca2þ currents produced by feedback are not reflected in large changes in the membrane potential of the photoreceptor.

Ephaptic Transmission between Horizontal Cells and Photoreceptor Terminals

An ephaptic effect has also been hypothesized to underlie the feedback signal from horizontal cells to rod and cone photoreceptors. Originally, this electrical feedback mechanism was proposed to involve only glutamate-gated channels in the tips of horizontal cell processes that invaginate cone synaptic terminals. More recently, evidence for hemichannels at the tips of horizontal cell processes added this conductance mechanism as an additional current sink in the horizontal cell dendrites. Current flowing through the bulk resistance of the interstitial space and into hemichannels and glutamate receptor ion channels is proposed to produce a voltage drop in the synaptic cleft. This extracellular negative potential, in effect, shifts the activation of presynaptic Ca2þ channels in the positive direction, reducing the amount of glutamate released by the photoreceptor synapse.

The amplitude of the extracellular voltage drop is a critical function of the current density and the interstitial resistivity, and there is no consensus yet that the amplitude is sufficient to carry the 5–10-mV feedback signals that presynaptic Ca2þ channels apparently sense. Furthermore, the time course of an ephaptic response should be nearly instantaneous since it is electrical in nature, but it is well known that there is a slow time course of the roll back of the horizontal cell light response (Figure 2). The more rapid depolarization of the photoreceptor (or OFF bipolar cell) in response to strong surround inhibition seems better suited kinetically to the ephaptic effect. Carbenoxolone-induced block of hemichannels has been cited as evidence for ephaptic transmission. However this drug also blocks Ca2þ currents in photoreceptors at concentrations used to block ephaptic transmission.

Proton Mediation of Horizontal Cell Feedback

Recent work in turtle, salamander, ground squirrel, primate, zebra fish, and goldfish retina indicates that modulation of the extracellular pH in the synaptic cleft between horizontal cells and photoreceptors may be used to signal feedback to photoreceptors. Evidence that protons modulate voltage-gated Ca2þ channels at photoreceptor terminals, carrying the feedback signal, is substantial. The principal evidence is that 1–20-mM HEPES and other pH buffers reversibly block feedback onto photoreceptors by eliminating the shift in activation of the photoreceptor Ca2þ channel current. The exact cellular mechanism that controls the pH of the synaptic cleft between photoreceptors and horizontal cells remains undefined, but horizontal cell plasma membrane V-ATPases, ENaCs, ASICs, and hemichannels are possible membrane mechanisms by which horizontal membrane potential could alter cleft pH. Depolarized horizontal cells would produce or contribute to cleft acidification by extruding protons and/or by not taking them up, while hyperpolarized horizontal cells would facilitate cleft alkalinization by not releasing protons and/or by taking them up. The sensitivity of presynaptic Ca2þ channels to alterations in extracellular pH suggest that cleft pH is modulated between pH 7.0, during the peak of inhibitory feedback signaling, and pH 7.8, during maximal horizontal cell hyperpolarization and the absence of presynaptic inhibition. Physiological measurements and estimates of cleft pH changes support the possibility that pH changes of this magnitude occur.

Functional Roles of Horizontal Cells

The proposed functional roles of mammalian horizontal cells are derived from the notion that these cells provide inhibitory feedback onto photoreceptors. This idea is based largely on investigations of nonmammalian model systems that show: (1) a global contribution to retinal adaptation to different mean levels of illumination; (2) a local contribution to spatial processing and contrast enhancement by a spectrally broadband, but spatially restricted feedback to create the antagonistic receptive-field surrounds of photoreceptors, bipolar cells, and ganglion cells; and (3) a local contribution to chromatic processing by a chromatically selective feedback to create color-opponent receptive fields of cones, bipolar cells, and ganglion cells.

Retinal Adaptation

The syncytium of horizontal cells formed through electrical coupling of homologous cells shows characteristic changes with different states of light adaptation. Dark adaptation reduces coupling (from space constant determinations, tracer coupling), smaller receptive-field sizes

(surround-to-center ratio), and decreased sensitivity of horizontal cells. The decreased electrical coupling would also increase input resistance of the cell, resulting in larger voltage changes to a given light stimulus. Several modulators of horizontal-cell gap-junctional coupling have been identified, including dopamine, nitric oxide, and retinoic acid, which appear to mediate the effects of adaptation.

The dopaminergic modulation of horizontal-cell gapjunction conductivity has been reported for both nonmammalian and mammalian retinas. During light stimulation, the levels of dopamine rise in the retina and, through activation of D1 dopamine receptors on horizontal cells in a cyclic adenosine monophosphate (cAMP)-dependent manner, the duration and frequency of gap-junction openings are reduced. This results in the uncoupling of horizontal cells, such that responses of a smaller pool of photoreceptors and, thus, input from a smaller visual area, influence the horizontal cell response, reflected in the reduced surround-to-center (annulus-to-spot) ratios. Findings in rabbit retina indicate that the network of coupled horizontal cells is greatest in dim, scotopic conditions (dim ambient light) and less extensive in darkness and in photopic conditions, that is, the degree of coupling reflects the adaptational state of the retina (Figure 5). The retinal circuit underlying the modulation of dopamine release appears to involve a pathway from photoreceptors to ON bipolar cells to dopaminergic amacrine cells to horizontal cells. In addition to differing adaptational states, retinal levels of dopamine vary with a circadian rhythm.

Similar to dopamine, nitric oxide appears to uncouple horizontal cells, modulating the electrical coupling through activation of soluble guanylate cyclase and a cyclic guanosine monophosphate (cGMP)-dependent cascade in horizontal cells. Interestingly, in rabbit retina, nitric oxide also appeared to increase the sensitivity of horizontal cells to light through possibly an indirect action on photoreceptor transduction or at the photoreceptor-horizontal cell synapse, in addition to the increased input resistance resulting from the reduced cellular coupling. This may occur to some extent through the modulation of the ionotropic glutamate receptors found on horizontal cells. It has been speculated that increased nitric oxide production by horizontal cells under dark-adapted conditions and by amacrine cells under light-adapted conditions may account for the biphasic modulation of horizontal cell coupling with adaptational state.

Illumination increases the levels of all trans-retinoic acid (at-RA), which is a byproduct of the phototransduction cycle, and thereby correlates with the amount of light illumination. at-RA can uncouple horizontal cells in mouse, rabbit, and carp in a stereospecific manner and can do so in the presence of D1 dopamine receptor antagonist, indicating that it is not acting through modulation of the dopaminergic pathway. In the presence of

Figure 5 Regulation of horizontal cell tracer coupling by exposure of rabbit retina to different light intensities. (Top) Exposure to dim light intensity (log –6.0) produced coupling of over 1200 cells. (Bottom) Exposure to bright light intensity

(log –1.0) produced coupling of 124 cells. Scale = 100 mm in top panel, 50 mm in bottom panel. Adapted from figures 7 and 8 of Xin, D. and Bloomfield, S. A. (1999). Darkand light-induced changes in coupling between horizontal cells in mammalian retina. Journal of Comparative Neurology 405: 75–87.

ã 1999, John Wiley & Sons, Inc. Reprinted with permission of John Wiley & Sons, Inc.

at-RA, the receptive-field sizes of horizontal cells, as measured by annulus-to-spot ratios, were reduced. In addition to its effects on spatial response characteristics of horizontal cells, at-RA application in dark-adapted retinas could induce effects resembling light adaptation, such as reduced light responsiveness, changes in chromatic properties of H2 horizontal cells in teleosts, decreased gapjunctional permeability, as well as spinule formation in fish horizontal cells.

Gain Control of Synapses in the Outer Retina

The gain of the graded potential synapses between photoreceptors and horizontal cells is defined as the postsynaptic amplitude divided by presynaptic amplitude. High-gain synapses in an open-loop system (e.g., no inhibitory feedback) are inherently unstable, tending to saturate their

postsynaptic targets. To maintain stability and to optimize signal-to-noise ratios, synaptic gain is controlled by reciprocal feedback signals so that gain is high and stable when signals are small, and gain is reduced when signals are large and potentially saturating. Having each photoreceptor synapse under closed-loop inhibitory feedback control imparts gain control to the system.

The ability of the horizontal cell network to adjust to different states of light adaptation permits in part the retina to operate optimally over 10 orders of magnitude of light intensities. The input-output relations of photoreceptor to second-order neurons are modulated by light and dark adaptation. For example, dim background illumination can increase the voltage gain of the rod output synapse by increasing the conductance of horizontal cell kainate receptors through a dopaminergic signaling pathway and enhancing rod Ca2þ channel activation. Tonic activation of the feedback synapse by the steady illumination of receptive-field surrounds shifts (or resets) the operating range of bipolar cells to the right along the intensity axis, such that a brighter light is now necessary to elicit a given response.

Spatial and Temporal Processing

The antagonistic center-surround receptive-field organization underlies our ability to detect edges, enhancing contrast between regions of varying brightness and color, and it is ultimately responsible for visual acuity. Baylor and colleagues demonstrated that the turtle cone photoreceptor light response was modulated by light intensity as well as by the pattern of light stimulation, where cone response to center illumination was modified by the stimulation of the surround. Moreover, hyperpolarization of horizontal cells could produce a depolarization in nearby cones. These data indicated that horizontal cells participate in generating antagonistic receptive-field surrounds of cone photoreceptors. The two morphological types of horizontal cells exhibit different spatial summation properties, owing to differing dendritic field sizes and degree of electrical coupling. The reduction of horizontal cell receptive-field sizes in darkness due to uncoupling would further improve spatial contrast ability. Because of their large dendritic fields and electrical coupling, in general, horizontal cells integrate light stimuli over a large area and thus respond well to large light stimuli (i.e., low spatial frequency), whereas small spot stimuli (i.e., high spatial frequency) evoke small responses. The knockout of connexin 57 (Cx57), a gap-junction protein specific to horizontal cells, in mice reduced the receptive-field sizes of horizontal cells, but did not eliminate the rollback in the horizontal cell light response, reflective of negative feedback to cones (Figure 4). The knockout diminished the tracer coupling of horizontal cells by 99%, which indicates that Cx57 is the principal connexin in horizontal

cells. Furthermore, the regulation of coupling by dopamine was lost, suggesting that gap junctions formed by Cx57 are the targets of this modulation.

In fish, D1 antagonists blocked the uncoupling of horizontal cells produced by flickering light, but not the uncoupling resulting from steady ambient light, suggesting that the temporal characteristics of the light stimulation may affect the pathway activated.

Chromatic Processing

The Stell model emerged from anatomical analysis of the connectivity of color-sensitive cones and three types of cone-driven horizontal cells in fish retina (Figure 6). The model accounted for findings that monophasic horizontal cells (H1) hyperpolarize irrespective of wavelength, but peak in the red or long wavelengths, biphasic horizontal cells (H2) hyperpolarize at short and medium wavelengths and depolarize at long wavelengths, and triphasic horizontal cells (H3) hyperpolarize at short and long wavelengths, while depolarizing at medium wavelengths. Hence, monophasic H1 cells signal luminance, whereas the other two types provide color-opponent signals. In the

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Figure 6 The Stell model of chromatic interactions in the goldfish retina. Cone types are labeled R, G, and B. The H1, H2, and H3 horizontal cells generate monophasic, biphasic, and triphasic spectral response functions by the pathways shown. Synaptic pathways from cones to horizontal cells are shown with filled arrows while feedback pathways are shown in open arrows. Reproduced from figure 2 of Stell, W. K., Lightfoot, D. O., Wheeler, T. G., and Leeper, H. F. (1975). Goldfish retina: Functional polarization of cone horizontal cell dendrites and synapses. Science 190(4218): 989–990. Reprinted with permission from AAAS.

case of the H2 red/green biphasic C-type cells, the depolarizing responses to long wavelengths appear to arise from feedback from red-sensitive L-type horizontal cells to green cones, which then synapse onto H2 cells, and, similarly, the depolarizations in the H3 come about through H2 feedback to short wavelength or blue cones, which then drive the H3 cells. Mammalian retinas do not appear to have color-opponent horizontal cells.

Conclusions

The visual system operates over a large range of stimulus intensities. That animals can see in the dark of a moonless night and in near-blinding sun-drenched scenes is a remarkable feat achieved by exploiting the dynamic range of numerous cascaded stages. Several adaptation stages have been described in rods and cones, beginning in the light-transducing outer segments. Modulation of the rod and cone output synapses is another critically important stage, and here adaptation results in large part from horizontal cell feedback and feed-forward, and may alter the form of some receptive fields. Many of the anatomical and biophysical features of the photoreceptor triad synapse are known in great detail, and regulation of the synapse by integrative feedback from horizontal cells is one area of critical importance in retinal neurobiology. Future studies will aid us in understanding the complex analysis of information in the visual system, and, in particular, how the visual system has evolved algorithms that optimize acuity under changing levels of ambient illumination.

Acknowledgment

This work was supported by NEI EY 15573 and a Veterans Administration Senior Career Scientist Award to NB, and CIHR grant MOP10968 to SB.

See also: The Circadian Clock in the Retina Regulates Rod and Cone Pathways; Cone Photoreceptor Cells: Soma and Synapse; GABA Receptors in the Retina; Information Processing in the Retina; Morphology of Interneurons: Bipolar Cells; Morphology of Interneurons: Horizontal Cells; Morphology of Interneurons: Interplexiform Cells; Neurotransmitters and Receptors: Dopamine Receptors; The Physiology of Photoreceptor Synapses and Other Ribbon Synapses; Rod Photoreceptor Cells: Soma and Synapse.

Further Reading

Baylor, D. A., Fuortes, M. G. F., and O’Bryan, P. M. (1971). Receptive fields of cones in the retina of the turtle. Journal of Physiology (London) 214: 265–294.

Bear, M. F., Connors, B. W., and Paradiso, M. A. (eds.) (2007).

Neuroscience: Exploring the Brain, 3rd edn. Philadelphia, PA: Lippincott Williams & Wilkins.

Brown, K. T. and Wiesel, T. N. (1959). Intraretinal recording with micropipette electrodes in the intact cat eye. Journal of Physiology (London) 159: 537–562.

Burkhardt, D. A. (1993). Synaptic feedback, depolarization, and color opponency in cone photoreceptors. Visual Neuroscience 10: 981–989.

Davenport, C. M., Detwiler, P. B., and Dacey, D. M. (2008). Effects of pH buffering on horizontal and ganglion cell light responses in primate retina: Evidence for the proton hypothesis of surround formation.

Journal of Neuroscience 28: 456–464.

Hirano, A. A., Brandsta¨tter, J. H., and Brecha, N. C. (2005). Cellular distribution and subcellular localization of molecular components of vesicular transmitter release in horizontal cells of rabbit retina.

Journal of Comparative Neurology 488: 70–81.

Hirasawa, H. and Kaneko, A. (2003). pH changes in the invaginating synaptic cleft mediate feedback from horizontal cells to cone photoreceptors by modulating Ca2þ channels. Journal of General Physiology 122: 657–671.

Jonz, M. G. and Barnes, S. (2007). Proton modulation of ion channels in isolated horizontal cells of the goldfish retina. Journal of Physiology (London) 581: 529–541.

Kamermans, M. and Fahrenfort, I. (2004). Ephaptic interactions within a chemical synapse: Hemichannel-mediated ephaptic inhibition in the retina. Current Opinion in Neurobiology 14:

531–541.

McMahon, D. G., Zhang, D. Q., Ponomareva, L., and Wagner, T. (2001). Synaptic mechanisms of network adaptation in horizontal cells.

Progress in Brain Research 131: 419–436.

Perlman, I., Kolb, H., and Nelson, R. (2003). Anatomy, circuitry, and physiology of vertebrate horizontal cells. In: Chalupa, L. M. and Werner, J. S. (eds.) The Visual Neurosciences vol. 1, pp. 369–394. Cambridge, MA: MIT Press.

Shelley, J., Dedek, K., Schubert, T., et al. (2006). Horizontal cell receptive fields are reduced in connexin57-deficient mice. European Journal of Neuroscience 23: 3176–3186.

Stell, W. K., Lightfoot, D. O., Wheeler, T. G., and Leeper, H. F. (1975). Goldfish retina: Functional polarization of cone horizontal cell dendrites and synapses. Science 190: 989–990.

Thoreson, W. B., Babai, N., and Bartoletti, T. M. (2008). Feedback from horizontal cells to rod photoreceptors in vertebrate retina. Journal of Neuroscience 28: 5691–5695.

Verweij, J., Hornstein, E. P., and Schnapf, J. L. (2003). Surround antagonism in macaque cone photoreceptors. Journal of Neuroscience 23: 10249–10257.

Verweij, J., Kamermans, M., and Spekreijse, H. (1996). Horizontal cells feed back to cones by shifting the cone calcium-current activation range. Vision Research 36: 3943–3953.

Weiler, R., Pottek, M., He, S., and Vaney, D. I. (2000). Modulation of coupling between retinal horizontal cells by retinoic acid and endogenous dopamine. Brain Research. Brain Research Reviews

32: 121–129.

Wu, S. M. (1994). Synaptic transmission in the outer retina. Annual Review of Physiology 56: 141–168.

Xin, D. and Bloomfield, S. A. (1999). Darkand light-induced changes in coupling between horizontal cells in mammalian retina. Journal of Comparative Neurology 405: 75–87.

F S Werblin, UC Berkeley, Berkeley, CA, USA

ã 2010 Elsevier Ltd. All rights reserved.

Glossary

Directional sensitive ganglion cell – Ganglion cells that are particularly sensitive to movement of an image in a specific direction across the retina.

Local edge detector (LED) – A ganglion cell that appears to be unique in that it is activated by a local edge at the center of its receptive field, and suppressed by edges in the surround.

OFF pathway – Retinal circuitry within the retina responding at the offset of light.

ON pathway – Retinal circuitry within the retina responding at the onset of light.

Starburst amacrine cell – Retinal amacrine cells with a large and symmetrical dendritic arbor that uses both actylcholine and gamma aminobutyric acid. These cells play an important role in directional selectivity.

Introduction

The retina creates a dozen different representations of the visual world, each embodied at a separate sublayer of the inner plexiform layer, and carried by a separate class of ganglion cell. These representations are not just enhanced edges, but are often also complex space–time abstractions of the visual world. The early studies of Barlow; Maturana, Lettvin, McCulloch, and Pitts; and Campbell and Robson suggested that the optic nerve contains information carried by a number of different channels, each formed as a result of sophisticated neural computations. In the frog, for example, the retinal output contains the trigger features that guide the frog’s behavior, including detectors for flys, edges, dimming, and contrast. As Barlow points out, the activity of individual neurons is not just a reflection of thought processes, but these activities are also thought processes. Therefore, what are these processes and how are they formed through neural interactions in the retina?

Over the last 40 years, visual neuroscientists have attempted to understand retinal function from a variety of perspectives. What is the nature of the representations of the visual world formed by the retina? Through what neural processes are these representations formed? Answering

these questions requires a merging of information from a variety of different disciplines. Retinal anatomists have defined both the morphology and the conductivity between retinal neurons at the light electron microscope levels. Retinal electrophysiologists have defined the response properties of each class of retinal neurons. Retinal circuitry has been analyzed, aided in great measure by pharmacological studies where specific synaptic pathways have been defined for the use of receptor agonists and antagonists. A number of general principles of organization and function have been gleaned from these studies.

For example, as predicted by Horace Barlow and later verified through experiment, most retinal neurons operate in a spikeless mode, whereby membrane potential and synaptic transmission are continuous and graded. Furthermore, under most ambient conditions, most graded-potential retinal neurons operate at or near the midpoint of their response range, capable of signaling both increments and decrements. Embedded in a complex circuitry including feedback, most neurons are constantly active, talking to each other with a continuous stream of activity. The presentation of visual stimuli offsets this ambient state, generating at least a dozen different space–time patterns of neural activity at the retinal output that correspond to, and represent, the visual input.

The Outer Retina, Gain and Level

Adjustment

One of the first steps in retinal processing performs the operations that match the response range of retinal neurons to the light input, setting the dynamic range. A significant amount of neural housekeeping is required to maintain the retina in a steady-state condition such that most neurons are operating near their mid-potential range. This set point control is achieved through a series of processes known as adaptation. Adaptation to luminance maintains the photoreceptors at an ambient potential level that varies little with the overall luminance state, over very many orders of magnitude. This is accomplished because cone gain decreases as ambient luminance increases. It is as though the cones put on sunglasses as the brightness of the environment increases. This adaptation is an inherent part of the transduction machinery, mediated at the outer segments of photoreceptors. Much more about the process of adaptation can be found in elsewhere in the encyclopedia.

Bifurcation of the Visual Pathways into ON and OFF streams

The pathway from cones to bipolar cells bifurcates at the bipolar dendrites into the ON and OFF streams of activity. Activity is initiated in OFF bipolars via ionotropic glutamate receptors in the bipolar dendrites; therefore, OFF bipolars polarize in phase with the photoreceptors. Activity is initiated in the ON bipolar dendrites via metabotropic receptors such that ON bipolar cells polarize out of phase with the photoreceptors. Both bipolar types drive ganglion cells via a-amino-3-hydroxyl-5-methyl-4- isoxazole-propionate (AMPA), kainate, and N-methyl-D- aspartic acid (NMDA) receptors; therefore, all ganglion cells respond in phase with their bipolar cell inputs. These differential streams are carried to different strata of the inner retina with most of the OFF streams in regions that are distal to the ON streams. These ON and OFF streams are then carried through many synapses in the visual system and can also be measured at the visual cortex. A sketch of the retinal pathways from cones to the ON and OFF bipolars, to the ON and OFF ganglion cells, is shown in Figure 1. More about bipolar cells can be found elsewhere in the encyclopedia.

Horizontal Cell Synaptic Interactions

The pathway from cones to bipolar cells is intersected by horizontal cells. Cones drive the horizontal cells, but horizontal cells are strongly electrically coupled; therefore, the neural image carried by horizontal cells is blurred. The coupled network of horizontal cells feeds forward to bipolar

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cells via gamma aminobutyric acid (GABA)ergic synapse. ON and OFF bipolar cells respond with opposite polarities to light; therefore, horizontal cells must polarize the ON and OFF bipolar cells in opposite directions: GABA depolarizes ON bipolar cells and hyperpolarizes OFF bipolar cells because the chloride concentrations, and therefore the reversal potentials for GABA input, are different in the two bipolar cell types. Horizontal cells also feed back to cones, but the feedback mechanism from horizontal cells to cones remains controversial. Feedback may be mediated by an electrical synaptic feedback, by GABA, or it might be controlled by pH. Experiments in different animals under different conditions have led to these diverse theories. The circuitry is shown in Figure 2, added to the ON–OFF streams shown above. The role of GABA in horizontal cells is described elsewhere in the encyclopedia.

Horizontal Cells and Local Gain Control

Feedback from horizontal cells to cones provides a form of local adaptation or gain control so that local bright spots do not saturate neural activity the way they might in a conventional camera where the level of light arriving at the sensor is controlled by aperture size. Local gain control is achieved by the electrical coupled horizontal cells network whose blurred image is subtracted from the sharper image carried by the cones and bipolar cells. This subtraction normalizes activity across the retina with respect to the blurred activity of horizontal cells. The subtraction has two major results: the neural representation of edges is

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Figure 1 General glutamatergic pathways in the retina from photoreceptors (top) to bipolar cells (B) to ganglion cells. ON and OFF pathways are initiated at the dendrites of the bipolar cells (B, orange arrows). ON and OFF ganglion cells (G) are driven by their respective ON and OFF bipolar cells (black arrows). OFF activity is located in the distal half of the outer plexiform layer, while ON activity is located in the proximal half.

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Figure 2 Horizontal cell feedback and feedforward added to the circuitry. Orange arrows represent glutamate pathways from cones to ON and OFF bipolar cells and to horizontal cells. Green arrows represent inhibitory pathways that mediate the horizontalmediated antagonistic surround. The synaptic mechanism underlying this feedback pathway is still not fully understood. This feedback pathway is also implicated in local gain control. GABA is also thought to be fed forward to both bipolar cell types.

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Response

Log intensity

Loca area Response

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Figure 3 Luminance and local gain changes. Upper traces: gain changes at the photoreceptors shift the intensity–response curves along the log intensity axis; as ambient illumination increases, the transduction gain is reduced. Lower traces: local adaptation mediated by horizontal cell feedback subtracts the luminance level from the cone-to-bipolar signal, leaving mainly the contrast signal.

sharpened by the subtraction, resulting in the presence of Mach bands. Put differently, broadly distributed luminance changes are lost, subtracted from the cone to bipolar patterns by the blurred horizontal cell image. The neural image that remains after this subtraction is primarily related to local contrast. It is the local contrast image that is then brought to the inner retina at the synaptic terminals of the ON and OFF bipolar cells. A family of adaption curves is shown in Figure 3.

Interactions at the Inner Retina:

Contrast Gain

The local gain-controlled neural image, brought to the inner retina, is subject to an additional adjustment by contrast gain control, that constrains signal magnitude so that postsynaptic neurons operate within their dynamic range. Contrast gain control is mediated by at least two mechanisms. Amacrine cell feedback to bipolar cells is thought to contribute to contrast gain control. In addition, a more significant mechanism, still not well understood, but likely located at the bipolar cell terminals, has been shown to increase contrast gain at low temporal contrast and to decrease gain at high temporal contrast. Contrast gain control is described elsewhere in the encyclopedia.

To summarize, there are three main gain control systems in the retina: luminance gain at the outer segments, local luminance gain at the horizontal cell system, and contrast gain control. These systems, taken together, allow the retina to detect dim objects at low contrast or bright objects at high contrast, with all neurons operating near their optimal gain and never saturating.

General Organizational Principles

Lateral Interactions are Concatenated

The results of an interaction that takes place early in visual processing are carried through and appear at later stages of processing. As an example, antagonistic lateral interactions at the outer retina, mediated by horizontal cell feedback and feedforward, form an initial antagonistic center-surround receptive field interaction. These concentric fields are first formed at the cone terminals, mediated by feedback from horizontal cells; however, this activity is read out by both the ON and OFF bipolar cell types. Therefore, bipolars, similar to cones, show concentric antagonistic receptive fields. Part of the antagonistic surround measured at ganglion cells derives from the interactions between cones and horizontal cells at the outer retina and carried to the ganglion cells via the bipolar cells. Additional antagonistic components are added through interactions at the inner retina, mediated by amacrine cells, and then measured in ganglion cells. Therefore, ganglion cells carry the results of lateral antagonism at the outer retina superimposed upon additional forms of lateral interaction formed at the inner retina. Ganglion cells can contain as many as five different lateral antagonistic components.

Mutual Antagonism is a Form of Amplification

Once again, lateral antagonism at the outer retina serves as an example of mutual antagonism because adjacent retinal regions, via horizontal cells antagonize, are mutually antagonistic. This mutual antagonism amplifies and generates the familiar Mach bands which enhance the neural image of edges in the visual world. As described later, the mutual antagonism between motion-detecting starburst amacrine cells amplifies directional differences. There are many other forms of mutual antagonism in the retina operating in different domains, and each of these serves to amplify the quality represented in that domain.

Redundant Feedforward and Feedback

Interactions

As shown above, the lateral antagonistic signal that is fed back to cones is also fed forward to both ON and OFF bipolar cells. In many cases of retinal interaction, the GABAergic signal that is fed back to bipolar cells by amacrine cells is also fed forward to ganglion cells as shown in Figure 4.

Interaction between the Two Complementary Visual Streams in the Visual System

The ON and OFF pathways do not remain independent, but interact at every neural level in the retina and continue to interact at each of the higher visual centers. This interaction between the ON and OFF pathways, called

Figure 4 GABAergic amacrine cell feedback and feedforward can provide an additional lateral antagonistic interaction, generating an additional receptive field surround superimposed upon the feedback and feed-forward interactions mediated by horizontal cells at the outer retina.

Glycine

Figure 5 Crossover circuitry isolated. The ON system inhibits the OFF system, and the OFF system inhibits the ON system by way of glycinergic amacrine cells that span the ON–OFF sublaminae. This interaction compensates for the nonlinearities introduced by synaptic transmission. The interaction is found in most bipolar, amacrine, and ganglion cells.

crossover inhibition, is mediated by glycinergic amacrine cells, and serves to relinearize signals that have been distorted by nonlinear transmission at synapses. It is necessary to provide this circuitry compensation at each stage of processing to maintain a linear signal stream because if a nonlinear signal is filtered, linearity can never be reconstructed. In the transistor world, analog signal processing design requires interactions between the equivalent of ON and OFF circuitry to compensate for the rectifying nonlinearities inherent in transistors.

The circuitry underlying crossover inhibition involves ON amacrine cells feeding the OFF pathway, and OFF amacrine cells feeding the ON pathway. The circuit module representing this crossover activity is shown in Figure 5.

The crossover circuitry is superimposed upon and intersects the glutamate pathways and the GABAergic inhibitory pathways. The overall circuitry is summarized in Figure 6. More on amacrine cells can be found in elsewhere in the encyclopedia.

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B Glycine B

Figure 6 Generalized retinal circuit including horizontal cells, lateral amacrine cells, and vertical amacrine cells. This general circuit includes feedback and feed-forward horizontal cell interactions, feed-forward and feedback GABAergic amacrine cell interactions, and ON to OFF as well as OFF to ON crossover circuitry. Each of these five interactions can generate a different antagonistic receptive field surround for ganglion cells.

This is a summary of a basic retinal design. It accounts for most of the general activity measured in bipolar, amacrine, and ganglion cells. In almost all cases, the inhibition carried by the vertical amacrine cell elements is mediated by glycine, while inhibition carried by the laterally oriented amacrine cells is mediated by GABA. These general circuitry rules underlie a more specific circuitry that generates the physiological behavior of each ganglion cell type. This additional circuitry has been described for a few ganglion cells. In each case, special variations to the basic circuitry endows these cell types with their specific characteristics. More on neurotransmitters and receptors can be found elsewhere in the encyclopedia.

Inner Retinal Processing: Circuitry for Feature Extraction

Having solved both the housekeeping problems related to adaptation to luminance contrast and the nonlinearity problem introduced by synaptic transmission through appropriate crossover circuitry, the stage is set for the real work of the retina, which is creating the appropriate representations of the visual world. Most of the interesting interactions take place at the inner plexiform layer that is itself a multilayered and exquisitely organized structure. There appear to be about 10 strata in every retina species that has been studied. The strata are defined by the 10 levels at which the dendrites of different ganglion cell types ramify. Remarkably, there also appear to be about 10 different types of bipolar cells, and the axon terminals of each of these bipolar cell types also terminate roughly in the same 10 strata as a ganglion cell dendrites.

To a first rough approximation, it appears that each ganglion cell type receives input from a separate bipolar cell type as shown in Figure 7. However, a close look at the bipolar terminals shows that they are often more diffusely distributed, and there are ganglion cells with multistratified dendritic arborizations. Physiologically, the connections must be more diffuse because most ganglion cells ramify in either the ON or the OFF sublamina; however, most ganglion cells appear to receive both ON and OFF inputs (although activity tends to be dominated by either ON or OFF excitation).

Although the excitatory pathway from photoreceptors to bipolars to ganglion cells appears to be relatively straightforward, there exists a bewildering array of amacrine cells that generate a variety of interactions at the inner plexiform layer. Amacrine cells come in many diverse morphologies, and there appear to be approximately 30 different types. Functional properties of these amacrine cells can be thought of at three different levels of refinement: (1) there are two major morphological classes of amacrine cells identified by their vertical versus lateral orientation in the retina, (2) there are circuitries involving amacrine cells that mediate specific functions, and (3) there are amacrine cells that possess unique physiological properties. Each level of functionality is described below.

Amacrine Cell Morphological Types

The majority of amacrine cells falls into one of two general classes. One consists of narrowly ramifying vertically oriented amacrine cells that span the ON and OFF sublamina. This class contains and releases glycine as its

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Figure 7 Schematic of the layering of the inner plexiform layer (IPL). Each of the 10 bipolar cell types sends its axon terminal to a distinct region of the IPL, approximately a single substratum of the IPL. Each of the ganglion cell types sends its dendrites to a distinct substratum. Roughly speaking, each bipolar cell type is associated with a unique ganglion cell type. This description is only approximate. In fact, some ganglion cell dendritic fields are bistratified, such as the direction selective (DS) cells, and the axon terminals of some bipolar cells are more diffuse.

inhibitory transmitter. These amacrine cells appear to be strategically located to carry information from the ON to the OFF and the OFF to be ON sublamina, and are probably the key players in mediating crossover inhibition described earlier. The other major class of amacrine cell consists of widely ramifying, but monostratified, amacrine cells, each stratifying in a separate sublamina. These amacrine cells contain and release GABA as their inhibitory transmitter and may be responsible for various forms of lateral inhibition mediated at the inner retina. In some cases, this lateral inhibition is mutual and when this is the case, it serves as an amplifier of the visual quality carried by that specific form of inhibition.

Specific Ganglion Cell Circuitries

Directional selectivity

There are a few amacrine cells that have now been identified with very specific personalities. For example, starburst amacrine cells, named for the characteristic starburst pattern of their processes, span about 200 mm. Starburst cells contain and release both GABA and acetylcholine. They are the key elements in the organization of directional selectivity in the retina. A large population of starburst amacrine cells is associated with each directionally selective (DS) ganglion cell, and neighboring DS ganglion cells likely share many starburst amacrine cells. Starburst cells are inherently DS, generating more release for centrifugal movement. One likely mechanism involves calciuminitiated calcium release, but this remains an area of intense exploration. Release occurs along the outer one-third of the starburst processes. These processes not only release GABA, but are also GABA sensitive. This creates a mutual inhibition between starburst cells that acts to amplify directional motion sensitivity as shown in Figure 8. Starburst cells inhibit the DS cells asymmetrically, with stronger inhibition arriving from the null side than from the preferred side. These three mechanisms, inherent directional selectivity in the starburst cells themselves, mutual antagonistic interaction between neighboring starburst cells, and asymmetrical inhibition acting both preand postsynaptically at the ganglion and bipolar cells endow the DS cell with some of its directional properties as shown in Figure 9. More on DS circuitry can be found elsewhere in the encyclopedia.

Figure 8 Mutual inhibition between starburst amacrine cells amplifies the directional properties of the starburst network. Here, two starburst amacrine cells, themselves directionally selective, are mutually inhibitory (green arrows). In the circuit of this figure, the right starburst cell supplies inhibition to the ganglion cell for movement in the null direction from right to left. The right starburst cell is turned off by the left starburst cell for movement from left to right.

The circuitry puzzle regarding the DS cells is far from solved; however, the general organizational rules listed above still apply. The lateral inhibitory interneuron is GABAergic, following the GABA rule for laterally oriented cells.

Functions of AII Amacrine Cells

AII amacrine cells serve a very specific function to transcribe signals in the rod bipolar cells to both the ON and OFF cone pathways. The circuitry underlying this function is now well defined. AII amacrine cells are driven by rod bipolar cells that respond at ON. The AIIs are electrically coupled to cone bipolars, and make glycinergic synaptic contact with the OFF pathway. Recently, the AII amacrine cells have been shown to serve other functions. For example, the AII amacrine cells appear to be the key elements in providing glycinergic inhibition to the so-called looming detectors and in alpha cells, both described elsewhere in the encyclopedia (Figure 10).

There are numerous other examples of special purpose circuitry that utilize laterally oriented amacrine cell interneurons. The polyaxonal amacrine cells are thought to mediate saccadic suppression. In other cases, the same cell type has been implicated in mediating object motion sensitivity. It is likely that other amacrine cell types also serve specific functions, but their properties have not yet been identified.

At about the time that Levick was characterizing the DS ganglion cell, he also described another ganglion cell

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Figure 10 Pathways underlying the behavior of the alpha cell/ looming detector. This ganglion cell appears to respond to a dark target at its receptive field center that increases in size, much like an approaching predator. It appears to receive glycinergic inhibition from two types of local amacrine cells: input from an AII amacrine cell that is electrically coupled to ON bipolar cells, and input from another amacrine cell class that receives excitatory glutamate input from ON bipolar cells.

that he termed the local edge detector (LED). This cell appears to be unique in that it was activated by a local edge at the center of its receptive field, and that activity was suppressed by edges in the surround. Van Wyk, Taylor, and Vaney have recently gone on to characterize some of the special temporal properties of this neuron. It receives excitation and also glycinergic inhibition at both ON and OFF, and is inhibited by edge stimuli presented at the surround via a GABAergic lateral pathway. Both inhibitory components follow the general rule of