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Previous Article | Next Article
The Journal of Neuroscience, April 1, 2003, 23(7):2645
Different Circuits for ON and OFF Retinal Ganglion Cells Cause Different Contrast Sensitivities
Kareem A. Zaghloul1, Kwabena Boahen2, and Jonathan B. Demb1 Departments of 1 Neuroscience and 2 Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6058
ABSTRACT
TOP
ABSTRACT
Introduction
The theory of "parallel pathways" predicts that, except for a sign reversal, ON and OFF ganglion cells are driven by a similar presynaptic circuit. To test this hypothesis, we measured synaptic inputs to ON and OFF cells as reflected in the subthreshold membrane potential. We made intracellular recordings from brisk-transient (Y) cells in the in vitro guinea pig retina and show that ON and OFF cells in fact express significant asymmetries in their synaptic inputs. An ON cell receives relatively linear input that modulates a single excitatory conductance; whereas an OFF cell receives rectified input that modulates both inhibitory and excitatory conductances. The ON pathway, blocked by L-AP-4, tonically inhibits an OFF cell at mean luminance and phasically inhibits an OFF cell during a light increment. Our results suggest that basal glutamate release is high at ON but not OFF bipolar terminals, and inhibition between pathways is unidirectional: ON
OFF. These circuit asymmetries explain asymmetric contrast sensitivity observed in spiking behavior.
Key words: white noise; linear-nonlinear model; receptive field center; APB; photopic vision;
cell
Introduction
ON and OFF ganglion cells form parallel pathways whose signals are relayed through the lateral geniculate nucleus (LGN) of the thalamus and ultimately converge onto the same cortical cell (Schiller, 1992
). The balance between ON and OFF cells can be disturbed by injecting L-AP-4 into the eye to hyperpolarize ON bipolar cells and therefore to block the output of ON ganglion cells (Shiells et al., 1981
A common assumption is that ON and OFF pathways are opposite in sign but otherwise equal in kinetics and sensitivity, i.e., truly "parallel." Consistent with the "parallel pathways" notion, ON and OFF cells of a given type (e.g., brisk-transient) show similar kinetics in their impulse response function (Devries and Baylor, 1997
Our goal was to discover the cellular mechanisms that cause the asymmetry in ON and OFF cell contrast sensitivity. We measured synaptic inputs to ganglion cells as reflected in the subthreshold membrane potential; these voltage measurements are influenced by intrinsic properties, but we expect little or no difference between ON and OFF cell intrinsic properties (O'Brien et al., 2002
Materials and Methods
Intracellular recording. From a guinea pig anesthetized with ketamine (100 mg/kg), xylazine (20 mg/kg), and pentobarbital (150 mg/kg), both eyes were removed, after which the animal was killed by anesthetic overdose (in accordance with University of Pennsylvania and National Institutes of Health guidelines). The whole retina, including the pigment epithelium, choroid, and sclera, was mounted flat in a chamber on a microscope stage. Retina was superfused (~4 ml/min) with oxygenated (95% O and 5% CO2) Ames medium (Sigma, St. Louis, MO) at 32-36°C. A glass electrode (tip resistance, 80-200 M
), filled with 1% pyranine (Molecular Probes, Eugene, OR) in 2 M potassium acetate, was used to penetrate the largest somas (diameter, 20-25 µm) in the visual streak, 2.6 ± 0.9 mm (mean ± SD) from the optic disk. L-2-Amino-4-phosphonobutyric acid (L-AP-4) and lidocaine N-ethyl bromide (QX-314) were purchased from Research Biochemicals (Natick, MA).
Membrane potential was amplified, continuously sampled at 5 kHz, and stored on computer as previously described (Demb et al., 1999
Visual stimulus. The stimulus was displayed on a miniature monochrome computer monitor (Lucivid MR1-103; Microbrightfield, Colchester, VT) projected through the top port of the microscope through a 2.5× objective and focused on the photoreceptors (mean luminance, ~105 isomerizations/cone/sec; resolution, 852 × 480 pixels; 60Hz vertical refresh). The relationship between gun voltage and monitor intensity was linearized in software with a look-up table. Light and dark flashes were defined by Weber contrast: (Iflash
Imean)/Imean, where Iflash is the flash intensity, and Imean is the luminance of the gray screen between flashes, set at the middle of the intensity range (i.e., contrast range,
White noise stimulus and analysis. To characterize the temporal response of a cell and to measure contrast sensitivity, we used a 2 min white noise modulation of a 500-µm-diameter spot centered over the cell body (Fig. 1) (Marmarelis and Marmarelis, 1978
We analyzed the response using a linear-nonlinear (L-NL) model described in detail previously (Fig. 1) (Victor, 1987
In several cells, we formally tested the predictive value of the model (n = 4 ON and 6 OFF cells). We first constructed an L-NL model for the cell, based on the response to a 2 min stimulus, and then used the model to predict the response to a 5 sec stimulus (repeated 20 times). For comparison with future studies, we offer two benchmarks of how well the model performs. One benchmark is the correlation between the average response to the 5 sec trial (averaged to reduce noise) and the predicted 5 sec response from the model; this represents the amount of variance explained by the model. For spikes, r2 = 0.67 ± 0.04 (mean ± SEM; best case, r2 = 0.79); for membrane potential, r2 = 0.88 ± 0.02 (best case, r2 = 0.95). A second benchmark is the predictability of a single trial response based on the maximum likelihood estimate (i.e., the average of the other 19 trials or "repeat prediction") versus the model prediction (Chichilnisky, 2001
We assumed that the L filter primarily reflects the response in presynaptic neurons and should therefore not be affected by polarizing the ganglion cell with current (Rieke, 2001
Current injection. In some experiments, steady current was injected through the pipette to determine whether responses were driven primarily by EPSPs (i.e., responses would decrease with depolarizing current and vice versa) or IPSPs (i.e., responses would increase with depolarizing current and vice versa). In most of these experiments, QX-314 (50 mM) was added to the pipette solution to block action potentials that would obscure the membrane response (Connors and Prince, 1982
While injecting current, we measured the membrane potential and a light response (deviation from baseline). We fit a line (linear regression) through the membrane potential versus response plot and estimated the reversal potential as the x-intercept (see below). Using sharp electrodes, one polarizes the soma and central dendrites to a greater extent than the peripheral dendrites. Thus, to interpret the measured reversal potentials, several points are worth considering. First, synaptic inputs to a ganglion cell lie on the dendrites, not the soma, and the distribution of dendritic membrane is "dome-like" with most membrane concentrated near the soma (Kier et al., 1995
Results
Basic properties of ON and OFF cells
From the visual streak, we recorded from 17 ON and 30 OFF brisk-transient (Y) cells. All showed the signature properties: a center-surround receptive field and a frequency-doubled spiking response to a contrast-reversing grating (see Materials and Methods; Enroth-Cugell and Robson, 1966
White noise stimulation and analysis quantifies the temporal and contrast sensitivity of a cell
We presented a spot modulated with intensities drawn from a Gaussian distribution (white noise; see Materials and Methods). In response, the membrane potential of a cell fluctuated about Vrest with ~50-100 msec depolarizations and single spikes or bursts of spikes riding on the depolarizations (Fig. 1A). We analyzed the response, separately for membrane potential and spikes, using a model that includes two stages: an L filter followed by a static (or instantaneous) NL (L-NL model; see Materials and Methods; Victor, 1987
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Figure 1. White noise stimulation and analysis. A, A spot covering the receptive field center of a cell modulated with intensities drawn from a Gaussian distribution (white noise; 16.7 msec frame). The top trace shows 300 msec of baseline response followed by 1 sec of white noise response. The bottom trace shows the 1 sec white noise response after removing spikes and filtering (see Materials and Methods). B, An L-NL model was used to analyze the response to white noise. Stimulus is convolved with a L filter to generate an L model of the response. The L model is passed through a static nonlinearity to generate an L-NL model of the response. The L filter reflects the temporal sensitivity of a cell; the NL function reflects the contrast sensitivity of a cell (see Results). Analysis was performed separately for subthreshold voltages (membrane) and spike rate (spikes). For comparison with the L-NL model, membrane and spike traces are average responses to 20 repeats (averaged to reduce noise; 700 msec shown of a 5 sec stimulus presentation). Filter units are in millivolt contrast per second (membrane filter) or spike rate contrast per second (spike filter). sp, Spikes.
Under our conditions (photopic mean luminance and high contrast), the average ON and OFF L filters were opposite in sign but otherwise nearly equal (Fig. 2A,B), as shown previously (Devries and Baylor, 1997
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Figure 2. Relative to an ON cell, an OFF cell receives more rectified synaptic input and transmits more rectified spike output. A, Membrane L filter and NL function for representative cells and the populations. The NL function of the ON cell reaches positive and negative amplitudes of similar extents, whereas that of the OFF cell reaches a maximum negative amplitude that is only half the maximum positive amplitude (i.e., rectification). For the L filter, response amplitude is normalized to the peak of the primary lobe (+1 for ON and -1 for OFF). For the NL input-output function, input is normalized from -1 to + 1; output is normalized so that the predicted response at 0 contrast is 0, and the maximum depolarization is 1. For single-cell NL functions, circles represent binned data points; the solid line represents a fit (see Materials and Methods). The shaded area around the average NL function represents ±SEM. An ON cell was slightly but significantly more biphasic (amplitude of peak to undershoot) than an OFF cell for both spike and membrane responses (p <0.05). B, Same format as in A for spikes. At low contrast (i.e., small values of input), an ON cell is nearly linear, whereas an OFF cell is strongly rectified. For both an ON and OFF cell, the spike L filter was more biphasic than the membrane L filter (p <0.01), consistent with high-pass filtering (Lankheet et al., 1989
Relative to an ON cell, an OFF cell receives more rectified synaptic input and transmits more rectified spike output
For both spikes and membrane potential, ON and OFF cells express distinct contrast sensitivities, as measured in the NL function. Key differences are observed at low contrast, reflected by moderate input levels (
To compare differences in absolute response range, we plotted the average NL function with original units of output (millivolts or spikes per second). For both membrane potential and spikes, an OFF cell uses a wider response range (Fig. 2C). Thus, an OFF cell requires relatively high contrast to begin spiking, but its range of voltage responses (13.7 ± 0.8, mean ± SEM) is higher than for an ON cell (9.1 ± 1.2 mV; p < 0.01), and its peak spike rate (120 ± 11 Hz) is higher than for an ON cell (71 ± 9 Hz; p < 0.01).
Across all cells, the membrane NL index correlated with the spike NL index. The correlation was significant when comparing the slopes at many ranges of input for the NL function; one representative range is plotted here, +0.5 to
Response to a brief contrast flash is more rectifying for an OFF cell than for an ON cell
We took a second approach to compare ON and OFF cell rectification using a stimulus and analysis that did not require a model. Relative to a gray background, a spot over the dendritic tree was flashed for a single frame (16.7 msec) at each of several positive and negative contrasts spanning the full range (Fig. 3). The initial response, before the onset of adaptational processes, should reflect the instantaneous response gain. We took the average response at 33-50 msec, but a similar result was obtained when plotting other ranges (e.g., 17-50, 17-67, and 33-67 msec).
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Figure 3. Response to a brief flash confirms that an OFF cell rectifies more than an ON cell. A, Flash response of a representative ON and OFF cell. Traces at top show the membrane response to light flashes increasing to twice the mean luminance (thin lines) and dark flashes decreasing to 0 (thick lines). Poststimulus time histograms at bottom show the corresponding spike response. The contrast-response function of each cell is shown (inset, responses averaged over a 33-50 msec time window indicated by the gray stripe; average of 15 flashes for both cells; stimulus was a 500-µm-diameter spot). B, Population contrast-response functions for normalized membrane potential and spike rate (mean ± SEM). Responses were normalized to the peak depolarization or spike rate. For comparison, population NL functions from Figure 2 are superimposed (line with shaded area). sp, Spikes.
An ON cell responded nearly linearly in its membrane potential, whereas an OFF cell responded with strong rectification at hyperpolarizing responses (Fig. 3A). Both cells responded with rectification in the spike rate, but an OFF cell responded with stronger rectification (Fig. 3A). The population analysis gave the same result (Fig. 3B). Furthermore, the population responses resemble the population NL functions from the white noise experiment (Fig. 2A,B). We conclude that an OFF cell rectifies more than an ON cell in both its synaptic input and its spike output.
We next analyzed the responses at low contrast to quantify differences between ON and OFF cell spike rates and to assess their relative abilities to signal differences from the baseline response at mean luminance (n = 6 for ON and OFF; Fig. 3). At the smallest contrast of optimal sign (+0.2 for ON and -0.2 for OFF), an ON cell fired spikes at a higher rate (36 ± 5 Hz, mean ± SEM) than an OFF cell (8 ± 3; p < 0.001). At the smallest increment (+0.2), an ON cell responded significantly above its baseline response (increase of 27 ± 7 Hz; p < 0.02); at the smallest decrement (-0.2), an ON cell responded significantly below baseline (decrease of 3 ± 1 Hz; p < 0.05). At the smallest decrement, an OFF cell responded not significantly differently from baseline (increase of 5 ± 2 Hz; p < 0.10, trend); at the next largest decrement (-0.4) an OFF cell responded significantly above baseline (increase of 44 ± 15 Hz; p < 0.05). At the lowest increment (+0.2), an OFF cell responded no differently from baseline (decrease of 0 ± 1 Hz; p > 0.10). Thus, an ON cell could signal a small increment or decrement in light intensity, whereas an OFF cell could only weakly signal a small decrement.
ON and OFF cell differences in rectification of synaptic input correspond to different mechanisms for inhibition
Greater rectification in an OFF cell can be explained by a relatively weak hyperpolarizing response. This suggests a possible difference in inhibitory mechanisms between an ON and OFF cell. To investigate this, we measured a hyperpolarizing light response while injecting steady current and estimated whether hyperpolarization is related to direct or indirect inhibition (Belgum et al., 1982
If the hyperpolarizing light response was caused by direct inhibition (opening a Cl
or K+ channel), injecting negative current should reduce the response, because driving force decreases, and positive current should enhance the response, because driving force increases. Direct inhibition was observed in an OFF cell to a 100 msec light flash, with estimated reversal negative to Vrest (Fig. 4A). However, an ON cell received indirect inhibition (i.e., reduced excitation); negative current increased the hyperpolarizing response to a dark flash, with estimated reversal positive to Vrest (Fig. 4A). In both cells, the depolarizing light response reversed positive to Vrest, consistent with direct excitation (Fig. 4A).
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Figure 4. Mechanism for inhibition is indirect for an ON cell but direct for an OFF cell. A, Response to a 100 msec flash of positive (1.0) or negative (-1.0) contrast was measured while injecting steady hyperpolarizing (hyp) or depolarizing (dep) current. The baseline membrane potential is plotted versus the peak of the depolarizing light response or the trough of the hyperpolarizing light response (averaged over 10 msec; gray stripe). For the ON cell, both the depolarizing response and hyperpolarizing response have apparent reversal positive to Vrest (approximately -20 mV). For the OFF cell, the depolarizing response reverses positive to Vrest (-40 mV), whereas the hyperpolarizing response reverses negative to Vrest (-100 mV). Numbers below the trace indicate membrane potential (in millivolts) before the stimulus in the depolarized (bold) and hyperpolarized condition. Dashed lines indicate linear regression. For the OFF cell, the recording electrode contained QX-314. B, White noise response was measured in a control condition (con) or while injecting steady hyperpolarizing current (hyp). For membrane NL function, the arrow indicates the direction of the effect of hyperpolarizing current on the hyperpolarizing light response (negative values of input axis). The effect of hyperpolarizing current on the membrane NL function was consistent with indirect inhibition in an ON cell but direct inhibition in an OFF cell (see Results). For the OFF cell, the control curve was measured with depolarizing current to enhance the effect of hyperpolarizing current. In both cells, hyperpolarizing current caused a rightward shift in the spike NL function, increasing output rectification. Insets show the corresponding L filter, which was normalized after injecting current to match the control peak amplitude (see Mateials and Methods). sp, Spikes.
We tested whether ON and OFF cells differed in their pattern of estimated reversal for inhibition: reversal positive to Vrest (four of four ON and zero of nine OFF cells) or negative to Vrest (zero of four ON and nine of nine OFF cells). A
2 test of independence showed a significant effect (p < 0.01). From the best cells (i.e., most data points and greatest stability), we estimate the following reversal potentials for the hyperpolarizing response: ON cell, -20.4 ± 6.4 (mean ± SEM; n = 3); and OFF cell, -95.0 ± 6.5 (n = 7). ON and OFF cells showed a similar reversal for the depolarizing response: ON cell, -11.4 ± 0.6 mV; and OFF cell, -20.8 ± 11.0. We observed the same pattern of results when we injected current and measured the depolarizing and hyperpolarizing responses to a 1 Hz step response (n = 2 ON cells and 2 OFF cells; data not shown). Input resistances of ON cells (27.1 ± 6.1 M
To further confirm the basic observation regarding different mechanisms for inhibition in an ON and OFF cell, we performed a similar experiment using white noise. We used standard electrodes (i.e., without QX-314) so we could measure the effect on spiking. For an ON cell, negative current increased the hyperpolarizing response (i.e., left side of the membrane NL function; n = 2; Fig. 4B), whereas for an OFF cell, negative current decreased the hyperpolarizing response (n = 3; Fig. 4B). Thus, these measurements confirm that the reversal potential for hyperpolarizing light responses is positive to Vrest for the ON cell but negative to Vrest for the OFF cell.
Polarizing the cell altered rectification of spiking responses
For an ON cell, hyperpolarizing current caused an increase in rectification at low contrast in the spike NL function (n = 2; Fig. 4B). This rectification in spikes occurred even though the membrane NL function remained nearly linear. Similarly, for the OFF cell, hyperpolarizing current caused an increase in rectification in the spike NL function (n = 3; Fig. 4B). A similar result was observed in an OFF cell when measuring responses to brief flashes of various contrast; the rectification in spike output at low contrast was reduced by injecting depolarizing current and raising the maintained discharge (n = 4; data not shown). Thus, simply altering the Vrest of a cell by injecting current could strongly influence rectification in the spike output of the cell. The increased rectification in spike output at slightly hyperpolarized potentials suggests that there does not exist a strong adaptive mechanism to bring the maintained spike rate to the same level regardless of a small (<5 mV) change in membrane potential.
Evidence that the hyperpolarizing response of an ON cell depends on a high basal rate of glutamate release
For an ON cell, both hyperpolarizing and depolarizing light responses have nearly the same estimated reversal potential (Fig. 4A); this suggests that the response to light and dark of an ON cell modulates the same conductance. Presumably this conductance is driven primarily by the glutamate release of the ON bipolar cell. Glutamate release would have to be high, nearly in the middle of its operating range, so that peak hyperpolarizing responses attributable to stopping glutamate release would equal peak depolarizing responses to doubling glutamate release (Figs. 2, 3).
To test for a high tonic level of glutamate release, we measured the response in the membrane potential of an ON cell at several points after tonically hyperpolarizing the ON bipolar cell with the agonist of its metabotropic glutamate receptor (mGluR6), L-AP-4 (25-50 µm; Shiells et al., 1981
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Figure 5. Evidence that the hyperpolarizing response of an ON cell depends on high basal glutamate release. The trace shows 500 msec of mean luminance followed by 1.5 cycles of a step response (full contrast). Initially (39 s), L-AP-4 reduced the membrane variance at mean luminance and eliminated the hyperpolarizing response to dark (h). Next (48 s), L-AP-4 eliminated the depolarizing response to light. The recovery during wash was in the opposite order; first (46 s) the depolarizing response recovered, and then (133 s) the variance increased, and the hyperpolarizing response returned. Apparently the hyperpolarizing response depends on basal glutamate release (which causes increased membrane variance at mean luminance) so that an excitatory signal can be withdrawn. The recording electrode contained QX-314 so that membrane variance could be assessed independent of spiking.
To test whether the hyperpolarizing response to dark depends on a high tonic level of glutamate release, we measured the time course of the block of hyperpolarizing versus depolarizing light responses. If the hyperpolarizing light response depends on the suppression of a high level of basal glutamate release, this response should be blocked before the depolarizing response, which does not depend on basal release. In fact, this was observed, and during the wash, the depolarizing response reappeared before the hyperpolarizing response (Fig. 5). In general, the hyperpolarizing response to dark was present only when there was high variance in the membrane potential at mean luminance. This implies that the hyperpolarizing response of an ON ganglion cell depends on a reduction in the high basal release of glutamate of the ON bipolar cell.
Evidence that an OFF cell is phasically inhibited by the ON pathway
For an OFF cell, the hyperpolarizing light response depends on direct inhibition at light onset (Figs. 4). This suggests that, unlike the ON pathway, the basal rate of OFF bipolar cell glutamate release is low and cannot itself be much inhibited. Instead, direct inhibition at light onset suggests that the OFF ganglion cell is directly inhibited by an ON amacrine cell. We tested this by measuring how direct inhibition in an OFF cell was affected by blocking the ON pathway with L-AP-4.
When the ON pathway was blocked, the hyperpolarizing response in an OFF cell remained but decreased in amplitude (Fig. 6A). However, the nature of the hyperpolarization changed from direct inhibition (reversal of approximately -100mV) to indirect inhibition (i.e., decreased excitation; reversal of ~0mV); the effect of L-AP-4 reversed at wash (Fig. 6A). L-AP-4 caused the reversal for inhibition to switch from negative to Vrest to positive to Vrest (four of five cells,
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Figure 6. The ON pathway inhibits an OFF cell phasically to a light flash and tonically at mean luminance. A, The response of an OFF cell was measured to a 100 msec bright or dark spot (full contrast). Initially, the hyperpolarizing (hyp) response had an apparent reversal negative to Vrest (approximately -100 mV). During L-AP-4, the hyperpolarizing response was altered; it became smaller and had an apparent reversal positive to Vrest (~0 mV). The effect of L-AP-4 reversed after washing. In all three conditions, the depolarizing (dep) response had similar apparent reversal (between -30 and -20 mV). Lines indicate a linear regression. The leftward point for the depolarizing response was not included in the fit; at the most hyperpolarized point, the depolarizing response to dark was delayed, so the amplitude in the time window (gray stripe) was reduced. Numbers below the trace indicate baseline potential (in millivolts) before the stimulus in the depolarized (bold) and hyperpolarized condition. The recording electrode contained QX-314. B, L-AP-4 depolarized an OFF cell and increased its spike rate. L-AP-4 caused an increase in membrane variance, even in the absence of spiking (QX-314 electrode). C, For the white noise response, the spike L filter and NL function change in the presence of L-AP-4 (standard electrode). In the presence of L-AP-4, the spike L filter became faster and less biphasic; the NL function became more linear at low contrast (less rectified), because the baseline spike rate increases from 0 to 30 Hz. L filters are normalized to their peak response (and NL functions are scaled accordingly; see Materials and Methods). sp, Spikes.
Evidence that an OFF cell is tonically inhibited by the ON pathway
When L-AP-4 was applied, an OFF cell tonically depolarized from -62 ± 2.1 mV (mean ± SEM) to -54.7 ± 2.8 mV (standard electrode, n = 3; QX-314 electrode, n = 7; Fig. 6B). When an OFF cell was tonically depolarized, the noise in the membrane potential increased, opposite to the effect observed in an ON cell (Fig. 6B), and there was an increase in input resistance (29 ± 14%; n = 6; p < 0.10, trend). For a cell recorded with a standard electrode, the spike rate also increased from 5.5 ± 4.0 to 19.5 ± 8.0 Hz (n = 3). A "burstiness" was observed in the spikes in the initial period after L-AP-4 (Fig. 6B). As a consequence of the increased spike rate, L-AP-4 reduced rectification in the NL function; thus an OFF cell could effectively respond to low contrasts (n = 3; Fig. 6C).
Discussion
Different circuits for ON and OFF
Our experiments suggest distinct circuits for ON and OFF cells (Fig. 7); the circuit diagrams refer to the receptive field "center" response to changes in light over the dendritic tree. The ON cell response is relatively straightforward: the basal release rate of glutamate of an ON bipolar cell is high and can be increased in response to brightening and decreased in response to darkening (Figs. 4, 5). In this sense, it simply follows the output of glutamate from the cone, except for a sign reversal (attributable to the metabotropic glutamate receptor at the dendrite of the ON bipolar cell). In addition, the ON bipolar cell excites an ON amacrine cell that provides "feedforward" inhibition to the ON ganglion cell. Thus, the reversal potential for the depolarizing response would be between the reversals for the excitatory conductance (~0 mV) and inhibitory conductance (approximately -80 mV). We estimate the reversal at the soma to be approximately -20 mV (Fig. 4). At the dendrites, where synapses are located, the reversal potential is probably more negative than -20 mV (see Materials and Methods); however, a more negative reversal in the dendrites (e.g., -30 mV) would also suggest mixed excitation and feedforward inhibition. In rabbit and salamander ganglion cells, the depolarizing spot response also reversed between -40 and -20 mV (Flores-Herr et al., 2001
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Figure 7. Circuit models for ON and OFF pathways. Left, The ON cell depolarizing response arises from a combination of excitation (cone
The OFF cell circuit is slightly more complex than the ON circuit (Fig. 7). An OFF cone bipolar cell has a low basal rate of glutamate release that can only increase in response to darkening (Fig. 4); this pathway also involves feedforward inhibition via an OFF amacrine cell, in parallel with the ON circuit (Fig. 4). However, an additional amacrine cell, driven by the ON pathway, directly inhibits the OFF ganglion in response to brightening (Fig. 6). A surprising aspect of ON and OFF circuits is the asymmetric cross talk between the two pathways; only the OFF pathway requires cross talk from the ON pathway.
In addition to phasic inhibition at light onset, the ON pathway tonically inhibits the OFF ganglion cell at mean luminance (Fig. 6). L-AP-4 caused an OFF cell to depolarize, increase its spike rate, and become bursty (i.e., increased variance of membrane voltage) even in the absence of spiking (Massey et al., 1983
The circuit diagram provides a simple explanation for our data based on differences in ON and OFF synaptic inputs. ON and OFF cells appear to express similar intrinsic properties (O'Brien et al., 2002
Different inhibitory mechanisms for ON and OFF
Previously, we observed that ON and OFF cells have different mechanisms for inhibition; an ON cell receives indirect inhibition (i.e., reduced excitation), reducing a conductance that reverses positive to Vrest, whereas an OFF cell receives direct inhibition, increasing a conductance that reverses negative to Vrest (Demb et al., 2001a
Temporal processing in ON and OFF
The linear component of the L-NL analysis reflects the impulse response function of a cell (given a fixed mean luminance and contrast). ON and OFF cells expressed opposite-signed but otherwise similar impulse responses (Fig. 2). Thus, under our conditions (photopic, high-contrast white noise) presynaptic inputs to ON and OFF ganglion cells temporally filter the stimulus in a similar way. In response to a discrete light pulse, the impulse response of a cell will shorten its integration time as contrast increases because of contrast adaptation; this will shorten the time to peak at high contrast relative to low contrast (Fig. 3). On average, the time to peak response at high contrast was shorter in ON cells (43.7 ± 2.5 msec) than OFF cells (57.0 ± 6.3 msec, mean ± SEM; p < 0.10, trend; Fig. 3). There were additional ON-OFF asymmetries in the waveform of the response to a 100 msec light pulse (Fig. 4). Thus, in general, ON and OFF cells express unique temporal properties, and these probably reflect asymmetries in the expression of contrast and light adaptations (Chander and Chichilnisky, 2001
Relationship between ON and OFF asymmetries in physiology and morphology
In several species (human, monkey, rat, and guinea pig) at a given retinal location, the dendritic area of an ON brisk-transient cell is ~40% larger than the area of an OFF brisk-transient cell (i.e., ON vs OFF parasol or
Alternative explanation for the action of L-AP-4
Group III metabotropic glutamate receptors are located on both the ON bipolar dendrite and the ON and OFF bipolar axon terminal (Brandstätter et al., 1996
Implications for vision
The response to white noise resembles the response to natural stimuli (Meister and Berry, 1999
Our results suggest a basis for the perceptual asymmetry in detecting a low-contrast increment or decrement. At threshold, a human observer is relatively more sensitive to a decrement (Short, 1966
FOOTNOTES Received Oct. 23, 2002; revised Jan. 16, 2003; accepted Jan. 22, 2003.
This work was supported by National Eye Institute Grants T32-EY07035 and RO1-EY08124. We thank Dr. E. J. Chichilnisky, Dr. Michael Freed, Dr. Edward Pugh Jr, and Dr. Peter Sterling for comments on this manuscript.
Correspondence should be addressed to Dr. Jonathan Demb, 123 Anatomy/Chemistry Building, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6058. E-mail: demb{at}retina.anatomy.upenn.edu.
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