Exp Brain Res (1992) 90:72-78

Experimental Brain Research �9 Springer-Verlag 1992

The pretectal cholinergic system is involved through two opposite ways in frog monocular OKN asymmetry B. Jardon and N. Bonaventure

Laboratoire de Neurophysiologie et de Biologic des Comportements, Centre de Neurochimie du C.N.R.S., 5, Rue Blaise Pascal, F-67084 Strasbourg Cedex, France

Received September 30, 1991 / Accepted February 18, 1992

Summary. Frog monocular horizontal optokinetic nys- tagmus (OKN) has been studied by coil recordings, be- fore and after unilateral microinjection of cholinergic drugs into the pretectum. The recorded eye was either contralateral or ipsilateral to the injected structure. Be- fore injection, monocular OKN displayed a directional asymmetry, reacting only to stimulations in the temporo- nasal (T-N) direction. The intrapretectal administration of a cholinergic muscarinic agonist (oxotremorine), as well as that of a nicotinic antagonist (D-tubocurarine), abolished the monocular OKN asymmetry, inducing the appearance of the naso-temporal (N-T) component; the difference between the slow phase velocity gain of both components was no longer significant. These data sug- gest that acetylcholine (ACh), at the level of the pretec- tum, acts in opposite ways through muscarinic and nico- tinic binding sites; monocular OKN asymmetry could result, at least partially, from a facilitating nicotinic effect and an inhibitory muscarinic effect. Possible interactions with other transmitter systems are discussed.

Key words: Optokinetic nystagmus - Directional asym- metry - Acetylcholine - Muscarinic receptors - Nicotinic receptors - Pretectum - Frog

Introduction

The optokinetic nystagmus (OKN) is a visuomotor reflex which stabilizes an image on the retina, with respect to movements of the animal or of its visual environment. It is composed of slow phases in the compensatory direc- tion, and of resetting fast phases in the opposite direc- tion. In monocular viewing conditions, lower vertebrates display an asymmetrical horizontal OKN, stimulations in the temporo-nasal (T-N) direction being always more efficient than stimulations in naso-temporal (N-T) direc- tion to induce the reflex; and in frogs, stimulation in the

Correspondence to: B. Jardon

N-T direction evokes almost no eye movements at all (Birukow 1937; Dieringer and Precht 1982).

Previous studies have shown that acetylcholine (ACh) is involved in frog monocular OKN asymmetry. Ad- ministration of ACh muscarinic agonists or of nicotinic antagonists into the viewing eye, totally abolished the head OKN triggered by this eye (Bonaventure et al. 1988). When injected either intraperitoneally or by in- travitreal route into the closed eye, these drugs induced the appearance of a N-T component in head and gaze OKN directed by the viewing eye (Bonaventure et al. 1988; Jardon et al. in press). These data have suggested that the appearance of this N-T component was due to a central effect of cholinergic drugs, conveyed by the blood stream to the central structures. Indeed, this effect was not suppressed following transection of the optic nerve of the injected closed eye (Bonaventure et al. 1988). However, in this experimental situation, it is clear that ACh drugs acted on all cholinergic receptors of the brain, and the problem remained to know the exact site(s) of their action on OKN. We had suggested that ACh could intervene by acting directly at the level of pretectum, involved in OKN genesis (Lazar et al. 1983; Montgom- ery et al. 1982; Yticel et al. 1991). This complex structure is composed of five nuclei: the posterior thalamic nucleus (PTn), the nucleus lentiformis mesencephali (nLM), the uncinate nucleus, and the posterocentral and pos- terolateral thalamic nuclei. The largest and better or- ganized are the PTn and the nLM. Each pretectal nucleus receives a direct retinal projection mainly from the con- tralateral eye (Montgomery et al. 1985). Electrophysio- logical studies have shown that pretectal cells respond preferentially to stimulation in the T-N direction, and are inhibited when the stimulation is in the N-T direction (Katte and Hoffmann 1980; Cochran et al. 1984).

Thus the aim of the present study was to see whether the effects of cholinergic drugs were, at least partially, direct effects on pretectal cells. For this purpose, we have recorded by the magnetic field-search coil technique monocular horizontal OKN of the viewing eye, before and after unilateral pretectal microinjection of ACh

Contralateral eye

preinjection postinjection

N-T

preinjection

1 deg/s N-T

Ipsilateral eye

postinjection

T - N ~

73

3 deg Is N - T ~

. - x

6 deg/s

N-T

lOs

N

I I , N-T ~ N-T ~ [

Fig. 1. Coil recordings of monocular eye 0 K N at different drum speeds, before and 1 h following unilateral microinjection of oxotre- morine into the nLM. Left: OKN recordings of the eye contralater- al to the injected nLM. Right: OKN recordings of the eye ipsilateral

N-T

6 deg/s

N-T

lOs

N-T

9 deg/s N-T N-T

to the injected nLM. The speed and the direction of the stimulus are indicated on the left of the recordings. Calibration: vertical bars: angular displacement of 5 deg; horizontal bars: 10 s duration

drugs. W e in jec ted a musca r in i c agonis t , oxo t r emor ine , or a n icot in ic an t agon i s t , D - t u b o c u r a r i n e , in to the n L M o f the frog. The viewing eye was ei ther con t r a l a t e r a l or ips i la te ra l to the in jec ted n L M .

A p o r t i o n o f this w o r k was r e p o r t e d in abs t r ac t f o rm ( J a r don et al. 1991). N ico t in i c agonis ts , in jected e i ther in to the v iewing eye or in to the c losed eye, were w i thou t effect on the f rog m o n o c u l a r O K N (Bonaven tu re et al. 1988); they were no t used in the p resen t s tudy.

Material and methods

Monocular eye 0 K N was recorded in frogs (Rana Esculenta) by the magnetic field-search coil technique, before and after unilateral microinjection of either oxotremorine, D-tubocurarine or atropine into the left nLM of the pretectum.

Stimulation

To evoke horizontal OKN, the animals were placed at the center of a drum (300 mm in diameter and 450 mm in height) with alternating black and white vertical stripes (10 mm wide), distribut- ed equally on its inner surface. The optokinetic drum rotated clock- wise and counterclockwise at constant speeds (1, 3, 6 and 9 deg/s) by means of a servo-controlled motor (Alsthom). Room illumina- tion was kept constant (80 lux) at the level of the frog's eye.

Search coil recording

In order to record eye OKN, a magnetic coil system was used (Koch, 1977). One pair of coils (200 mm in diameter) carrying a current of 50 kHz frequency generates a homogenous magnetic field. The sensor coil (1 rag, inner diameter 2 mm, 70 turns, Soky- mat) was fixed under local anesthesia (Cebesine, Chauvin-Blache) on the eyeball with a drop of glue; it was oriented perpendicularly to the interaural axis, and placed at the center of the magnetic field. The voltage in the sensor coil, proportional to the sine of the horizontal angular displacement, was amplified, rectified, filtered

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and recorded on a paper recorder (BBC). The system was calibrated before each recording by checking the linear relationship between the sensor coil angular displacement and the voltage induced in the sensor coil. The slow phase speed was measured by tracing the cumulative curve of at least three successive eye movements at steady state, after elimination of the eye resetting fast phases. The slow phase velocity gain (the ratio between the slow phase speed and the drum speed) was then calculated.

Surgery

Frogs were prepared the day before the experiment under general anesthesia (MS-222, Sandoz). A nut was fixed on the skull, to immobilize the head, and a permanent stainless-steel guide cannula (o.d. =0.4 mm, i.d.=0.3 mm) was chronically implanted using stereotaxic procedure. The coordinates, according to the atlas of Wada et al. (1980), were A/P=0.9 mm, M/L=0.5 mm with head angle up 20 deg; the intersection of the anterior border of the left tectum and the sagital midline was taken as reference. The cannula penetrated dorsoventrally 0.4 mm from the surface of the brain. The guide cannula as well as the nut were anchored to the skull using retaining screws and dental acrylic cement. A stainless-steel sterile mandrel (o.d. = 0.27 ram) of the same length was inserted into the guide cannula to avoid obstruction. The lids of the left eye or those of the right eye were sutured, in order to study the OKN triggered either by the eye contralateral or ipsilateral to the injected nLM.

Drugs

Oxotremorine sesquifumarate, D-tubocurarine chloride and atropine sulfate (all provided by Sigma, St. Louis, U.S.A.) were dissolved in phosphate buffered saline (PBS) (pH = 7.3). The same volume of PBS was injected as control. The concentrations used for each drug were determined from previous studies (Bonaventure et al. 1988; Jardon et al. 1992). They were respectively 10 -5 M for oxotremorine, 10 -4 M for D-tubocurarine, and 5.10 -4 M for atropine.

Drug injection and recording

Unilateral microinjections were performed in awake animals; a stainless-steel injection cannula (o.d.=0.28 mm, i.d.=0.18 mm) was introduced into the guide cannula, so that it extended 0.1 mm beyond the tip of the guide cannula. This injection cannula was connected to a 1 lal Hamilton microsyringe via polyethylene tubing filled with distilled water; it was filled by aspiration with the drug. A small air gap separated the two liquids. The drugs or vehicle were administered in a volume of 0.2 gl over 20 s; the injected quantity was 0.76 ng for oxotremorine, 68.17 ng for D-tubocurarine and 67.68 ng for atropine. Movement of the air gap down the tubing was indicative of a successful administration. The injection cannula was left in place for an additional 30 s following drug administration, and the mandrel was replaced into the guide cannula after that.

The sclera of the open eye was exposed 30 min before control recording, by removing the superior eyelid under local anesthesia (Cebesine, Chauvin-Blache). For recording, the frog's head was restrained by attaching the nut to the bar placed in the drum. Each animal was used once only, getting one drug microinjection only.

Histology

To detect the injection site, frogs were deeply anesthetized in MS-222 following 8 days of post injection survival time. After intracardiac perfusion with 0.9% saline followed by 4% formalin, brains were removed and placed in 4% formalin. Paraffinembedded brains were cut in 20 gm-sections and processed with Cresyl violet

stain. All animals in which the cannula track could not be clearly localized were excluded from this study.

Data analysis

For statistical treatment, the experimental data were expressed as the mean (=E standard deviation); the analysis of variance and the Wilcoxon signed ranks test (Conover 1971) were used.

Results

No spon taneous eye movements , in either light or dark- ness, were observed, irrespective of the drug injected.

Control conditions

Before any injection, frog's viewing eye followed pre- d o m i n a n t l y the stripes mov ing in the T - N direct ion

1.0

c -8 0.8 O']

o ~ 0.6

,.~ 0 . 4

o .

o ~ 0.2

0

A

o Oxotremorine []

~ I A N-T preinjection

I ~ t ~ ~ : T--NI postinjection

3 6 9 Drum speed (deg/s)

o 1.0 Oxotremorine p

o T-N ) c 0.8 A N-T preinjection A

0.6 �9 N-TI postinjeetion 03 >

~0

0.4 r- [3_

_o 0.2 O0

0 A- #. ~ ~__

0 3 6 9

B Drum speed (deg/s)

Fig. 2A, B. Mean values of slow phase velocity gain of monocular eye OKN before (open symbols) and 1 h following unilateral mi- croinjection of oxotremorine into the nLM (filled symbols). A Velocity gain of the OKN directed by the eye eontralateral to the injected nLM (n = 7). B Velocity gain of the OKN directed by the eye ipsilateral to the injected nLM (n = 7). The velocity gain is plotted on the ordinate and the drum speed (in deg/s) on the abscissa. The arrow indicates the injected nLM (square); the open circle stands for the viewing eye; the filled circle stands for the closed eye. The vertical bars indicate the standard deviation

Contralateral eye

preinjection postinjection

1 degis N-T ~"

/1 I , . j I

3 degls N-T

T - N ~ 10 s

6 deg/s

N - T ~

,4

9

Fig. 3. Coil recordings of monocular eye OKN at different drum speeds before and 30 rain following unilateral microinjection of D-tubocurarine into the nLM. Left: OKN recordings of the eye contralateral to the injected nLM. Right: OKN recordings of the

Ipsilateral eye

preinjection postinjection

75

1 deg/s N-T

3 deg/s N-T ~

l o s

.2-< N_T

T-N ~ f ~ 9 deg/s

N-T~ N-'F--~

eye ipsilateral to the injected nLM. The speed and the direction of the stimulus are indicated on the left of the recordings. Calibration: vertical bars: angular displacement of 5 deg; horizontal bars: 10 s duration

(n = 35). When the stimulation was applied in the N-T direction, no eye movement could be detected, irrespec- tive of the drum speed tested (Fig. 1, 3 and 5). The slow phase velocity gain of the T -N component was signifi- cantly (p < 0.005) higher than that of the N - T component (Fig. 2, 4 and 6).

Microinjection of the vehicle did not change the OKN directed by the eye either contralateral (n= 3) or ip- silateral (n = 3) to the injected nLM.

Effects of pretectal microinjections of oxotremorine

Contralateral eye OKN recordings. Immediately after the end of injection, frogs (n = 7) not only followed stripes

moving in the T-N direction, but also those moving in the N - T direction: slow phases and resetting fast phases were observed for both directions of stimulation (Fig. 1 left). The slow phase velocity gain of the T - N component was not significantly modified (p > 0.5) compared to that of the control (Fig. 2A). The slow phase velocity gain, which was almost nil for a N - T stimulation before injec- tion, increased significantly (/)<0.005) after oxotre- morine, and this was observed for the 4 drum speeds tested (Fig. 2A).

Ipsilateral eye OKN recordings. Frogs (n = 7), displayed an OKN with slow phases and resetting fast phases for both directions of stimulation (Fig. 1 right). The T-N component did not change significantly compared to its control value (p> 0.5) (Fig. 2B), and in this case also, the

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slow phase velocity gain of the N-T component in- creased significantly (p< 0.005) so that the differences observed between the gains of both components did not reach statistical significance (p > 0.1) (Fig. 2B). It must be noticed that the effect of oxotremorine upon the OKN directed by the eye ipsilateral to the injected structure was not immediate; the N-T component appeared 30 rain after the end of oxotremorine injection. This con- trasts with what was observed on the contralateral side, where the effect was immediate. The effect of oxotre- morine administration lasted about two hours and was totally reversible.

Effects of pretectal microinjections of D-tubocurarine

Contralateral eye OKN recordings. Frogs (n=6) dis- played an almost symmetrical monocular OKN immedi- ately after the end of d-tubocurarine injection. Slow phases and resetting fast phases were observed for both

c

03

Q_

0

1.0

0.8

0.6

0.4

0.2

0 0

D-Tubocurarine �9 o

I ~ i-_N f preinjeetion

�9 :-N t postinjection

3 6 9 A Drum speed (deg/s)

o �9 1.0 / D-Tubocurarine )u []

~ 0.8 preinjection

~- ~, �9 T-N t postinjection 0.6 �9 N-T )

0 . 4

0.2

0 A---_____~^ 4- 4- 0 3 6 9

B Drum speed (deg/s)

Fig. 4A, B. Mean values of slow phase velocity gain of monocular eye OKN before (open symbols) and 30 min following unilateral microinjection of D-tubocurarine into the nLM (filled symbols). A Velocity gain of the OKN directed by the eye contralateral to the injected nLM (n = 6). B Velocity gain of the OKN directed by the eye ipsilateral to the injected nLM (n = 5). The velocity gain is plotted on the ordinate and the drum speed (in deg/s) on the abscissa. The arrows indicates the injected nLM (square); the open circle stands for the viewing eye; the filled circle stands for the closed eye. The vertical bars indicate the standard deviation

Contralateral eye

preinjection postinjection

1 degls N-T N-T . . . .

3 degls N-T

l o s

6 deg/s N-T N-T

9 degls N-T N-T

I o 1.0 Atropine )a []

~, o T-N f preinjeetion [] N-/ )

~ 0.8 \ \ �9 T . t >" postinjection

o \ \ �9 N-T) o 0.6 >

0.4

0.2

0 T ~ 3 6 9

Drum speed (deg/s)

Fig. 5. Top: coil recordings of monocular eye OKN at different drum speeds before and 1 h following microinjection of atropine into the nLM. The recorded eye was contralateral to the injected nLM. The speed and the direction of the stimulus are indicated on the left of the recordings. Calibration: vertical bar: angtdar dis- placement of 5 deg; horizontal bar: 10 s duration, Bottom: mean values of slow phase velocity gain of monocular eye OKN before (open symbols) and 1 h following unilateral microinjection of atropine into the nLM (filled symbols). The recorded eye was contralateral to the injected nLM (n = 4). The velocity gain is plot- ted on the ordinate and the drum speed (in deg/s) on the abscissa. The arrow indicates the injected nLM (square); the open circle stands for the viewing eye, the filled circle stands for the closed eye. The vertical bars indicate the standard deviation

directions of stimulation (Fig. 3 left). The T-N com- ponent was not modified, only a significant (p < 0.005) increase in its slow phase velocity gain was observed, for the two slowest drum speeds (Fig. 4A). The slow phase velocity gain of the N-T component also increased sig-

77

nificantly (p <0.005) compared to its control value, so that the differences observed between the gains of both components did not reach statistical significance (Fig. 41).

Ipsilateral eye OKN recordings. In this case, N-T com- ponent appeared immediately after the end of injection, displaying slow phases and resetting fast phases (Fig. 3 right). The slow phase velocity gain of T-N component increased significantly (p < 0.005) (n = 5) but only for the lowest drum speed (1 deg/s) (Fig. 4B). The increase in the slow phase velocity gain of the N-T component was such that the differences observed between the gains of both components did not reach statistical significance (p > 0.2) (Fig. 4B).

The effect of D-tubocurarine was reversible and lasted about two hours.

Effects of pretectal microinjections of atropine

Contralateral eye OKN recordingjs. Neither an immediate (after the end of injection), nor a delayed appearance of a N-T component in monocular OKN was observed (n=4). Both components were not much modified fol- lowing atropine administration (Fig. 5 left). The slow phase velocity gain of T-N component was similar to the control value (p > 0.1), except for the slowest drum speed, for which it was significantly (p < 0.005) increased (Fig. 5 right). The slow phase velocity gain of N-T component, which was almost nil in the control, remained nil after injection, so that the difference between these two values, observed for the four drum speeds tested, did not reach statistical significance (p > 0.1) (Fig. 5 right).

Ipsilateral eye OKN was not recorded.

Discussion

In monocular viewing conditions, frogs display an asym- metrical horizontal OKN, reacting only to stimulations in the T-N direction, and not to stimulations in the opposite direction. However, local unilateral microinjec- tion of oxotremorine (an ACh muscarinic agonist) or that of D-tubocurarine (an ACh nicotinic antagonist) into the nLM caused, during about two hours, the ap- pearance and the increase of a N-T component, so that the asymmetry of the reflex was almost abolished. Thus, at the nLM level, the action of ACh on frog OKN appears to be driven through two opposite mechanisms, one facilitatory, exerted through muscarinic receptors, and the other inhibitory, through nicotinic receptors. Moreover, muscarinic receptors have been found in the mesencephalic nuclei responsible for OKN, in the frog pretectun (Jardon et al. 1991), as well as in the pigeon's nucleus of the basal optic root (nBOR) (Dietl et al. 1988). Nicotinic receptors were also found in the nBOR of the pigeon (Britto et al. 1989). These data agree with the present results which confirm the hypothesis for at least a direct effect of ACh upon pretectal nuclei, when cholin- ergic drugs were administrated intravitreally into the

closed eye, or intraperitoneally (Bonaventure et al. 1988; Jardon et al. 1992).

However, we do not know the origin of ACh input to the nLM. The synthesizing enzyme for ACh (choline- acetyl transferase: CHAT) has been found in the nBOR of the pigeon (Britto et al. 1989). Thus, taking into account the homolateral and crossed interconnections existing between mesencephalic structures involved in OKN (pretectum and nBOR) in frogs (Montgomery et al. 1985) and pigeons (Gioanni et al. 1983), it is suggested that the cholinergic input to nLM could come from the nBOR. Then, asymmetry of monocular horizontal OKN could be the resultant of such interrelations between mesencephalic nuclei.

On the other hand, ACh was shown to be involved in the directional selectivity of numerous visual neurons (Ariel and Daw 1982); then, it can be supposed that this neurotransmitter could have a similar role on pretectal visual cells, and be involved in their directional selectiv- ity, these neurons underlying, at least partially, the direc- tional asymmetry observed in monocular OKN (Katte and Hoffmann 1980; Kondrashev and Orlov 1976).

The delay of action of oxotremorine versus that of D-tubocurarine was longer when the viewing eye was ipsilateral to the injected nLM. The N-T component appeared immediately after D-tubocurarine injection, while a 30 rain latency was necessary to observe the N-T component appearance following oxotremorine injec- tion. The immediate effect of D-tubocurarine on ip- silateral eye can be explained by a direct synaptic trans- mission of ACh nicotinic system signal from one nLM to the contralateral one or to the oculomotor nuclei. But the 30 min delay observed following oxotremorine injec- tion is too long to be explained in terms of synaptic transmission from the injected nLM to the contralateral one. We suggest that this delay can be due to the diffusion of the drug from one nLM to the other. Microinjections of labelled oxotemorine could give a possible response to this problem.

The appearance of a N-T component following uni- lateral pretectal microinjection of cholinergic muscarinic agonist or nicotinic antagonist can be compared to that obtained in the same monocular condition using SR 95531, a GABAergic antagonist. SR 95531, when ad- ministrated into the frog nLM, provoked the appearance of a N-T component and its increase up to the level of the T-N component (Yticel et al. 1991). Then GABAer- gic and cholinergic nicotinic systems appear to act on the frog pretectum by maintaining an inhibition on the N-T component of horizontal monocular OKN. GABA- synthesizing neurons were found in the frog nLM, with- out knowing whether they are interneurons or projecting neurons (Yiicel et al. 1988). Further studies are necessary to show whether both GABAergic and cholinergic sys- tems are related and whether the pretectal GABAergic neurons are sensitive to ACh, or inversely. Such interac- tions were already described in different structures of the central nervous system (Krnjevic et al. 1981 ; Rastogi et al. 1985; Massey and Redburn 1982).

Taking into account all these data, we propose the following model: activation of cholinergic pretectal mus-

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car inic recep tors leads to the a p p e a r a n c e o f a N - T com- p o n e n t and pre tec ta l G A B A e r g i c neu rons exer t an in- h ib i t ion u p o n the invo lved chol inerg ic processes. A C h , by a negat ive feed-back loop , m o d u l a t e s t h r o u g h nicot in- ic recep tors the G A B A e r g i c inh ib i t ion . But this m o d e l r emains to be demons t r a t ed .

In conclus ion , we have shown tha t A C h is invo lved t h r ough two oppos i t e ways in the p re tec ta l inh ib i t ion o f f rog m o n o c u l a r O K N N - T c o m p o n e n t : n icot in ic system, l ike G A B A e r g i c system, faci l i ta tes the inh ib i t ion u p o n N - T c o m p o n e n t , while the musca r in i c sys tem counte rs this inhibi t ion .

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