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The Journal of Neurophysiology Vol. 79 No. 5 May 1998, pp. 2568-2580
Copyright ©1998 by the American Physiological Society
1 Faculty of Health and Sport Sciences, Osaka University, Toyonaka, Osaka 560; and 2 Department of Neurosurgery, School of Medicine, Gunma University, Maebashi, Gunma 371, Japan
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Watanabe, Katsushige and Minoru Kimura. Dopamine receptor-mediated mechanisms involved in the expression of learned activity of primate striatal neurons. J. Neurophysiol. 79: 2568-2580, 1998. To understand the mechanisms by which basal ganglia neurons express acquired activities during and after behavioral learning, selective dopamine (DA) receptor antagonists were applied while recording the activity of striatal neurons in monkeys performing behavioral tasks. In experiment 1, a monkey was trained to associate a click sound with a drop of reward water. DA receptor antagonists were administered by micropressure using a stainless steel injection cannula (300 µm ID) through which a Teflon-coated tungsten wire for recording neuronal activity had been threaded. Responses to sound by tonically active neurons (TANs), a class of neurons in the primate striatum, were recorded through a tungsten wire electrode during the application of either D1- or D2-class DA receptor antagonists (total volume <1 µl, at a rate of 1 µl/5-10 min). Application of the D2-class antagonist, (
)-sulpiride (20 µg/µl, 58 mM, pH 6.8), abolished the responses of four of five TANs examined. In another five TANs, neither the D2-class antagonist nor the D1-class antagonists, SCH23390 (10 µg/µl, 31 mM, pH 5.7) or cis-flupenthixol (30 µg/µl, 59 mM, pH 6.6) significantly suppressed responses. In experiment 2, four- or five-barreled glass microelectrodes were inserted into the striatum. The central barrel was used for extracellular recording of activity of TANs. Each DA receptor antagonist was iontophoretically applied through one of the surrounding barrels. SCH23390 (10 mM, pH 4.5) and ()-sulpiride (10 mM, pH 4.5) were used. The effects of iontophoresis of both D1- and D2-class antagonists were examined in 40 TANs. Of 40 TANs from which recordings were made, responses were suppressed exclusively by the D2-class antagonist in 19 TANs, exclusively by the D1-class antagonist in 3 TANs, and by both D1- and D2-class antagonists in 7 TANs. When 0.9% NaCl, saline, was applied by pressure (<1 µl) or by iontophoresis (<30 nA) as a control, neither the background discharge rates nor the responses of TANs were significantly influenced. Background discharge rate of TANs was also not affected by D1- or D2-class antagonists applied by either micropressure injection or iontophoresis. It was concluded that the nigrostriatal DA system enables TANs to express learned activity primarily through D2-class and partly through D1-class receptor-mediated mechanisms in the striatum.
To acquire a new behavioral repertoire under new environmental conditions is one of the most important functions of the brain. It is especially true for humans, who have a large variety of behavioral repertoires. It has been suggested that the cerebellum and its related subcortical structures are critically involved in motor learning, such as adaptive learning in the vestibuloocular reflex (Ito 1984 We performed two types of experiments using two macaque monkeys (Macaca fuscata) weighing 6.0 kg (monkey A) and 9.0 kg (monkey B). The experiments were carried out in compliance with the guidelines for the care and use of experimental animals by the Physiological Society of Japan. The monkeys were trained to sit in a primate chair in an isolated, electrically shielded room. Each monkey was trained to associate the click sound of a solenoid valve with a liquid reward delivered to a spoon in front of its mouth. The monkey's head was mechanically fixed to the chair through two bolts to record striatal neuron activity and to apply drugs to the recorded neurons during task performance. The drop of reward water on the spoon was not visible to the animals. The behavior of the animals was routinely monitored by a video camera.
Behavioral procedures
In experiment 1, activities of single TANs were recorded in the caudate nucleus and putamen of monkey A, before and after the acquisition of behavioral association of a solenoid click with reward water (auditory click-reward association task). A drop of water was delivered at irregular 5- to 10-s intervals on a spoon in front of the monkey's mouth 280 ms after the click sound of solenoid valve (Fig. 1A).
Electrophysiological procedures
The activity of single neurons was recorded extracellularly with either glass-insulated elgiloy microelectrodes (Suzuki and Azuma 1976 Surgical procedures
In experiment 1, surgery of monkey A was performed under initial anesthesia with Ketamine (15 mg/kg im) and then pentobarbital sodium (initial 30 mg/kg im, supplement 5 mg·kg
Application of DA receptor antagonists
In experiment 1, DA receptor antagonists were administered locally in the striatum by pressure microinjection. We used a stainless steel injection cannula (300 µm ID) through which a Teflon-coated tungsten wire (50-µm base diameter, 75-µm coated diameter) for recording neuronal activity had been threaded with its cut tip protruding 0.7-0.8 mm from the tip of the cannula. The proximal end of the cannula was connected to a microsyringe (1 µl, Hamilton) with Teflon tubing. A guide tube was fixed to a microdrive, and the injection-recording device was positioned inside the guide tube. After the tip of the guide tube was inserted 10 mm below the dura matter into the brain, the injection-recording device was advanced to the striatum while neuronal activity was recorded. Once responses of TANs to sensory cues were recorded through the tungsten wire electrode, either D1- or D2-class DA receptor antagonist was injected (total volume <1 µl, at a rate of 1 µl/5-10 min). SCH23390 (10 µg/µl in saline, 31 mM, pH 5.7; RBI) or cis-flupenthixol (30 µg/µl in saline, 59 mM, pH 6.6; RBI) were used as the D1-class antagonists. (
Data analysis
Data analysis was performed off-line using a NEC PC98BA computer. Responses of TANs were defined as increasing or decreasing discharge rate after LED or solenoid click relative to that before each stimulus if they achieved at a significance level ofP < 0.05 using a two-tailed Wilcoxon test (Kimura 1986
Histological reconstruction
Several small electrolytic lesions were made in each hemisphere to mark the recording sites by passing a positive DC current through the elgiloy microelectrode (20 µA for 30 s). After all the experiments were completed, the animals were then deeply anesthetized with an overdose of pentobarbital sodium (70 mg/kg im) and were perfused transcardially with heparin-containing saline and then 10% formaldehyde. Each brain was cut into several blocks, and frozen sections of 50-µm thickness were made in the coronal plane and stained with cresyl violet. Comparison of electrode tracks and electrolytic lesions with descriptions of depth profiles of electrical activity in the penetrations during the recording sessions allowed us to reconstruct the recording tracks and recording sites in the striatum (Fig. 2).
In experiment 1, monkey A was tested with the auditory click-reward association task, and in experiment 2, monkey B was tested by both the auditory click-reward association task and visually guided push button task.
Effects of DA receptor antagonists on background discharge rate of TANs
It has been suggested that DA in the striatum would set the baseline firing rate very low, based on the observation of a dramatic decrease of spontaneous discharge rates of striatal neurons of monkeys that were performing behavioral tasks (Rolls et al. 1984
Effects of topical application of DA receptor antagonists on learned responses of TANs
TANs have been proposed to be cholinergic interneurons in the striatum with large, elongated dendrites extending up to 600 µm on an average (Aosaki et al. 1995
Effects of iontophoretic application of DA receptor antagonists on learned responses of TANs
We applied DA receptor antagonists to the TANs iontophoretically in experiment 2. Sample records of the effects of iontophoretic application of both D1- and D2-class antagonists on a TAN are illustrated in Fig. 5. After the monkey had learned the visually guided push button task, almost no TAN responded to the reward-associated click, but instead responded to LED illumination (Fig. 5A). Thus it is suggested that TANs respond to the LED as a reward-predictive stimulus. An application of (
Effects of DA receptor antagonists on learned behavior
To examine the effects of iontophoresis of DA receptor antagonists on learned behavior, reaction times of button pushing movements after LED onset were measured in the visually guided push button task in experiment 2. The average reaction time was 663.3 ± 109.1 (SD) ms before administration of drugs, whereas it was 661.2 ± 96.0 ms during administration of D1-class antagonists and 674.8 ± 109.2 ms during administration of D2-class antagonists. The average reaction times after the administration of D1-class andD2-class antagonists were not significantly different from those before the administration (P > 0.05, paired t-test). It was concluded that the reaction time of button pushing after LED onset was not affected by the application of either class of DA receptor antagonists. Thus the observed effects of DA receptor antagonists on the responses of TANs were not because of altered task performance.
Control experiments
As a control, saline was iontophoretically applied to confirm that the observed suppression of learned responses of TANs by the application of DA receptor antagonists was not induced by the electric current itself. In one neuron, the iontophoretic administration of D2-class antagonist with a current of +30 nA abolished the conditioned response of the TAN (Fig. 7B, P > 0.05). The conditioned response of the TAN recovered in 14 min after the administration of D2-class receptor antagonist (Fig. 7C). In the same neuron, saline was subsequently applied with a current of +30 nA, but the response of the TAN was not influenced (Fig. 7, D and E, P < 0.05). In all TANs examined in this way (n = 4), iontophoretic application of saline with <50 µA had no significant effects on the responses of TANs to conditioned stimuli. From these observations, it was concluded that the very strong suppressive effects of DA receptor antagonists on the responses of TANs were not artificially induced by ejecting current but directly caused by the DA receptor antagonists.
Localization of recording sites
The TANs were usually encountered at intervals of 300-700 µm along the recording microelectrode tracks both in the caudate nucleus and in the putamen. We sampled TANs in both nuclei in the right hemisphere of monkey A in experiment 1, and in both nuclei in both hemispheres of monkey B in experiment 2. The recording sites in the striatum covered about the dorsal two-thirds of the nuclei at the level caudal to the anterior commissure. The locations at which responses of TANs to sensory cues were influenced by the application of D1-class and/or D2-class antagonists are indicated on the electrode tracks with different symbols in Fig. 8 (experiment 1) and Fig. 9 (experiment 2). No clear difference in the distribution in the striatum was observed between TANs sensitive to D1-class antagonist and those sensitive to D2-class antagonist in either monkey.
Nigrostriatal DA system enables TANs to express learned activity primarily through D2-class receptor-mediated mechanisms in the striatum
In the present study, the pause responses of 65% (26/40) of TANs examined with iontophoretic application of DA receptor antagonists were abolished by D2-class antagonist, whereas micropressure application of the D2-class but not D1-class antagonist abolished the responses of TANs. In 2 of 10 experiments using micropressure injection, we recorded 3 TANs beneath the injection site of DA receptor antagonist in the same electrode track. After the application of 0.7 µl of the D2-class antagonist, ( Midbrain DA neurons and TANs may have contrasting response plasticity during behavioral learning
Schultz and his colleagues reported a systematic reward-related response plasticity of midbrain DA-containing neurons in behaving monkeys (Ljungberg et al. 1992 Possible origins of characteristic responses of TANs in the striatum
Because the present study has revealed that the responsiveness of TANs is controlled primarily through D2-class and partly through D1-class receptors, it is very important to know which afferent inputs to TANs are modulated by the nigrostriatal dopaminergic system. It is known that striatal cholinergic interneurons receive direct innervation from the cortex and the thalamus. Lapper and Bolam (1992) Background discharges of TANs before and after application of DA receptor antagonists
Background discharge rate of TANs was affected by neither D1- nor D2-class antagonists. In both experiments 1 and 2, the average discharge rates of TANs before administration of both D1-class and D2-class antagonists were not significantly different from those after and during administration. These results are concordant with previous observations showing that there were no apparent changes of spontaneous discharge rates of TANs both in chronically MPTP-infused striatum and in acutely haloperidol-injected striatum (Aosaki et al. 1994a
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
; Raymond and Lisberger 1996), conditioned eye blink response (Krupa et al. 1993), and coordination in limb movement control (Thach et al. 1992).
,b; Cools 1980; Hikosaka 1992; Kimura 1995; Schultz et al. 1997). Marsden (1982) drew a conclusion that the basal ganglia are responsible for automatic execution of learned motor plans, based on the observations of motor abnormalities in a large number of Parkinson's disease patients. The involvement of the basal ganglia in learning seems different from that of the cerebellum. Cools (1980) suggested that the nigrostriatal dopamine (DA) system takes part in sequencing and selecting behavioral strategies. In a positron emission tomography (PET) study using human subjects, Seitz and Roland (1992) demonstrated a selective increase of regional blood flow in the putamen and globus pallidus in the process of learning sequential finger movements. Matsumoto et al. (1994) showed that there is a selective impairment of learning arm movement sequences after destruction of the nigrostriatal DA system by local infusion of dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP).
; Mirenowicz and Schultz 1996; Schultz et al. 1993). These DA neurons are activated by appetitive but not aversive stimuli (Mirenowicz and Schultz 1996), and thus respond to stimuli predictive of reward. Interestingly, the response of the DA neurons to reward predictive stimuli gradually disappeared when monkeys became able to execute behavioral tasks automatically through overtraining (Ljungberg et al. 1992; Schultz et al. 1993). The other finding is the modification of striatal neuron activity through behavioral learning and its control by the nigrostriatal DA system. Aosaki et al. (1994b) recorded the activity of a class of striatal neurons of monkeys, tonically active neurons (TANs), which are believed to be cholinergic interneurons in the striatum (Aosaki et al. 1995; Kawaguchi 1992; Kimura et al. 1996; Wilson et al. 1990). The monkeys were trained to associate sensory stimuli with reward. These authors demonstrated that there is a remarkable increase in the number of TANs (from 10-20% to 50-70% of TANs examined) that responded to reward-associated stimuli through the process of learning for ~3 wk. Quite importantly, it was found that the acquired responses of TANs almost disappeared when the nigrostriatal DA system was inactivated either permanently by MPTP or reversibly by the DA receptor antagonist, haloperidol (Aosaki et al. 1994a). Thus it was suggested that the nigrostriatal DA system is indispensable for the expression of learned activities of the striatal neurons, TANs.
). These receptors can be grouped into D1 (D1a, D1b) and D2 (D2, D3, and D4) classes. How these DA receptors are distributed among the classes of neurons in the striatum has been the subject of debate. In situ hybridization studies suggested that D1a and D2 mRNA are segregated primarily in the two major projection neuron classes, one projecting to substantia nigra and the other projecting to the globus pallidus (Gerfen 1992; Le Moine and Bloch 1995). Electrophysiological studies revealed that striatal neurons respond not only to D1-class but also to D2-class DA receptor agonists (Cepeda et al. 1993; Uchimura et al. 1986). On the other hand, most cholinergic interneurons in the striatum have D2-class receptors and some of them have D1-class receptors (Le Moine et al. 1991; Levey et al. 1993; Weiner et al. 1991; Yan et al. 1997).
).
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
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FIG. 1.
Experimental paradigms used in the present study. A: in experiment 1, monkey A was trained to associate the click sound of a solenoid valve with a drop of water as a reward. B: in experiment 2, monkey B performed a visually guided push button task. When a light-emitting diode (LED) on the board, placed in front of the animal, was illuminated, the monkey pushed the button to obtain a reward delivered with a solenoid click.
) or Teflon-coated tungsten wire electrodes in an injection-recording device (experiment 1) or carbon fiber electrodes in multibarreled glass microelectrodes (experiment 2). Electrical signals from the electrodes were amplified and filtered in a conventional manner. Action potentials of single neurons were detected using a time-amplitude window discriminator and were registered in computer memory (NEC PC98BA). Bipolar Teflon-coated stainless steel wire electrodes were chronically and/or acutely implanted in the prime mover muscles for the task performance to record an electromyogram (EMG). These were digastrics, triceps and biceps brachii. Single-neuron activity and EMG activity were displayed on the computer display in the form of peristimulus time histograms during the experiment. The computer controlled the behavioral tasks.
1·h1). Local anesthetic, 1 and 8% lidocaine hydrochloride, was also used to reduce pain. A stainless steel recording chamber was stereotaxically positioned over the skull of the right hemisphere and tilted laterally by 45° to avoid damage to the motor cortex and internal capsule. Four T-shape bolts were implanted in the skull with dental acrylic cement to fix the chamber on the skull, and to fix the head to the chair head holder during the experiment.
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FIG. 2.
Photograph of a coronal histological section at the plane of the recording sites in the right hemisphere of monkey A. Arrow indicates electrolytic lesion mark made by the recording electrode in the putamen. Stars indicate microelectrode tracks directed to the putamen. Recording sites in the striatum covered about the dorsal 2/3s of the nuclei at the level caudal to the anterior commissure. Top and left correspond to dorsal and lateral, respectively. Cd N., caudate nucleus; Put., putamen; IC, internal capsule; GPe, external segment of globus pallidus; GPi, internal segment of globus pallidus. Calibration bar: 5 mm.
)-Sulpiride (20 µg/µl in saline, 58 mM, pH 6.8; RBI) was used as the D2-class antagonist. As a control experiment, we applied saline (<1 µl) to confirm that the activity of TANs was not significantly influenced.
View this table:
TABLE 1.
Effects of dopamine receptor antagonists on background discharge rate of TANs
impedance measured at 1 kHz). This was used for extracellular recording of the activity of TANs. Each DA receptor antagonist was iontophoretically applied through one of the barrels. We used SCH23390 (10 mM in saline, pH 4.5; RBI) as the D1-class antagonist and ()-sulpiride (10 mM in saline, pH 4.5; RBI) as theD2-class antagonist. During recording, a small retaining current (<10 nA) was applied to prevent the leakage of the DA receptor antagonists from the injection pipettes. When TANs responsive to conditioned cues were encountered, their activity was recorded for >30 successive trials in ~5 min. Then one class of DA receptor antagonist was iontophoretically applied with current of <50nA (anodal current) through a Micro Iontophoretic Injector(SEZ-3104, Nihon Kohden) to examine the effects of application of the DA receptor antagonists on the activity of TANs. The effects of both D1- and D2-class antagonists were examined in most of the recorded neurons. Recovery from the effects of DA receptor antagonists of TAN responses to either the LED that triggered button pushing or the click associated with reward was confirmed.
). The onset time of a response was defined as the first of three consecutive 15-ms bins of peristimulus time histogram in which the increase or decrease of activity first became significant.
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FIG. 3.
Specimen records of the effects of micropressure application of dopamine (DA) receptor antagonists on the activities of 2 tonically active neurons (TANs): one was suppressed by D2-class antagonist [( )-sulpiride, 0.7 µl, A-D], the other was not suppressed by D1-class antagonist (cis-flupentixol, 0.7 µl, E-H). Activity of a TAN is shown before (A), and 9 min (B), 31 min (C), and 81 min (D) after injection of D2-class antagonist. Activity of another TAN is shown before (E), and 16 min (F), 46 min (G) and 107 min (H) after injection of D1-class antagonist. Each row in the raster display indicates a spike train in a single trial, with dots representing single spike discharges. Histograms are constructed by summation of spike discharge in each raster. Neuronal activity is aligned at the time of the click preceding the reward.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
; Apicella et al. 1991; Kimura 1986; Raz et al. 1996).
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FIG. 4.
Specimen records of the population response of TANs to reward-associated click that was suppressed byD2-class antagonist [( )-sulpiride; A], but was not sensitive to application of D1-class antagonist (SCH23390 and cis-flupentixol) by pressure (B). Neuronal activity is aligned at the time of the click with reward.
). This let us examine the effects of DA receptor antagonists on the background discharge rates of TANs in both experiment 1 and experiment 2. Average background discharge rates of TANs before and after application of DA receptor antagonists are summarized in Table 1. In both experiment 1, in which DA receptor antagonists were applied by micropressure, and experiment 2, in which DA receptor antagonists were iontophoretically applied, the discharge rates of TANs after administration of bothD1-class and D2-class antagonists were not significantly different from those before administration (P > 0.05, paired t-test). Therefore neither D1- nor D2-class antagonists affect the mechanisms that set the background discharge ratesof TANs.
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TABLE 2.
Effects of pressure application of dopamine receptor antagonists on the response of TANs
; Kawaguchi 1992; Kimura et al. 1996; Wilson et al. 1990; Yelnik et al. 1993). Thus in experiment 1, we locally applied either selective D1- or D2-class antagonist by micropressure, while recording the activity of TANs, to examine the effects of DA receptor antagonists on the acquired responses of TANs to the conditioned stimuli.
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FIG. 5.
Effects of iontophoretic application of D1-class and D2-class receptor antagonists on the responses of a TAN to the LED used as a trigger stimulus for the button push task. A-C: application of ( )-sulpiride with +30 nA current abolished responses to the LED. D-F: in the same neuron, no effect on activity of the application of SCH23390 using +30 nA current was observed. Histograms are centered at the time of presentation of the LED. The raster display was reordered sequentially from top to bottom based on the time between LED onset and the button push (reaction time).
)-sulpiride suppressed the pause response 9 min after application (Fig. 3B). The suppression of the pause response continued at least 81 min after the application of the drug. The late excitation, on the other hand, persisted after application of ()-sulpiride (Fig. 3, B-D). We could test the effects of only a single DA receptor antagonist on the responses of an individual TAN, because the effects of pressure application continued for a few hours. Another TAN illustrated in Fig. 3, E-H, showed no significant sensitivity to D1-class antagonist (cis-flupentixol). A pause in firing flanked by initial and late excitations triggered by the click associated with the reward continued to appear at least 107 min after application of the drug.
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FIG. 6.
Population response of TANs to LED illumination as a trigger for the button pushing movement task to summarize the effects of iontophoretic application of DA receptor antagonists. A: population activities of 31 of 49 TANs examined that were sensitive to D2-class antagonists. B: population activities of 11 of 41 TANs examined that were sensitive to D1-class antagonists. Population histograms are centered at the time of LED onset. Number of neurons included for each histogram is shown in parentheses.
)-sulpiride (0.9 µl), was suppressed similarly to the response of the TAN recorded at the injection site, whereas response of another TAN located 1,200 µm beneath the injection site was apparently unaffected.
)-sulpiride with a current of +30 nA suppressed the pause response of the TAN (P > 0.05, Wilcoxon test, Fig. 5B). The response of the TAN recovered in 16 min after the administration (Fig. 5C). When the response had fully recovered from administration of ()-sulpiride, the D1-class antagonist, SCH23390, was applied with a current of +30 nA. SCH23390 did nothave significant effects on the response of the TAN (Fig.5, D-F).
View this table:
TABLE 3.
Effects of iontophoresis of dopamine receptor antagonists on the responses of TANs
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FIG. 7.
Effects of application of physiological saline on the response of TANs as a control. The iontophoretic administration of D2-class antagonist using +30 nA current suppressed the conditioned response of a TAN (A-C). Subsequent application of saline with +30 nA did not affect the response of the TAN (D). E: response recorded 12 min after the saline application. Neuronal activities are centered at the time of LED illumination.
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FIG. 8.
Locations of micropressure injection in the striatum in experiment 1. Tracks of the injection cannula with recording wire electrode were drawn on 4 levels of coronal sections of the right hemisphere in monkey A, based on the histological reconstruction of the tracks. Symbols indicate locations where TANs were recorded and single DA receptor antagonists were administered. 
, SCH23390 (not sensitive); 
, cis-flupentixol (not sensitive); 
, ()-sulpiride (sensitive); 
, ()-sulpiride (not sensitive); 
, saline (not sensitive). Cd N., caudate nucleus; Put., putamen.
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FIG. 9.
Location of iontophoresis in experiment 2. Drawings of electrode tracks on the coronal sections of the left and right hemispheres in monkey B. Symbols indicate the administration sites of DA receptor antagonists where TANs were sensitive exclusively to D1-class ( 
), exclusively to D2-class (), and to both D1- and D2-class () receptor antagonists, respectively. Filled symbols indicate sites where both D1- and D2-class antagonists were tested. Open symbols indicate sites where only 1 antagonist was tested. Cd N., caudate nucleus; Put., putamen; AC, anterior commissure; GPe, external segment of globus pallidus; GPi, internal segment of globus pallidus.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
)-sulpiride, the response of a TAN 600 µm beneath the injection site was suppressed similarly to the response of the TAN at the injection site, whereas the response of another TAN 1,200 µm beneath the same injection site remained.
; Freund et al. 1984; Kubota et al. 1987). Yelnik et al. (1993) reported that the cholinergic interneurons in the primate striatum have large elongated dendrites extending up to 600 µm on an average. TANs are thought to be the striatal cholinergic interneurons, based on their slow tonic firing, morphology of cell soma and dendritic arbors (Kawaguchi 1992; Wilson et al. 1990), and preferential distribution at striosome/matrix borders in the striatum (Aosaki et al. 1995).
). In situ hybridization studies have shown that cholinergic interneurons expressD2- and/or D1-class receptor mRNA (Le Moine et al. 1991; Weiner et al. 1991). Recent investigation by the use of reverse transcription-polymerase chain reaction analysis (RT-PCR) of dissociated striatal cells provided evidence that cholinergic interneurons express primarily D2 and D1b receptor mRNAs (Yan et al. 1997). These studies indicate that most cholinergic interneurons in the striatum possess D2-class DA receptors and some of them have bothD1-class and D2-class DA receptors.
investigated the actions of DA receptor agonists on the striatal cholinergic interneurons in the slice preparation using whole cell patch-clamp technique. Application of the D1-class agonist, SKF38393, almost always induced an inward current, and thus caused burst discharges of these neurons. On the other hand, a D2-class agonist, quinpirole, induced an outward current and suppressed spike discharges in one-half of them and induced inward current and burst discharges in the other half of them. In a study that used an acute dissociated cell preparation (Yan et al. 1997), it was reported that activation of D2 DA receptors in cholinergic interneurons reducesN-type Ca2+ current. This D2 receptor-mediated reduction of N-type Ca2+ current should not only attenuate the dendritic invasion of initial segment spikes (Spruston et al. 1995) but also attenuate the active augmentation of excitatory synaptic events arising from cortical or thalamic sources (Bernander et al. 1994; Kim and Connors 1993; Wilson 1993).
). But an initial excitation preceding the pause remains after MPTP infusion. Quite similarly, our study demonstrates that application of specific DA receptor antagonists largely reduced pause responses of TANs to stimuli that were predictive of reward, but the initial excitation remained. The initial excitatory response of TANs thus must be mediated through mechanisms that are not related or poorly related to DA receptors. Aosaki et al. (1994a) demonstrated that application of the DA receptor agonist, apomorphine, reinstated responses of TANs in striatum previously infused with MPTP. The present results explain, at least partly, the mechanisms of action of the nigrostriatal DA system on TANs that are working when animals are performing learned behavioral tasks. First, the nigrostriatal DA system does not seem to convey specific, sensory inputs to TANs, but rather to supply control signals for TANs to express responses to inputs. Second, the control of responsiveness of TANs by the nigrostriatal DA system seems to be mediated primarily through D2-class, but partly through D1-class receptor mechanisms. Therefore it can be concluded that the nigrostriatal DA system enables TANs to express learned activities primarily through D2-class and partly through D1-class receptor-mediated mechanisms in the striatum.
that 10-20% of TANs respond to a solenoid click before conditioning. Responses of most of the TANs to the conditioned stimuli thus must have been acquired through the conditioning process. Therefore the present results strongly suggest that tonic DA receptor stimulation enables the striatal neurons to express learned activities, although activity in a small percentage (10-20%) of neurons may depend on DA receptor stimulation independent of learning.
-aminobutyric acid (GABA)-mediated inhibitory transmission of the strioentopeduncular neurons containing substance P (SP) (Ferre et al. 1996). This observation was supported by other studies (Girault et al. 1986; Reid et al. 1990). On the other hand, the most consistent response of TANs to sensory stimuli is the pause of tonic discharge, which is presumably mediated by either inhibitory mechanisms or resetting of tonic background discharges (Aosaki et al. 1995). If GABAergic striatal projection neurons containing SP send their axon collaterals to TANs that are supposed to be cholinergic (Bolam et al. 1983, 1986), administration of D1-class antagonist would diminish inhibitoryGABAergic neurotransmission to TANs. This could lead to the suppression of the pause response of TANs by D1-class antagonist. This mechanism may be responsible for the observation that sensory response of some TANs were significantly reduced by D1-class antagonist.
showed that D1 antagonists can selectively potentiate the "memory fields" of prefrontal neurons that subserve working memory. This might reflect specificity in the cellular mechanisms of DA receptors involved in learning and memory of actions in different brain areas. On the other hand, it remains to be studied which class of DA receptors is involved in the acquisition of new activities in both TANs and the other class of striatal neurons, phasically active neurons (PANs), which are believed to be projection neurons to the globus pallidus and substantia nigra.
; Schultz 1986; Schultz et al. 1993). DA neurons were activated by primary food and fluid rewards. But when the rewards were predicted by a sensory stimulus used as a behavioral cue, the DA neurons became responsive to visual or auditory stimuli predictive of reward (Ljungberg et al. 1992). In the striatum, the majority of TANs responded to a reward-associated click, when animals were trained to associate sensory stimuli with reward. But when animals learned a visually guided push button task, TANs responded to the visual trigger stimulus and showed no significant responses to the reward-associated click. This suggests the interesting possibility that the TANs in the striatum exhibit responses to behavioral events predictive of reward under the strong influence of inputs from the DA-containing neurons in the substantia nigra pars compacta (SNc).
; Schultz et al. 1993). By contrast, the TANs, once having acquired responses to the reward-predictive stimuli, maintained the responses even with prolonged overtraining, when the conditioned behavior became highly automatized (Aosaki et al. 1994b). This contrasting property in activity suggests that nigrostriatal DA neurons and TANs are involved in different aspects of mechanisms in behavioral learning. That is, DA-containing neurons may transmit motivation- or reinforcement-related information to the striatum with phasic release of DA in the striatum through which TANs acquire responses to behavioral events predictive of reward. When DA neurons lose their responsiveness through overtraining, TANs might express activities encoding reward predictability in terms of the baseline release of DA in the striatum. Because the main targets of TAN axons are nearby projection neurons in the striatum (Aosaki et al. 1995), the projection neurons would receive innervation by both the nigrostriatal DA neurons and TANs. Therefore the contrasting response plasticity of nigrostriatal DA neurons and TANs in the striatum may constitute fundamental role in basal ganglia mechanisms involved in acquisition and retrieval of purposeful behavior.
showed that cholinergic interneurons of the striatum receive strong inputs from the intralaminar thalamic nuclei. The latencies and electrophysiological properties of the excitatory postsynaptic potentials of striatal cholinergic interneurons evoked by electrical stimulation of the cerebral cortex and thalamus were consistent with monosynaptic inputs from both structures (Wilson et al. 1990). In addition to the above evidence, recent studies in our laboratory have revealed that centromedian-parafascicular (CM-Pf) nuclei of thalamus are candidates structures for supplying the conditioning input to TANs (Matsumoto et al. 1996, 1997). Neurons in CM-Pf nuclei were found to respond not only to reward-associated but also to nonreward-associated stimuli. Inactivation of CM-Pf nuclei by local injection of muscimol almost completely abolished responsiveness of TANs in the ipsilateral striatum to reward-associated stimuli. This evidence suggests the possibility that striatal TANs receive two characteristic inputs, one from the nigrostriatal DA system and the other from CM-Pf thalamus, and that CM-Pf nuclei supply conditioning inputs, whereas the nigrostriatal DA system modulates conditioning input mainly through D2- and partly through D1-class receptor-mediated mechanisms in a context-dependent manner.
). On the other hand, Rolls et al. (1984) observed a decrease in spontaneous firing rates of primate striatal and prefrontal cortex neurons in response to iontophoretically applied DA, and drew their conclusion that DA sets the baseline firing rate very low so that the DA can control the signal-to-noise ratio of processing in the striatum. It is not possible to compare directly the results of Rolls et al. with the present observations, because they recorded the activity of striatal projection neurons, but not TANs, and because they did not examine effects of specific D1- and D2-class antagonists.
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ACKNOWLEDGEMENTS |
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We are grateful to Prof. C. Ohye for advice and constant encouragement, to Dr. Ann M. Graybiel for valuable advice, to Drs. M. Inase and H. Sato for technical advice, and to N. Matsumoto, Y. Ueda, T. Sato, and T. Minamimoto for participation in a part of this study. We thank Dr. Edward S. Ruthazer for correcting English expression of the manuscript.
This study was supported by grants from the Ministry of Education of Japan (96L00201, 07408035, and 40118451) to M. Kimura.
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FOOTNOTES |
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Address for reprint requests: M. Kimura, Faculty of Health and Sport Sciences, Osaka University, Toyonaka, Osaka 560, Japan.
Received 18 September 1997; accepted in final form 10 February 1998.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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