Proc Natl Acad Sci U S A 1992 Jan 1;89(1):236-240

Computational model of the on-alpha ganglion cell receptive field based on bipolar cell circuitry.

Freed MA, Smith RG, Sterling P

Laboratory of Neurophysiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.

The on-alpha ganglion cell in the area centralis of the cat retina receives approximately 450 synapses from type b1 cone bipolar cells. This bipolar type forms a closely spaced array (9 microns), which contributes from 1 to 7 synapses per b1 cell throu ghout the on-alpha dendritic field. Here we use a compartmental model of an on-alpha cell, based on a reconstruction from electron micrographs of serial sections, to compute the contribution of the b1 array to the on-alpha receptive field. The computation shows that, for a physiologic range of specific membrane resistance (9500-68,000 omega.cm2) and a linear synapse, inputs are equally effective at all points on the on-alpha dendritic tree. This implies that the electrotonic properties of the dendritic tree contribute very little to the domed shapes of the receptive field center and surround. Rather, these shapes arise from the domed distribution of synapses across the on-alpha dendritic field. Various sources of "jitter" in the anatomical circuit, such as variation in bipolar cell spacing and fluctuations in the number of synapses per bipolar cell, are smoothed by the overall circuit design. However, the computed center retains some minor asymmetries and lumps, due to anatomical jitter, as found in actual alpha-cell receptive fields.

In the exact center of the area centralis, cone density reaches 30,000-40,000/mm2 (Wassle and Riemann, 1978; Williams et al., 1993), but the circuitry has been studied slightly off center (1 deg eccentricity) where the cone density is about 24,000/mm2 and rod density is about 350,000/mm2 (Sterling et al., 1988). Here, due to the natural blur of the cat's optics (Wassle, 1971; Robson and Enroth-Cugell, 1978), the minimum number of photoreceptors stimulated from a point source is about 10 cones and 140 rods (Figure 13.1a, 2b). This is many more receptors than converging on a single bipolar cell, so even the finest spatial stimulus falling on either type of receptor will affect many bipolar cells. We review first the circuits for daylight that lead from cones because various portions of this circuit are parasitized by the circuits for twilight and starlight that lead from rods (Figure 13.2).

J Neurosci Methods 1987 Sep;21(1):55-69

Montage: a system for three-dimensional reconstruction by personal computer.

Smith RG

Department of Anatomy, School of Medicine, University of Pennsylvania, Philadelphia 19104-6058.

This paper describes a simplified system for serial section three-dimensional (3-D) reconstruction. A set of 9 software programs runs on a standard personal computer and produces camera-ready illustrations suitable for publication. The user enters trace points on a digitizing tablet from sections that have been already aligned. A 3-D view of the reconstructed object is generated which can be displayed with hidden lines removed. Analysis of volume, surface area and autoradiographic grain density are performed automatically. A relational database query language allows display and analysis of a selected subset of the data. The system runs under the UNIX operating system which allows the programs to be easily transported to new hardware or modified for other purposes.

J Neurosci Methods 1992 Jul;43(2-3):83-108

NeuronC: a computational language for investigating functional architecture of neural circuits.

Smith RG

Department of Anatomy, University of Pennsylvania, Philadelphia 19104-6058.

A computational language was developed to simulate neural circuits. A model of a neural circuit with up to 50,000 compartments is constructed from predefined parts of neurons, called "neural elements". A 2-dimensional (2-D) light stimulus and a photoreceptor model allow simulating a visual physiology experiment. Circuit function is computed by integrating difference equations according to standard methods. Large-scale structure in the neural circuit, such as whole neurons, their synaptic connections, and arrays of neurons, are constructed with procedural rules. The language was evaluated with a simulation of the receptive field of a single cone in cat retina, which required a model of cone-horizontal cell network on the order of 1000 neurons. The model was calibrated by adjusting biophysical parameters to match known physiological data. Eliminating specific synaptic connections from the circuit suggested the influence of individual neuron types on the receptive field of a single cone. An advantage of using neural elements in such a model is to simplify the description of a neuron's structure. An advantage of using procedural rules to define connections between neurons is to simplify the network definition.

Vis Neurosci 1995 May;12(3):545-561

Simulation of an anatomically defined local circuit: the cone-horizontal cell network in cat retina.

Smith RG

Department of Neuroscience, University of Pennsylvania, Philadelphia 19104-6058, USA.

The outer plexiform layer of the retina contains a neural circuit in which cone synaptic terminals are electrically coupled and release glutamate onto wide-field and narrow-field horizontal cells. These are also electrically coupled and feed back through a GABAergic synapse to cones. In cat this circuit's structure is known in some detail, and much of the chemical architecture and neural responses are also known, yet there has been no attempt to synthesize this knowledge. We constructed a large-scale compartmental model (up to 50,000 compartments) to incorporate the known anatomical and biophysical facts. The goal was to discover how the various circuit components interact to form the cone receptive field, and thereby what possible function is implied. The simulation reproduced many features known from intracellular recordings: (1) linear response of cone and horizontal cell to intensity, (2) some aspects of temporal responses of cone and horizontal cell, (3) broad receptive field of the wide-field horizontal cell, and (4) center-surround cone receptive field (derived from a "deconvolution model"). With the network calibrated in this manner, we determined which of its features are necessary to give the cone receptive field a Gaussian center-surround shape. A Gaussian-like center that matches the center derived from the ganglion cell requires both optical blur and cone coupling: blur alone is too narrow, coupling alone gives an exponential shape without a central dome-shaped peak. A Gaussian-like surround requires both types of horizontal cell: the narrow-field type for the deep, proximal region and the wide-field type for the shallow, distal region. These results suggest that the function of the cone-horizontal cell circuit is to reduce the influence of noise by spatio-temporally filtering the cone signal before it passes through the first chemical synapse on the pathway to the brain.

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PMID 3794785

J Neurosci 1986 Dec;6(12):3505-3517

Microcircuitry of the dark-adapted cat retina: functional architecture of the rod-cone network.

Smith RG, Freed MA, Sterling P

The structure of the rod-cone network in the area centralis of cat retina was studied by reconstruction from serial electron micrographs. About 48 rods converge on each cone via gap junctions between the rod spherules and the basal processes of the cone pedicle. One rod diverges to 2.4 cones through these gap junctions, and each cone connects to 8 other cones, also through gap junctions. A static cable model of this network showed that at mesopic intensities, when all rods converging on a cone pedicle are continuously active, the collective rod signal would be efficiently conveyed to the pedicle. At scotopic intensities sufficiently low for only one of the converging rods to receive a single photon within its integration time, the quantal rod signal would be poorly transmitted to the cone pedicle. This is because the tiny signal would be dissipated by the large network into which the individual rod diverges. Under this condition, the rod signal would also be poorly conveyed to the rod spherule. If, however, the rods are electrically disconnected from the network, the quantal signal would be efficiently conveyed to the rod spherule. This analysis suggests that the rod signal is conveyed at mesopic intensities by the cone bipolar pathway and, at scotopic intensities, by the rod bipolar pathway, in accordance with the results of Nelson (1977, 1982; Nelson and Kolb, 1985).

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PMID 2288894

Vis Neurosci 1990 Nov;5(5):453-461

Cone receptive field in cat retina computed from microcircuitry.

Smith RG, Sterling P

The receptive-field profile of the cone in cat-retina was computed. The computation was based on (1) the known anatomical circuit connecting cones via narrow-field bipolar cells to the on-beta ganglion cell; (2) the known physiological receptive-field profile of the on-beta (X) cell at the corresponding eccentricity; and (3) a model in which the beta receptive field arises by linear superposition of cone receptive fields. The computed cone receptive field has a center/surround organization with a center almost as broad as that of the beta cell center. The cone surround is comparably broad to that of the beta cell but somewhat lower in peak amplitude. The problems to which the center/surround receptive field are the solution, namely, signal compression and noise reduction, apparently must be solved before the first synapse of the visual pathway.

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[PMID 8924409]

Vis Neurosci 1995 Sep;12(5):851-860

Simulation of the AII amacrine cell of mammalian retina: functional consequences of electrical coupling and regenerative membrane properties.

Smith RG, Vardi N

Department of Neuroscience, University of Pennsylvania, Philadelphia 19104-6058, USA.

The AII amacrine cell of mammalian retina collects signals from several hundred rods and is hypothesized to transmit quantal "single-photon" signals at scotopic (starlight) intensities. One problem for this theory is that the quantal signal from one rod when summed with noise from neighboring rods would be lost if some mechanism did not exist for removing the noise. Several features of the AII might together accomplish such a noise removal operation: The AII is interconnected into a syncytial network by gap junctions, suggesting a noise-averaging function, and a quantal signal from one rod appears in five AII cells due to anatomical divergence. Furthermore, the AII contains voltage-gated Na+ and K+ channels and fires slow action potentials in vitro, suggesting that it could selectively amplify quantal photon signals embedded in uncorrelated noise. To test this hypothesis, we simulated a square array of AII somas (Rm = 25,000 Ohm-cm2) interconnected by gap junctions using a compartmental model. Simulated noisy inputs to the AII produced noise (3.5 mV) uncorrelated between adjacent cells, and a gap junction conductance of 200 pS reduced the noise by a factor of 2.5, consistent with theory. Voltage-gated Na+ and K+ channels (Na+: 4 nS, K+: 0.4 nS) produced slow action potentials similar to those found in vitro in the presence of noise. For a narrow range of Na+ and coupling conductance, quantal photon events (approximately 5-10 mV) were amplified nonlinearly by subthreshold regenerative events in the presence of noise. A lower coupling conductance produced spurious action potentials, and a greater conductance reduced amplification. Since the presence of noise in the weakly coupled circuit readily initiates action potentials that tend to spread throughout the AII network, we speculate that this tendency might be controlled in a negative feedback loop by up-modulating coupling or other synaptic conductances in response to spiking activity.

Microcircuitry and functional architecture of the cat retina.

Sterling P, Freed M, Smith RG

Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia 19104-6058.

Neurons in the cat retina belong to specific types. Each type is characterized by a specific corresponddence between morphology and physiology and forms a regular array that connects lawfully to the arrays of certain other types. Two circuits have been traced quantitatively through these arrays from photoreceptors to alpha- and beta-ganglion cells. The 'cone-bipolar circuit' appears to convery the centre-surround receptive field to gangion cells, using cones in daylight and rods (via gap junctions to cones) in twilight. A 'rod-bipolar circuit' appears to convey the quantal signal and the pure center receptive field to the ganglion cells in starlight.

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PMID 3317147

Neurosci Res Suppl 1987;6:S269-S285

Microcircuitry of the on-beta ganglion cell in daylight, twilight, and starlight.

Sterling P, Cohen E, Freed MA, Smith RG

Department of Anatomy, University of Pennsylvania Medical School, Philadelphia 19104-6058.

Between noon and the end of nightfall, the intensity of light in the environment declines by about ten billion-fold. MOst of the drama in the human experience of this change occurs during the hours that we call "twilight". Colors gradually shift in hue and then desaturate, but spatial resolution is preserved for a while longer. Thus, in a garden the red roses turn purple and then black, but the structure of the bush remains distinct. Only later, as the stars appear, do the details of the foliage dissolve into shadow.

Our experience of these transitions is paralleled to some extent by the behavior of individual ganglion cells in cat retina. So remarkable is their capacity to adapt that they remain responsive to visual stimuli over the full ten log unit range of envioronmental light intensity [1]. In this essay, we review some salient features of this adaptation process. We then summarize recent anatomical studies of the circuits connecting photoreceptors to the ganglion cells and speculate upon the relation of the neural architecture to the function. Only one type of ganglion cell is considered: the ON-center cell known to physiologists as "X" or "brisk-sustained" and to morphologists as "beta" [2-5]. All of the measurements considered here, both physiological and anatomical, refer to neurons in the area centralis.

J Neurosci 1988 Feb;8(2):623-642

Functional architecture of rod and cone circuits to the on-beta ganglion cell.

Sterling P, Freed MA, Smith RG

Department of Anatomy, University of Pennsylvania, Philadelphia 19104.

Photoreceptors connect to the on-beta ganglion cell through parallel circuits involving rod bipolar (RB) and cone bipolar (CB) neurons. We estimated for a small patch in the area centralis of one retina the 3-dimensional architecture of both circuits. This was accomplished by reconstructing neurons and synapses from electron micrographs of 189 serial sections. There were (per mm2) 27,000 cones, 450,000 rods, 6500 CBb1, 30,300 RB, 4100 All amacrines, and 2000 on-beta ganglion cells. The tangential spread of processes was determined for each cell type, and, with the densities, this allowed us to calculate the potential convergence and divergence of each array upon the next. The actual numbers of cells converging and diverging were estimated from serial sections, as were the approximate numbers of chemical synapses involved. The cone bipolar circuit showed narrow convergence and divergence: 16 cones->4 CBb1->1 on-beta 1 cone->1 CBb1->1.2 on-beta This circuit is thought to contribute significantly to the on-beta cell's photopic receptive field because the CBb1 has a center-surround receptive field whose center diameter is greater than the spacing between adjacent CBb1s. Consequently, the receptive fields of the CBb1s converging on a beta cell are probably largely concentric and thus mutually reinforcing in their contributions to the on-beta. The rod bipolar circuit showed a wider convergence and divergence: 1500 rods->100 RB->5 AII->4 CBb1->1 on-beta 1 rod->2 RB->5 AII->8 CBb1->2 on-beta The 1500 rods converging via this circuit account for the spatial extent of the beta cell's dark-adapted receptive field. This convergence also accounts for the ganglion cell's maintained discharge, which is thought to arise from about 6 quantal "dark events" per second. This many dark events would appear in the ganglion cell if each rod in the circuit contributed 0.004 dark events per second, and this is close to what has been measured in monkey rods (Baylor et al., 1984). Divergence in this circuit serves to expand the number of copies of the quantal signal (1 rod->8 CBb1) and so to engage large numbers of chemical synapses that provide amplification. Reconvergence at the last stage (8 CBb1->2 on-beta) may reduce (by signal averaging) the synaptic noise that would otherwise accumulate along the pathway.

Proc Natl Acad Sci U S A 1990 Mar;87(5):1860-1864

"Collective coding" of correlated cone signals in the retinal ganglion cell.

Tsukamoto Y, Smith RG, Sterling P

Department of Anatomy, School of Medicine, University of Pennsylvania, Philadelphia 19104.

The signals in neighboring cones are partially correlated due to local correlations of luminance in the visual scene. By summing these partially correlated signals, the retinal ganglion cell improves its signal/noise ratio (compared to the signal/noise ratio in a cone) and expands the variance of its response to fill its dynamic range. Our computations prove that the optimal weighting function for this summation is dome-shaped. The computations also show that (assuming a particular space constant for the correlation function) ganglion cell collecting area and cone density are matched at all eccentricities such that the signal/noise ratio improves by a constant factor. The signal/noise improvement factor for beta ganglion cells in cat retina is about 4.

[PMID 8994576]

Vision Res 1996 Dec;36(23):3743-3757

The AII amacrine network: coupling can increase correlated activity.

Vardi N, Smith RG

Department of Neuroscience, University of Pennsylvania, Philadelphia 19104, USA. noga@retina.anatomy.upenn.edu

Retinal ganglion cells in the cat respond to single rhodopsin isomerizations with one to three spikes. This quantal signal is transmitted in the retina by the rod bipolar pathway: rod-->rod bipolar-->AII-->cone bipolar-->ganglion cell. The two-dimensional circuit underlying this pathway includes extensive convergence from rods to an AII amacrine cell, divergence from a rod to several AII and ganglion cells, and coupling between the AII amacrine cells. In this study we explored the function of coupling by reconstructing several AII amacrine cells and the gap junctions between them from electron micrographs; and simulating the AII network with and without coupling. The simulation showed that coupling in the AII network can: (1) improve the signal/noise ratio in the AII network; (2) improve the signal/noise ratio for a single rhodopsin isomerization striking in the periphery of the ganglion cell receptive field center, and therefore in most ganglion cells responding to a single isomerization; (3) expand the AII and ganglion cells' receptive field center; and (4) expand the "correlation field". All of these effects have one major outcome: an increase in correlation between ganglion cell activity. Well correlated activity between the ganglion cells could improve the brain's ability to discriminate few absorbed external photons from the high background of spontaneous thermal isomerizations. Based on the possible benefits of coupling in the AII network, we suggest that coupling occurs at low scotopic luminances.

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[PMID:9764523]

Visual Neurosci. (1998) Sep-Oct 15(5):809-21

Noise removal at the rod synapse of mammalian retina.

van Rossum MC. and Smith RG.

Dept. Neuroscience, University of Pennsylvania, Philadelphia 19104-6058, USA.

Mammalian rods respond to single photons with a hyperpolarization of about 1 mV which is accompanied by continuous noise. Since the mammalian rod bipolar cell collects signals from 20-100 rods, the noise from the converging rods would overwhelm the single-photon signal from one rod at scotopic intensities (starlight) if the bipolar cell summed signals linearly (Baylor et al., 1984). However, it is known that at scotopic intensities the retina preserves single-photon responses (Barlow et al., 1971; Mastronarde, 1983). To explore noise summation in the rod bipolar pathway, we simulated an array of rods synaptically connected to a rod bipolar cell using a compartmental model. The performance of the circuit was evaluated with a discriminator measuring errors in photon detection as false positives and false negatives, which were compared to physiologically and psychophysically measured error rates. When only one rod was connected to the rod bipolar, a Poisson rate of 80 vesicles/s was necessary for reliable transmission of the single-photon signal. When 25 rods converged through a linear synapse the noise caused an unacceptably high false positive rate, even when either dark continuous noise or synaptic noise where completely removed. We propose that a threshold nonlinearity is provided by the mGluR6 receptor in the rod bipolar dendrite (Shiells & Falk, 1994) to yield a synapse with a noise removing mechanism. With the threshold nonlinearity the synapse removed most of the noise. These results suggest that a threshold provided by the mGluR6 receptor in the rod bipolar cell is necessary for proper functioning of the retina at scotopic intensities and that the metabotropic domains in the rod bipolar are distinct. Such a nonlinear threshold could also reduce synaptic noise for cortical circuits in which sparse signals converge.

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J Optical Soc. Am. A 2000 Mar 17:(3) 635-640.

Cost of cone coupling to trichromacy in primate fovea.

Hsu A, Smith RG, Buchsbaum G, Sterling P

Cone synaptic terminals couple electrically to their neighbors. This reduces the amplitude of temporally uncorrelated voltage differences between neighbors. For an achromatic stimulus coarser than the cone mosaic, the uncorrelated voltage difference between neighbors represents mostly noise; so noise is reduced more than the signal. Here coupling improves signal-to-noise ratio and enhances contrast sensitivity. But for a chromatic stimulus the uncorrelated voltage difference between neighbors of different spectral type represents mostly signal; so signal would be reduced more than the noise. This cost of cone coupling to encoding chromatic signals was evaluated using a compartmental model of the foveal cone array. When cones sensitive to middle (M) and long (L) wavelengths alternated regularly, and the conductance between a cone and all of its immediate neighbors was 1000 pS (similar to 2 connexons/cone pair), coupling reduced the difference between the L and M action spectra by nearly fivefold, from about 38% to 8%. However, L and M cones distribute randomly in the mosaic, forming small patches of like type, and within a patch the responses to a chromatic stimulus are correlated. In such a mosaic, coupling still reduced the difference between the L and M action spectra, but only by 2.4-fold, to about 18%. This result is independent of the L/M ratio. Thus "patchiness" of the L/M mosaic allows cone coupling to improve achromatic contrast sensitivity while minimizing the cost to chromatic sensitivity.

Here we review the functional archkitecture of the circuit in cat retina that connects cones to one type of ganglion cell. This is the "on-beta" ("X") cell (Boycott and Wassle, 1974), which responds linearly (Enroth-Cugell and Robson, 1966), and whose receptive field is fitted by a difference-of-Gaussians function (Linsenmeier et al., 1982). The on-beta cell and its complement, the "off-beta", have the highest sampling densities and the narrowest sampling apertures in the cat retina (Wassle et al., 1981; Cleland et al., 1979). The beta cell arrays apparently relay to the higher visual areas the finest grained neural image. We describe the structure of the cone circuit to the on-beta and suggest how the architecture might contribute to efficient coding of a fine, low contrast, neural image.

Vision Res. (1998) 38:2539-2549

Functional architecture of primate cone and rod axons

Hsu, A., Tsukamoto, Y., Smith, R.G., and Sterling, P.

The cone axon is nearly four times thicker than the rod axon (1.6 vs. 0.45 um diameter). To assess how signal transfer and integration at the terminal depend on cable dimensions, a transducer (cone = ohmic conductance, rod = current source) coupled via passive cable to a sphere with a chloride conductance (representing GABAa receptor) was modelled. For a small signal in peripheral cone with a short axon, a steady photosignal transfers independently of axon diameter despite a significant chloride conductance at the cone terminal. A temporally varying photosignal also transfers independently of axon diameter up to 20 Hz and is attenuated only 20% at 50 Hz. Thus, to accomplish the basic electrical functions of a peripheral cone, a thin axon would suffice. For a foveal cone with a long axon, a steady photosignal transfers independently of axon diameter, but a temporally varying photosignal is attenuated 5-fold at 50 Hz for a thick axon and 10-fold for a thin axon. This might contribute to the lower sensitivity of central retina to high temporal frequencies. The cone axon contains 14-fold more microtubules than the rod axon, and its terminal contains at least 20-fold more ribbon synapses than the rod's. Since ribbon synapses sustain high rates of exocytosis, the additional microtubules (which require a thicker axon) may be needed to support a greater flux of synaptic vesicle components.

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[PMID:12740401]

Effects of Noise on the Spike Timing Precision of Retinal Ganglion Cells.

van Rossum, MCW., O'Brien BJ. and Smith, RG. J. Neurophysiol. 2003 89: 2406-2419;

Information in a spike train is limited by variability in the spike timing. This variability is caused by noise from several sources including synapses and membrane channels, but how deleterious each noise source is and how they affect spike train coding is unknown. Combining physiology and a multi-compartment model we studied the effect of synaptic input noise and voltage-gated channel noise on spike train reliability for a mammalian ganglion cell. For tonic stimuli the standard deviation of the interspike intervals increased supra-linearly with increasing interspike interval. Voltage gated channel noise and synaptic noise caused fluctuations in the interspike interval of comparable amplitude. Spikes initiated on the dendrites caused additional spike timing fluctuations. Ca and KCa channels present in the model reduced spike train variability. For transient stimuli, synaptic noise was dominant. Spontaneous background activity strongly increased fluctuations in spike timing, but decreased the latency before the first spike. These results constrain the neural coding strategy.

Electrical coupling between mammalian cones

DeVries S; Qi X; Smith R; Makous W; Sterling P

Background

Cone photoreceptors are noisy because of random fluctuations of photon absorption, signaling molecules, and ion channels. However, each cones noise is independent of the others, whereas their signals are partially shared. Therefore, electrically coupling the synaptic terminals prior to forward transmission and subsequent nonlinear processing can appreciably reduce noise relative to the signal. This signal-processing strategy has been demonstrated in lower vertebrates with rather coarse vision, but its occurrence in mammals with fine acuity has been doubted (even though gap junctions are present) because coupling would blur the neural image.

Results

In ground squirrel retina, whose triangular cone lattice resembles the human fovea, paired electrical recordings from adjacent cones demonstrated electrical coupling with an average conductance of approximately 320 pS. Blur caused by this degree of coupling had a space constant of approximately 0.5 cone diameters. Psychophysical measurements employing laser interferometry to bypass the eyes optics suggest that human foveal cones experience a similar degree of neural blur and that it is invariant with light intensity. This neural blur is narrower than the eye's optical blur, and we calculate that it should improve the signal-to-noise ratio at the cone terminal by about 77%.

Conclusions

We conclude that the gap junctions observed between mammalian cones, including those in the human fovea, represent genuine electrical coupling. Because the space constant of the resulting neural blur is less than that of the optical blur, the signal-to-noise ratio can be markedly improved before the nonlinear stages with little compromise to visual acuity.

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Contrast Threshold of a Brisk-Transient ganglion cell

Dhingra NK, Kao YH, Sterling P, Smith RG

Abstract

We have measured the contrast threshold for a mammalian brisk-transient ganglion cell. The intact retina (guinea pig) was maintained in vitro, and extracellular spikes were recorded to a spot with sharp onset, flashed for 100 ms over the receptive field center. An "ideal observer" was given the spike responses from 100 trials at each contrast and then asked to predict the stimulus contrast on 100 additional trials in a single-interval, two-alternative forced-choice procedure. The prediction was based on spike count, latency or temporal pattern. Brisk-transient cells near 37(C detected contrasts as low as 0.8% (mean ( SEM = 2.8 ( 0.2%) and discriminated contrast increments with about 40% greater sensitivity. Performance was temperature sensitive, declining with a Q10 ~2, similar to that of retinal metabolism. These measurements of performance provide an important benchmark for comparison to retinal cell types upstream of the ganglion cell and downstream - to behavior. For example, human psychophysical threshold for a stimulus that just covers the dendritic field of one human brisk-transient cell is the same as found here. This suggests that neural processing across many levels of noisy central synapses might be highly efficient.

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Timing of quantal release from the retinal bipolar terminal is regulated by a feedback circuit

Michael A. Freed, Robert G. Smith, and Peter Sterling

Summary

In isolation, a presynaptic terminal generally releases quanta according to Poisson statistics, but in a circuit its release statistics might be shaped by local feedback. We monitored quantal release of glutamate from retinal bipolar cell terminals (which receive GABA-ergic feedback from amacrine cells) by recording spontaneous EPSCs in their postsynaptic amacrine and ganglion cells. EPSCs were temporally correlated in about one third of these cells, arriving in brief bursts (~20 ms) more often than expected from a Poisson process. Correlations were suppressed by antagonizing the GABAC receptor (expressed on bipolar terminals), and correlations were induced by raising extracellular calcium or osmolarity (which increase release probability). Simulations of the feedback circuit produced ``bursty'' release when the bipolar cell escaped intermittently from inhibition. Correlations of similar strength and duration were also present in light-evoked EPSCs and ganglion cell spikes. These correlations were also suppressed by a GABAC antagonist, indicating that bursts of glutamate from bipolar terminals induce spike bursts in ganglion cells.

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[PMID 15044530]

Spike generator limits efficiency of information transfer in a retinal ganglion cell

Dhingra NK and Smith RG

Summary

The quality of the signal a retinal ganglion cell transmits to the brain is important for preception because it sets the minimum detectable stimulus. The ganglion cell converts graded potentials into a spike train with a selective filter but in the process adds noise. To explorehow efficiently information is transferred to spikes, we measured contrast detection threshold and increment threshold from graded potential and spike responses of brisk-transient ganglion cells. Intracellular responses to a spot flashed over the receptive field center of the cell were recorded in an intact mammalian retina maintained in vitro at 37°C. Thresholds were measured in a single-interval forced-choice procedure with an ideal observer. The graded potential gave a detection threshold of 1.5% contrast, whereas spikes gave 3.8%. The graded potential also gave increment thresholds approximately twofold lower and carried 60% more gray levels. Increment threshold dipped below the detection threshold at a low contrast ( < 5%) but increased rapidly at higher contrasts. The magnitude of the dipper for both graded potential and spikes could be predicted from a threshold nonlinearity in the responses. Depolarization of the cell by current injection reduced the detection threshold for spikes but also reduced the range of contrasts they can transmit. This suggests that contrast sensitivity and dynamic range are related in an essential trade-off.

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How efficiently a ganglion cell codes the visual signal

Smith RG, Dhingra NK, Kao YH, Sterling P

Summary

The retina's visual message is transmitted to the brain by ganglion cells that integrate noisy synaptic inputs to create a spike train. We asked how efficiently the retinal ganglion cell spike generator creates the spike train message. Intracellular and extracellular recordings were made from in vitro guinea pig retina, in response to a spot of light flashed over the receptive field center. Responses were analyzed with an "ideal observer," a program that discriminated between two contrasts based on an optimal decision rule. Spike trains from ganglion cells had thresholds as low as 1% contrast, but thresholds for the corresponding graded potentials were lower by a factor of 2. Using a computational model of the ganglion cell, we asked what factors in the spike generator mechanism are responsible for the spike train's loss in performance. The model included dendritic/axonal morphology, noisy synaptic inputs and membrane channels. Adaptation of spike rate was provided by K(Ca) channels which were activated by Ca2+ flux during spikes. When K(Ca) channels were included, they controlled the duration of the inter-spike interval and thus set the level of noise in the spike train. These results imply that the spike generator adds noise to the spike train signal.

One stimulus that we detect very efficiently is a small square that just covers the dendritic field of a brisk-transient ganglion cell. Since this cell type is the most sensitive of the geniculo-striate projecting ganglion cells, it may largely mediate this behavior. To compare the neuron's sensitivity to that of psychophysical detection we measured its visual threshold with a method borrowed from psychophysics. Recordings were extracellular from a mammalian brisk-transient ganglion cell (guinea pig), whose impulse response was nearly identical to that of the primate brisk-transient cell. The stimulus, a 100 ms spot covering the receptive field center, was detected by an "ideal observer" with knowledge of the spike patterns from 100 trials at each contrast. Based on this knowledge, the ideal observer used a single-interval, forced-choice procedure to predict the stimulus contrast on 100 additional trials. Brisk-transient cells at 37°C detected contrasts as low as 0.8% (mean ± SD = 2.8 % ± 0.2 ) and discriminated between contrast increments with about 40% greater sensitivity. These thresholds are the same as human psychophysical thresholds for comparable stimuli, suggesting that across many levels of noisy central synapses, little or no information is lost. Recording intracellularly, we found detection threshold of the ganglion cell's graded potential to be about half that of the spike response, implying a considerable loss in converting the signals from analog-to-digital. To reach detection threshold ganglion cell needed ~1000 quanta, and to respond at full contrast it needed ~2000 quanta. Since the ribbon synapses that contact this cell contain an aggregate of ~10,000 releasable vesicles, the safety factor for this circuit seems to be about 5.

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[PMID: 15579224]

Direction selectivity in a model of the starburst amacrine cell

Tukker JJ Taylor WR, and Smith RG

Summary

The starburst amacrine cell (SBAC), found in all mammalian retinas, is thought to provide the directional inhibitory input recorded in On-Off direction selective ganglion cells (DSGCs). While voltage recordings from the somas of SBACs have not shown robust direction selectivity (DS), the dendritic tips of these cells display direction-selective calcium signals, even when gamma aminobutyric acid (GABAa,c) channels are blocked, implying that inhibition is not necessary to generate DS. This suggested that the distinctive morphology of the starburst could generate a DS signal at the dendritic tips, where most of its synaptic output is located. To explore this possibility, we constructed a compartmental model incorporating realistic morphological structure, passive membrane properties, and excitatory inputs. We found robust direction selectivity at the dendritic tips but not at the soma. Thin bars produced robust DS, but two-spot apparent motion and annulus radial motion gave little DS. For these stimuli, DS was caused by the interaction of a local synaptic input signal with a temporally delayed "global" signal, that is, an excitatory postsynaptic potential (EPSP) that spread from the activated inputs into the soma and throughout the dendritic tree. In the preferred direction the signals in the dendritic tips coincided, allowing summation, whereas in the null direction the local signal preceded the global, preventing summation. Sine-wave gratings gave the greatest amount of DS, especially at high velocities and low spatial frequencies. The sine-wave DS responses could be accounted for by a simple model which summed phase-shifted signals from different parts of the cell. By testing different artificial morphologies, we discovered DS was relatively independent of the detailed morphology, but depended on having a sufficient number of inputs at the distal tips and a limited electrotonic isolation. Adding voltage-gated calcium channels to the model showed that their threshold effect can amplify DS in the intracellular calcium signal.

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[PMID: 15535994]

Transmission of scotopic signals from the rod to rod-bipolar cell in the mammalian retina.

Taylor WR, and Smith RG

Summary

Mammals can see at low scotopic light levels where only 1 rod in several thousand transduces a photon. The single photon signal is transmitted to the brain by the ganglion cell, which collects signals from more than 1000 rods to provide enough amplification. If the system were linear, such convergence would increase the neural noise enough to overwhelm the tiny rod signal. Recent studies provide evidence for a threshold nonlinearity in the rod to rod bipolar synapse, which removes much of the background neural noise. We argue that the height of the threshold should be 0.85 times the amplitude of the single photon signal, consistent with the saturation observed for the single photon signal. At this level, the rate of false positive events due to neural noise would be masked by the higher rate of dark thermal events. The evidence presented suggests that this synapse is optimized to transmit the single photon signal at low scotopic light levels.

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Transmission of single photon signals through a binary synapse in the mammalian retina

Berntson A, Smith RG, and Taylor WR

Summary

At very low light levels the sensitivity of the visual system is determined by the efficiency with which single photons are captured, and the resulting signal transmitted from the rod photoreceptors through the retinal circuitry to the ganglion cells and on to the brain. Although the tiny electrical signals due to single photons have been observed in rod photoreceptors, little is known about how these signals are preserved during subsequent transmission to the optic nerve. We find that the synaptic currents elicited by single photons in mouse rod bipolar cells have a peak amplitude of 5-6 pA, and that about 20 rod photoreceptors converge upon each rod bipolar cell. The data indicates that the first synapse, between rod photoreceptors and rod bipolar cells, signals a binary event: the detection, or not, of a photon or photons in the connected rod photoreceptors. We present a simple model that demonstrates how a threshold nonlinearity during synaptic transfer allows transmission of the single photon signal, while rejecting the convergent neural noise from the 20 other rod photoreceptors feeding into this first synapse.

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Postsynaptic calcium feedback between rods and rod bipolar cells in the mouse retina

Berntson A, Smith RG, and Taylor WR

Summary

Light-evoked currents were recorded from rod bipolar cells in a dark-adapted mouse retinal slice preparation. Low-intensity light steps evoked a sustained inward current. Saturating light steps evoked an inward current with an initial peak that inactivated, with a time constant of about 60-70 ms, to a steady plateau level that was maintained for the duration of the step. The inactivation was strongest at hyperpolarized potentials, and absent at positive potentials. Inactivation was mediated by an increase in the intracellular calcium concentration, as it was abolished in cells dialyzed with 10 mM BAPTA, but was present in cells dialyzed with 1 mM EGTA. Moreover, responses to brief flashes of light were broader in the presence of intracellular BAPTA indicating that the calcium feedback actively shapes the time course of the light responses. Recovery from inactivation observed for paired-pulse stimuli occurred with a time constant of about 375 ms. Calcium feedback could act to increase the dynamic range of the bipolar cells, and to reduce variability in the amplitude and duration of the single-photon signal. This may be important for nonlinear processing at downstream sites of convergence from rod bipolar cells to AII amacrine cells. A model in which intracellular calcium rapidly binds to the light-gated channel and reduces the conductance can account for the results.

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Sluggish and brisk ganglion cells detect contrast with similar sensitivity

Xu Y, Dhingra NK, Smith RG, Sterling P

Summary

Roughly half of all ganglion cells in mammalian retina belong to the broad class, termed "sluggish". Many of these cells have small receptive fields and project via lateral geniculate nuclei to visual cortex. However, their possible contributions to perception have been largely ignored because sluggish cells seem to respond weakly compared to the more easily studied "brisk" cells. By selecting small somas under infrared DIC optics and recording with a loose seal, we could routinely isolate sluggish cells. When a spot was matched spatially and temporally to the receptive field center, most sluggish cells could detect the same low contrasts as brisk cells. Detection thresholds for the two groups determined by an "ideal observer" were similar: threshold contrast for sluggish cells was 4.7 ± 0.5% (mean ± SE), and for brisk cells was 3.4 ± 0.3% (Mann-Whitney test: p>0.05). Signal-to-noise ratios for the two classes were also similar at low contrast. However, sluggish cells saturated at somewhat lower contrasts (contrast for half-maximum response was 14 ± 1% vs. 19 ± 2% for brisk cells) and were less sensitive to higher temporal frequencies (when the stimulus frequency was increased from 2 Hz to 4 Hz, the response rate fell by 1.6-fold). Thus the sluggish cells covered a narrower dynamic range and a narrower temporal bandwidth, consistent with their reported lower information rates. Because information per spike is greater at lower firing rates, sluggish cells may represent "cheaper" channels that convey less urgent visual information at a lower energy cost.

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[PMID: 16135767]

Voltage-gated sodium channels improve contrast sensitivity of a retinal ganglion cell.

Dhingra NK, Freed, MA, Smith RG

Summary

Voltage-gated channels in a retinal ganglion cell are necessary for spike generation. However, they also add noise to the graded potential and spike train of the ganglion cell, which may degrade its contrast sensitivity, and they may also amplify the graded potential signal. We studied the effect of blocking Na+ channels in a ganglion cell on its signal and noise amplitudes and its contrast sensitivity. A spot was flashed at 1- 4 Hz over the receptive field center of a brisk transient ganglion cell in an intact mammalian retina maintained in vitro. We measured signal and noise amplitudes from its intracellularly recorded graded potential light response and measured its contrast detection thresholds with an "ideal observer." When Na+ channels in the ganglion cell were blocked with intracellular lidocaine N-ethyl bromide (QX-314), the signal-to-noise ratio (SNR) decreased (p < 0.05) at all tested contrasts (2-100%). Likewise, bath application of tetrodotoxin (TTX) reduced the SNR and contrast sensitivity but only at lower contrasts (50%), whereas at higher contrasts, it increased the SNR and sensitivity. The opposite effect of TTX at high contrasts suggested involvement of an inhibitory surround mechanism in the inner retina. To test this hypothesis, we blocked glycinergic and GABAergic inputs with strychnine and picrotoxin and found that TTX in this case had the same effect as QX-314: a reduction in the SNR at all contrasts. Noise analysis suggested that blocking Na+ channels with QX-314 or TTX attenuates the amplitude of quantal synaptic voltages. These results demonstrate that Na+ channels in a ganglion cell amplify the synaptic voltage, enhancing the SNR and contrast sensitivity.

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Chromatic properties of horizontal and ganglion cell responses follow a dual gradient in cone opsin expression.

Yin L, Smith RG, Sterling P, Brainard DH

Summary

In guinea pig retina, immunostaining reveals a dual gradient of opsins: cones expressing opsin sensitive to medium wavelengths (M) predominate in the upper retina, whereas cones expressing opsin sensitive to shorter wavelengths (S) predominate in the lower retina. Whether these gradients correspond to functional gradients in postreceptoral neurons is essentially unknown. Using monochromatic flashes, we measured the relative weights with which M, S, and rod signals contribute to horizontal cell responses. For a background that produced 4.76 log10 photoisomerizations per rod per second (Rh*/rod/s), mean weights in superior retina were 52% (M), 2% (S), and 46% (rod). Mean weights in inferior retina were 9% (M), 50% (S), and 41% (rod). In superior retina, cone opsin weights agreed quantitatively with relative pigment density estimates from immunostaining. In inferior retina, cone opsin weights agreed qualitatively with relative pigment density estimates, but quantitative comparison was impossible because individual cones coexpress both opsins to varying and unquantifiable degrees. We further characterized the functional gradients in horizontal and brisk-transient ganglion cells using flickering stimuli produced by various mixtures of blue and green primary lights. Cone weights for both cell types resembled those obtained for horizontal cells using monochromatic flashes. Because the brisk-transient ganglion cell is thought to mediate behavioral detection of luminance contrast, our results are consistent with the hypothesis that the dual gradient of cone opsins assists achromatic contrast detection against different spectral backgrounds. In our preparation, rod responses did not completely saturate, even at background light levels typical of outdoor sunlight (5.14 log10 Rh*/rod/s).

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Design of a Neuronal Array

Borghuis BG, Ratliff CP, Smith RG, Sterling P, Balasubramanian V.

Summary

Retinal ganglion cells of a given type overlap their dendritic fields such that every point in space is covered by three to four cells. We investigated what function is served by such extensive overlap. Recording from pairs of ON or OFF brisk-transient ganglion cells at photopic intensities, we confirmed that this overlap causes the Gaussian receptive field centers to be spaced at2 SDs (). This, together with response nonlinearities and variability, was just sufficient to provide an ideal observer with uniform contrast sensitivity across the retina for both threshold and suprathreshold stimuli. We hypothesized that overlap might maximize the information represented from natural images, thereby optimizing retinal performance for many tasks. Indeed, tested with natural images (which contain statistical correlations), a model ganglion cell array maximized information represented in its population responses with 2spacing, i.e., the overlap observed in the retina. Yet, tested with white noise (which lacks statistical correlations), an array maximized its information by minimizing overlap. In both cases, optimal overlap balanced greater signal-to-noise ratio (from larger receptive fields) against greater redundancy (because of larger receptive field overlap). Thus, dendritic overlap improves vision by taking optimal advantage of the statistical correlations of natural scenes.

Xu, Y, Sulaiman, P, Fedderson, R., Liu, J., Smith, R.G. and Vardi, N.

Summary

PCP2, a member of the GoLoco domain-containing family, is present exclusively in cerebellar Purkinje cells and retinal ON-bipolar cells. Its function in these tissues is unknown. Biochemical and expression system studies suggest that PCP2 is a guanine nucleotide dissociation inhibitor, though a guanine nucleotide exchange factor has also been suggested. Here we studied the function of PCP2 in ON bipolar cells because their light response depends on Gao1, which is known to interact with PCP2. We identified a new splice variant of PCP2 (Ret-PCP2) and localized it to rod bipolar and ON cone bipolar cells. Electroretinogram recordings from PCP2-null mice showed a normal a-wave but a slower falling phase of the b-wave (generated by activity of ON bipolar cells) relative to the wild type. Whole-cell recordings from rod bipolar cells showed, both under Ames solution and after blocking GABAA/C and glycine receptors, that PCP2-null rod bipolar cells were more depolarized than wild type cells with greater inward current when clamped to -60 mV. Also under both conditions, the rise time of the response to intense light was slower by 28% (Ames) and 44% (inhibitory blockers) in the null cells. Under Ames we also observed >30% longer decay time in the PCP2 null rod bipolar cells. We conclude that PCP2 facilitates cation channels' closure in the dark, shortens the rise time of the light response directly, and accelerates the decay time indirectly via the inhibitory network. These data can be most easily explained if Ret-PCP2 serves as a guanine nucleotide exchange factor.

Yin L, Smith, R.G., Sterling, P. and Brainard D.H

Summary

Most mammals are dichromats, having short-wavelength sensitive (S) and middle-wavelength sensitive (M) cones. Smaller terrestrial species commonly express a dual gradient in opsins, with M opsin concentrated superiorly and declining inferiorly, and vice-versa for S opsin. Some ganglion cells in these retinas combine S and M-cone inputs antagonistically, but no direct evidence links this physiological opponency with morphology; nor is it known whether opponency varies with the opsin gradients. By recording from more than 3000 ganglion cells in guinea pig, we identified small numbers of color-opponent cells. Chromatic properties were characterized by responses to monochromatic spots and/or spots produced by mixtures of two primary lights. Superior retina contained cells with strong S+/M- and M+/S- opponency, whereas inferior retina contained cells with weak opponency. In superior retina, the opponent cells had well-balanced M and S weights, while in inferior retina the weights were unbalanced, with the M weights being much weaker. The M and S components of opponent cell receptive fields had approximately the same diameter. Opponent cells injected with Lucifer yellow restricted their dendrites to the ON stratum of the inner plexiform layer and provided sufficient membrane area (~2.1e+4 µm2) to collect ~3.9e+3 bipolar synapses. Two bistratified cells studied were non-opponent. The apparent decline in S/M opponency from superior to inferior retina is consistent with the dual gradient and a model where photoreceptor signals in both superior and inferior retina are processed by the same post-receptoral circuitry.

[PMID: 19279241]

Borghuis, B.G., Sterling, P. and Smith, R.G.

Summary

A low contrast spot that activates just one ganglion cell in the retina is detected in the cell's spike train with about the same sensitivity as it is detected behaviorally. This is consistent with Barlow's proposal that the ganglion cell and later stages of spiking neurons transfer information essentially without loss. Yet, when losses of sensitivity by all preneural factors are accounted for, predicted sensitivity near threshold is considerably greater than behavioral sensitivity, implying that somewhere in the brain information is lost. We hypothesized that the losses occur mainly in the retina - where graded signals are processed by analog circuits that transfer information at high rates and low metabolic cost. To test this, we constructed a model that included all preneural losses for an in vitro mammalian retina, and evaluated the model to predict sensitivity at the cone output. Recording graded responses postsynaptic to the cones (from the type A horizontal cell) and comparing to predicted preneural sensitivity, we found substantial loss of sensitivity (4.2-fold) across the first visual synapse. Recording spike responses from brisk-transient ganglion cells stimulated with the same spot, we found a similar loss (3.5-fold) across the second synapse. The total retinal loss approximated the known overall loss, supporting the hypothesis that from stimulus to perception, most loss near threshold is retinal.

Smith, R.G.

Summary

Photoreceptors are the vertebrate retina's primary site for transduction of light into a neural signal. The cone photoreceptor plays a crucial role in daylight vision because it transmits fast changes in light contrast. To improve its sensitivity over 5 log units of background illumination, the cone contains several mechanisms for adaptation: the transduction cascade, biophysical properties, and in the ribbon synapse. The ribbon is part of a complex local circuit called the triad that combines adaptation with spatial filtering to maximize the amount of information the cone transmits to second-order neurons.

Smith, R.G.

Summary

The rod photoreceptor is responsible for vision at night over the range of starlight through moonlight to twilight. In starlight, the rod receives a photon about once in 20 minutes, requiring spatial summation, but this would amplify the dark noise if the visual pathway were linear. The rod synapse is specialized to transmit single-photon signals by removing the dark continuous noise with a threshold nonlinearity. At twilight, the rod receives more than one photon per integration time (~200 ms in mammals) and thus cannot transmit single-photon signals. Instead its signals at twilight are coupled to cones through gap junctions.

Smith, R.G. and Dhingra, N.K.

Refereed review article

Summary

The function of the retina is crucial, for it must encode visual signals so the brain can detect objects in the visual world. However, the biological mechanisms of the retina add noise to the visual signal and therefore reduce its quality and capacity to inform about the world. Because an organism's survival depends on its ability to unambiguously detect visual stimuli in the presence of noise, its retinal circuits must have evolved to maximize signal quality, suggesting that each retinal circuit has a specific functional role. Here we explain how an ideal observer can measure signal quality to determine the functional roles of retinal circuits. In a visual discrimination task the ideal observer can measure from a neural response the increment threshold, the number of distinguishable response levels, and the neural code, which are fundamental measures of signal quality relevant to behavior. It can compare the signal quality in stimulus and response to determine the optimal stimulus, and can measure the specific loss of signal quality by a neuron's receptive field for non-optimal stimuli. Taking into account noise correlations, the ideal observer can track the signal to noise ratio available from one stage to the next, allowing one to determine each stage's role in preserving signal quality. A comparison between the ideal performance of the photon flux absorbed from the stimulus and actual performance of a retinal ganglion cell shows that in daylight a ganglion cell and its presynaptic circuit loses a factor of ~10-fold in contrast sensitivity, suggesting specific signal-processing roles for synaptic connections and other neural circuit elements. The ideal observer is a powerful tool for characterizing signal processing in single neurons and arrays along a neural pathway.

Lipin MK, Smith RG, Taylor WR (2010)

Summary

The outer retina removes the first-order correlation, the background light level, and thus more efficiently transmits contrast. This removal is accomplished by negative feedback from horizontal cell to photoreceptors. However, the optimal feedback gain to maximize the contrast sensitivity and spatial resolution is not known. The objective of this study was to determine, from the known structure of the outer retina, the synaptic gains that optimize the response to spatial and temporal contrast within natural images. We modeled the outer retina as a continuous 2D extension of the discrete 1D model of Yagi et al. (Proc Int Joint Conf Neural Netw 1: 787-789, 1989). We determined the spatio-temporal impulse response of the model using small-signal analysis, assuming that the stimulus did not perturb the resting state of the feedback system. In order to maximize the efficiency of the feedback system, we derived the relationships between time constants, space constants, and synaptic gains that give the fastest temporal adaptation and the highest spatial resolution of the photoreceptor input to bipolar cells. We found that feedback which directly modulated photoreceptor calcium channel activation, as opposed to changing photoreceptor voltage, provides faster adaptation to light onset and higher spatial resolution. The optimal solution suggests that the feedback gain from horizontal cells to photoreceptors should be approximately 0.5. The model can be extended to retinas that have two or more horizontal cell networks with different space constants. The theoretical predictions closely match experimental observations of outer retinal function.

[PMID: 20808894]

Schachter MJ, Oesch N, Smith RG, Taylor WR

Summary

The On-Off direction-selective ganglion cell (DSGC) in mammalian retinas responds most strongly to a stimulus moving in a specific direction. The DSGC initiates spikes in its dendritic tree, which are thought to propagate to the soma with high probability. Both dendritic and somatic spikes in the DSGC display strong directional tuning, whereas somatic PSPs (postsynaptic potentials) are only weakly directional, indicating that spike generation includes marked enhancement of the directional signal. We used a realistic computational model based on anatomical and physiological measurements to determine the source of the enhancement. Our results indicate that the DSGC dendritic tree is partitioned into separate electrotonic regions, each summing its local excitatory and inhibitory synaptic inputs to initiate spikes. Within each local region the local spike threshold nonlinearly amplifies the preferred response over the null response on the basis of PSP amplitude. Using inhibitory conductances previously measured in DSGCs, the simulation results showed that inhibition is only sufficient to prevent spike initiation and cannot affect spike propagation. Therefore, inhibition will only act locally within the dendritic arbor. We identified the role of three mechanisms that generate directional selectivity (DS) in the local dendritic regions. First, a mechanism for DS intrinsic to the dendritic structure of the DSGC enhances DS on the null side of the cell's dendritic tree and weakens it on the preferred side. Second, spatially offset postsynaptic inhibition generates robust DS in the isolated dendritic tips but weak DS near the soma. Third, presynaptic DS is apparently necessary because it is more robust across the dendritic tree. The pre- and postsynaptic mechanisms together can overcome the local intrinsic DS. These local dendritic mechanisms can perform independent nonlinear computations to make a decision, and there could be analogous mechanisms within cortical circuitry.

Taylor WR, Smith RG.

Summary

This review focuses on recent advances in our understanding of how neural divergence and convergence give rise to complex encoding properties of retinal ganglion cells. We describe the apparent mismatch between the number of cone bipolar cell types, and the diversity of excitatory input to retinal ganglion cells, and outline two possible solutions. One proposal is for diversity in the excitatory pathways to be generated within axon terminals of cone bipolar cells, and the second invokes narrow-field glycinergic amacrine cells that can apparently act like bipolar cells by providing excitatory drive to ganglion cells. Finally we highlight two advances in technique that promise to provide future insights; automation of electron microscope data collection and analysis, and the use of the ideal observer to quantitatively compare neural performance at all levels.

Trenholm S, Johnson K, Li X,Smith RG, Awatramani GB (2011)

Summary

In the retina, presynaptic inhibitory mechanisms that shape directionally selective (DS) responses in output ganglion cells are well established. However, the nature of inhibition-independent forms of directional selectivity remains poorly defined. Here, we describe a genetically specified set of ON-OFF DS ganglion cells (DSGCs) that code anterior motion. This entire population of DSGCs exhibits asymmetric dendritic arborizations that orientate toward the preferred direction. We demonstrate that morphological asym- metries along with nonlinear dendritic conductances generate a centrifugal (soma-to-dendrite) preference that does not critically depend upon, but works in parallel with the GABAergic circuitry. We also show that in symmetrical DSGCs, such dendritic DS mech- anisms are aligned with, or are in opposition to, the inhibitory DS circuitry in distinct dendritic subfields where they differentially interact to promote or weaken directional preferences. Thus, pre- and post- synaptic DS mechanisms interact uniquely in distinct ganglion cell populations, enabling efficient DS coding under diverse conditions.

Taylor WR, Smith RG. (2012)

Summary

Starburst amacrine cells (SBACs) within the adult mammalian retina provide the critical inhibition that underlies the receptive field properties of direction-selective ganglion cells (DSGCs). The SBACs generate direction-selective output of GABA that differentially inhibits the DSGCs. We review the biophysical mechanisms that produce directional GABA release from SBACs and test a network model that predicts the effects of reciprocal inhibition between adjacent SBACs. The results of the model simulations suggest that reciprocal inhibitory connections between closely spaced SBACs should be spatially selective, while connections between more widely spaced cells could be indiscriminate. SBACs were initially identified as cholinergic neurons and were subsequently shown to contain release both acetylcholine and GABA. While the role of the GABAergic transmission is well established, the role of the cholinergic transmission remains unclear.

Nikonov SS, Lyubarsky A, Fina ME, Nikonova ES, Sengupta A, Chinniah C, Ding X-Q, Smith RG, Pugh EN Jr, Vardi N, Dhingra A.

Summary

Mammalian cones respond to light by closing a cGMP-gated channel via a cascade that includes a heterotrimeric G-protein, cone transducin, comprising GAt2, GB3 and GGt2 subunits. The function of GBG in this cascade has not been examined. Here, we investigate the role of GB3 by assessing cone structure and function in GB3-null mouse (Gnb3 -/-). We found that GB3 is required for the normal expression of its partners, because in the Gnb3 -/- cone outer segments, the levels of GAt2 and GGt2 are reduced by fourfold to sixfold, whereas other components of the cascade remain unaltered. Surprisingly, Gnb3 cones produce stable responses with normal kinetics and saturating response amplitudes similar to that of the wild-type, suggesting that cone phototransduction can function efficiently without a GB subunit. However, light sensitivity was reduced by approximately fourfold in the knock-out cones. Because the reduction in sensitivity was similar in magnitude to the reduction in Gat2 level in the cone outer segment, we conclude that activation of GAt2 in Gnb3-/- cones proceeds at a rate approximately proportional to its outer segment concentration, and that activation of phosphodiesterase and downstream cascade components is normal. These results suggest that the main role of GB3 in cones is to establish optimal levels of transducin heteromer in the outer segment, thereby indirectly contributing to robust response properties.

Abbas SY, Hamade KC, Yang EJ, Nawy S, Smith RG, Pettit DL

Summary

Retinal ganglion cells receive inputs from multiple bipolar cells which must be integrated before a decision to fire is made. Theoretical studies have provided clues about how this integration is accomplished but have not directly determined the rules regulating summation of closely timed inputs along single or multiple dendrites. Here we have examined dendritic summation of multiple inputs along On ganglion cell dendrites in whole mount rat retina. We activated inputs at targeted locations by uncaging glutamate sequentially to generate apparent motion along On ganglion cell dendrites in whole mount retina. Summation was directional and dependent on input sequence. Input moving away from the soma (centrifugal) resulted in supralinear summation, while activation sequences moving toward the soma (centripetal) were linear. Enhanced summation for centrifugal activation was robust as it was also observed in cultured retinal ganglion cells. This directional summation was dependent on hyperpolarization activated cyclic nucleotide-gated (HCN) channels as blockade with ZD7288 eliminated directionality. A computational model confirms that activation of HCN channels can override a preference for centripetal summation expected from cell anatomy. This type of direction selectivity could play a role in coding movement similar to the axial selectivity seen in locust ganglion cells which detect looming stimuli. More generally, these results suggest that non-directional retinal ganglion cells can discriminate between input sequences independent of the retina network.

Puthussery T, Venkataramani S, Gayet-Primo J, Smith RG, Taylor WR

Summary

In the primate visual system, the ganglion cells of the magnocellular pathway underlie motion and flicker detection and are relatively transient, while the more sustained ganglion cells of the parvocellular pathway have comparatively lower temporal resolution, but encode higher spatial frequencies. Although it is presumed that functional differences in bipolar cells contribute to the tuning of the two pathways, the properties of the relevant bipolar cells have not yet been examined in detail. Here, by making patch-clamp recordings in acute slices of macaque retina, we show that the bipolar cells within the magnocellular pathway, but not the parvocellular pathway, exhibit voltage-gated sodium (NaV), T-type calcium (CaV), and hyperpolarization-activated, cyclic nucleotide-gated (HCN) currents, and can generate action potentials. Using immunohistochemistry in macaque and human retinae, we show that NaV1.1 is concentrated in an axon initial segment (AIS)-like region of magnocellular pathway bipolar cells, a specialization not seen in transient bipolar cells of other vertebrates. In contrast, CaV3.1 channels were localized to the somatodendritic compartment and proximal axon, but were excluded from the AIS, while HCN1 channels were concentrated in the axon terminal boutons. Simulations using a compartmental model reproduced physiological results and indicate that magnocellular pathway bipolar cells initiate spikes in the AIS. Finally, we demonstrate that NaV channels in bipolar cells augment excitatory input to parasol ganglion cells of the magnocellular pathway. Overall, the results demonstrate that selective expression of voltage-gated channels contributes to the establishment of parallel processing in the major visual pathways of the primate retina.

Smith RG, Delaney KR, Awatramani GB

Summary

The very first rays of the rising sun enrich our visual world with spectacular detail. A recent study reveals how retinal circuits downstream of photoreceptors 'functionally re-wire' to trade-off sensitivity for high spatial acuity during night-day transitions.

Trenholm S, McLaughlin AJ, Schwab DJ, Turner MH, Smith RG, Rieke F, Awatramani GB. (2014)

Summary

Throughout the CNS, gap junction-mediated electrical signals synchronize neural activity on millisecond timescales via cooperative interactions with chemical synapses. However, gap junction-mediated synchrony has rarely been studied in the context of varying spatiotemporal patterns of electrical and chemical synaptic activity. Thus, the mechanism underlying fine-scale synchrony and its relationship to neural coding remain unclear. We examined spike synchrony in pairs of genetically identified, electrically coupled ganglion cells in mouse retina. We found that coincident electrical and chemical synaptic inputs, but not electrical inputs alone, elicited synchronized dendritic spikes in subregions of coupled dendritic trees. The resulting nonlinear integration produced fine-scale synchrony in the cells' spike output, specifically for light stimuli driving input to the regions of dendritic overlap. In addition, the strength of synchrony varied inversely with spike rate. Together, these features may allow synchronized activity to encode information about the spatial distribution of light that is ambiguous on the basis of spike rate alone.

[PMID: 26063782]

Lipin, MY, Taylor WR, Smith RG. (2015)

Summary

Direction selective ganglion cells (DSGCs) respond selectively to motion towards a "preferred" direction, but much less to motion towards the opposite "null" direction. Directional signals in the DSGC depend on GABAergic inhibition, and are observed over a wide range of speeds, which precludes motion detection based on a fixed temporal correlation. A voltage-clamp analysis, using narrow bar stimuli similar in width to the receptive field center, demonstrated that inhibition to DSGCs saturates rapidly above a threshold contrast. However, for wide bar stimuli that activate both the center and surround, inhibition depends more linearly on contrast. Excitation for both wide and narrow bars was also more linear. We propose that positive feedback, likely within the starburst amacrine cell or its network, produces steep saturation of inhibition at relatively low contrast, which renders GABA-release essentially contrast and speed invariant, and thereby enhances the signal-to-noise ratio for direction selective signals in the spike train over a wide range of stimulus conditions. This mechanism enhances directional signals at the expense of lower sensitivity to other stimulus features such as contrast and speed. This renders GABA-release essentially contrast and speed invariant, which enhances directional signals for small objects, and thereby increases the signal-to-noise ratio for direction selective signals in the spike train over a wide range of stimulus conditions. The steep saturation of inhibition confers to a neuron immunity to noise in its spike train because when inhibition is strong, no spikes are initiated.

Stincic T, Smith RG, Taylor WR. (2016)

Summary

Direction selectivity in the retina relies critically on directionally asymmetric GABA release from the dendritic tips of starburst amacrine cells (SBACs). GABA release from each radially directed dendrite is larger for motion outward from the soma toward the dendritic tips than for motion inwards toward the soma. The biophysical mechanisms generating these directional signals remain controversial. A model based on electron-microscopic reconstructions of the mouse retina proposed that an ordered arrangement of kinetically distinct bipolar cell inputs to ON and OFF type SBACs could produce directional GABA release. We tested this prediction by measuring the time-course of EPSCs in ON type SBACs in the mouse retina, activated by proximal and distal light stimulation. Contrary to the prediction, the kinetics of the excitatory inputs were independent of dendritic location. Computer simulations based on 3D reconstructions of SBAC dendrites demonstrated that the response kinetics of distal inputs were not significantly altered by dendritic filtering. These direct physiological measurements, do not support the hypothesis that directional signals in SBACs arise from the ordered arrangement of kinetically distinct bipolar cell inputs.

Ding H, Smith RG, Poleg-Polsky A, Diamond JS, Briggman KL. (2016)

Summary

Directionally tuned signaling in starburst amacrine cell (SAC) dendrites lies at the heart of the direction selective (DS) circuit in the mammalian retina. The relative contributions of intrinsic cellular properties and network connectivity to SAC DS remain unclear. We present a detailed connectomic reconstruction of SAC circuitry in mouse retina and describe previously unknown features of synapse distributions along SAC dendrites: 1) input and output synapses are segregated, with inputs restricted to proximal dendrites; 2) the distribution of inhibitory inputs is fundamentally different from that observed in rabbit retina. An anatomically constrained SAC network model suggests that SAC-SAC wiring differences between mouse and rabbit retina underlie distinct contributions of synaptic inhibition to velocity and contrast tuning and receptive field structure. In particular, the model indicates that mouse connectivity enables SACs to encode lower linear velocities that account for smaller eye diameter, thereby conserving angular velocity tuning. These predictions are confirmed with calcium imaging of mouse SAC dendrites in response to directional stimuli.

Percival KA, Venkataramani S, Smith RG, Taylor WR (2019)

Summary

Directional responses in retinal ganglion cells are generated in large part by direction-selective release of GABA from starburst amacrine cells onto direction-selective ganglion cells (DSGCs). The excitatory inputs to DSGCs are also widely reported to be direction-selective, however, recent evidence suggests that glutamate release from bipolar cells is not directional, and directional excitation seen in patch-clamp analyses may be an artifact resulting from incomplete voltage control. Here we test this voltage-clamp-artifact hypothesis in recordings from 62 On-Off DSGCs in the rabbit retina. The strength of the directional excitatory signal varies considerably across the sample of cells, but is not correlated with the strength of directional inhibition, as required for a voltage-clamp artifact. These results implicate additional mechanisms in generating directional excitatory inputs to DSGCs.

Krizaj D, Smith RG (2017)

doi:10.1016/B978-0-12-809324-5.01516-9

Summary

The rod photoreceptor is responsible for vision at night over the range of starlight through moonlight to twilight. Its structure is specialized to maximize photon capture, optimize metabolic efficiency and sustain continual synaptic activation. Rods are depolarized in the darkness, the light signal induced by capture of photons consists of a hyperpolarization that lowers the concentration of intracellular calcium ions within the rod terminal and suppresses release of the rod neurotransmitter glutamate. Mutations that change rod morphology, calcium signaling and/or glutamate release may compromise their viability and cause blindness.

Howlett MH, Smith RG, Kamermans M(2017)

Summary

An animal's ability to survive depends on its sensory systems being able to adapt to a wide range of environmental conditions, by maximizing the information extracted and reducing the noise transmitted. The visual system does this by adapting to luminance and contrast. While luminance adaptation can begin at the retinal photoreceptors, contrast adaptation has been shown to start at later stages in the retina. Photoreceptors adapt to changes in luminance over multiple time scales ranging from tens of milliseconds to minutes, with the adaptive changes arising from processes within the phototransduction cascade. Here we show a new form of adaptation in cones that is independent of the phototransduction process. Rather, it is mediated by voltage-gated ion channels in the cone membrane and acts by changing the frequency response of cones such that their responses speed up as the membrane potential modulation depth increases and slow down as the membrane potential modulation depth decreases. This mechanism is effectively activated by high-contrast stimuli dominated by low frequencies such as natural stimuli. However, the more generally used Gaussian white noise stimuli were not effective since they did not modulate the cone membrane potential to the same extent. This new adaptive process had a time constant of less than a second. A critical component of the underlying mechanism is the hyperpolarization-activated current, Ih, as pharmacologically blocking it prevented the long- and mid- wavelength sensitive cone photoreceptors (L- and M-cones) from adapting. Consistent with this, short- wavelength sensitive cone photoreceptors (S-cones) did not show the adaptive response, and we found they also lacked a prominent Ih. The adaptive filtering mechanism identified here improves the information flow by removing higher-frequency noise during lower signal-to-noise ratio conditions, as occurs when contrast levels are low. Although this new adaptive mechanism can be driven by contrast, it is not a contrast adaptation mechanism in its strictest sense, as will be argued in the Discussion.

Borghuis BG, Ratliff CP, Smith RG (2018)

Summary

A persistent change in illumination causes light-adaptive changes in retinal neurons. Light adaptation improves visual encoding by preventing saturation, and by adjusting spatio-temporal integration to increase the signal-to-noise ratio (SNR) and utilize signaling bandwidth efficiently. In dim light, the visual input contains a greater relative amount of quantal noise and vertebrate receptive fields are extended in space and time to increase SNR. While in bright light SNR of the visual input is high, the rate of synaptic vesicle release from the photoreceptors is low so that quantal noise in synaptic output may limit SNR postsynaptically. Whether and how reduced synaptic SNR impacts spatio-temporal integration in postsynaptic neurons remains unclear. To address this, we measured spatio-temporal integration in retinal horizontal cells and ganglion cells in the guinea pig retina across a broad illumination range, from low to high-photopic. In both cell types, the extent of spatial and temporal integration changed according to an inverted U-shaped function consistent with adaptation to low SNR at both low and high light levels. We show how a simple mechanistic model with interacting, opponent filters can generate the observed changes in ganglion cell spatio-temporal receptive fields across light-adaptive states and postulate that retinal neurons postsynaptic to the cones in bright light adopt low-pass spatio-temporal response characteristics to improve visual encoding under conditions of low synaptic SNR.

Bligard GW, DeBrecht J, Smith RG, Lukasiewicz PD (2020)

Summary

In the retina, modulation of the amplitude of dim visual signals primarily occurs at axon terminals of rod bipolar cells (RBCs). These effects are largely facilitated by GABA and glycine inhibitory neurotransmitter receptors and the excitatory amino acid transporter 5 (EAAT5). EAATs clear glutamate from the synapse, but they also have a glutamate-gated chloride conductance. EAAT5, in particular, acts primarily as an inhibitory glutamate-gated chloride channel. The relative role of visually-evoked EAAT5 inhibition compared to GABA and glycine inhibition has not been addressed. In this study, we determine the contribution of EAAT5-mediated inhibition onto RBCs in response to light stimuli in mouse retinal slices. We find differences and similarities in the two forms of inhibition. Our results show that GABA and glycine mediate nearly all lateral inhibition onto RBCs, as EAAT5 is solely a mediator of RBC feedback inhibition. We also find that EAAT5 and conventional GABA inhibition both contribute to feedback inhibition at all stimulus intensities. Finally, our in silico modeling compares and contrasts EAAT5-mediated to GABA- and glycine-mediated feedback inhibition. Both forms of inhibition have a substantial impact on synaptic transmission to the downstream AII amacrine cell. Our results suggest that the late phase EAAT5 inhibition acts with the early phase conventional, reciprocal inhibition to modulate the rod signaling pathway between rod bipolar cells and their downstream synaptic targets.

Oesterle J, Behrens C, Schröder C, Hermann T, Euler T, Franke K, Smith RG, Zeck G, Berens P. (2020)

Summary

While multicompartment models have long been used to study the biophysics of neurons, it is still challenging to infer the parameters of such models from data including uncertainty estimates. Here, we performed Bayesian inference for the parameters of detailed neuron models of a photoreceptor and an OFF- and an ON-cone bipolar cell from the mouse retina based on two-photon imaging data. We obtained multivariate posterior distributions specifying plausible parameter ranges consistent with the data and allowing to identify parameters poorly constrained by the data. To demonstrate the potential of such mechanistic data-driven neuron models, we created a simulation environment for external electrical stimulation of the retina and optimized stimulus waveforms to target OFF- and ON-cone bipolar cells, a current major problem of retinal neuroprosthetics.

Chen Q, Smith RG, Huang X, Wei W (2020)

Summary

Previously, we found that in the mammalian retina, inhibitory inputs onto starburst amacrine cells (SACs) are required for robust direction selectivity of On-Off direction-selective ganglion cells (On-Off DSGCs) against noisy backgrounds (Chen et al., 2016). However, the source of the inhibitory inputs to SACs and how this inhibition confers noise resilience of DSGCs are unknown. Here, we show that when visual noise is present in the background, the motion-evoked inhibition to an On-Off DSGC is preserved by a disinhibitory motif consisting of a serially connected network of neighboring SACs presynaptic to the DSGC. This preservation of inhibition by a disinhibitory motif arises from the interaction between visually evoked network dynamics and short-term synaptic plasticity at the SAC-DSGC synapse. While the disinhibitory microcircuit is well studied for its disinhibitory function in brain circuits, our results highlight the algorithmic flexibility of this motif beyond disinhibition due to the mutual influence between network and synaptic plasticity mechanisms.

Hellmer CB, Hall LM, Bohl JM, Sharpe ZJ, Smith RG, Ichinose T (2021)

Summary

Retinal bipolar cells are second-order neurons that transmit basic features of the visual scene to postsynaptic partners. However, their contribution to motion detection has not been fully appreciated. Here, we demonstrate that cholinergic feedback from starburst amacrine cells (SACs) to certain presynaptic bipolar cells via alpha-7 nicotinic acetylcholine receptors (alpha-7-nAChRs) promotes direction-selective signaling. Patch clamp recordings reveal that distinct bipolar cell types making synapses at proximal SAC dendrites also express alpha-7-nAChRs, producing directionally skewed excitatory inputs. Asymmetric SAC excitation contributes to motion detection in On-Off direction-selective ganglion cells (On-Off DSGCs), predicted by computational modeling of SAC dendrites and supported by patch clamp recordings from On-Off DSGCs when bipolar cell alpha-7-nAChRs is eliminated pharmacologically or by conditional knockout. Altogether, these results show that cholinergic feedback to bipolar cells enhances direction-selective signaling in postsynaptic SACs and DSGCs, illustrating how bipolar cells provide a scaffold for postsynaptic microcircuits to cooperatively enhance retinal motion detection.

Behrens C, Yadav SC, Korympidou MM, Zhang Y, Haverkamp S, Irsen S, Schaedler A, Lu X, Liu Z, Lause J, St-Pierre F, Franke K, Vlasits A, Dedek K, Smith RG, Euler T, Berens P, Schubert T (2021)

Summary

In the outer plexiform layer (OPL) of the mammalian retina, cone photoreceptors (cones) provide input to more than a dozen types of cone bipolar cells (CBCs). In the mouse, this transmission is modulated by a single horizontal cell (HC) type. HCs perform global signaling within their laterally coupled network but also provide local, cone-specific feedback. However, it is unknown how HCs provide local feedback to cones at the same time as global forward signaling to CBCs and where the underlying synapses are located. To assess how HCs simultaneously perform different modes of signaling, we reconstructed the dendritic trees of five HCs as well as cone axon terminals and CBC dendrites in a serial block-face electron microscopy volume and analyzed their connectivity. In addition to the fine HC dendritic tips invaginating cone axon terminals, we also identified "bulbs," short segments of increased dendritic diameter on the primary dendrites of HCs. These bulbs are in an OPL stratum well below the cone axon terminal base and make contacts with other HCs and CBCs. Our results from immunolabeling, electron microscopy, and glutamate imaging suggest that HC bulbs represent GABAergic synapses that do not receive any direct photoreceptor input. Together, our data suggest the existence of two synaptic strata in the mouse OPL, spatially separating cone-specific feedback and feedforward signaling to CBCs. A biophysical model of a HC dendritic branch and voltage imaging support the hypothesis that this spatial arrangement of synaptic contacts allows for simultaneous local feedback and global feedforward signaling by HCs.

Jain V, Hanson L, Sethuramanujam S, Michaels T, Gawley J, Gregg RG, Pyle I, Zhang C, Smith RG, Berson D, McCall MA, Awatramani GB (2022)

Summary

In the retina, ON starburst amacrine cells (SACs) play a crucial role in the direction-selective circuit, but the sources of inhibition that shape their response properties remain unclear. Previous studies demonstrate that ~95% of their inhibitory synapses are GABAergic, yet we find that the light-evoked inhibitory currents measured in SACs are predominantly glycinergic. Glycinergic inhibition is extremely slow, relying on non-canonical glycine receptors containing alpha4 subunits, and is driven by both the ON and OFF retinal pathways. These attributes enable glycine inputs to summate and effectively control the output gain of SACs, expanding the range over which they compute direction. Serial electron microscopic reconstructions reveal three specific types of ON and OFF narrow-field amacrine cells as the presumptive sources of glycinergic inhibition. Together, these results establish an unexpected role for specific glycinergic amacrine cells in the retinal computation of stimulus direction by SACs.

Kim YJ, Peterson BB, Crook JD, Joo HR, Wu J, Puller C, Robinson FR, Gamlin PD, Yau K-W, Viana F, Troy JB, Smith RG, Packer OS, Detwiler PB, Dacey DM (2022)

Summary

From mouse to primate, there is a striking discontinuity in our current understanding of the neural coding of motion direction. In non-primate mammals, directionally selective cell types and circuits are a signature feature of the retina, situated at the earliest stage of the visual process. In primates, by contrast, direction selectivity is a hallmark of motion processing areas in visual cortex, but has not been found in the retina, despite significant effort. Here we combined functional recordings of light-evoked responses and connectomic reconstruction to identify diverse direction-selective cell types in the macaque monkey retina with distinctive physiological properties and synaptic motifs. This circuitry includes an ON-OFF ganglion cell type, a spiking, ON-OFF polyaxonal amacrine cell and the starburst amacrine cell, all of which show direction selectivity. Moreover, we discovered that macaque starburst cells possess a strong, non-GABAergic, antagonistic surround mediated by input from excitatory bipolar cells that is critical for the generation of radial motion sensitivity in these cells. Our findings open a door to investigation of a precortical circuitry that computes motion direction in the primate visual system.

Huang X, Kim AJ, Ledesma HA, Ding J, Smith RG, Wei W (2022)

Summary

Experience-dependent modulation of neuronal responses is a key attribute in sensory processing. In the mammalian retina, the On-Off direction-selective ganglion cell (DSGC) is well known for its robust direction selectivity. However, how the On-Off DSGC light responsiveness dynamically adjusts to the changing visual environment is underexplored. Here, we report that On-Off DSGCs tuned to posterior motion direction [i.e. posterior DSGCs (pDSGCs)] in mice of both sexes can be transiently sensitized by prior stimuli. Notably, distinct sensitization patterns are found in dorsal and ventral pDSGCs. Although responses of both dorsal and ventral pDSGCs to dark stimuli (Off responses) are sensitized, only dorsal cells show the sensitization of responses to bright stimuli (On responses). Visual stimulation to the dorsal retina potentiates a sustained excitatory input from Off bipolar cells, leading to tonic depolarization of pDSGCs. Such tonic depolarization propagates from the Off to the On dendritic arbor of the pDSGC to sensitize its On response. We also identified a previously overlooked feature of DSGC dendritic architecture that can support dendritic integration between On and Off dendritic layers bypassing the soma. By contrast, ventral pDSGCs lack a sensitized tonic depolarization and thus do not exhibit sensitization of their On responses. Our results highlight a topographic difference in Off bipolar cell inputs underlying divergent sensitization patterns of dorsal and ventral pDSGCs. Moreover, substantial crossovers between dendritic layers of On-Off DSGCs suggest an interactive dendritic algorithm for processing On and Off signals before they reach the soma.

Wu J, Kim YJ, Dacey DM, Troy JB, Smith, RG (2023)

Abstract

In a recent study, visual signals were recorded for the first time in starburst amacrine cells of the macaque retina, and, as for mouse and rabbit, a directional bias observed in calcium signals was recorded from near the dendritic tips. Stimulus motion from the soma toward the tip generated a larger calcium signal than motion from the tip toward the soma. Two mechanisms affecting the spatiotemporal summation of excitatory postsynaptic currents have been proposed to contribute to directional signaling at the dendritic tips of starbursts: (1) a "morphological" mechanism in which electrotonic propagation of excitatory synaptic currents along a dendrite sums bipolar cell inputs at the dendritic tip preferentially for stimulus motion in the centrifugal direction; (2) a "space-time" mechanism that relies on differences in the time-courses of proximal and distal bipolar cell inputs to favor centrifugal stimulus motion. To explore the contributions of these two mechanisms in the primate, we developed a realistic computational model based on connectomic reconstruction of a macaque starburst cell and the distribution of its synaptic inputs from sustained and transient bipolar cell types. Our model suggests that both mechanisms can initiate direction selectivity in starburst dendrites, but their contributions differ depending on the spatiotemporal properties of the stimulus. Specifically, the morphological mechanism dominates when small visual objects are moving at high velocities, and the space-time mechanism contributes most for large visual objects moving at low velocities.

Smith RG (2018)

http://dx.doi.org/10.1016/b978-0-12-809324-5.21547-2

Summary

Photoreceptors are the vertebrate retina's primary site for transduction of light into a neural signal. The cone photoreceptor plays a crucial role in daylight vision because it transmits fast changes in light contrast. To improve its sensitivity over 5 log units of background illumination, the cone contains several mechanisms for adaptation: the transduction cascade, biophysical properties, and in the ribbon synapse. The ribbon is part of a complex local circuit called the triad that combines adaptation with spatial filtering to maximize the amount of information the cone transmits to second-order neurons.

https://doi.org/10.1016/B978-0-443-13820-1.00045-1

Summary

Photoreceptors are the vertebrate retina's primary site for transduction of light into a neural signal. The cone photoreceptor plays a crucial role in daylight vision because it transmits fast changes in light contrast. To improve its sensitivity over 5 log units of background illumination, the cone contains several mechanisms for adaptation: the transduction cascade, biophysical properties, and in the ribbon synapse. The ribbon is part of a complex local circuit called the triad that combines adaptation with spatial filtering to maximize the amount of information the cone transmits to second-order neurons.

https://doi.org/10.1016/B978-0-443-13820-1.00044-X

Summary

The rod photoreceptor is responsible for vision at night over the range of starlight through moonlight to twilight. In starlight, the rod receives a photon about once in 20 min, requiring spatial summation, but this would amplify the dark noise if the visual pathway were linear. The rod synapse is specialized to transmit single-photon signals by removing the dark continuous noise with a threshold nonlinearity. At twilight, the rod receives more than one photon per integration time (~200 ms in mammals) and thus cannot transmit single-photon signals. Instead, its signals at twilight are coupled to cones through gap junctions.