0042-6989/92 $5.00 + 0.00 Copyright 0 1992 Pergamon Press plc

Vision Res. Vol. 32, No. 3, pp. 541-547, 1992 Printed in Great Britain. All rights reserved

Directional Asymmetry of the Frog Monocular Optokinetic Nystagmus: Cholinergic Modulation BLANDINE

JARDON,*$

YEN1 H. YUCEL,P NICOLE

BONAVENTURE*

Received 2 February 1991; in revisedform 20 June 1991

The frog monocular optokinetic gaze nystagmus (OKN) was studied by coil recordings after intravitreal administration of cholinergic drugs into the closed eye. Before injection, the frog displayed OKN for stimulations in the temporo-nasal (T-N) direction only. The injection of muscarinic agonists, as well as that of nicotinic antagonists, provoked the appearance of a naso-temporal (N-T) component, the slow phase velocity gain then being strongly and signtjicantly increased. The abolition of the OKN directional asymmetry indicates that acetylcholine seems to act in opposite ways through muscarinic and nicotinic binding sites. The GABAergic and cholinergic systems may interact to generate and modulate OKN in the frog.

Optokinetic nystagrnus receptors

Acetylcholine

Subcortical visual pathways

INTRODUCTION

optokinetic nystagmus (OKN) is a visuomotor reflex by which an image is stabilized on the retina, during the movements of the animal or of its visual environment. It is composed of slow phases in the direction of the visual pattern motion, and of resetting fast phases. In lower vertebrates and in monocular viewing conditions, the horizontal OKN is asymmetrical. The stimulation in the temporc+nasal (T-N) direction is always more efficient than the stimulation in the naso-temporal (N-T) direction in evoking the reflex. The origin of the directional asymmetry of horizontal monocular OKN is not well known. It has been related to the absence of a fovea (Tauber & Atkin, 1968), to the total decussation of the optic nerve (Fukuda, 1959), to the lateral position of the eyes (Gioanni, Rey, Villalobos & Dalbera, 1984) or the low cortical development, but none of these hypotheses explains completely the absence of the OKN directional symmetry. The GABAergic system was previously shown to be involved in the control of the directional asymmetry of the monocular frog OKN: indeed the administration The

*D.N.B.C., Centre de Neurochimie du CNRS, 5 rue Blake Pascal, F-67084 Strasbourg-Cedex, France. TDepartment of Ophthalmology, Faculty of Medicine, The University of British Columbia, 2550 Willow Street, Vancouver, B.C., Canada V5Z 3N9. $To whom all correspondence should be addressed.

Frog

Muscarinic and nicotinic

of GABA antagonists, either by systemic route (Bonaventure, Wioland & Bigenwald, 1983; Bonaventure, Wioland & Jardon, 1985; Yiicel, Jardon, Kim & Bonaventure, 1990), or directly into the pretectal nuclei (Yticel, Jardon & Bonaventure, 1991), provoked a large increase in the N-T component, up to suppressing the directional asymmetry of the reflex. The aim of the present study was to determine whether the cholinergic system also plays a role in the determination of the directional asymmetry of the frog OKN. We have recently shown that in a monocular viewing condition, an intravitreal administration of acetylcholine (ACh) muscarinic agonists or nicotinic antagonists into the open eye provoked the disappearance of the head OKN triggered by this injected eye. When administered into the closed eye, or intraperitoneally, these drugs induced the appearance of a N-T component (absent in the control) in the head OKN triggered by the noninjected open eye (Bonaventure, Jardon, Wioland, Yiicel & Rudolf, 1988). In contrast, muscarinic antagonists or nicotinic agonists, injected into the open or into the closed eye, did not modify the monocular OKN of the frog. In this previous study, the head OKN was evaluated by visual inspection. The parameter measured was the OKN extinction frequency, i.e. the highest visual image frequency still provoking a head OKN. By the use of the search coil technique, we intended here to quantify more precisely the effects of muscarinic agonists and nicotinic antagonists on the frog monocular OKN, and to test the involvement of the central cholinergic system in the directional asymmetry of the reflex. 541

542

BLANDINE

Based upon results previously obtained, monocular OKN triggered by the open eye was recorded when drugs were injected into the closed contralateral eye only. Indeed, as previously indicated, the oculomotor reflex totally disappeared following injection of cholinergic muscarinic agonists or nicotinic antagonists into the open eye. In the frog, eye OKN is weak and eye movements are of small amplitude (Dieringer & Precht, 1982); their occurrence was even denied (Birukow, 1937). On the contrary, head OKN is more developed. That is why, in this study, we have recorded gaze OKN, which is the result of eye and head OKN.

Gaze monocular

OKN was recorded in frogs (Rana

esculenta) by means of the search coil technique, before

and after injection of cholinergic muscarinic agonists, or of nicotinic antagonists, into the closed non recorded eye. Stimulation

The frogs were placed in an optokinetic drum (300 mm in dia and 450 mm in height) with alternative black and white vertical stripes, dist~buted equally on its inner surface (10 mm wide). The drum was rotated clockwise and counterclockwise at constant speeds varying between 0.4 and 50deg/sec, by means of an electronic control system. The range of the constant drum speeds used was between 1 and 9 deg/sec for gaze OKN. Room ill~ination was kept constant at 80 lx at the level of the frog’s eye. Gaze OKN recording In order to record gaze OKN, we used a magnetic coil system as described by Koch (1977). One pair of coils (ZOOmm dia) carrying a current of 50 kHz frequency, generates a homogenous magnetic field. These coils were mounted on an immobile platform. The sensing coil (1 mg, diameter of the copper wire 50 pm, inner diameter of the coil 2 mm, 70 turns, provided by Sokymat, Switzerland), fixed on the eyeball and oriented perpendicularly to the interaural axis, was placed in the center of the magnetic field. The voltage in the sensing coil, proportional to the sine of the horizontal angular displacement, was amplified, rectified, filtered and recorded on a paper recorder (BBC). These voltages were digitized through an analog-to-digital converter, stored in the memory of a PC/AT computer, and used to calculate the gain of the OKN slow phase. To record monocular OKN, the lids of one eye were sutured while the sclera of the other was exposed by removing the superior eyelid, under local anesthesia (Cebesine, Chauvin Blache). The animal’s head was free, the frog’s hind legs were restrained by a plaster on the immobile platform, and the sensing coil secured under local anesthesia on the sclera with a drop of glue just before the experiment. The electrical connection between this coil and the detection equipment was made by a pair

JARDON

et al.

of flexible isolated wires. The animal was placed in the optokinetic drum on the immobile platform, the sensing coil at the center of the magnetic field. Before each recording, the system was calibrated: the linear relationship between the angular displacement of the sensing coil and the voltage was measured. Then the voltage induced in the sensing coil by a displacement of 1 deg was calculated. The speed of the slow phase was measured from eye movement linear tracings, after elimination of both components of the resetting fast phases. Indeed, in the frog, the gaze resetting fast phases, like the eye resetting fast phases, may be divided into two components: a primary resetting fast phase carrying the eye and the head back across its center position at rest, and a secondary mov~ent, smaller in amplitude, similar in velocity but opposite in direction (Dieringer, Precht & Blight, 1982). The slow phase speed and the slow phase velocity gain (the ratio between the slow phase speed and the drum speed) were calculated by software developed in the laboratory. The muscarinic agents used were ACh musca~nic agonists, the antagonists failing to provoke any effect on frog OKN (Bonaventure et al., 1988); they were DLmuscarine chloride and oxotremorine sesquifumarate. The nicotinic agents used were only ACh nicotinic antagonists, the agonists being without action upon the reflex. The nicotinic antagonists were hexamethonium bromide, D-tubocurarine chloride and a-bungarotoxin. All drugs were provided by Sigma. The concentrations used were respectively: 5 x lop4 M for the muscarinic agonists (muscarine and oxotremorine), and 4 x lop5 M for hexamethonium, 2 x 10e3 M for D-tubocurarine and 5 x lop6 M for a-bungarotoxin. These are of the same order than the concentrations for which maximal effects were observed at the retinal level (Bonaventure, Jardon, Wioland & Rudolf, 1987). All these agents were diluted in phosphate buffer 0.02 M (pH = 7.4), and kept at 4°C for 1 week, except muscarine and a-bungarotoxin which were prepared daily. Thirty microliters of the solution were injected intravitreally by means of a microsyringe into the closed eye, under local anesthesia (Cebesine, Chauvine Blache). Gaze OKN was recorded before administration of the drug, as well as 1 and 3 hr afterwards. Some recordings were made 24 hr after the drug administration, to test the reversibility of its effects. Each animal has received only one drug injection, and was used for only one experiment. For testing the effects of both cholinergic agonists and of the three nicotinic antagonists, 30 frogs were used and divided into five groups. Thus six different animals were tested with each drug, but were taken into account only the frogs which totally recovered from the drug injection. From the six animals tested in each experimental condition, six recovered from the hexamethonium injection (n = 6). However, only four recovered completely their control monocular OKN after muscarine, oxotremorine, D-tubocurarine or a-bungarotoxin. Thus, IE= 4 for each of these groups. In this way, six successful experiments were achieved for each drug, but all of them have not been taken into account.

CHOLINERGIC

MODULATION

For statistical treatment, the standard deviation was noted in parentheses after the median value. We used the Wilcoxon signed ranks test and we indicated the level of significance (P) (Conover, 1971). RESULTS (I)

543

OF THE FROG OKN

and that evoked by a N-T stimulation was statistically significant (P c 0.005) with all drum speeds tested (1, 3, 6 and 9 deg/sec). (2) The injection of the vehicle (phosphate buffer 0.02 M, pH 7.4) had no effect on gaze OKN parameters (n = 4). No significant differences with the control values were observed.

Control conditions

(1) Before injection (n = 26), in a monocular viewing condition, no spontaneous eye or head movement was recorded. The frog’s eye and head followed predominantly the stripes moving in the T-N direction, the stimulation in the N-T direction being significantly (P c 0.005) less efficient (Figs 1 and 3). For T-N stimulation, frogs displayed a gaze OKN with slow phases following the stripe motion and resetting fast phases recentering head and eye position. The average velocity gain measured with a drum speed of 1 deg/sec was 0.591 ( f 0.215); it progressively decreased with stimulus velocity, reaching 0.138 (& 0.069) when the drum speed was 9 deg/sec (n = 26) (Figs 2 and 4). For N-T stimulation, the frog’s head or eye did not follow the stripes, or did it very slowly with no resetting fast phases: The average velocity gain was 0.067 (kO.055) for a drum speed of 1 deg/sec. Before any injection, the difference between the velocity gain of gaze OKN evoked by a T-N stimulation

(II) Effects of muscarinic agonists After drug injection, no spontaneous head or eye movement was observed. For T-N stimulation, no change was noticed in the monocular horizontal gaze OKN when compared to that recorded before injection: the difference in the velocity gain between before (control) and after muscarine injection was not significant (P > 0.2) (n = 4). Following oxotremorine administration, the average velocity gain did not change significantly from the control value (P > 0.2) (n = 4) (Figs 1 and 2). For N-T stimulation, the frogs displayed a gaze OKN with slow phases following the stripe motion, and resetting fast phases which did not exist in the control. The average velocity gain increased significantly for all drum speeds tested (P c 0.05) and for both injected drugs (Figs 1 and 2). These effects were reversible less than 6 hr after injection. The difference between the velocity gain of

CONTROL

CONTROL

N-

I

I--

OXOTREMORINE

N-T

?-Lb--k -

I

Tt

9’,6 f_ W-T

FIGURE 1. Coil recordings of monocular gaze OKN at different drum speeds before (control) and 1 hr after muscarine (left) or oxotremorine (right) injection into the closed eye. The speed and the direction of the stimulus are indicated on the left of each recording. Arrows point to onset and offset of the stimulation. Calibration: vertical bars, angular displacement of 5”; horizontal bars, 10 set duration.

544

BLANDINE

JARDON

el al.

CONTROL

BE 5.10-4

1.0 _

HEXAMETHONIUM

T-N

Y

0.a

D-WBOCURARlNE

CONTROL

0.0 0.4 0.2 0 9

0

3

1 0 DRUM

‘\bi L

WEED”(~~,~~3

a

0

FIGURE 2. Group respective mean values of slow phase velocity gain of monocular gaze OKN before (circles) and 1 hr (triangles) after muscarine (n = 4 frogs, top) or oxotremorine (n = 4 frogs, bottom) injection into the closed eye. The velocity gain is plotted on the ordinate and the drum speed (in deg/sec) on the abscissa. The OKN gain in response to T-N stimulus is drawn on the right (open symbols) and the OKN gain in response to N-T stimulus on the left of the graph (solid symbols). The vertical bars indicate the standard deviation.

CONTROL

U -6UNCAROTOXIN

gaze OKN evoked by a T-N stimulation and that evoked by a N-T stimulation, which was significant before injection (above mentioned), was no longer significant after muscarinic agonist administration (P > 0.2). After muscarine injection, and for a drug speed of 9 deg/sec, the difference was significant (P < O.OS), but reverse, i.e. in favor of the gaze OKN velocity gain evoked by a N-T stimulation. (IZZ) Efects of nicotinic antagonists No spontaneous head or eye movement was elicited after drug injection. For T-N stimulation, no change could be recorded in the gaze OKN velocity gain after nicotinic antagonists administration, for all drum speeds tested (P > 0.1) (Figs 3 and 4). For N-T stimulation, frogs displayed a gaze OKN with slow phases following the stripe motion, and head and eye resetting fast phases, contrary to what was recorded before injection. One hour after drug administration, the average velocity gain was increased significantly for all drum speeds used (P < 0.05), and with the three drugs (hexamethonium, D-tubocurarine or cr-bungarotoxin, (Figs 3 and 4). These effects were reversible less than 15 hr after injection. The difference between the OKN velocity gain evoked by a T-N stimulation and that evoked by a N-T stimulation was no longer significant (P > O.l), except after hexamethonium at the highest drum speeds (6 and

FIGURE 3. Coil recordings of monocular gaze OKN at two drum speeds (1 and 3 deg/sec) before (control) and 1 hr after hexamethonium (top), o-tubocurarine (middle) or a-bungarotoxin (bottom) injection into the closed eye. The speed and the direction of the stimulus are indicated on the left of each recording. Arrows point to onset and oflset of the stimulation. Calibration: vertical bars, angular displacement of 5”; horizontal bars, 10 set duration.

9 deg/sec) (P < 0.05). Following D-tubocurarine and CXbungarotoxin injection, at drum speeds respectively 3 and 1 deg/sec, the difference was significant but reverse, i.e. in favor of the velocity gain of gaze OKN evoked by a N-T stimulation (P < 0.05). DISCUSSION

In this study, gaze OKN was recorded, not only eye movements. In gaze OKN, both eye and head positions are measured simultaneously. Inputs from retina, neck

CHOLINERCZC

MODULATION

OF THE FROG OKN

545

asymmetry displayed by the OKN triggered by the open non injected eye. The intraperitoneal administration of these drugs gave identical results. The slow phase velocity gain of the N-T component, which was significantly lower than that of the T-N component in the control, became identical after injection of the drugs; the T-N component velocity gain was not modified. These data are in agreement with our previous observations, based on the quantifi~tion of the OKN extinction speed, namely the highest frequency of stimulation which still evokes a head OKN (Bonaventure et al., 1988). In these previous experiments, an involvement of cholinergic mechanisms in the directional asymmetry of monocular head OKN was shown. The muscarinic agonists and the nicotinic antago~sts, when injected into the open eye, provoked the suppression of the OKN related to this injected open eye. When administered into the closed eye or intraperitoneally, these drugs provoked the appearance of a N-T component (absent in the control) in the OKN triggered by the contralateral non injected eye ~Bonaventure ef af., 1988). All these results suggested that cholinergic drugs intravitreally injected act through two distinct mechanisms:

m”

owtd

w

.sfEEo”&g/.)3

FIGURE 4. Group respective mean values of slow phase velocity gain of monocular gaze OKN before (circles) and 1 hr (triangles) after hexamethonium (n = 6 frogs, top), D-tubocurarine (n = 4 frogs, middle) or a-bungarotoxin (n =4 frogs, bottom) injection into the closed eye. The velocity gain is plotted on the ordinate and the drum speed (in degjsec) on the abscissa. The OKN gain in response to T-N stimulus is drawn on the right (open symbols) and the OKN gain in response to N-T stimulus on the left (solid symbols) of the graph. The vertical bars indicate the standard deviation.

proprioception and semicircular canals interact in this complex system; thereby the analysis of results is more difficult than that made after eye OKN recordings alone. But eye OKN was not easily recorded in this study, eye movements being of weak amplitude with scarce fast phases. However, in some experiments, eye OKN was recorded, and results were qualitatively similar to those obtained after gaze OKN recordings. The horizontal OKN of the frog is asymmetrical in monocular viewing condition, the T-N stimulation being more efficient than the N-T in evoking the reflex, as it was already observed by Birukow (1937), Dieringer and Precht (1982), Bonaventure et al. (1983, 1985, 1988), Yiicel, Jardon and Bonaventure (1989) and Yeeel et al. (1990). The intravitreal administration of cholinergic muscarinic agonists (muscarine, oxotremorine) or of nicotinic antagonists (hexamethonium, D-tubocurarine, a-bungarotoxin) into the closed eye suppressed the

a retinal mechanism evidenced by the suppression of the OKN triggered by the injected open eye, without knowing the exact origin of this effect; a central mechanism responsible for the monocular asymmetry, this mechanism being evidenced by the appearance of a N-T component in the contralateral OKN after administration of either ACh muscarinic agonists or nicotinic antagonists. This central effect implies a direct action of the cholinergic drugs on central structures, where they are conveyed by the blood stream. This conclusion is supported by the remaining effect of the drug following optic nerve transection of the injected closed eye (Bonaventure et al., 1988). A supplemental argument is given by the fact that, when intravitreally injected, tritiated scopolamine is found in the brain (unpublished observations). However, it is obvious that ACh drugs act on all cholinergic receptors of the brain, but we do not know the exact site(s) of their action on OKN. We suggest that ACh could intervene in the horizontal OKN directional asymmetry by acting directly at the level of pretectal nuclei involved in the genesis of this reflex (Lazar, Alkonyi & Toth, 1983; Montgomery, Fite, Taylor & Bengston, 1982; Yiicel et al., 1991). Direct microinjections of ACh agonists and an~gonists into the accessory optic system (AOS) and pretectal nuclei will allow us to respond to this important question (work now in progress in our laboratory). A high density of muscarinic receptors was found in the pretectal nuclei of the rat (CortCs & Palacios, 1986; Mash & Potter, 1986; Regenold, Araujo & Quirion, 1989), and in the pigeon’s nucleus of the basal optic root (nBOR) (Dietl, Corms & Palacios, 1988). The synthesizing enzyme from ACh (ChAT) was found in the nBOR of the pigeon where nicotinic ACh receptors were also observed (B&to, Hamassaki, Keyser & Karten, 1989), similarly to what

546

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has been described in the rat and in the mouse (Swanson, Simmons, Whiting t Lindstrom, 1987). But their precise role is unknown. Nicotine has been demonstrated to increase the metabolic activity of the rat visual neurons (London, Dam & Fanelli, 1988), and at least 40% of retinal displaced ganglion cells projecting to the chick nBOR contain nicotinic ACh receptors (Keyser, Hughes, Whiting, Lindstrom & Karten, 1988). ACh might then be considered as an important modulatory system for AOS function, mediated by nicotinic receptors (Britto er al., 1989), but also by muscarinic receptors. The appearance of a N-T component following intravitreal administration of choline@ muscarinic agonists or of nicotinic antagonists, is comparable to that obtained in the same monocular condition using GABAergic antagonists. Allylglycine, picrotoxin, bicuculline and SR 95103, when administered into the closed eye or intraperitoneally, provoked the appearance of a N-T component and its increase up to the level of the T-N component (Bonaventure et al., 1983, 1985; Yticel et al., 1990). It appears then that ACh, like GABA, could be involved in the directional asymmetry of the frog’s monocular OKN, by acting in opposite ways through muscarinic and nicotinic receptors. However numerous questions remain. In particular, does ACh interact with the GABAergic transmission at the level of the pretectal nuclei of the frog? In this case what system could be controlled or modulated by the other? It was already shown that pretectal and AOS nuclei of the frog (Yiicel, Hindelang, Stoeckel & Bonaventure, 1988), the pigeon (Britto et al., 1989), the rat and the gerbil (Giolli, Peterson, Ribak, McDonald, Blanks & Fallon, 1985) contain numerous GAD (glutamic acid decarboxylase: the synthesizing enzyme for GABA)-positive terminals and perikarya. Knowing that GABA is responsible for the directional selectivity of visual neurons in the rabbit retina (Caldwell, Daw & Wyatt, 1978) and in the cat visual cortex (Sillito, 1977), it is likely that this neurotransmitter is responsible for the directional selectivity of frog pretectal neurons which could underlay the OKN directional asymmetry (Katte & Hoffman, 1980; Kondrashev & Orlov, 1976). From these data and those just previously described, ACh could rather be regarded as a neuromodulator (McCormick & Prince, 1986) at the level of pretectal neurons through muscarinic and nicotinic receptors as well. Thus, ACh, like GABA, is involved in the monocular OKN asymmetry, acting in opposite ways through muscarinic and nicotinic receptors. In a further study, we want to examine the possible relationship between both systems of neurotransmitter triggering the frog OKN.

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Acknowledgements-The authors wish to thank E. Dreyfus for electronic help, I-l. Salci for the software and G. Rudolf for iconography.