Possible interaction between the inferior colliculus and the substantia nigra in audiogenic seizures in Wistar rats

Physiology& Behavior, Vol. 50, pp. 421-427. ©Pergamon Press plc, 1991. Printed in the U.S.A.

0031-9384/91 $3.00 + .00

Possible Interaction Between the Inferior Colliculus and the Substantia Nigra in Audiogenic Seizures in Wistar Rats N. G A R C I A - C A I R A S C O .1 A N D R. M. E. S A B B A T I N I t

*Laborattrio de Neurofisiologia e Neuroetologia Experimental, Departamento de Fisiologia Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo Ribeirao Preto, 14049, Sao Paulo, Brasil "pNticleo de Inforrruitica Biomddica, Faculdade de Ci~ncias Mddicas, Hospital das Clfnicas Universidade Estadual de Campinas, Campinas, 13100, Sao Paulo, Brasil R e c e i v e d 16 O c t o b e r 1990 GARCIA-CAIRASCO, N. AND R. M. E. SABBATINI. Possible interaction between the inferior coUiculus and the substantia nigra in audiogenic seizures in Wistar rats. PHYSIOL BEHAV 50(2) 421-427, 1991.--Male Wistar rats were tested for sensitivity to audiogenic seizures (AS; 110 dB), using an andiogenic severity index (SI). Sensitive (S) animals were subjected to bilateral lesion of the inferior colliculus (IC) and/or the lateral lemniscus (LL). Resistant (R) animals were subjected to bilateral lesions of the IC, unilateral sequential lesions of the substantia nigra reticulata (SN) and/or IC (contralateral to one another), and unilateral thalamic and sham lesions. Bilateral lesions of the IC and LL abolish AS in S rats. Lesion of the SN resulted in more pronounced sensitivity to AS than unilateral lesion of IC, in R rats. When the SN lesion was contralateral to a previous IC lesion, the effect was not only an increase in the SI, but also a reversal of the asymmetry generated by IC lesion. Although the behavioral effects resulting from IC lesions are due to alterations in the primary structures involved in the origin of AS, unilateral SN lesions can alter critical substrates of sensorimotor integration involved in the control and expression of AS. Audiogenic seizures Inferior colliculus

Midbrain

Sensorimotor interaction

EXPERIMENTS involving large cortical or thalamic lesions indicate that the acoustic cortex and the medial geniculate body (1, 3, 6, 18, 22, 23, 40) play only a minor role in the initiation of audiogenic seizures (AS). AS susceptibility can be modified by experimental manipulations of the inferior colliculus (IC) and substantia nigra (SN), reinforcing the concept of subcortical mechanisms in the origin of AS. Bagri et al. (2) demonstrated that AS can be induced in sensitive rats with massive telencephalic ablations. Animals with mesencephalic or pontine reticular formation (RF) lesions manifested running fits (procursive phase), but not tonic-clonic convulsions (4,22), and rats with bilateral lesions of the IC did not exhibit AS (22). Unilateral lesions of the IC can abolish AS when performed on the contralateral side of the so-called dominant auditory pathway, ipsilateral to the motor symptoms (36). Collins (5) and Ward (38) have demonstrated that AS susceptibility can be modified or inhibited by manipulations of the contralateral IC of mice unilaterally primed. The neurons of the SN appear to be part of an important control mechanism which inhibits propagation of generalized convulsions. The SN has been identified as an anatomical substrate for anticonvulsant activity mediated by gamma-amino-butyric acid (GABA), because convulsions induced by bicuculline or elec-

Neuroethology

Substantia nigra

troshock can be blocked by increasing GABA activity in this structure (12,19). Muscimol injection into the SN reticulata of ethanol-dependent rats undergoing withdrawal, either blocks (16) or produces little effect (11) in sensitivity to AS. At the same time that microinjection of excitatory amino acids into the IC enhances AS in genetic epilepsy-prone rats (GEPR) (28), bilateral nigral injections of excitatory amino acid antagonists protect GEPR from AS (29). Restricted bilateral striatal lesions (22) produce AS sensitivity in previously resistant animals. Furthermore, unilateral 6-hydroxydopamine (6-OHDA) lesions of the SN compacta produce dopamine-dependent asymmetrical postures and circling but not AS, while unilateral lesion of the SN reticulata (13) produces AS susceptibility in R rats. Previous work in our laboratory (14) has demonstrated that massive mesencephalic denervation in hemidetelencephalated rats produces severe AS in R animals, probably because of an alteration of the inhibitory tonus of the SN. Because experimental manipulation of the IC and SN can modify AS susceptibility, in the present study we evaluated the effects of bilateral IC and LL lesions on AS in S animals and the interaction between unilateral and contralateral IC and SN lesions in R animals. We hypothesize that the asymmetric ma-

~Requests for reprints should be addressed to N. Garcia-Cairasco, Ph.D., Neurophysiology and Neuroethology Laboratory, Department of Physiology, School of Medicine of Ribeirao Preto, University of Silo Paulo, 14049 Ribeirifo Paulo, SP, Brazil. 421

422

GARCIA-CAIRASCO AND SABBATINI

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nipulations of sensorimotor substrates using the combined unilateral lesions produces discrete imbalance between the sensory processing of acoustic stimuli and the mechanisms of sensorimotor coordination in the brainstem that can modulate or explain AS. We utilized an ethological method (13,14), to qualitatively and quantitatively evaluate the motor patterns of behavioral sequences in AS.

C

METHOD

Animals '

Sixty-one adult male Wistar rats from the main breeding stock of the Medical School of Ribeir,~io Preto, each weighing 250-350 g. The rats were housed in individual cages, given access to food and water ad lib, and subjected to an artificial lighting system (lights on at 0600 h, lights off at 2000 h).

\

Acoustic Stimulation Procedure M

CICVL

The testing apparatus consisted of a 32 x 36 × 32 cm stainless steel cage placed inside a larger sound-proof box which had a door and front glass window for observation. The animal was observed in the dark except for a small 15-W red bulb inside the cage. Acoustic stimulation was administered with a door bell (110.3 dB) affixed to the ceiling of the inner cage. Behavior was observed for one minute, after which the door bell rang for a maximum of 1 minute. If at least one tonic convulsion occurred the stimulus was discontinued and, during the poststimulation phase, the righting and antinociceptive (tail pinching) reflexes were evaluated. Tests were conducted every 48 hours between 1800 h and 1900 h.

Recording and Analysis of Behavioral Data

FIG. 1. Schematic representation of the major (sniped) and minor (solid) areas of bilateral electrolytic lesions of the IC (A) or LL (B); ICCVL: ventrolateral central nucleus: EIC: external nucleus; PCIC: cortical nucleus of the inferior colliculus; ICCDM: dorso-medial central nucleus of the inferior colliculus; CIC: commissure of the inferior colliculus; AQ: aqueduct; CG: central gray matter; ENT: entorhinal cortex; DLL: dorsal nucleus of the lateral lemuiscus; VLL: ventral nucleus of the lateral lemniscus: MFL: medial longitudinal fasciculus; PNO: nucleus reticularis pontis oralis; SOL: superior oliva; l~: pyramid. Nomenclature based on Paxinos and Watson (32).

Animal behavior was recorded before, during, and after acoustic stimulation. Behavior was assessed by direct and systematic observation, using an ethogram (14) containing a set of discrete behavioral categories most commonly observed in the testing situation and identified by special abbreviations (see Fig. 4). An andiogenic severity index (SI) was calculated as previously described (14), and is as follows: Wild running 2.6 = 0.1JP + 0 . 2 A F + 0.3C~ + 0 . 4 C 2

+ Tonic-clonic 0.1CCVp + 0.2CCVg + 0.3CLS + CaTCV

TABLE 1 F.FFF_L~SOF BILATERALIC AND LL LESIONSON AS SI Group

Pre

Post

STA

L M H

0.08(0.02)* 0.21(0.01)* 0.53(0.04) °

0 0 0

R

0.00

0

2/6 3/8 3/9 8/12

"p<0.05 in all cases. Wilcoxon signed rank test for incidence of AS responses after lesions. Numbers in parentheses are SEM. STA, postlesioning startle (absent/total). L=0
Each entry indicates the presence or absence of the behaviorai items: C~ = short running fits not followed by convulsions; C 2 = long running fits not followed by convulsions; AF = atonic fails; J P = j u m p s during the running fits; CCVg=generaiized (forelegs and hindlegs) clonic convulsions; CCVp=partial (only forelegs or hindlegs) clonic convulsions; C L S = c l o n i c spasms; C3TCV = short running fits followed by tonic convulsions. The index includes a graded linear scale which determines a range of severity between S I = 0 and S I = 0 . 8 5 (maximum). The maximum value will never be 1.0 because, by definition, when C2 is present, TCV is not present and vice versa. Although our Wistar rats are not a genetically inbred strain for AS, unlike the Sprague Dawley-derived GEPR strain (21), 10-15% of the rats in our stock showed AS susceptibility. Furthermore, comparison of the SI with Jobe's scale (21), which was developed for

NIGRO-COLLICULAR INTERACTIONS AND SEIZURES

423

BREGMA i AP "4.3

-5J! AP

-6.3 "5.3t I'~

-6.8

R!

8REGMA

AP - 7'.3

"8.8 AP

"9.3 "7.8

"&3

-10.3

FIG. 2. Schematic histological representation based on Paxinos and Watson (32) of unilateral combined (A) SNR and (B) IC lesions. Observe that the position of the IC lesions is mostly in the cortical nucleus.

GEPR, revealed that our behavioral descriptions do not correspond to those of the above scale. The SI was especially suited to an ethological method and the present data are in agreement with findings on AS in Wistar rats (24,26).

Lesioning Procedures With the animal under pentobarbital anesthesia (40 mg/kg IP), stereotaxically placed lesions were produced with an anodal current of 1-2 mA applied for 5 seconds. Straight stainless steel electrodes 0.33 mm in diameter, insulated throughout except at the tip (0.33 ram), were utilized. The stereotaxic coordinates (32) for the IC were: AP, 1.2-1.3 mm posterior to the lambda; L, 1.8-2.0 mm; V, 4.5 mm (dura, central nucleus); P, 4.5 mm (bone, cortical nucleus). For the lateral lemniscus, LL: AP, 1.3 mm posterior to the lambda; L, 2.3-2.4 ram; V, 6.0 ram. For

the SN, AP, 5.8 mm posterior to the bregma; L, 2.3 mm; V, 8.0 mm. Bilateral IC or LL lesions were completed dttring the same surgical act. Behavioral effects were analyzed 10 days after surgery. In the experiments involving combined lesions, preoperative SI was calculated by 2--4 tests conducted every 48 hours. The time interval between lesion 1 and lesion 2 was approximately 1 month. Since the SN and IC lesions were done sequentially and contralaterally to each other, the terms "combined lesion" or "nigro-collicular" lesion used in the text denote this fact.

Functional Determination of Asymmetries To determine the presence of asymmetries due to nigral or collicular manipulations, all animals in the combined lesion group (n= 19) were evaluated for rotational behavior for 15

424

GARCIA-CAIRASCO AND SABBATINI

TABLE 2 EFFECTSOF COMBINEDNIGRALAND COLLICULARLESIONSON SOUND-AND AMPHETAMINE-EVOKEDASYMMETRICPATrERNS

13 . . L

Postlesion 1 Item

Right

Left

Right

Left

t

Cl/C 3

8/10"

3/10

7/10"

1/10

93.8

93.5

95.0

94.3

7/9*

0/9

0/9

7/9*

93.3

89.2

91.7

92.8

SNR-IC

t IC-SNR

AI% AMPH gyri

/++-/

Postlesion 2

Lesions

AI% AMPH gyri C1/C3

AUTOMATISM8

Asymmetric responses evoked by sound (Ct/C3) or evoked by amphetamine (AMPH) were evaluated as right or left. p<0.005, X2 and Fisher exact tests. All AI% values above 75% are statistically significant (30). fThe first lesion was made always on the left side. minutes after IP injection of 0,9% saline and for 30 min after IP injection of 1.5 mg/kg d-amphetamine (AMPH). Rotational behavior was assessed by the following asymmetry index (30): AI(%)=[turns (dominant direction)/turns (both directions)] x 100. Only values above 75% were considered statistically significant.

EXPLORATION EN,ER,IM.EO+WI~

0.9

I"

0.8

I A IC-SNR I

SNR-IC I 41-

45

i

i

t9

0.7 X M.I 0.6 z_ 0.5 0.4 er 0.3 0.2 ILl 0.1 0.0

45

45

+

+

EXPLORATION

t

TNER,TNBL

[

GROOMING

+TACHYPNEA FREEZING

L

ji

D TACHYPNEA 1

'"W/

eXPLOn~mN IXPLOR~ION EN.EN.IM.EC.~

\ ORIENTATION

Identification of the Experimental Groups Susceptible (S) animals included those who presented any type of positive response to the acoustic stimulus. Resistant (R) animals included those who did not present any positive procursive or convulsive response to the acoustic stimulus. The sample was divided into 4 subgroups: 1) S animals subjected to bilateral IC or LL electrolytic lesions (n= 23); 2) R animals subjected to IC or LL bilateral electrolytic lesions, ( n = 14); 3) R animals subjected to unilateral SN and IC lesions (n-- 19); 4) R animals subjected to unilateral thalamic or sham SNR lesions (n = 5).

PIVOTING

GROOMING 8OR/t NO,LIC

PROCUREIVE

TONIC

BEHAVlORE

Jt

J

FIG. 4. (A) Flow chart of behavioral sequences of control R animals (group 3) before the lesions. Each rectangle indicates individual patterns or cluster of behaviors. The arrows indicate the direction of the interactions. ER, Erect posture; GRO, grooming (body, face, neck, genitals); IM, immobility; LI, licking; LIC, licking of claws; MT, masticatory movements; SC, scanning; SCR, scratching; SH, head shaking; SN, sniffing; TC, teeth chattering; TNB, tonic neck and body turning (L, left; R, right); WA, walking. (B) Flow chart of behavioral sequences of control R animals from (A) subjected to IC and later to SNR lesions. Nomenclature is the same as in (A). Other items: G, gyrating (R, right; L, left); JP, jumping; AF, atonic falling; The open arrows indicate interactions between cluster or individual items after IC lesions. Some of these behaviors are present after SN lesions. The black rectangles and arrows indicate items exclusively presented after SN lesions. The small arrows inside the rectangles indicate a decrease of these items.

Histological Determination of Lesion Sites and Sizes 0

3 4 L1 AMPH L2 AUDIOGENIC TESTS

i

7

FIG. 3. Mean SI values before (PRE) and after (POST), f'Lrst (L1) and second (L2), rligral (SNR) and collicular (IC) lesions (group 3), and after amphetamine (AMPH) treatment. *p<0,05, Student's t-test.

At the conclusion of the behavioral evaluations the animals were killed with an overdose of pentobarbital, Their brains were perfused with 0.9% saline and 10% formalin and fixed for at least 24 h. The material was embedded in paraffin, cut into 4-1.~m sections and stained with cresyl violet to determine the sites of lesion. Another group of frozen sections (30 ~m) were myelinstained with Sudan Black B.

NIGRO-COLLICULAR INTERACTIONS AND SEIZURES

Statistical Analysis Preoperative and postoperative SI values and asymmetrical behaviors (AI%) were evaluated by the Student's t-test (means), and by ×2 and Fisher exact tests (percentage) (34). RESULTS Bilateral Electrolytic IC and LL Lesions Abolish AS in S Rats Because of the homogeneity in the behavioral responses after bilateral IC (Fig. 1A) or LL (Fig. 1B) lesions the animals were grouped by SI values, e.g., low (L), medium (M) or high (H) susceptibility (see Table 1). In all cases, the lesions produced many alterations in behavioral patterns of susceptibility. Before any lesion, highly susceptible animals manifested at least tonic convulsions (TCV), in addition to procursive preconvulsive behavior (C1, C3, JP, AF; see SI description). In the IC or LL lesioned animals, instead of these reactions, "displaced" behaviors (facial automatisms), such as masticatory movements (MT), trembling (TR), teeth chattering (TC), licking (LI) and head shaking (SH), occurred which corresponded to the stereotypical behavior of R control animals (see Fig. 4A). Both exploration and self-grooming were manifested after the lesions. In IC lesioned animals, the startle reaction (visual and not myographic observation) was almost normal, preceding the behavioral item withdrawing (WI). In the majority of animals with deeper lesions near the LL dorsal nucleus, the startle reaction did not appear. In R animals (Table I), bilateral lesions of both IC and LL did not produce any changes in AS susceptibility. Although this was not a common feature, some animals presented lesions in the surrounding area of the LL; e,g., cuneiform nucleus and pedunculopontine nucleus. Unilateral SN Lesion Induces AS in R Animals and a Reversal of Asymmetrical Patterns Produced by Previous Contralateral IC Lesion Figure 2 shows an example of histological evaluation of combined lesions. The IC lesions were preferentially located in the IC cortical and dorsomedial central nuclei (Fig. 2A). The SN lesions (Fig. 2B) were extensive, including portions of the dorsal SN compacta. Table 2 illustrates the asymmetrical behavioral effects of combined SN and IC lesions. In the SN-IC group, SN lesion on the left side produced a significant enhancement of asymmetrical contralateral (right) procursive behaviors. Later, when this group was submitted to IC lesions, there were no changes in the sound evoked gyri, which continued to be contralateral to the left SN. In the IC-SN group, the left IC lesion also produced contralateral asymmetries. However, SN lesion reversed the asymmetry of the IC lesion, and the animals turned contralaterally to the right SNR. The appearance of tonic convulsions (TCV) also differed as a function of the sequence of the lesions. In the SN-IC group, there was a significant increase in the SI (Fig. 3) and TCV incidence (5/10, p<0.05), following the SN lesion. After the IC lesion, there was a nonsignificant decrease of the SI value and of TCV incidence. In the IC-SN group, the SI value and TCV incidence (1/9, p>0.05) were not modified after IC lesion, but were significantly increased after nigral lesions (TCV incidence, 6/9, p<0.005), with values identical to or higher than those of initially SN-lesioned animals (group SN-IC). Figure 3 also shows that pretreatment with amphetamine (AI evaluation made 24 hours before) significantly enhanced the SI in both groups. AI-

425 though the occurrence of asymmetrical patterns after lesions, reached statistical significance (all AI values above 75%), there were no differences in right or left amphetamine-induced asymmetries (Table 2). In summary, the asymmetrical pattern after acoustical stimulation was always contralateral to the SN lesion, independently of the presence or absence of a previous IC lesion. In the IC case, the asymmetrical pattern was only contralateral when this was the first lesion. Unpublished observations from our Laboratory suggest that in chronic experiments the latency and severity of procursive or convulsive behaviors related to SI and TCV modifications are different from those seen in more acute experiments. Thus, more animals in chronic conditions need to be evaluated to determine the differences. Figure 4A is a flow chart of behavioral sequences in R control animals before any lesion, and Fig. 4B illustrates the flow chart of behavioral sequences of the same animals after IC-SN lesions. The control group, e.g., thalamic and sham-lesioned animals, did not present any kind of behavioral alteration or AS susceptibility. The thalamic group was chosen because this area frequently suffers mechanical lesions when electrodes are placed in the SN. DISCUSSION The IC in the Acoustic Midbrain is a Critical Nucleus for the Initiation of AS The present experiments show that bilateral lesions of IC central nucleus blocked AS, confirming previous reports on its important role in triggering this epileptic behavior (15, 18, 22, 41). Since lesions of the auditory cortex (6) and of the medial geniculate body (3, 24, 40) showed no primary involvement of these structures in the origin of AS, the effects of IC lesions on the onset of AS could be due to the lesion in the rostral-most auditory portion necessary to trigger the crisis (22, 23, 41). The AS blockade by lemniscal lesion would be explained by the absence of a large share of fibers to the inferior colliculus from the primary acoustic pathway. It is interesting to note that the acoustic startle reaction, which was evaluated visually and not myographically, is only abolished by sub-collicular lesions (7). Our results conf'Lrrn this effect which occurs most frequently after lesions of the lemniscus-colliculus transition. The startle reaction is practically absent after lesions of the LL itself. Looking for Midbrain Networks of Acoustic-Motor Integration The following information relates IC to possible neuroanatomical and functional substrates for AS in the midbrain. Lesions of the deep layers of the superior colliculus (SC) in DBA/2J mice abolish the AS (41) and mesencephalic or pontine RF lesions abolish the convulsive phase but not the procursive phase of AS (3, 4, 22). Furthermore, both the intermediate and deep layers of SC and the RF are morphologically interconnected with the SN (9,31). Activation of these systems is GABA-dependent (20,39) and is expressed such as circling and explosive running behaviors which are asymmetric motor manifestations. Similarly, there are bilateral projections from the deep layers of the SC into the RF (31) and from the IC to the pontine nuclei (17). Likewise, both the cortical and external IC nuclei and the ventral LL nucleus also project into the SC, resulting in a broad polysensorial interaction (35). Our results of unilateral IC lesion confLrrn the observed increase in AS susceptibility in similar alterations of the auditory pathway (18,33) but to a lower extent if compared with the SN lesion. Collins (5) and Ward (38) have demonstrated modification of AS sensitivity by contralateral IC

426

GARCIA-CAIRASCO AND SABBATINI

manipulations in primed mice. In the present study, unilateral IC lesions produced AS in R rats probably due to an asymmetrical modification of acoustic substrates related to the origin or development of AS sensitivity (afferent pathway). In the case of SN lesion, our results conf'n-med a previous report of augmented AS susceptibility after nigral GABA-ergic and not dopaminergic manipulations (13) (efferent pathway). A recent demonstration of GABA-receptor binding decrease in the SN of GEPR (10) may represent an endogenous situation related to our experimental data. In conjunction with that observation we recently demonstrated that microinjections of clobazam a 1-5 benzodiazepine into the SN can block audiogenic-like seizures evoked by application of bicuculline, a GABAa antagonist in the IC (15).

The SN Participates in the Sensorimotor Interface of AS Expression Data related to polysensory mesencephalic mechanisms have shown that the IC can process acoustical, visual and somatosensory modalities in a broad manner (1, 27, 37). Evoked potentials have been recorded in the deep layers of the SC by electrical stimulation of the IC (36) and electrical stimulation of the cortical collicular nuclei can evoke audiogenic-like behavior (25). Gonzalez and Hettinger (16) have demonstrated that muscimol in the SN selectively blocked AS in abstinent ethanol-dependent animals, a special situation where AS susceptibility is augmented. Although Frye et al. (11) report little blockade of AS in the same syndrome by application of muscimol to the SN, Millan et al (29) have demonstrated that antagonists of excitatory amino acids in the SN or mesencephalic and pontine RF abolish AS in GEPR. Finally, Depaulis et al. (8) find no in-

volvement of the nigro-tectal GABAergic pathway in the control of AS, but they do not discard the potential participation of the SC in this process. Likewise, we have recently demonstrated that bicuculline-induced audiogenic-like seizures are blocked by knife cuts between the IC and SC (15). Despite the important role played by the IC in the origin of AS (shown by the fact that IC and LL lesions abolish AS), it seems clear that the SN can modify the acoustic processing or the sensorimotor integration necessary for the expression of AS (shown by the fact that SN lesions affect AS sensitization). The SN and IC relationship is expressed in asymmetrical behavioral patterns after the sequential lesions studied in the present investigations, butthe nigral lesion effect is stronger than that of the IC lesion. The induced AS sensitivity (R animals) after unilateral SN lesions could be explained by asymmetrical alterations of endogenous antiepileptic and sensorimotor coordinating brainstem systems. We suggest also that nigro-collicular interactions are made possible through the intermediate or deep layers of the SC and RF as sensorimotor interfaces to express AS activity. Quantitative neuroethological work is currently under way to evaluate these hypotheses and to better understand the neuroanatomical and neurochemical complexities of these midbrain systems. ACKNOWLEDGEMENTS We are grateful to Dr. Michele Simonatto for reviewing and commenting on the manuscript, to Jeanine Wheless for editorial work and to Oswaldo del Vecchio for technical assistance. We are also indebted to Denise de Paula Hussar for typing the original manuscript. Research support by FAPESP and FINEP (Brazil).

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