© 2005 Nature Publishing Group http://www.nature.com/natureneuroscience

ARTICLES

Synchronized retinal oscillations encode essential
information for escape behavior in frogs
Hiroshi Ishikane1,2, Mie Gangi1, Shoko Honda1 & Masao Tachibana1
Synchronized oscillatory activity is generated among visual neurons in a manner that depends on certain key features of visual
stimulation. Although this activity may be important for perceptual integration, its functional significance has yet to be explained.
Here we find a very strong correlation between synchronized oscillatory activity in a class of frog retinal ganglion cells (dimming
detectors) and a well-known escape response, as shown by behavioral tests and multi-electrode recordings from isolated retinas.
Escape behavior elicited by an expanding dark spot was suppressed and potentiated by intraocular injection of GABAA receptor
and GABAC receptor antagonists, respectively. Changes in escape behavior correlated with antagonist-evoked changes insynchronized oscillatory activity but not with changes in the discharge rate of dimming detectors. These antagonists did not affectthe expanding dark spot–induced responses in retinal ganglion cells other than dimming detectors. Thus, synchronizedoscillations in the retina are likely to encode escape-related information in frogs.

Synchronized activity accompanied by g-range (B20 to B80 Hz)
oscillations is frequently observed in various nervous systems, and thisneural activity may be related to perception, attention and memory1–13.
In the visual system, synchronized oscillatory activity is found invarious regions, such as the retina14,15, the lateral geniculate
nucleus14,15, the primary visual cortex1,2,16 and the posteromedial
lateral suprasylvian sulcus17. Furthermore, synchronized oscillatory
activity is found not only among neurons located within one region
but also among neurons in different regions17,18. The synchronizedoscillatory activity depends on certain stimulus features such ascontinuity and direction of motion2,19,20, and thus it may serve to
integrate spatially distributed features1,2,14,15,21,22. However, its functional significance remains unclear.
Frogs jump away when a predator approaches, and the characteristic
stimulus that elicits escape behavior is a looming or expanding
dark object23,24. In the frog retina, ganglion cells are categorized
into four classes on the basis of their response properties: sustained
contrast detectors, net convexity detectors, moving-edge detectors
and dimming detectors25. A large darkening or dimming lightevokes off-sustained spike discharges in the dimming detector but
elicits only a few spike discharges transiently in other cell classes(the non-dimming detector classes)25. Of these cell classes, thedimming detectors are of note, as it has been reported that pharmacological blockade of their activity selectively suppresses escape behavior without affecting prey-catching behavior24. However, it is notevident how dimming detectors encode escape-related information,although coding by discharge rate is commonly assumed. A possible
candidate is synchronized oscillatory spike discharge, which is gener-

ated among dimming detectors when a large retinal area is stimulated
by a dimming light26.
As we have already shown in the frog retina, the g-range oscillations induced in dimming detectors by a large dimming stimulus
are suppressed by a GABAA receptor (GABAAR) antagonist,bicuculline26,27, whereas these activities are enhanced by a GABACR
antagonist, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid
(TPMPA)27. In the present study, using these GABAR antagonists asa tool, we examined the relationship between visually guided behaviors
and light-evoked spike discharges of ganglion cells in isolated retinas.
Our results indicate that synchronized oscillatory activity among
retinal dimming detectors may have an important role in escaperelated visual information processing in frogs.
RESULTS
Suppression of escape behavior by a GABAAR antagonist
An expanding dark spot that emulated the shadow of an approachingpredator evoked escape behavior in frogs (Fig. 1a). The escape rate
(number of escape trials / total number of trials) increased withincreasing expansion speed (Fig. 1b; final spot diameter, 551) andfinal diameter (Fig. 1c; expansion speed, 431 s1) of the dark spot.
When we presented a dark spot expanding from 01 to 551 at a speed of
431 s1, the escape rate reached B0.85 (Fig. 1c), and the reaction timefor escape was 1.01 7 0.03 s (mean 7 s.e.m., n ¼ 5 frogs) from thestart of spot expansion. Notably, escape behavior was elicited neither
by an expanding bright spot nor by an expanding dark ring (n ¼ 3
frogs), stimuli which activate the non-dimming detector classes25(see Supplementary Fig. 1 online). These behavioral tests support

1Department of Psychology, Graduate School of Humanities and Sociology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 2Present address:
Laboratory for Neuroinformatics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Correspondence should be addressed to M.T.
(Ltmasao@L.u-tokyo.ac.jp).

Published online 3 July 2005; doi:10.1038/nn1497

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times) with the expanding dark spot, theparameters of which were similar to those
1.0
used for the behavioral test (from 01 to 601
at the speed of 431 s1; Fig. 1d). We recorded
0.5
0.5
spike discharges from various cell classes, thereceptive fields of which were located within
0.0
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the stimulated area. Then we constructed peri10 2030
40 50 60020
40
60Spot diameter (deg)
Speed of expansion (deg/s)
stimulus time histograms (PSTHs, 50-ms bin
width) and autocorrelograms (2-ms bin
width) to analyze the temporal pattern ofdespike discharges (Fig. 2).
****
Dimming detectors generated sustained
1.0
1.0
discharges to the expanding dark spot
(Fig. 2a, top). Autocorrelation analysis
0.5
0.5
showed a pattern with periodic peaks atregular intervals. The power spectrum,0.0
0.0
which is the Fourier transform of the autoControl
Std
Washout
Control
Bic
Washout
correlation function, showed a clear peak at
32.15 7 1.28 Hz (mean 7 s.e.m., n ¼ 13
Figure 1 Bicuculline suppressed escape behavior in response to the expanding dark spot. (a) Visuallyelicited escape behavior of a frog was examined with an expanding dark spot presented on a computercells), indicating the presence of g-range oscilcontrolled display. (b) Relationship between the expansion speed of a dark spot and the escape rate
lations. Bicuculline suppressed the periodic(mean 7 s.e.m., n ¼ 6 frogs). (c) Relationship between the final diameter of an expanding dark spot
peaks in the autocorrelogram and the peak inand the escape rate (mean 7 s.e.m., n ¼ 5 frogs). (d) Suppression of escape behavior by intraocular
the g range (Fig. 2a, bottom), indicating theinjection of a GABAAR antagonist, bicuculline. Behavioral experiments were performed before (Control),suppression of g-range oscillations.
2 h after (‘Bic’) and 1 d after (Washout) injection. The dark spot expanded from 01 to 551 at theBoth sustained contrast and/or net convexexpansion speed of 431 s1. The escape rate was normalized to the value obtained before injection
ity detectors and moving-edge detectors(Control). Mean 7 s.e.m., n ¼ 5 frogs. **P o 0.01. (e) Effect of intraocular injection of the standard
saline without bicuculline (mean 7 s.e.m., n ¼ 5 frogs). The experimental procedure was the same as
evoked transient discharges to the expandingthat employed in d.
dark spot (1.73 7 0.42 spikes/trial in 11
sustained contrast and/or net convexity
detectors and 2.72 7 0.46 spikes/trial in
the hypothesis that dimming detectors may be critical in eliciting 14 moving edge detectors; Fig. 2b,c, top). The autocorrelograms andpower spectra do not indicate any detectable g-range oscillations inescape behavior24.
The oscillatory discharges that are evoked by a large dimming these non-dimming detector classes (Fig. 2b,c). Bicuculline did not
stimulus in dimming detectors of frog’s retinas are suppressed by induce any obvious changes in the profiles of PSTHs, autocorrelograms
GABAAR antagonists26,27. Thus, we injected bicuculline into both eyes or power spectra (Fig. 2b,c, bottom). Among all cell classes, only
under anesthesia and allowed the frogs to recover (B2 h). We tested dimming detectors showed a significant increase in the number of spike
escape behavior with an optimal expanding dark spot (expansion discharges (P o 0.05, t-test, n ¼ 7 cells; Fig. 2d, left) and a significant
speed, 431 s1; final spot diameter, 551; Fig. 1b,c). This pharmaco- decrease in the oscillation index (see Methods; P o 0.01, t-test,
logical treatment significantly suppressed escape behavior (P o 0.01, n ¼ 7 cells; Fig. 2d, right) in response to bicuculline. Thus, behavioral
repeated-measures ANOVA followed by Tukey’s method, n ¼ 5 frogs; changes induced by intraocular injection of bicuculline may not
Fig. 1d). The suppressive effect of bicuculline was recovered 1 d after be ascribed to changes in the activity of cell classes other than
bicuculline injection (Fig. 1d). Intraocular injection of physiological dimming detectors.
Applying a planar multi-electrode array to the isolated retinas29,
saline without bicuculline did not change escape behavior (P ¼ 0.46,
repeated-measures ANOVA, n ¼ 5 frogs; Fig. 1e), indicating that we closely examined the effects of bicuculline on the activities ofsuppression of escape behavior (Fig. 1d) could not be ascribed to dimming detectors. We mapped each receptive field center of recorded
experimental artifacts such as the effect of anesthesia.
dimming detectors using a small flashing spot (Fig. 3a). Then we
projected a dark spot that expanded from 01 (0 s) to 601 (1.4 s) on the
Effects of bicuculline on retinal ganglion cells
retina (Fig. 3a,b). Figure 3c (top) illustrates an example of the spike
To examine how bicuculline affected the responses induced by the trains simultaneously recorded from seven dimming detectors during a
expanding dark spot in retinal ganglion cells, we recorded spike single presentation of the expanding dark spot. In the control condidischarges extracellularly from isolated frog retinas. Each ganglion cell tion, when the spot diameter exceeded B401 (B0.9 s after stimulus
class was identified as follows: cells that generated off-sustained spike onset), the inter-spike intervals became regular, and spike discharges
discharges to a full-field stimulus (44 mm in diameter on the retina) were phase-locked across dimming detectors. Notably, for each dimwere identified as dimming detectors, cells that generated transient ming detector the latency of the first spike as well as the emergence of
spike discharges at the onset and offset of the full-field stimulus as regular inter-spike intervals after the start of dark spot expansion variedmoving-edge detectors, and cells that evoked transient spike discharges from trial to trial (Supplementary Fig. 2). A PSTH (50-ms bin width)
to a small flashing spot (B100 mm in diameter) but no spike discharges was constructed from the simultaneous spike trains recorded fromto the full-field stimulus as sustained contrast and/or net convexity seven dimming detectors during the single stimulus presentation
detectors. The sustained contrast and/or net convexity detectors were (Fig. 3c). The number of spikes/bin increased as the dark spot
categorized as one group because these cells respond similarly to a expanded. The profile of PSTH seemed similar before (Fig. 3c) andmoving dark stimulus28. We stimulated the retinas repeatedly (100 during application of bicuculline (Fig. 3d). However, the regularity of

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Figure 2 Effects of bicuculline on the activities of retinal ganglion cells. (a–c) Spikes were recorded during 100 repetitive trials from dimming detectors (a),sustained contrast and/or net convexity detectors (b), and moving-edge detectors (c). The dark spot expanded from 01 (0 s) to 601 (1.4 s) at the speed of
431 s1 and then was maintained for 3 s. The PSTHs (left; 50-ms bin width), autocorrelograms (middle; 2-ms bin width) and power spectra (right) were
calculated before (control) and during application of 10 mM bicuculline. In this and the following figures, the number shown in each autocorrelogram indicatesthe peak value at zero time shift. (d) Summary of the effects of bicuculline on the number of spikes (left) and the oscillation index (right). Mean 7 s.e.m.
Data obtained from seven dimming detectors, six sustained contrast and/or net convexity detectors (SC/NC detectors), and seven moving-edge detectors(ME detectors). *P o 0.05, **P o 0.01.

oscillations of each dimming detector (see Fig. 2a, control autocorrelogram and power spectrum) were phase-locked or synchronized. To
demonstrate the synchrony of oscillations plainly, we extracted asynchronized event (Fig. 4b, top) where spikes were generated within
2 ms in multiple (Z2) dimming detectors (Fig. 4b, inset), and we
calculated the autocorrelation (Fig. 4b, bottom left) and power
spectrum (Fig. 4b, bottom right) from the synchronized event train.

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Figure 3 Spike trains evoked by an expanding
dark spot in multiple dimming detectors in theisolated retina. (a) Map of receptive field centersof the seven recorded dimming detectors. The
dark spot started expanding from the receptive
field center of cell #1. Scale bar indicates
1.0 mm, which corresponds to B101 of subtense.
(b) Changes in spot size (diameter) with time.
(c) A single-trial record of simultaneous spiketrains in the control condition. Top: the rasterplots of discharges simultaneously recorded fromseven cells shown in a. Bottom: the peri-stimulus
time histogram (PSTH, 50-ms bin width)
calculated from the simultaneous spike trains
shown above. (d) The raster plots (top) and PSTH
(bottom) obtained from the same cells in thepresence of 10 mM bicuculline.

b
Spot size (deg)inter-spike intervals (Fig. 3c, top) seemed to be obscured by bicuculline(Fig. 3d, top).
To analyze the temporal pattern of spike trains, we created an
ensemble spike train from the simultaneous spike trains recorded
from several dimming detectors during repetitive presentations of the
expanding dark spot. In the control condition, an autocorrelogram ofthe ensemble spike train showed a pattern with periodic peaks atregular intervals (Fig. 4a, left), and the power
spectrum of the autocorrelation function
showed a clear peak at B40 Hz (Fig. 4a,right). Because the response period of eachdimming detector was mostly overlapping
during each stimulus presentation (Fig. 3c,top), these results indicate that the g-range

Spikes/bin© 2005 Nature Publishing Group http://www.nature.com/natureneuroscience

Bicuculline

Number of coincidences

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each; t-test, n ¼ 5 retinas; Fig. 4e; see Methods). However, blockade of inhibitory inter1,000
actions mediated by GABAARs increased
40
40
500
the number of spike discharges (P o 0.05),
20
20
resulting in an increase in the number ofsynchronized events (P o 0.05). These
0
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results strongly suggest that the bicucullineTime shift (ms)Frequency (Hz)Time shift (ms)Frequency (Hz)induced suppression of escape behavior(Fig. 1d) may be caused by impairment ofbdthe synchronized g-range oscillations among
1.
1.
...
...
dimming detectors.
...
...
..
..
To clarify the relationship between the77synchronized oscillation and the distance
between dimming detectors, we calculated
1.5
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cross-correlations for each pair of dimming
Time (s)detectors before and during application of
bicuculline (Fig. 5a). In the control condition,
cross-correlograms demonstrated a patternwith a central peak and periodic side peaks
1.42
1.44
1.46
(Fig. 5a, top), indicating the presence of
100
538
394
synchronization (the central peak) accompa0.5
0.5
50
nied by oscillations (the side peaks). The shift
predictors were almost flat (Fig. 5a, top,
inset), indicating that the synchronization0000
and oscillations had a neural origin. During
–150
0
150
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100
200
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0
100
200
bicuculline application the oscillations disapTime shift (ms)Frequency (Hz)Time shift (ms)Frequency (Hz)peared in all cell pairs (Fig. 5a). However, theesynchronization
still remained in near-cell*
1.5*
Figure 4 Bicuculline impaired the synchronizedpairs (0 to 0.5 mm; Fig. 5a) whereas it was
oscillations among dimming detectors. (a) Analysis
obscured in remote-cell pairs (0.5 to
1.0of the ensemble spike train. Data were obtained
1 mm, and 41 mm; Fig. 5a). We foundfrom seven dimming detectors shown in Figure 3a**that during bicuculline application, the**during ten repetitive presentations of the expanding
0.5
synchronization index (see Methods) did
dark spot. Autocorrelogram of the ensemble spikenot change in near-cell pairs (0 to 0.5 mm,train (left) and its power spectrum (right). (b) Top:0.0
a part of the simultaneous spike trains shown inn ¼ 9 pairs; Fig. 5b) but became significantly
Osci# SyncOS# Spikes
Figure 3c and the extracted synchronized event train
small in remote-cell pairs (0.5 to 1 mm,(‘Sync event’). Inset, the simultaneous spike trainsn ¼ 11 pairs; 41 mm, n ¼ 49 pairs; P owere grouped in 2-ms bins (vertical lines) and the synchronized events were extracted. Bottom:
0.01 each, t-test; Fig. 5b). These results sugautocorrelogram of the synchronized event train (left) and its power spectrum (right). (c) Effects ofgest that suppression of oscillations by
bicuculline (10 mM) on the ensemble spike train. Autocorrelogram of the ensemble spike train (left) andbicuculline may impair the long-range synits power spectrum (right). (d) Top: a part of the simultaneous spike trains in the presence of bicuculline
shown in Figure 3d and the extracted synchronized events. Bottom: effects of bicuculline on thechrony of spike discharges without affecting
synchronized event train. Autocorrelogram of the synchronized event train (left) and its power spectrum
the local synchrony.
(right). (e) Effects of bicuculline on the number of spikes (‘# Spikes’), the oscillation index (‘Osci’), theWe also calculated time-resolved slidingnumber of synchronized events (‘# Sync’), and the oscillatory synchronization index (‘OS’). Each value
window cross-correlograms (200-ms time
was normalized to the control condition. Mean 7 s.e.m., n ¼ 5 retinas. *P o 0.05, **P o 0.01.
window, 20-ms sliding steps; see Methods) to
examine how the synchronization and oscillations developed with increasing spot size
These analyses indicate that the synchronized event occurred in (Fig. 5c, bottom). In the control condition, for both near- andremote-cell pairs, a clear striped pattern was observed along the time
oscillation (39.84 7 3.36 Hz, n ¼ 5 retinas).
Bicuculline impaired the oscillations (Fig. 4c) and the oscillatory axis (4B1 s), indicating the presence of synchronization (the horsynchronization (Fig. 4d). Periodic peaks disappeared both in the izontal center line at zero time shift) and oscillations (horizontal lines
autocorrelogram calculated from the ensemble spike train (Fig. 4c, left) nearly parallel to the center line). With time the inter-stripe widthand in that from the synchronized event train (Fig. 4d, bottom left). In became wider, suggesting that the frequency of oscillations decreased
the power spectra there was no clear peak in the g-range frequency gradually. Bicuculline obscured the striped pattern in both pairs,(Fig. 4c, right and 4d, bottom right). Note that under this condition indicating the suppression of oscillations. However, the center line
both spikes and synchronized events were generated with random (indicating synchronization) remained in the near-cell pair, whereas it
intervals because the number of coincidences in the autocorrelograms disappeared in the remote-cell pair.
was almost constant besides the central peak (Fig. 4c, left and 4d,Potentiation of escape behavior by a GABACR antagonist
bottom left).
Bicuculline significantly decreased both the oscillation index and the It is critical to know whether escape behavior is potentiated whenoscillatory synchronization index of dimming detectors (P o 0.01 for retinal synchronized oscillatory activity is enhanced. We have already
Number of coincidences

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event

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Power

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3,044

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Figure 5 Effects of bicuculline on synchronizationand oscillations. Cross-correlograms were
calculated from spike discharges recorded from apair of dimming detectors during ten repetitive
presentations of the expanding dark spot. The
spot size was increased from 01 (0 s) to 601(1.4 s) at the speed of 431 s1 and then wasmaintained for 3 s. (a) Examples of crosscorrelograms and shift predictors (inset) obtained
from three pairs of dimming detectors before (top)and during (bottom) application of bicuculline.
Distance between receptive field centers ofdimming detectors was categorized into threegroups (top). (b) Distance-dependent suppressionof the synchronization by bicuculline. The
synchronization index in the presence of bicuculline was normalized to that in the control condition. Mean 7 s.e.m., n ¼ 5 retinas. **P o 0.01.
(c) Left: sliding-window cross-correlograms
obtained from the near-cell pair shown in a
(0–0.5 mm) before (Control) and during
application of bicuculline. Right: sliding window
cross-correlograms obtained from the remote-cellpair shown in a (41.0 mm). The vertical andhorizontal axes indicate time shift (ms) and thetime course of stimulus presentation, respectively.
Gray scale bar (right) indicates the number ofcoincidences normalized by the mean value of thecorresponding shift predictor.

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shown that the oscillations evoked by a large dimming stimulus indimming detectors are enhanced by a GABACR antagonist, TPMPA27.
It is probable that blockade of the GABACR-mediated negative feedback from amacrine cells to bipolar cells increases glutamate releasefrom bipolar cells30,31. In contrast to injection of bicuculline, intraocular injection of TPMPA potentiated escape behavior in response to
the expanding dark spot (n ¼ 5 frogs) (Fig. 6a). Frogs responded tosmaller dark spots with a higher escape rate B2 h after TPMPA
injection (Fig. 6a, filled squares) than in the control condition(Fig. 6a, open circles). The TPMPA-induced potentiation of escapebehavior recovered 1 d after injection (Fig. 6a, open triangles). TPMPA
shifted the relationship between the final spot diameter and the escaperate along the abscissa, suggesting that GABACRs in the retina may
contribute to controlling the sensitivity to escape behavior.
Effects of TPMPA on retinal ganglion cells
To examine the effects of TPMPA on the activities of retinal ganglion
cells, we recorded spike discharges extracellularly from various cellclasses within a retinal area that was stimulated by a dark spot
expanding from 01 to 301. TPMPA (10 mM) increased the number of
spike discharges and enormously enhanced the g-range oscillations indimming detectors (Fig. 6b), whereas TPMPA did not change theprofiles of PSTHs, autocorrelograms and power spectra in sustained
contrast and/or net convexity detectors (Fig. 6c) or in moving-edge
detectors (Fig. 6d). TPMPA induced a significant increase in thenumber of spike discharges and in the oscillation index only indimming detectors (P o 0.01 each, t-test, n ¼ 6 cells; Fig. 6e).
Applying a multi-electrode array to the isolated retinas, we
simultaneously recorded the responses of several dimming detectors
to a dark spot expanding from 01 to 301, and we calculated
autocorrelations from the ensemble spike train (Fig. 7a) and thesynchronized event train (Fig. 7b). These analyses showed that
TPMPA (10 mM) enhanced synchronized oscillatory activity.
Power spectrum analysis indicated that TPMPA markedly increased

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Time (s)the peak power of g-range oscillations without changing their peakfrequency (Fig. 7a,b). TPMPA significantly increased the oscillationindex, the oscillatory synchronization index, the number of spike
discharges and the occurrence of synchronized events in dimming
detectors (P o 0.05 each, t-test, n ¼ 5 retinas; Fig. 7c). Examination ofthese results and the bicuculline results (Fig. 4) suggests that theoscillation index and the oscillatory synchronization index seem tobe good predictors of changes in escape behavior.
Effects of GABAR antagonists on optokinetic behavior
One may argue that GABAR antagonists might cause nonspecificdisruption of retinal function. However, this seems unlikely. We
examined the effects of GABAR antagonists on optokinetic responses
to horizontally drifting stripes (Fig. 8a). Frogs pursued reciprocating
motion of stripes by rotating their head. Approximately 2 h after
intraocular injection of bicuculline, the frogs did not escapein response to the expanding dark spot (Fig. 1d), but the samefrogs displayed optokinetic responses to the drifting stripes (Fig. 8b).
The maximal angle of optokinetic head rotation did not change
significantly (P ¼ 0.98, repeated-measures ANOVA, n ¼ 5 frogs).
Furthermore, intraocular injection of TPMPA did not affect optokinetic responses (P ¼ 0.30, repeated-measures ANOVA, n ¼ 5 frogs;
Fig. 8c). Therefore, the retinal system that was required to induce
optokinetic responses was still functioning after the pharmacologicaltreatments that markedly changed escape behavior.
DISCUSSION
In the present study, we examined the relationship between visually
guided behavior and the activity of retinal ganglion cells in frogs.
Intraocular injection of GABAAR and GABACR antagonists caused
suppression and potentiation of escape behavior, respectively, in
response to an expanding dark spot (Figs. 1d and 6a). The changes
in escape behavior were not correlated with the discharge rate ofganglion cells but rather with changes in the synchronized oscillatory

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activity of dimming detectors (Figs. 2–7). We also found that both theescape rate of frogs (Fig. 1b,c) and the oscillatory activities of dimming
detectors (Supplementary Fig. 3) were similarly affected by the
expansion speed and final diameter of the dark spot in the control
condition (that is, without pharmacological treatment). Furthermore,
escape behavior was strongly modified by the GABAR antagonists,
whereas other behaviors, such as optokinetic responses to the drifting

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Figure 6 Effects of a GABACR antagonist on escape behavior and theactivities of retinal ganglion cells. (a) Relationship between the escape rate
and the final spot diameter before (open circles), 2 h after (filled squares)
and 1 d after (open triangles) intraocular injection of TPMPA. R2 values ofthe Weibull function fitted to the data (solid and dotted lines) were 0.985(control), 0.996 (TPMPA) and 0.985 (washout). (b–d) Effects of bath-applied
TPMPA (10 mM) on the activities of dimming detectors (b), sustained
contrast and/or net convexity detectors (c) and moving-edge detectors (d).
The PSTHs (left; 50-ms bin width), autocorrelograms (middle; 2-ms bin
width) and power spectra (right) were calculated from spikes that occurred
during 100 repetitive presentations of the expanding dark spot (from 01 to
301 at an expansion speed of 431 s1). (e) Effects of TPMPA on the numberof spikes (left) and the oscillation index (right). Mean 7 s.e.m. Data wereobtained from six dimming detectors, eight sustained contrast and/or net
convexity detectors (SC/NC detectors) and four moving-edge detectors(ME detectors). **P o 0.01.

stripes, were not (Fig. 8). These results, therefore, suggest a strong tie
between synchronized oscillatory activity among dimming detectors
and escape behavior.
Although these results are strongly suggestive, they are not unequivocal. Proving that the synchronized oscillations in dimming detectors
are responsible for escape behavior would require one of two things:(i) a demonstration that the GABAR antagonists we used to perturb
escape behavior does not affect cell classes other than the dimming
detector, or (ii) a demonstration that the dimming detector is the only
cell class involved in this particular behavioral response. If the latter isthe case, then effects of GABAR antagonists on other cell classes become
irrelevant. It is difficult to prove either of these, and thus we havegathered substantial evidence in both directions.
First, we have shown that the firing patterns of the non-dimming
detector classes were not changed by the GABAR antagonists (Figs. 2
and 6), as measured by changes in the profiles of the PSTHs,
autocorrelograms and power spectra. (For this analysis we used firing
patterns produced by an expanding dark spot, as this was the stimulusthat evoked the escape behavior. However, this stimulus might not be
optimal for detecting the effects of GABAR antagonists on the activitiesof the non-dimming detector classes because it has been reported that
responses to bright light stimuli were modified by GABAR antagonists
in frog retinal ganglion cells32.) Second, we have shown that the firing
patterns of the non-dimming detector classes were not as tightly linked
to escape behavior as the firing patterns of dimming detectors. The
non-dimming detector classes generated significantly stronger transient responses to the expanding dark ring than to the expanding dark
spot, but the former stimulus did not elicit escape behavior (Supplementary Fig. 1). However, in dimming detectors both the number of
spike discharges and the oscillation index were significantly reduced forthe expanding dark ring than for the expanding dark spot (Supplementary Fig. 1). Thus, the non-dimming detector classes may havesome role in escape behavior, but it is likely to be a lesser role than thatof dimming detectors, whose responses are tightly correlated with the
expanding dark spot stimulus.
In remote pairs of dimming detectors bicuculline suppressed bothoscillations and synchronization (Fig. 5). However, in nearby pairs ofdimming detectors bicuculline suppressed the oscillations but did not
impair synchronization, perhaps because adjacent dimming detectors
may have received excitatory common inputs and/or electricallycoupled inputs26,27,33. The synchrony of spike discharges that occurred
randomly in multiple local regions would be insufficient to evoke
escape behavior. The g-range oscillations may serve to adjust the local
synchronizations in phase and to establish the synchronization between
dimming detectors widely across the retina26,34. The long-range lateral

VOLUME 8 [ NUMBER 8 [ AUGUST 2005 NATURE NEUROSCIENCE

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Figure 7 TPMPA enhanced the synchronized oscillatory activity among dimming detectors. Autocorrelograms were calculated from spike discharges recorded
during ten repetitive presentations of the expanding dark spot (from 01 to 301 at the expansion speed of 431 s1). (a) Enhancement of the oscillations by bathapplied TPMPA (10 mM). Analysis of the ensemble spike train obtained from seven simultaneously recorded dimming detectors before (control) and during
application of TPMPA as shown by autocorrelograms (top) and power spectra (bottom). (b) Enhancement of the oscillatory synchronization by TPMPA. Analysisof the synchronized event train before (Control) and during application of TPMPA as shown by autocorrelograms (top) and power spectra (bottom). (c) Effects of
TPMPA on the number of spikes (‘# Spikes’), the oscillation index (‘Osci’), the number of synchronized events (‘# Sync’) and the oscillatory synchronizationindex (‘OS’). Each value was normalized to that in the control condition. Mean 7 s.e.m., n ¼ 5 retinas. *P o 0.05.

interactions between dimming detectors may be mediated by Na+
spikes because blockade of Na+ channels by tetrodotoxin suppresses
oscillatory synaptic inputs to dimming detectors27.
Na+ spikes trigger the release of GABA from amacrine cells35,36, andthus GABAergic amacrine cells may be important in the network thatgenerates oscillations in the inner retina. Oscillatory activity among
dimming detectors was suppressed by bicuculline, an antagonist
specific to GABAARs, whereas this activity was enhanced by TPMPA,an antagonist specific to GABACRs. Both GABARs exist in the inner
plexiform layer37–39. GABACRs are expressed mostly at the axon
terminals of bipolar cells39. It has been suggested that the GABACRmediated negative feedback from amacrine cells to bipolar cells may be
used to control the gain of glutamatergic transmission30,31. Therefore,
blockade of GABACRs may increase the release of glutamate frombipolar cells and enhance the direct excitatory input to dimming
detectors and/or the inhibitory activity of amacrine cells, resulting inenhancement of the oscillatory activities of dimming detectors. Whenpicrotoxin, which blocks both GABAARs and GABACRs in the frog
retina38, is applied, the oscillatory activity of dimming detectors is

a

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0
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NATURE NEUROSCIENCE VOLUME 8 [ NUMBER 8 [ AUGUST 2005

suppressed26. It is likely that GABAARs may be essential for generating
the oscillatory activities in the inner retina, whereas GABACRs may
have a different role, such as gain control. After blockade of GABACRs,
frogs show escape behavior in response to small spots that elicit little orno escape behavior under control condition (Fig. 6a). Activation of
GABACRs in the retina may attenuate the oscillatory activity ofdimming detectors and may optimize the stimulus size tuning foreliciting escape behavior. Such adjustment may be useful to avoid
unnecessary escape from tiny prey or a distant predator.
Synchronized oscillations among dimming detectors in a wide
retinal area seems to convey essential escape-related visual information
to the frog’s brain. However, it is not evident which aspect of thisactivity is analyzed by central visual neurons such as neurons in thetectum40. There may be at least three possibilities: (i) synchronization,(ii) synchronization accompanied by g-range oscillations and (iii)g-range oscillations. In the first case, central visual neurons may behave
as coincidence detectors. These neurons respond only to synchrony ofdischarges from many dimming detectors without taking into accountoscillations. The function of oscillations may be limited only toestablishing the synchronization of discharges among dimming detectors widely across the retina. Coincidence detection with a narrow time
window may improve both noise tolerance and input discriminability41–43. In the second case, central visual neurons may fire only whensynchronized events arrive repetitively at regular (B20 to B30 ms)
intervals. Such a mechanism may improve input discriminability andprevent false alarms. However, the probability of falling victim to
predators would increase if central neurons responded only after thearrival of a large number of synchronized events at periodic intervals. A
few synchronized events should trigger spikes in central neurons toelicit escape behavior. In the third case, central neurons may be tuned
to a specific frequency of g-range oscillations. These neurons would be

Figure 8 Effects of GABAR antagonists on optokinetic responses.
(a) Horizontally drifting stripes (square wave) were presented on two
displays in front of a frog. (b) The maximum angle of head rotation before(Control), 2 h after (‘Bic’) and 1 d after (Washout) intraocular injection of
bicuculline (mean 7 s.e.m., n ¼ 5 frogs). (c) The maximum angle of headrotation before (Control), 2 h after (TPMPA) and 1 d after (Washout)intraocular injection of TPMPA (mean 7 s.e.m., n ¼ 5 frogs).

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activated strongly if the frequency of postsynaptic potentials evoked byretinal inputs fit their resonance frequency44, which would be determined by their intrinsic membrane properties or by a neuronal
network. Further experiments are required to elucidate how thefrog’s brain decodes the synchronized retinal oscillations.

© 2005 Nature Publishing Group http://www.nature.com/natureneuroscience

METHODS
Bullfrogs (Rana catesbeiana) were used for behavioral and electrophysiologicalexperiments in accordance with the guidelines for the care and use of animals(The University of Tokyo and The Physiological Society of Japan).
Intraocular injection and behavioral experiments. Frogs were deeply anesthetized with ethyl 3-aminobenzoate methanesulfonate (3 g/l; MS-222, Sigma)
before intraocular injection of GABA receptor antagonists. Bicuculline or
TPMPA (500 mM; both from Tocris) dissolved in the standard solution (see‘Electrophysiology’) was intravitreously injected into both eyes by a syringe (60ml/eye). The final drug concentration in each eye was estimated to be B50 mM.
After sufficient recovery from anesthesia, we started behavioral experiments(B2 h after injection). To evaluate experimental artifacts, the standard solution
without GABAR antagonists was injected into both eyes of a different group offrogs with the same protocol. Behavioral experiments were performed in a darkbox (65  72  75 cm), and behavior of a frog placed in a transparent acrylic
dome (30 cm in diameter) was monitored by a video camera under infrared
illumination. For the test of escape behavior, a liquid crystal display (LCD,
NANAO) was positioned 28.5 cm away from either eye (+1351 (right eye) or
1351 (left eye) from the median plane, 451 elevation from the horizontal; theplane of LCD was slanted off the horizontal), and an expanding dark spot
(stimulus contrast, spot:background ¼ 1:17) was presented (Fig. 1a). When the
final spot diameter was changed, the spot diameter was increased from 01 to a
final size (101 to 551 of subtense) at the speed of 431 s1 and then maintainedfor 1 s during each trial. When the expansion speed was changed in the range
between 51 s1 and 501 s1, the final spot diameter was fixed to 551. Twosessions were performed under each condition (Fig. 1b: eight trials per session,
Figs. 1c and 6a: 12 trials per session, Fig. 1d,e: six trials per session). To prevent
habituation, a 460-s pause was inserted between trials and a 15-min pause
between sessions, and the stimulus was presented alternately to each eye. The
escape rate under each condition was the ratio of the number of trials where
escape behavior was elicited to the total number of trials. The relationshipbetween the spot diameter and the escape rate could be fitted with Weibull
function by the Levenberg-Marquardt algorithm using Origin (OriginLab)
software (Fig. 6a). For the test of optokinetic head rotation, two LCDs
(Mitsubishi Electronics) were positioned in front of a frog (Fig. 8a). Vertical
stripes (contrast ¼ 0.89; spatial frequency of the square wave 0.1 cycles/degree,
50% duty cycle) were moved horizontally at a sinusoidally modulated speed(0.067 Hz, maximum speed +161 s1 (right), 161 s1 (left)). The reciprocating motion of the vertical stripes was presented for two cycles per trial, andthree trials were performed under each condition. The maximum angle of headrotation in three trials was measured from digital video images with Matlab(Mathworks) software.
Electrophysiology. Experimental procedures and equipment has been
described previously in detail26. Briefly, under a dim red light, a frog was
double pithed and eyes were enucleated. The eyeball was hemisected, and thecornea and lens were separated from the posterior part. The eyecup was cut
into several pieces and the retina was isolated carefully from the pigment
epithelium. The isolated retina was transferred onto a planar multi-electrodearray with the ganglion cell layer facing down and was superfused with astandard solution. The standard solution contained (in mM) 100.0 NaCl, 2.5KCl, 1.6 MgCl2, 1.0 CaCl2, 18.0 NaHCO3 and 10.0 D-glucose and was bubbled
with 95% O2/5% CO2. To hold the ganglion cell bodies near the electrodesurface, a Teflon ring frame holding a tightly stretched sheet of transparent
dialysis membrane (50-kDa exclusion limit) was inserted into the recording
chamber over the retina. Bicuculline (10 mM) or TPMPA (10 mM) was
dissolved in the standard solution and bath-applied. Light-evoked spike
discharges from ganglion cells were picked up by a multi-electrode array (8 8 array, electrode size 50  50 mm, interpolar distance 300 mm, MED-P5305,
Alpha MED Sciences). The signals were amplified by a multi-channel

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differential amplifier and stored on a digital audio tape at a 24-kHz samplingrate. The spikes originating from an arbitrary ganglion cell were sorted by
the template-matching technique26. Light stimuli presented on a cathode-ray
tube display (Iiyama) were projected onto the retina through optics. Parametersof light stimuli used for electrophysiological experiments were similar to thosefor behavioral experiments. Using a laser beam, we confirmed experimentallythat 101 of subtense corresponded to B1.0 mm on the retina. Each time weused a new piece of isolated retina, we first examined receptive field positions
and cell types from light-evoked spike discharges based on a previously
described method45.
Spike analyses. After spike sorting, peri-stimulus time histograms (PSTHs)
were constructed, and auto- and cross-correlations were calculated with a bin
width of 2 ms in a 7160 ms range. Shift predictors were computed to evaluate
correlations from stimulus-locked coordination. The pattern of shift predictors
was almost flat in all cases (Fig. 5a, inset). To investigate the temporal profile of
spike trains simultaneously recorded from multiple ganglion cells, an ensemble
spike train was created by superimposing the simultaneous spike trains. The
strength of oscillations was assessed from the power spectrum, which was thefast Fourier transform (FFT) of the autocorrelogram calculated from theensemble spike train. An oscillation index was defined as the ratio of the peak
power in the g range (20 to 60 Hz) to the mean power between 150 and 250 Hz
in the power spectrum, because the power spectrum showed no peaks beyond
150 Hz46 (Figs. 2,4,6 and 7). We extracted the synchronized event where spikes
were generated within 2 ms in multiple (Z2) dimming detectors and createdthe synchronized event train. The occurrence time of the synchronized event
was defined as the center of the bin that included multiple spikes. The
autocorrelogram and power spectrum were calculated from the synchronized
event train. An oscillatory synchronization index was defined as the peak powerin the g range to the mean power between 150 and 250 Hz in the power
spectrum. A synchronization index was defined as the ratio of the number ofcoincidences at zero time shift in the raw cross-correlogram to the mean valueof the shift predictor (7160 ms) for each cell pair. In time-resolved slidingwindow cross-correlograms, the number of coincidences of the raw crosscorrelogram for each window (200-ms width) was normalized to the mean
number of coincidences of the shift predictor for the corresponding window
to avoid the effect of changes in discharge rate, and the window was moved in
20-ms steps.
Note: Supplementary information is available on the Nature Neuroscience website.

ACKNOWLEDGMENTS
We thank L.H. Pinto, T. Takahashi, I. Arai and J. Hasegawa for discussion andcomments and Y. Horiuchi for excellent technical assistance. This work was
supported by Grant-in-Aid for Scientific Research (12053212 and 17022014 to
M.T., 14710040 and 17730424 to H.I., 1610444 to M.G.) and the Special
Coordination Funds for Promoting Science and Technology (The
Neuroinformatics Research in Vision Project to M.T.) from the Ministryof Education, Science, Sports and Culture. M.G. is a research fellow of theJapan Society for Promotion of Science.
COMPETING INTERESTS STATEMENT
The authors declare that they have no competing financial interests.
Received 3 March; accepted 8 June 2005
Published online at http://www.nature.com/natureneuroscience/

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