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1From Discoveries in Sight, Devers Eye Institute, Legacy Health System, Portland, Oregon; and the 2Kenneth C. Swan Ocular Neurobiology Laboratory, Casey Eye Institute, Oregon Health Sciences University, Portland, Oregon.
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Abstract |
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METHODS. Unilateral elevation of IOP was produced by hypertonic saline injection into an episcleral vein in 20 adult male Brown-Norway rats. IOP was measured in both eyes of awake animals four to five times per week. After 5 weeks, animals were dark adapted overnight (>12 hours) and full-field electroretinograms (ERGs) were obtained simultaneously from both eyes. Scotopic ERG stimuli were brief white flashes (–6.64–2.72 log cd-s/m2). Photopic responses were also obtained (0.97–2.72 log cd-s/m2) after 15 minutes of light adaptation (150 cd/m2). Eyes were processed the following day for histologic evaluation by light microscopy, including masked determination of optic nerve injury grade (ONIG; 1, normal; 5, severe, diffuse damage).
RESULTS. Among experimental eyes, the group average IOP (±SD) was 34.5 ± 4.1 mm Hg, whereas the average for control eyes was 28.1 ± 0.5 mm Hg (t = 7.1, P < 0.0001). The average ONIG for experimental and control eye groups, respectively, was 3.4 ± 1.7 and 1.0 ± 0.02 (t = 6.3, P < 0.0001). The ONIG increased with mean IOP in experimental eyes (r2 = 0.78, P < 0.0001) and was unrelated to mean IOP in control eyes (r2 = 0.09, P = 0.18). In experimental eyes with relatively mild IOP elevation (mean IOP < 31 mm Hg) and no structural (histologic) damage to the optic nerve evident by light microscopy (ONIG = 1.1 ± 0.2, n = 5), there was a selective reduction of the positive scotopic threshold response (pSTR; P < 0.001), whereas other ERG components remained unaltered. In four of the five eyes, pSTR amplitude was reduced by more than 50%, whereas all five had normal scotopic a-wave, b-wave, and OP amplitudes. Eyes with mean IOP of more than 35 mm Hg had reduced a-wave, b-wave, and oscillatory potential (OP) amplitudes.
CONCLUSIONS. As demonstrated by prior studies, selective loss of the pSTR is indicative of selective retinal ganglion cell (RGC) injury. In this rat model of experimental glaucoma, selective RGC functional injury occurred before the onset of structural damage, as assessed by light microscopy of optic nerve tissue. The highest IOP levels resulted in nonselective functional loss. Thus, in rodent models of experimental glaucoma, lower levels of chronically elevated IOP may be more relevant to human primary chronic glaucoma.
The ERG technique most typically used to study retinal function in rodent models is the dark-adapted (scotopic) full-field ERG. However, it has long been recognized that the full-field ERG is not particularly useful for assessment of GC function.2 Rather, the pattern-ERG (PERG) has received extensive scrutiny and prevailed as one of the most useful techniques for this purpose.2 16 17 Although it has been used successfully in rodents,2 18 the PERG is technically much more difficult to record than the full-field ERG. Hence, it is of interest that careful investigations of the dark-adapted, full-field ERG have shown that the response to a very dim stimulus, near the scotopic threshold, is a reflection of inner retinal activity in cats,19 20 21 mice,22 rats,23 24 monkeys,25 26 and humans.27 28 Accordingly, this ERG response has been called the scotopic threshold response (STR).19 Recently, the STR of the rat has been shown to be directly dependent on intact RGC function,24 suggesting that it may be suitable for assessment of function in experimental models of glaucoma in the rat.
Previously, studies that have used the full-field ERG to monitor retinal function in rat experimental models of glaucoma have examined only the response to relatively bright stimulus flashes under scotopic or photopic (light-adapted) conditions.7 11 13 However, alterations in the rat ERG response to these brighter full-field flashes, particularly under scotopic conditions, are most likely to represent functional damage to retinal cells other than RGCs.24 Therefore, the purpose of the present study was to examine the full-field ERG response over a wide range of stimulus intensity, to include the STR, after 5 weeks of elevated intraocular pressure (IOP) in a rat model of experimental glaucoma. In particular, our goal was to compare functional changes across various levels of chronically elevated IOP and to determine what range might result in selective RGC functional loss.
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Methods |
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Electroretinography
Animals were dark adapted overnight (>12 hours) and prepared for recording under dim red light (
> 600 nm). Anesthesia was initially induced with an intramuscular injection of ketamine (55 mg/kg, Ketaset; Fort Dodge Animal Health, Fort Dodge, IA), xylazine (5 mg/kg, X-ject E; Phoenix Scientific Inc., St. Joseph, MO) and acepromazine maleate (1 mg/kg, Aceproject; Phoenix Scientific, Inc.). Supplemental anesthesia was provided approximately 50 minutes after initial induction using a mixture of ketamine, xylazine, and acepromazine (30:2:1 mg/kg, intramuscularly). Pupils were dilated with 1 drop each of 0.5% tropicamide (Alcon Laboratories, Inc.) and phenylephrine (2.5%, Bausch and Lomb Pharmaceuticals, Inc., Tampa, FL). Corneal anesthesia was achieved with 1 drop of 0.5% proparacaine hydrochloride (Alcon Laboratories, Inc.). Animals were lightly secured to a stage with Velcro strips across the upper and lower back to ensure a stable, reproducible position for ERG recording. Body temperature was maintained between 37°C and 38°C with a pumped-water heating pad (TP500 T/Pump; Gaymar Industries, Orchard Park, NY) that was fixed to the top of the stage. The duration of the ERG recording session was 75 minutes for each animal, after which animals fully recovered from anesthesia while resting on a heated pad.
Full-field ERGs were recorded (UTAS-E3000; LKC Technologies, Gaithersburg, MD) in both eyes simultaneously with custom silver-chloride electrodes. The tip of the active electrode was placed at the corneal apex and was referenced to a ring-shaped electrode positioned against the scleral conjunctiva around the equator of the eye. Eyes were lubricated after electrode placement and periodically throughout the session with 1.0% carboxymethylcellulose sodium (Allergan, Irvine, CA). A platinum electrode (Grass-Telefactor, West Warwick, RI) placed in the tail served as the ground. Simultaneous recording from both eyes effectively halved the recording time and allowed ERGs to be obtained from the control and treated eyes under identical states of anesthesia and adaptation.
Stimuli were brief white flashes (xenon arc discharge, x = 0.32, y = 0.33) delivered through a Ganzfeld integrating sphere (UTAS-3000; LKC Technologies). Stimulus intensities were measured with a calibrated photometer (Spectra Pritchard PR-1980B; Photo Research, Chatsworth, CA) with a (human) scotopic luminosity filter in place. STR responses were obtained for flash intensities ranging from –6.64 to –3.30 log cd-s/m2 in 0.2-log-unit increments, by averaging 20 to 60 responses per intensity (60 for the dimmest and 20 for the higher intensities), with an interstimulus interval of 2 seconds. Scotopic ERGs obtained for all intensities above –3.30 log cd-s/m2 were recorded as single flash responses. For stimulus intensities between –3.04 to 2.72 log cd-s/m2 the interval between flashes was progressively lengthened from 10 to 120 seconds to allow complete recovery of b-wave amplitude. After completion of the scotopic ERG intensity series, animals were light-adapted for 15 minutes to a steady white background (150 cd/m2, x = 0.44, y = 0.41). Photopic flash responses were recorded for intensities between 0.97 and 2.72 log cd-s/m2 in 0.25-log-unit increments. Each record was an average of 20 responses obtained with a 2-second interstimulus interval. STR records were acquired at 1 kHz with high- and low-pass filters set to 0.3 and 30 Hz, respectively. All other ERG records were acquired at 2 kHz with high- and low-pass filters set to 0.3 and 500 Hz, respectively.
ERG Data Analysis
ERG component amplitudes were measured relative to prestimulus baseline at fixed times after the stimulus. Criterion times were chosen to correspond with the peak (120 ms) and trough (220 ms) of control responses to dim flashes. For responses to brighter flashes, an 8-ms criterion time was used to measure a-wave amplitude. The amplitude of the photopic b-wave was measured using a 50-ms criterion time. To measure the amplitudes of scotopic and photopic oscillatory potentials (OPs), raw data were first band-pass filtered (–3 dB at 50 and 280 Hz), then the root-mean-square (RMS) amplitude of the entire OP complex, beginning at the trough preceding the first OP and ending at the trough after the last OP, was summed.
Statistics
Analysis of variance (ANOVA; Prism, ver. 4.0; GraphPad Software, Inc., San Diego, CA) was applied to test the null hypotheses, which in general, could be stated as no difference between control and experimental eyes (i.e., no treatment effect). Two-way ANOVA (ERG amplitude vs. treatment and intensity) was used to evaluate the effect of experimental treatment for each ERG parameter. In all cases, the 
level was adjusted to 0.01 to correct for multiple comparisons (i.e., to limit type 2 errors, given that seven ERG parameters were evaluated). One-way ANOVA (ERG amplitude versus treatment) was applied to the analysis presented in Figure 5 . Bonferroni post hoc tests were used to evaluate differences between experimental groups by intensity. Nonparametric ANOVAs with Dunn post hoc tests were used to evaluate differences between experimental groups for optic nerve injury grade.
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Optic Nerve Head and Retinal Histology.
All eyes were postfixed in a 4% formaldehyde-paraformaldehyde solution after enucleation. Eyes were processed by paraffin embedding, and longitudinal sections (6 µm) were cut through the globe along the anterior–posterior axis. Thus, retinal sections were vertically oriented, containing both inferior and superior retina. Sections were deparaffinized and rehydrated, stained with 0.1% Mayer hematoxylin (Sigma-Aldrich, St. Louis, MO) and mounted for microscopy and photography. Sections closest to the plane through the center of the anterior optic nerve were used to compare experimental with control eyes, thus matching lateral eccentricity as best as possible.
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Results |
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Figure 1C shows that the ONIG increased with mean IOP in experimental eyes (r2 = 0.78, P < 0.0001), but not in control eyes (r2 = 0.09, P = 0.18). The average ONIG in the experimental and control eye groups, respectively, was 3.4 ± 1.7 and 1.0 ± 0.02 (t = 6.3, P < 0.0001). In experimental eyes, the mean IOP was a better predictor of ONIG than was peak IOP (r2 = 0.66). Thus, structural and functional outcome measures are henceforth related to mean IOP.
For the initial analyses of retinal function, eyes were grouped by degree of IOP elevation: group 1 consisted of all control eyes (n = 20); group 2, experimental eyes with mean IOP less than 31 mm Hg (n = 5); group 3, IOP 31 to 35 mm Hg (n = 6); group 4, IOP more than 35 mm Hg (n = 9). Table 1 provides summary data for these four groups.
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In contrast, the two groups with higher mean IOP developed significant morphologic changes in the optic nerve (P < 0.0001, Kruskal-Wallis ANOVA, see Table 1 ). Group 3 eyes had an average ONIG of 3.1 (P < 0.01 vs. control eyes), and group 4 eyes had an average ONIG of 4.8 (P < 0.001 vs. control eyes). As shown in Figures 2C and 2D (middle row), eyes with higher ONIGs also manifested morphologic changes in the anterior optic nerve. In group 3 eyes with mild-to-moderate focal optic nerve damage (ONIG 
1.5–4.5), neural degeneration, and gliosis were evident within the anterior optic nerve, as shown by disorganization of the normal columnar structure and increased glial cell density (Figure 2C , middle). Retinal changes in this group, however, were not striking (Figure 2C , bottom).
Experimental eyes in group 4 with the highest IOP and the most severe optic nerve injury also had the greatest damage evident within the anterior optic nerve and retina (Figure 2D) . In this group, longitudinal sections through the anterior optic nerve revealed enlargement of the scleral canal and extensive gliosis. Retinal sections from most eyes in this group were thinner overall, with marked reduction of ganglion cell layer density. In some group 4 eyes, the inner nuclear layer appeared to be thinner and to contain fewer nuclei than control eyes.
Figure 3 shows ERG results for individual animals whose experimental eyes are representative for group 2 (column 3A), group 3 (column 3B), and group 4 (column 3C). Dark-adapted (scotopic) responses to increasing stimulus intensity are shown, beginning with the STR at the bottom of each column (–6.04 log cd-s/m2, approximately 0.6 log units above the ERG threshold), through the middle of each column where responses to bright flashes are shown (up to 2.22 log cd-s/m2), and on to the top of each column where light-adapted (photopic) responses are shown. In all cases, the bold records represent the responses of experimental eyes, and the thin traces show control responses from the fellow control eye. The isolated OPs are also shown to the right of the corresponding raw waveforms.
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The bold traces in Figure 3 show ERG data for one representative experimental eye from each of the three groups. The ERGs for a group 2 eye with relatively mild IOP elevation (mean IOP = 30.2) are shown in the left column (Fig. 3A) . Despite a lack of morphologic evidence for optic nerve or retinal damage (ONIG = 1.05), the pSTR was markedly reduced, a finding that was especially evident at the dimmest stimulus intensities. The nSTR was also substantially smaller than that of the control eye, but a small remnant negative potential persisted even at the dimmest stimulus intensity. All aspects of the scotopic responses to brighter flashes; however, were very similar between this eye and its fellow control: the a- and b-wave implicit times were identical with control levels, whereas amplitudes were approximately 5% to 10% lower. Although the summed amplitudes of the scotopic OPs were also similar to those of the control, the shape and timing of individual wavelets were slightly altered for moderate flash intensities. The photopic b-waves were also slightly smaller, compared with the control eye, but the photopic OPs were similar in the two eyes.
Figure 3B demonstrates the ERG findings for a group 3 animal with slightly greater IOP elevation (mean IOP = 31.1 mm Hg) and clear signs of optic nerve damage (ONIG = 3.1, mild-to-moderate focal optic nerve damage). In this eye, the pSTR appeared to be nearly completely eliminated, as the waveform never rose above baseline, whereas again, a small remnant nSTR persisted for flashes above –6.04 log cd-s/m2. The scotopic b-wave was substantially smaller and delayed in the damaged eye, as were a-waves for moderately bright flashes. However, the a-wave for the brightest stimulus flashes was only slightly smaller and slower than the control eye. Both scotopic and photopic OPs were well below control eye values, and the photopic b-wave was reduced by approximately 40%.
The ERGs for a group 4 animal with more substantial IOP elevation (mean IOP = 37.8 mm Hg) and severe diffuse optic nerve damage (ONIG = 5.0) are shown in Figure 3C . At this stage, the pSTR was completely abolished, leaving only a small negative waveform for responses up to –3.72 log cd-s/m2. The amplitudes of scotopic a- and b-waves, as well as photopic b-waves, were all reduced to less than 30% of the control eye. Similarly, both scotopic and photopic OPs were markedly attenuated.
The amplitude versus intensity functions for each ERG parameter, measured across the full spectrum of stimulus intensity, are shown in Figure 4 (note, amplitudes are measured at criterion times as described in the Methods section). Data for these intensity–response functions are grouped by IOP level as described in Table 1 and plotted as the group mean (±SEM).
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1 log unit) in comparison to the control (P < 0.0001). Post hoc evaluation by intensity revealed that the pSTR amplitude differences between group 2 eyes and control eyes were most significant for intensities between –5.36 and –4.97 log cd-s/m2 (P < 0.001). The nSTR amplitude (Fig. 4B) in group 2 eyes was also smaller than control amplitudes for all intensities up to –4.38 log cd-s/m2, where its saturated amplitude ultimately became equal to the control group maximum amplitude. The nSTR intensity–response function was also shifted to the right by nearly 1 log unit. The larger negative values in the group 2 eyes, compared with the control, for stimuli near –4.38 log cd-s/m2, represent loss of opposing positive potentials at the 220-ms criterion time.
As flash intensity increased, the amplitude of the scotopic b-wave (Fig. 4C) in group 2 eyes became more like that of the control group, eventually saturating at approximately 80% of the latter. Similarly, scotopic a-wave amplitude (Fig. 4D) was reduced by only approximately 10% in the group with mild damage. The amplitudes of both scotopic and photopic OPs were unaffected by this mild degree of injury (Figs. 4F 4G , respectively), whereas reduction of the photopic b-wave (Fig. 4E) was evident only at the highest flash intensities. Post hoc analysis by intensity revealed that none of the ERG parameters other than pSTR amplitude exhibited significant differences between group 2 eyes and control eyes. Thus, the pSTR amplitude differences represent selective functional loss in the lowest IOP group.
ERG abnormalities in group 3 eyes (Fig. 4 , open diamonds) were more widespread. The pSTR amplitude was 0 (or negative) until flash intensity surpassed –4 log cd-s/m2; representing more than a 2-log-unit increase in threshold. The negative pSTRs observed between –5 and –4 log cd-s/m2 represent the effect of an unopposed remnant negative potential which is apparent in Figure 3B . In fact, Figure 4B shows that there was a small remnant nSTR with a maximum amplitude that was approximately half that of the control eye group. Moderate elevation of mean IOP was also associated with a slightly larger reduction of the scotopic b-wave saturated amplitude (Fig. 4C) , as well as substantial losses in the scotopic a-wave (Fig. 4D) and OPs (Fig. 4F) . Scotopic b-wave (P < 0.001) and OP amplitude changes (P < 0.01) were most significant for lower intensities, whereas a-wave changes (P < 0.001) were most significant at higher intensities. The photopic b-wave (Fig. 4E) and OPs (Fig. 4G) were also attenuated in this group. Amplitude changes in these two photopic ERG parameters were most significant for flash intensities between 1.71 and 2.72 log cd/m2 (P < 0.001).
Lastly, the group of eyes with the highest IOP (>35 mm Hg; filled triangles) manifested the most severe functional abnormalities. Figures 4A and 4B show that the amplitudes of the pSTR and nSTR, respectively, were further reduced in group 4 eyes and that their intensity response functions were shifted farther to the right. Similarly, the scotopic b-wave and OP amplitudes were more significantly affected in group 4 eyes, as were photopic b-wave and OP amplitudes. For these parameters, relative amplitude differences and the intensity range over which significant amplitude differences were observed were both larger in group 4 eyes compared with the other three groups. In contrast, there was little additional decline in the scotopic a-wave amplitude between groups 3 and 4 (Fig. 4D) .
The sensitivity to detect functional loss was compared across the various ERG parameters. Figure 5 shows the distribution of amplitudes observed among the group of control eyes (n = 20) for each of the seven ERG components measured (scotopic ERG: pSTR, nSTR, a-wave, b-wave, OPs; photopic ERG: b-wave and OPs). In each case, the box plot represents the mean (horizontal hash mark) and interquartile range, while the whiskers outline the 5th and 95th percentiles of the control eye distribution. The symbols to the right of each control group distribution represent the individual data for the three groups of experimental eyes described earlier. Those data that fall below the lower limit of the "normal" range (lower whisker) can be considered abnormal relative to a fixed specificity of 95%. For clarity, the amplitude of each ERG component is shown for only a single representative intensity (pSTR and nSTR: –4.97; all others: 2.22 log cd-s/m2); amplitudes were measured as described in the Methods section. The overall effect of experimental treatment was significant (P < 0.0001) for each of the seven ERG parameters.
Figure 5 shows that the two groups of experimental eyes with the highest mean IOP had the poorest function, on average, across all ERG parameters, as expected from Figure 4 . Post hoc analyses revealed no significant differences between the mean amplitudes of group 3 (diamonds) and group 4 (triangles) for any of these seven ERG parameters. When the percentages of eyes with below-normal function were compared, groups 3 and 4 were also quite similar. Both of these groups had 100% of eyes below the normal limit for the pSTR and photopic OPs, and most eyes in both groups also had abnormally small photopic b-waves. Approximately half of the eyes in both groups had scotopic a-wave, b-wave, and OP amplitudes below normal limits.
More important, the results for group 2 (circles) revealed a more selective pattern of functional abnormalities. All the eyes in this group (n = 5) were within normal limits for the scotopic a-wave, b-wave, and OPs and most had normal amplitudes for the photopic b-wave and OPs as well. But the pSTR amplitude was normal in only one of these group 2 eyes and only two had normal nSTR amplitudes. Only the amplitude of the pSTR was found to be significantly different after post hoc comparisons between the mild damage group and control group (t = 3.8, P < 0.01).
The amplitudes of each ERG parameter (for the same intensities as Fig. 5 ) are plotted against mean IOP in Figure 6 . For each of the 20 experimental eyes in the study, amplitude is expressed relative to the amplitude of the fellow eye (%) so that comparisons can be made between ERG parameters. In addition, the 95% limits of agreement34 for interocular amplitude—that is, the range of interocular reliability—was calculated for each parameter based on data collected separately in 16 naive animals. One direction of the range is plotted in each panel (Fig. 6 , shaded zone) to show the criterion used to determine significance (P < 0.05) of a reduction in relative amplitude (note, the range is not symmetric around 1.0 on the linear scale used here).
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Discussion |
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These results suggest that selective RGC damage is produced by a relatively mild elevation of IOP. The rat STR, particularly the pSTR, is dependent on intact RGC function,24 but scotopic ERG responses to brighter flashes are only negligibly affected by substantial RGC loss.24 Taken together, these studies suggest that the highest levels of elevated IOP result in nonselective retinal damage, perhaps directly, but perhaps also by indirect mechanisms such as ischemia.35 36 37 38 Retinal ischemia is well known to affect the scotopic ERG b-wave in rodents,4 10 and if severe enough, also the a-wave5 12 15 —components that reflect inner nuclear layer and photoreceptor function, respectively.
Previous studies that have used the full-field ERG to monitor retinal function in rat experimental models of glaucoma have only examined the response to relatively bright stimulus flashes (WoldeMussie E, et al. IOVS 2003;44:ARVO E-Abstract 41).6 7 8 11 13 Alterations in the response to brighter flashes would be indicative of effects on retinal cells other than RGCs.24 This suggests that lower levels of elevated IOP should be sought in rodent models of experimental glaucoma for such models to be most relevant to human chronic open-angle glaucoma.
For mild elevations of IOP in the present model, RGC functional losses assessed using the STR were observed before structural changes evaluated using standard histologic techniques. The exquisite sensitivity of the scotopic psychophysical threshold, and subsequently also of the STR, are thought to depend on extensive pooling and progressive convergence of retinal signals from rods to rod bipolar cells and eventually to RGCs through AII amacrine cells and cone bipolar cells.19 22 23 28 39 40 41 Retraction of RGC dendritic arbors, as has been shown to occur in experimental glaucoma before RGC death,42 may well reduce the efficiency of signal processing within the inner plexiform layer and thus raise the threshold of the STR. In the present study, the STR intensity-response function was shifted rightward, suggesting a threshold elevation of approximately one log unit in the mild (selective) damage group. This is substantially larger than the effect that would be produced by a small reduction of maximally dilated pupil diameter (from 4.5 to 3.0 mm) observed in some of these eyes (the latter could account for 0.35 log units elevation). Elevated scotopic thresholds have been measured psychophysically in early human glaucoma43 44 45 and selective reduction of the STR has been observed in nonhuman primates with experimental glaucoma.26 However, selective STR abnormalities have not yet been reported in human glaucoma.46 Indeed, the human STR may not be as sensitive to RGC loss47 compared with the STR of rats24 or monkeys.26
In summary, selective RGC functional loss was observed in this experimental model of glaucoma before the onset of optic nerve structural changes, as assessed by standard histologic techniques and light microscopy of optic nerve tissue. Selective loss of the STR occurred at low levels of chronically elevated IOP. The highest IOP levels resulted in nonselective functional loss. Thus, in rodent models of experimental glaucoma, careful monitoring of IOP in awake animals is crucial, because lower levels of chronically elevated IOP may be more relevant to human primary chronic glaucoma.
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Footnotes |
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Submitted for publication December 30, 2003; revised February 6, 2004; accepted February 16, 2004.
Disclosure: B. Fortune, None; B.V. Bui, None; J.C. Morrison, None; E.C. Johnson, None; J. Dong, None; W.O. Cepurna, None; L.-J. Jia, None; S. Barber, None; G.A. Cioffi, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Brad Fortune, Discoveries in Sight, Legacy Clinical Research and Technology Center, 1225 NE Second Avenue, Portland, OR 97232; bfortune{at}discoveriesinsight.org.
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, n = 6), and 4 (
, n = 9). (A) pSTR (left) and nSTR (right); (B) scotopic a-wave (left) b-wave, (middle), and OPs (right); (C) photopic b-wave (left) and OPs (right).
31, 
35 mm Hg), and group 4 (D; IOP > 35 mm Hg). Top: portion of optic nerve cross-sections used for masked determination of optic nerve injury grade; middle: vertically oriented longitudinal sections through the anterior optic nerve; bottom: portion of same retinal cross-sections from a location centered 0.5 mm inferior to optic nerve.
, n = 20) and experimental eyes from groups 2 (•, n = 5), 3 (