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The Journal of Neuroscience, October 1, 2002, 22(19):8711-8719
Behavioral Consequences of Bicuculline Injection in the Subthalamic Nucleus and the Zona Incerta in Rat
Céline Périer, Léon Tremblay, Jean Féger, and Etienne C. Hirsch Institut National de la Santé et de la Recherche Médicale U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75013 Paris, France
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
The subthalamic nucleus (STN) plays a crucial role in basal ganglia functions and has been shown to be hyperactive in parkinsonian syndromes. The zona incerta (ZI), located dorsally to the STN, is also reported to be overactive after nigrostriatal denervation. In this study, we examined the behavioral consequences of an increased activity of the STN or the ZI in awake, freely moving rats. Unilateral microinjections of a GABAA receptor antagonist (bicuculline; 25, 50, and 100 µg/µl) were performed in the STN or in the ZI of rats, and locomotor activity, spontaneous behaviors, and the occurrence of abnormal movements were quantified. Microinjection of bicuculline (50 and 100 µg/µl) into the STN did not modify spontaneous locomotor activity, whereas it induced an increase in locomotion when injected into the ZI. Furthermore, when injected into the STN or ZI, these same doses of bicuculline produced changes in spontaneous behaviors (sniffing and grooming decreased whereas chewing and rearing increased) and the appearance of abnormal movements directed contralaterally to the injection side. Application of a lower dose of bicuculline (25 ng/µl) in the STN or ZI did not modify behavior. This study suggests that the subthalamic region including the ZI, and not the STN per se, might be involved in the induction of abnormal movements. In addition, these data suggest that the hyperactivity of neurons in this region may have different consequences in the normal state and in the pathological state.
Key words: bicuculline; zona incerta; subthalamic nucleus; behavior; rat; microinjection
INTRODUCTION
Within the basal ganglia, the subthalamic nucleus (STN) plays a key role in the control of motor functions. Several lines of evidence suggest that in humans, lesion of the STN provokes the appearance of hemiballism characterized by gross involuntary movements of the limbs on one side of the body (Martin, 1927
). Other studies, in monkey, have demonstrated a direct relationship between hemiballism and discrete lesions of the STN destroying only 20% of the structure (Whittier and Mettler, 1949
We recently demonstrated, using metabolic and electrophysiologic measurements, that the zona incerta (ZI), a structure dorsal to the STN in the rat, is also hyperactive after a lesion of the dopaminergic neurons in rats (Périer et al., 2000
The main goal of our study was to determine whether a local hyperactivity of STN and ZI neurons in the normal rat could induce parkinsonian signs. A local and reversible neuronal hyperactivity was therefore induced by a local, unilateral microinjection of the GABAA receptor antagonist bicuculline in these two structures. The concentrations of bicuculline used in our study were close to those reported to induce a significant increase in the mean spontaneous neuronal discharge rate (Féger et al., 1989
MATERIALS AND METHODS
Animals. Male Sprague Dawley rats weighing 280-350 gm (CERJ, Le Genest St-Isle, France) were housed on a 12 hr light/dark cycle under constant temperature and humidity conditions and given ad libitum access to food and water. All studies were performed in accordance with the Declaration of Helsinki and the Guide for the Care and Use of Laboratory Animals adopted and promulgated by National Institutes of Health. The number of animals used was distributed as follows: bicuculline microinjection into the STN at 25 ng/µl (n = 8), 50 ng/µl (n = 7), and 100 ng/µl (n = 7), and into the ZI at 25 ng/µl (n = 13), 50 ng/µl (n = 18), and 100 ng/µl (n = 11).
Implantation of intracerebral guide cannulas. Rats were prepared surgically 4-5 d before experimental testing. The rats were anesthetized with 0.2 ml/100 gm (intramuscularly) of a solution containing 50 mg/ml of ketamine and 80 mg/ml of xylazine, and a chronic intracerebral guide cannula was then stereotaxically implanted on one side of the brain. Guide cannulas were positioned 2 mm dorsally to the target structures using the rat brain atlas of Paxinos and Watson (1986)
3.2 to
Microinjections. Bicuculline methiodide (Sigma, St. Quentin Fallavier, France) was dissolved in saline at three concentrations: 25, 50, or 100 ng/µl.
Injections were performed over a period of 2 min at a rate of 0.1 µl/min in awake, freely moving rats. Drug solutions were injected via an acute injection cannula (28 gauge) inserted into the guide cannula (22 gauge). The injection cannula, which extended 2 mm beyond the tip of the guide cannula, was connected by a catheter to a microsyringe (10 µl airtight, Hamilton) mounted on a motorized driver. The injection cannula was left in place for 1 min after each injection before removal.
All testing was done between 8:00 A.M. and 3:00 P.M. in an isolated room. After a habituation period, each rat was given five injections at minimum intervals of 24 hr. Bicuculline injection were preceded and followed by a 0.9% saline injection. Each animal received two unilateral bicuculline injections in the ZI or the STN of either 25, 50, or 100 ng/µl (Fig. 1).
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Figure 1. Experimental design of the behavioral analysis. After surgery, all rats were kept in their cages with ad libitum access to food and water and were regularly habituated to the experimenter. The two first sessions were conducted to habituate the animals to the cages used for behavioral analysis. Three saline injections alternated with the bicuculline injections to ascertain that the behaviors observed after bicuculline injection were specific to the injection and were not caused by a possible long-term residual effect of the injection or habituation to the test environment. In some cases, electrophysiological recordings were made after the third saline injection.
Behavioral analysis. Behavior was observed and recorded with a camera placed above the cage, immediately after each microinjection for a period of 30 min. During this observation period, the animals were placed in a 37 × 37 cm clear plastic cage. Motor behavior was analyzed using Vigiprimate software (Viewpoint, Lyon, France), which allows the motor activity of the animals to be finely analyzed. This software uses a window discriminator to distinguish three levels of movement: (1) immobility, or absence of movement, which may represent a measurement of akinesia or freezing; (2) movement without displacement, during which rats display behaviors such as grooming, sniffing, etc., and (3) displacement within the cage.
To further characterize spontaneous behaviors and the occurrence of abnormal movements, we counted and quantified each behavior or abnormal movements by observation on videotape. Our study included the analysis of four kinds of behavior, namely sniffing, grooming, chewing, and rearing and five types of abnormal movement, namely head movements, axial torsion, jumping, and limb movements (flexions/extensions and extension movements). The forelimb movements consisted in successive alternate flexion and extension when animals were on the floor and in repetitive striking, extension movements of the forelimb during rearing.
The intensity of various behaviors or movements (sniffing, grooming, chewing, flexions/extensions, and extension movements) was assessed according to a modified version of the scoring scale of Creese and Iversen (1974)
Electrophysiology. After the behavioral observation period, electrophysiological recordings were performed on some of the animals to verify that the cannula did not produce a lesion. Unit activity was recorded using Teflon- and epoxylite-insulated tungsten microelectrodes (stem of 76 µm outer diameter, tapered down over 0.5 mm to exposed tips of 1.5-5.0 µm in diameter and 5-25 µm in length) with an impedance of 1.5-6.0 M
. Briefly, a cannula (30 gauge) containing the microelectrode was inserted into the guide cannula, and extracellular single-unit recordings were made. The signals were amplified (DAM5 WPI), displayed on a storage oscilloscope and recorded on a computer. Single-unit activity was processed using a window discriminator providing pulses that were sent to the input of an integrator or processed using a computer (Interface micro 1401 and Spike-2 software; Cambridge Electronic Design, Cambridge, UK).
Histology. After testing, the animals were killed with an overdose of pentobarbital, and the brains were removed and frozen in isopentane. Serial sections (50-µm-thick) containing evidence of the needle tracks were mounted directly onto glass slides and stained with cresyl violet. Staining for gliosis along the needle tracks allowed the location of the deepest point of penetration to be identified. This point was taken as the center of the injection site (Fig. 2) and marked on coronal sections modified from the atlas of Paxinos and Watson (1986)
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Figure 2. Localization of the center of injection. A, Photomicrograph showing a coronal section stained with cresyl violet. The injected structure is easily visible as a gliosis seen at the center of the injection. The dotted line represents the track of the metallic electrode used to record neurons. Multiple neuronal activity was recorded (B) in the thalamus dorsal to the ZI, and single neuronal activity was recorded (C) in the ZI and (D) in the STN. cp, Cerebral peduncle; STN, subthalamic nucleus; ZI, zona incerta.
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Figure 3. Coronal sections depicting areas of microinjections into the STN, ZI, and dorsal to the subthalamic region. For histology, coronal sections were cut in the plane corresponding to the atlas of Paxinos and Watson (1986)
Statistical analysis. Data are presented as mean ± SEM. For a given injection site (STN or ZI), comparisons between the different doses of bicuculline were made by one-way ANOVA or, in the event of a failure in the test of normality, by one-way ANOVA on ranks (Kruskal-Wallis test). When ANOVA showed a statistically significant difference, it was followed by Fisher's LSD post hoc analysis or, when the Kruskal-Wallis test was used, by Dunn's test. To determine whether there was any interaction between injection site and bicuculline dose, a two-way ANOVA followed by a Fisher's LSD post hoc analysis was used (Sigmastat software).
RESULTS
Validation of the behavioral experimental design
Preliminary studies showed that after two sessions of habituation the behavior of the animals was stable, indicating that the rats were accustomed to their test environment.
After the first saline injection, the rats exhibited the same behavior as those that had not been injected (data not shown). Each rat had a specific spontaneous behavior, characterized by sniffing, grooming, chewing, and rearing, and no abnormal movements were induced by saline microinjections. During the 30 min session, a decrease in the behavioral score was observed for sniffing, grooming, chewing, and rearing (Fig. 4). No differences were observed whether saline injections were made into the ZI or the STN. After five consecutive saline microinjections into the same structure, we did not observe any behavioral differences between the first and the fifth session, indicating that five penetrations of the cannula did not induce a lesion capable of modifying the rats' behaviors or movements. The absence of lesion was also demonstrated by the presence of active neurons in 10 rats of 13 recorded rats, detected by extracellular electrophysiological recordings after the five microinjections (Fig. 2). The mean discharge rate was 9.92 ± 2.05 for the STN neurons and 4.82 ± 1.72 for the ZI neurons. These values were close to those previously reported (Périer et al., 2000
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Figure 4. Behavioral scores analyzed during 5 min periods for 30 min after a saline injection, showing the variability between rats. Horizontal line represents group mean values ± SEM of scores for the various behaviors after saline microinjection in the STN. Each dot represents the behavioral score of an individual rat. Behavioral scores were made for 5 min at the indicated time points. T = 0 corresponds to the microinjection time.
Observations of spontaneous behavior in rats receiving saline injections, as well as in noninjected rats (data not shown), evidenced a considerable degree of behavioral variability between animals (Fig. 4). This observation led us to choose a behavioral experimental design in which each animal was its own control to analyze the effect of bicuculline injection. This also allowed us to keep the number of animals used to a minimum. Thus, to test whether bicuculline injection had a residual effect, behaviors were compared for saline microinjections made before and after the two bicuculline injections. Except for sniffing behavior, which differed between the first saline injection and the other two, no differences were found between the three saline microinjections for any of the studied behaviors (Table 1), suggesting that there was no residual behavior after bicuculline injection.
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Table 1. Comparison of spontaneous behaviors after three saline injections alternating with two bicuculline injections (for details, see Materials and Methods) Moreover, to assess that the observed effects were not caused by a diffusion toward the thalamus, we realized some injections in the thalamus (Fig. 3). Seven injections were made for the two highest concentrations of bicuculline, 50 ng/µl (n = 7) and 100 ng/µl (n = 6). No injections of bicuculline at 25 ng/µl were realized, because no difference in spontaneous behaviors were observed for these two highest concentrations compared with saline injections (Table 2). No appearance of abnormal movements was observed after microinjection of bicuculline into the thalamus.
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Table 2. Behavioral effects of bicuculline injection into the thalamus Immobility and locomotor effects of bicuculline microinjection into the STN and the ZI
Unilateral microinjection of bicuculline, at any of the three concentrations, did not induce significant changes in the immobility score when injected into the STN or the ZI.
Microinjection of bicuculline did not induce significant changes in locomotor activity when microinjected into the STN but, at the highest two doses, induced a marked increase in locomotor activity when microinjected into the ZI (Fig. 5). Thus, at the lowest concentration (25 ng/µl), no increase in spontaneous locomotor activity was observed when injected into either the STN or the ZI. In contrast, when bicuculline was injected into the ZI at a concentration of 50 or 100 ng/µl, a significant increase in spontaneous locomotor activity was observed. This increased level of motor activity remained constant for up to 20 min after injection, thereafter returning to the control level. For the middle (50 ng/µl) and highest (100 ng/µl) concentrations of bicuculline injected into the STN, no increase in locomotion was found, but the rats showed a greater variation in their behavior.
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Figure 5. Immobility and locomotor activity after bicuculline injection into the STN (first column) and the ZI (second column). Values represent group mean values ± SEM of immobility score (A, A') or displacement score (B, B') determined by the Vigiprimate software. This software permits us to distinguish, with a window discriminator, (1) immobility or absence of movement, which may represent a measurement of akinesia or freezing, and (2) displacement within the cage. Bicuculline (black bars) was injected in separate groups of rats into the STN or ZI at three concentrations. A, B, Microinjection of bicuculline at 25 ng/µl (n = 8), 50 ng/µl (n = 7), and 100 ng/µl (n = 7) into the STN. A', B', Microinjection of bicuculline at 25 ng/µl (n = 13), 50 ng/µl (n = 18), and 100 ng/µl (n = 11) into the ZI. Asterisks indicate significant difference from respective control values obtained after a saline injection (white bars) (ANOVA and Fisher's post hoc analysis; *p < 0.05).
Behavioral and movement effects of bicuculline microinjection into the STN and the ZI
At no time during the observation period were catalepsy or tremor observed after bicuculline microinjection into the STN or the ZI.
The number and intensity of sniffing and grooming behaviors normally displayed by the animals decreased after bicuculline microinjection into the STN and ZI, whereas those of chewing and rearing increased (Fig. 6). Microinjection of bicuculline into the STN or the ZI resulted in the appearance of axial torsions and head movements toward the side contralateral to the injection. These abnormal movements were accompanied by jumping and limb movements (flexions/extensions and extension movements). Jumping and axial torsions were sometimes followed by falls.
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Figure 6. Behavioral effects of bicuculline injection into the STN and the ZI. Values represent group mean values ± SEM of the different behavioral scores on a 30 min session. White bars, Saline injections; from light to dark gray: 25, 50, and 100 ng/µl of bicuculline. A, Behavioral changes after bicuculline microinjection into the STN at 25 ng/µl (n = 8), 50 ng/µl (n = 7), and 100 ng/µl (n = 7). A', Behavioral changes after bicuculline microinjection into the ZI at 25 ng/µl (n = 13), 50 ng/µl (n = 18), and 100 ng/µl (n = 11). B, Production of abnormal movements after bicuculline microinjection into the STN and (B') into the ZI at three concentrations. Asterisks indicate significant difference with saline injection (ANOVA and Fisher's post hoc analysis; *p < 0.05, **p < 0.01).
In the STN, the lowest concentration (25 ng/µl) of bicuculline used induced only an increase in the frequency of rearing. The same concentration injected into the ZI provoked an increase in the frequency of chewing and of rearing. An injection of bicuculline at a higher concentration (50 and 100 ng/µl) into the STN or the ZI induced (1) a decrease in sniffing and grooming, (2) an increase in chewing and rearing, and (3) abnormal movements. With these two higher concentrations, the intensity of the abnormal movements was always less when the injection was made into the ZI than into the STN (Fig. 6).
Modification of each behavior (sniffing, grooming, chewing, and rearing) appeared at the onset of the bicuculline microinjection and continued even in the presence of abnormal movements, which appeared between 10 and 15 min after injection into the STN but between 15 and 25 min after injection into the ZI.
Site variation effect in the STN and in the ZI
No difference in effect could be evidenced between the different injection sites in the STN.
When the different injection sites in the ZI were compared, the behavioral changes caused by bicuculline injection were found to be more pronounced in the lateral ZI than in the medial ZI (Fig. 7). Indeed, in most cases, there was no difference between control injections and injections of bicuculline in the medial ZI (Fig. 7).
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Figure 7. Site specificity of the behavioral changes induced by bicuculline (100 ng/µl). Values represent group mean values ± SEM of behavioral scores. Dagger indicates significant difference from saline injection (ANOVA and Fisher's post hoc analysis; p < 0.05); asterisks indicate significant differences among STN, medial ZI, and lateral ZI bicuculline-injected groups (ANOVA and Fisher's post hoc analysis; *p < 0.05).
DISCUSSION
As might be expected, a local hyperactivity of STN neurons in normal rats induced a diminution of behaviors such as sniffing and grooming. However, no changes in the immobility score, which may represent an index of hypokinesia, were observed after bicuculline microinjection. This study also demonstrates that an unilateral application of a GABAA antagonist (bicuculline) into the rat STN did not modify the spontaneous locomotor activity, whereas it induced an increase of locomotion when injected into the ZI. Moreover, bicuculline microinjection into both the STN and the ZI induced abnormal movements, such as jumping, axial torsion, and abnormal head and limb movements. The intensity of these abnormal movements was greater when the microinjection was in the STN than in the ZI taken as a whole, and their onset was also more rapid after STN injection. Nevertheless, few differences were found between the STN and the lateral ZI, suggesting that they both play a role in the genesis of these movements. Finally, the decrease in sniffing and grooming preceded the appearance of abnormal movements and did not stop when these movements appeared, suggesting that the decrease of these behaviors and the occurrence of abnormal movements may be the consequence of different mechanisms.
One potential difficulty in interpreting data on intracranial microinjections of pharmacological agents in a given structure is that the observed effects may be caused by drug diffusion to adjacent structures. However, several lines of evidence suggest that this was not the case in our study. First, a diffusion into the thalamus may be ruled out because injections into the thalamus did not induce the behavioral changes observed after injections into the STN or the ZI. Second, a diffusion into the hypothalamus can also be ruled out because no behavioral effects were observed after microinjection into the medial ZI. Finally, it is unlikely that the drug could have diffused from the ZI to the STN because different effects were observed depending on whether the injections were made into the STN or the ZI: greater locomotor activity was observed after activation of the ZI than the STN. Furthermore, the rapid onset and short latency of the occurrence of different behaviors after microinjections in the STN or in the ZI argues against drug diffusion being responsible for the observed effects. Nevertheless, the time between the microinjection and the induction of abnormal movements was always shorter when the microinjection was in the STN compared with the ZI, suggesting that we cannot exclude the possibility that drug diffusion from the ZI injection site to the STN was responsible for these abnormal movements.
Another technical issue raised by our study concerns the five consecutive injections in the same animal. Yet, although we cannot totally exclude the presence of a lesion, this is unlikely to have influenced our results, because neurons could be recorded at the end of the sessions. Moreover, behaviors were not different between control sessions either side of the bicuculline injections, indicating that the previous injection had no residual effect.
In the present study, bicuculline was used to increase the activity of STN neurons. Electrophysiological studies have shown that bicuculline increases the activity of subthalamic neurons (Féger et al., 1989
The most surprising result of our study is the absence of parkinsonian signs, such as akinesia and postural rigidity, when hyperactivity of the STN was induced. Indeed, because STN neurons are hyperactive in parkinsonian syndrome after nigrostriatal degeneration, one would expect a hyperactivity of this structure to produce a parkinsonian syndrome. Yet, in our study, this was not the case. Moreover, activation of the ZI induced a locomotor activity and the same kind of behavioral effects as those induced by an activation of the STN. Our results are in agreement with previous studies in various species. (1) Crossman et al. (1984)
Although these findings are consistent with each other, they are quite unexpected according to the classical model of the basal ganglia circuitry. Such discrepancies with this model have already been described in non-parkinsonian animals regarding the neuronal activity of the substantia nigra pars reticulata. Indeed, Waszczak et al. (2001)
Another possible explanation for the unexpected consequences of bicuculline injection in the STN may be related to a local effect of the drug, as has already been reported in the pallidum by Matsumura et al. (1995)
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Figure 8. Possible explanation for the consequences of bicuculline microinjection into the STN. (1) Bicuculline microinjection provoked an increase in the neuronal activity of subthalamic neurons, initially leading to an increase in neuronal activity in the output structures of the basal ganglia, which is known to cause behavior suppression. In the rat, STN neurons are highly collateralized, and single STN neurons send axon collaterals to the GP, EP, and SNr. Thus, (2) GP neurons could subsequently display an increase in neuronal activity, leading to an over-inhibition of neuronal activity in the output structures of the basal ganglia, eventually enabling behaviors to occur. These consequences may occur during the peak action of bicuculline, ~15 min after the microinjection. Moreover, it is important to note that the projection from the STN to the EP/SNr accounts for ~10% of the total population of terminals and is evenly spread over perikarya and dendrites (Bevan et al., 1994a
As far as the ZI is concerned, it is of interest to note that the most pronounced effects were observed in the lateral ZI and that this part of the ZI displayed a more pronounced hyperactivity in 6-OHDA-lesioned rats (Périer et al., 2000
In summary, our data are in agreement with the notion that the STN is involved in the pathophysiology of movement disorders, and we have shown that the ZI, and particularly the lateral part, may be implicated in the control of movement, suggesting that the subthalamic region, and not the STN per se, might be involved in the induction of abnormal movements. Nevertheless, it seems that in rats, a unique local hyperactivity of STN neurons is not sufficient to produce parkinsonian symptoms, suggesting that there are certainly major differences between the functioning of these structures in the normal and the pathological state.
FOOTNOTES Received May 7, 2002; revised July 9, 2002; accepted July 10, 2002.
This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM) and the National Parkinson Foundation (Miami, FL). C.P. was supported by a fellowship grant from the Ministère de l'Education Nationale et de la Recherche and from the Fondation pour la Recherche Medicale (France). We thank M. H. Thiebot (INSERM U288) for providing the behavioral testing cage.
Correspondence should be addressed to Etienne C. Hirsch, Institut National de la Santé et de la Recherche Médicale U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France. E-mail: hirsch{at}ccr.jussieu.fr.
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