Abstract

The current model of basal ganglia organization postulates their functional division into sensorimotor, associative, and limbic territories, implicated, respectively, in motor, cognitive, and motivational aspects of behavior. Based on this model, we previously demonstrated, in the external segment of globus pallidus of monkeys, that the same neuronal dysfunction induced dyskinesia or abnormal behavior depending on the functional territory. To extend these findings, we performed bicuculline microinjections into the different functional territories of the striatum in 6 monkeys. Abnormal movements were observed after microinjections into the posterior putamen, corresponding to the sensorimotor territory, and into the dorsal part of the anterior striatum, corresponding to the associative functional territory. Within the ventral striatum, referred to as the limbic functional territory, we identified 3 subregions corresponding to different types of abnormal behaviors. Simultaneous neuronal recordings performed close to the microinjection sites confirmed that bicuculline produced a focal increase of neuronal activity surrounded by a zone with neuronal hypoactivity. This study provides new evidence for the involvement of specific striatal regions in movement as well as in a large spectrum of behavioral disorders and suggests that local inhibitory dysfunction could be a pathological mechanism of various neurological and psychiatric disorders.

Introduction

The basal ganglia (BG) determine behavioral expression not only through movement control but also through the well-known action triggers such as cognition, motivation, and emotion.

The motor and nonmotor BG functions arise from the massive topographically and functionally organized cortical projections (Alexander et al 1986; Haber 2003), which provide anatomical support for the functional subdivision of the BG into sensorimotor, associative, and limbic territories, leading to the concept that cortical information is processed through functionally segregated BG circuits (Alexander et al. 1986; Parent and Hazrati 1995; Middleton and Strick 2002). In accordance with this model, we addressed the hypothesis that movement and behavioral disorders could arise from a dysfunction of different functional territories of the BG in a previous study on monkeys (Grabli et al. 2004). We demonstrated that, in the external segment of the globus pallidus (GPe), pharmacologically induced neuronal dysfunction resulted in abnormal movements when performed in the sensorimotor part and behavioral disorders when performed in the associative or limbic parts. The main goal of the present study was to extend this hypothesis to the striatum.

Corticostriatal projections are indeed organized in such a way that sensorimotor cortical areas and the dorsolateral prefrontal cortex, which determine the motor and associative functional territories, project primarily to the dorsolateral striatum. In contrast, limbic-related cortical areas, such as the orbital and medial prefrontal cortices, project to the ventral part of the striatum (Flaherty and Graybiel 1994; Kunishio and Haber 1994; Haber et al. 1995).

There is growing evidence from pharmacological studies in animal models and neuroimaging studies in humans to suggest that the dorsal and ventral striatum may have distinct functions. Thus, the dorsal striatum has been shown to contribute to motor and cognitive control, especially action selection and initiation, as well as to associative learning (Tremblay et al. 1998; Barnes et al. 2005; Williams and Eskandar 2006). The ventral striatum, and particularly the nucleus accumbens, has been shown to be involved in reward and motivation processing (O'Doherty 2004; Atallah et al. 2007).

In addition, numerous neuroimaging studies have demonstrated the perturbation of BG activity, and particularly that of the striatum, in the expression of such neuropsychiatric disorders as Huntington disease and Tourette's syndrome (Stern et al. 2000; Peterson et al. 2003; Gavazzi et al. 2007; Johnson et al. 2007), as well as several psychiatric disorders, such as obsessive–compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), depression, and addiction (Riffkin et al. 2005; Castellanos et al. 2006; Mah et al. 2006; Le Moal and Koob 2007).

The present study was designed to evaluate the behavioral and movement manifestations in monkeys resulting from a pharmacological neuronal perturbation induced by microinjections of a γ-aminobutyric acid (GABA)ergic antagonist (bicuculline) into different regions throughout the various functional territories of the striatum. In accordance with previous results obtained in the GPe, we expected movement disorders to be induced by microinjections into the dorsolateral striatum, corresponding to the sensorimotor functional territory. We also hypothesized that behavioral abnormalities could be induced by microinjections into the dorsal part of the anterior and ventral striatum, which would thus correspond to the associative and limbic functional territories. We also performed electrophysiological recordings to determine the diffusion pattern of bicuculline within the striatum.

Materials and Methods

Subjects

Experiments were performed on 4 male African green monkeys (Cercopithecus aethiops sabaeus), 1 male rhesus monkey (Macaca mulatta), and 1 male fascicularis monkey (Macaca fascicularis), all weighing 4–6 kg. Care and treatment of these monkeys, A, B, C, H, N, and S, were in strict accordance with National Institutes of Health guidelines (1996) and the recommendations of the EEC (86/609) and the French National Committee (87/848).

Surgical Procedure

The surgical procedure was the same for all 6 animals. Under gaseous anesthesia, a rectangular stainless steel chamber was implanted stereotactically on the interhemispheric line under aseptic conditions. The skull under the chamber was removed, but the animal's dura mater was left intact. The chamber was positioned with respect to the anterior commissure (AC) and posterior commissure coordinates obtained by ventriculography.

Bicuculline Microinjections and General Experimental Design

The site of microinjection was determined by anteroposterior and lateral coordinates according to striatum stereotaxic maps obtained from the anatomical data of African green monkeys studied in our laboratory, a rhesus monkey brain atlas (Paxinos et al. 2000), and primate brain maps (Martin and Bowden 2000). In addition, extracellular single-unit electrophysiological recordings enabled us to determine dorsoventral coordinates. The striatum was thus identified by its specific neuronal activity, and the exact depth of the microinjection was therefore determined. Before the experimental sessions, a perforated grid (1 × 1 mm spacing) was installed in the chamber to position the microinjection cannula at the chosen coordinates. The microinjection cannula was mounted on a mechanical microdrive and connected to a 10-μL microsyringe (Hamilton) filled with bicuculline. A Teflon- and epoxylite-insulated tungsten microelectrode was inserted in the cannula for electrophysiological recording. Once the tip of the cannula was positioned at the chosen site, the control behavioral observation started. The cannula was left in place during the entire experiment (about 90–120 min). Bicuculline was then delivered by pressure at a rate of 1 μL/min in steps of 0.5 μL. The volume used for microinjections was from 1.5 to 3.0 μL of sterile bicuculline methiodide (Sigma, Saint Quentin Fallavier, France) at a concentration of 15 μg/μL (29.5 mmol/L).

During experimental sessions, the animals were placed in a standard primate chair enabling head movements to be restrained. Spontaneous behavior and the performance of the first task (T1) were evaluated during a control period of 15 min before the microinjections of bicuculline. The first postinjection observational period of 21 min was followed by the first set of postinjection tasks (T2 and T3); the second observational period, also of 21 min, was followed by the final set of tasks (T4 and T5). Depending on the duration of the effect, the last task sessions were performed either during the end of the effect or during the recovery time. The design of control sessions was similar to that of experimental sessions, including all manipulations relating to the preparation of the microinjection, but without the cannula in the monkey's brain. The control sessions were performed to detect any possible contextual induction of abnormal behavior. The monkeys were accustomed to the daily procedure and learned the task before the surgical operation.

Electrophysiological Recordings

The neuronal recordings were performed on 2 African green monkeys. We used a technical approach similar to that described by Matsumura et al. (1995) for the GPe. Thus, we chose to record the neuronal activity at 2 different distances from the orifice of the injection cannula: 600–700 μm for 1.5 μL and 1000 μm for 3.0 μL of bicuculline. The greater distance for the bicuculline volume of 3.0 μL was chosen to avoid the loss of recorded units due to injection pressure that was observed with shorter distances (less than 700 μm). Unit activity was recorded using Teflon- and epoxylite-insulated tungsten microelectrodes (stem with an outer diameter of 76 μm, tapered down over 0.5 mm to the exposed tips 1.5–5.0 μm in diameter and 5–25 μm in length, and an impedance of 1.5–6.0 MΩ), placed in the injection cannula or with a second electrode positioned 1000 μm lateral to the injection cannula (Fig. 6A). The signals were amplified (DAM WPI 5), displayed on an oscilloscope, and digitized at 12.5 kHz (Spike 2; Cambridge Electronic Design, Cambridge, UK). Single-unit activity was processed using a time–voltage template built by Spike 2 software, to discriminate and produce a pulse for each spike with a temporal resolution of 0.1 ms.

Behavioral Analysis

Spontaneous behaviors and task performance were observed during each experimental session and recorded using a quadravision video system designed to visualize behavioral sequences from 4 positions (lateral, dorsal, and 2 frontal). Behaviors were defined as follows: 1) resting without other behaviors; 2) body examination; 3) grooming (cleaning its fur with its fingers); 4) leg, 5) arm, or 6) mouth movements (normal movements without a goal); 7) licking and/or biting fingers; 8) touching equipment; 9) vocalizations; 10) erection and ejaculation; and 11) other (behaviors characteristic of each monkey). All types of behavior and abnormal movements were evaluated in 3-min segments during a control period before microinjection and during 2 postinjection periods. The frequency and duration of each behavior or abnormal movement were quantified separately during observation on videotapes and compared with the measurements in the control sessions. The microinjection was considered to have produced an effect if the frequency and duration of one or more behaviors or movements were statistically different from control measurements (see also Statistical analysis). Each microinjection inducing a behavioral effect or abnormal movement was characterized by the latency, intensity, and duration of the effect (see Table 1). In the case of microinjections with multiple effects, the latency and duration of each observed effect were measured; the intensity was characterized for the effect with the shortest latency.

Table 1

Summary of the effect of striatal microinjections in 6 monkeys

No Monkey Volume (μL) Territory Dyskinesia type Topography Intensity Behavioral effect Task Latency (min) Duration (min) 
3.0 SM Chorea Right UL — 16 30 
1.5 SM Chorea Left UL/LL *** Vocalization MP 56 
1.5 SM Chorea Left UL *** — MP 90 
3.0 SM Chorea Left UL(a), LL(b) ** — MP a7b9 100 
3.0 SM Chorea Left UL *** — MP 40 
3.0 SM Chorea UL(a), LL(b) ** — MP a5b6 ab330 
3.0 IC/SM Myoclonia Right UL *** — Slow 14 46 
3.0 SM/Ass Myoclonia Left LL, Tail(a), left UL(b) *** — MP a8b23 ab76 
3.0 SM/Ass Myoclonia Tail ** — 39 57 
10 3.0 SM/Ass Myoclonia Eyelids(a), upper lip(b), UL(c) *** — MP a2b2c8 114 
11 2.0 SM/Ass Myoclonia Face, left UL/LL *** — NP 140 
12 3.0 SM/Ass Myoclonia Upper lip(a) ** Hypoactivity(b), vomiting(c) Slow a6b21c50 a94bcNA 
13 3.0 Ass Myoclonia Upper lip(a) ** Hypoactivity(b) Reject a2b21 a35b55 
14 3.0 Ass Myoclonia Eyes deviation(a), right UL(b) *** — MP a21b43 60 
15 3.0 Ass Myoclonia Eyelids(a) ** Hyperactivity, touching(b) a50b5 a33b47 
16 3.0 Ass — — *** Hyperactivity, touching 60 
17 3.0 Ass — — ** Hyperactivity, touching 60 
18 3.0 Ass — — ** Touching(a), stereotypias(b) a3b20 a15b21 
19 3.0 Ass/Lim Myoclonia Eyelids(a) *** Hypoactivity(b), vomiting(c) Slow, reject a40b1c63 a140b120 
20 3.0 Ass/Lim Myoclonia Inferior lip, LL(a) *** Hypoactivity(b) Reject a48b46 a34b58 
21 3.0 Ass/Lim — — *** Hypoactivity Reject 21 42 
22 1.5 Ass/Lim — — Hypoactivity Slow 57 
23 3.0 Ass/Lim — — ** Hypoactivity(a), vomiting(b) Slow, reject a21b80 a60 
24 3.0 Ass/Lim — — *** Hypoactivity Slow, reject 30 90 
25 3.0 Ass/Lim — — ** Erection Reject NA 
26 3.0 Ass/Lim — — Shivering NA NA 
27 3.0 Ass/Lim — — Erection (a), vocalization(b) Reject a5b30 13 
28 3.0 Ass/Lim   Hypoactivity, erection(b) a1b8 a17b15 
29 3.0 Ass/Lim — — *** Shivering, erection, ejaculation Reject 20 
30 3.0 Ass/Lim Myoclonia Tail(a), left UL(b) ** Stereotypias(c) Slow a21b43c5 ab74c80 
31 3.0 Ass/Lim — — ** Stereotypias Reject 14 57 
32 3.0 Ass/Lim — — *** Stereotypias 75 
33 3.0 Ass/Lim Myoclonia Eyelids(a) Stereotypias(b) a7b1 aNAb60 
34 3.0 Lim — — *** Stereotypias 45 
35 3.0 Lim — — *** Stereotypias 50 
36 3.0 Lim — — *** Stereotypias 10 60 
37 3.0 Lim — — *** Stereotypias 49 
38 3.0 Lim — — *** Stereotypias 55 
39 3.0 Lim — — *** Shivering, erection, ejaculation Reject 30 
40 3.0 Lim — — ** Erection(a), touching(b), vomiting(c) Slow a12b10c72 ab60 
41 3.0 Lim — — ** Erection(a), vocalization(b) Reject a2b42 a26bNA 
42 3.0 Lim — — *** Shivering(a), erection(b) Rejected ab17 a25b5 
43 3.0 Lim — — *** Erection Reject 45 
44 3.0 Lim Myoclonia Upper lip(a) ** Hypoativity(b) vomiting(c) Slow, reject a48b10c82 a39b93 
45 3.0 Lim — — *** Hypoactivity Reject 240 
46 3.0 Lim — — *** Hypoactivity(a), vomiting(b) Reject a1b2 77 
No Monkey Volume (μL) Territory Dyskinesia type Topography Intensity Behavioral effect Task Latency (min) Duration (min) 
3.0 SM Chorea Right UL — 16 30 
1.5 SM Chorea Left UL/LL *** Vocalization MP 56 
1.5 SM Chorea Left UL *** — MP 90 
3.0 SM Chorea Left UL(a), LL(b) ** — MP a7b9 100 
3.0 SM Chorea Left UL *** — MP 40 
3.0 SM Chorea UL(a), LL(b) ** — MP a5b6 ab330 
3.0 IC/SM Myoclonia Right UL *** — Slow 14 46 
3.0 SM/Ass Myoclonia Left LL, Tail(a), left UL(b) *** — MP a8b23 ab76 
3.0 SM/Ass Myoclonia Tail ** — 39 57 
10 3.0 SM/Ass Myoclonia Eyelids(a), upper lip(b), UL(c) *** — MP a2b2c8 114 
11 2.0 SM/Ass Myoclonia Face, left UL/LL *** — NP 140 
12 3.0 SM/Ass Myoclonia Upper lip(a) ** Hypoactivity(b), vomiting(c) Slow a6b21c50 a94bcNA 
13 3.0 Ass Myoclonia Upper lip(a) ** Hypoactivity(b) Reject a2b21 a35b55 
14 3.0 Ass Myoclonia Eyes deviation(a), right UL(b) *** — MP a21b43 60 
15 3.0 Ass Myoclonia Eyelids(a) ** Hyperactivity, touching(b) a50b5 a33b47 
16 3.0 Ass — — *** Hyperactivity, touching 60 
17 3.0 Ass — — ** Hyperactivity, touching 60 
18 3.0 Ass — — ** Touching(a), stereotypias(b) a3b20 a15b21 
19 3.0 Ass/Lim Myoclonia Eyelids(a) *** Hypoactivity(b), vomiting(c) Slow, reject a40b1c63 a140b120 
20 3.0 Ass/Lim Myoclonia Inferior lip, LL(a) *** Hypoactivity(b) Reject a48b46 a34b58 
21 3.0 Ass/Lim — — *** Hypoactivity Reject 21 42 
22 1.5 Ass/Lim — — Hypoactivity Slow 57 
23 3.0 Ass/Lim — — ** Hypoactivity(a), vomiting(b) Slow, reject a21b80 a60 
24 3.0 Ass/Lim — — *** Hypoactivity Slow, reject 30 90 
25 3.0 Ass/Lim — — ** Erection Reject NA 
26 3.0 Ass/Lim — — Shivering NA NA 
27 3.0 Ass/Lim — — Erection (a), vocalization(b) Reject a5b30 13 
28 3.0 Ass/Lim   Hypoactivity, erection(b) a1b8 a17b15 
29 3.0 Ass/Lim — — *** Shivering, erection, ejaculation Reject 20 
30 3.0 Ass/Lim Myoclonia Tail(a), left UL(b) ** Stereotypias(c) Slow a21b43c5 ab74c80 
31 3.0 Ass/Lim — — ** Stereotypias Reject 14 57 
32 3.0 Ass/Lim — — *** Stereotypias 75 
33 3.0 Ass/Lim Myoclonia Eyelids(a) Stereotypias(b) a7b1 aNAb60 
34 3.0 Lim — — *** Stereotypias 45 
35 3.0 Lim — — *** Stereotypias 50 
36 3.0 Lim — — *** Stereotypias 10 60 
37 3.0 Lim — — *** Stereotypias 49 
38 3.0 Lim — — *** Stereotypias 55 
39 3.0 Lim — — *** Shivering, erection, ejaculation Reject 30 
40 3.0 Lim — — ** Erection(a), touching(b), vomiting(c) Slow a12b10c72 ab60 
41 3.0 Lim — — ** Erection(a), vocalization(b) Reject a2b42 a26bNA 
42 3.0 Lim — — *** Shivering(a), erection(b) Rejected ab17 a25b5 
43 3.0 Lim — — *** Erection Reject 45 
44 3.0 Lim Myoclonia Upper lip(a) ** Hypoativity(b) vomiting(c) Slow, reject a48b10c82 a39b93 
45 3.0 Lim — — *** Hypoactivity Reject 240 
46 3.0 Lim — — *** Hypoactivity(a), vomiting(b) Reject a1b2 77 

Note: SM, sensorimotor territory; IC, internal capsule; Ass, associative; Lim, limbic territory; UL, upper limb; LL, lower limb; N, normal; MP, motor perturbation.

Simple Food Retrieval Task

The monkeys were trained to perform a simple choice task that consisted of grasping and retrieving food from an 18-well board placed in front of them. The left and right sides of the board were separated by a central plaque. During the training period, the monkeys learned to pick up rewards from the left and right part of the board with their left and right hand, respectively. This training enabled us to study each monkey's own spatial strategy, and its perturbation, under the different experimental conditions. We identified the errors in the task: crossover hand errors and non-taken rewards, the latter defined as the difference between the rewards available and the number of rewards retrieved. We also measured the average retrieval time, defined as the time taken to perform the task divided by the number of rewards retrieved. Non-taken rewards and retrieval times are considered to be behavioral markers of motivation (Pessiglione et al. 2004). To distinguish motor perturbation from a changed motivational state in task execution, we evaluated the temporal organization of average retrieval time, which included 2 supplementary measures: 1) time of movement to retrieve, which represented the time from the movement initiation to pickup and consumption of the reward, and 2) interretrieval time, measured between 2 movement initiations. Both measures were analyzed using “Vigie Primates” software (View-point, Lyon, France), which enables images recorded by video cameras to be digitized every 40 ms and shown on a computer screen. The software detects and measures movement between 2 successive images by analyzing the number of pixels that have changed in brightness. Within the digitalized image, we defined 2 windows over the reward board to record the hand movements for the right and left hand, respectively. Further details of the Vigie Primates software are given in Pessiglione et al. (2003). For statistical validity, from 4 to 6 task sessions were conducted during each experimental session. We pooled data according to the type of effect and the monkey.

Statistical Analysis

For the analysis of spontaneous behaviors, the duration and frequency of each type of behavior observed after a bicuculline microinjection were each compared with the control measurements from the same day and during the preceding and following control days by 2-way analysis of variance test. The mean numbers of errors in the task as well as the mean duration of movement to retrieve rewards and mean interretrieval time during the microinjection effect were compared with those of the control sessions using a Mann–Whitney test. Results with P < 0.05 were considered significant for all the analyses.

Histological Procedures

At the end of the experiments, the monkeys received an overdose of anesthetic drug and were transcardially perfused with a solution of 0.9% NaCl followed by 4% paraformaldehyde in 0.1 M phosphate-buffered solution (PBS; pH 7.4, 4 °C) and PBS with 5% sucrose. The brains were removed, immersed in PBS with 20% sucrose for 48 h, frozen, and cut into 50-μm-thick frontal sections on a microtome (François et al. 2004). The microinjection sites were reconstructed from cresyl violet–stained and calbindin-immunoreactive sections of each monkey on the basis of their microdrive coordinates and traces due to the passage of the cannula. The correspondence of the microinjection site to the sensorimotor, associative, or limbic functional territory of the striatum was ascertained: 1) according to the distribution of corticostriatal projections (Haber and McFarland 1999; Fudge and Haber 2002) and 2) by comparison of calbindin-immunoreactive sections of each monkey with previous studies of the distribution of calbindin immunoreactivity in the striatum (François et al. 1994; Parent et al. 1996) (see Supplementary material). Consequently, the regions of weak, moderate, and intense calbindin immunoreactivity defined, respectively, the sensorimotor, associative, and limbic territories within the striatum, similarly to the GPe (François et al. 1994, 2004). As a strict border line between the associative and limbic territories could not be determined on the most anterior explored level of the striatum (A +4), we distinguished the functional territory as follows (Fig. 1A): the injections in the most dorsal third of the striatum were labeled in the associative territory, whereas those in the most ventral third of the striatum were labeled in the limbic territory. The injections in the intermediate third of the striatum were labeled in the associative/limbic territory. The frontal brain sections with microinjection sites were transferred to a cartographic presentation, showing 4 anteroposterior planes AC +4, AC 0, AC −2, and AC −4 and compared with the borders of the striatal functional territories.

Figure 1.

Representation of the functional territories and localization of the microinjection sites within the striatum. (A) Delineation of functional territories according to the topography of corticostriatal projections. (B) An overview of the localization of microinjection sites throughout the striatal functional territories performed on 6 monkeys at 4 levels relative to the AC. SM, sensorimotor functional territory; Ass, associative functional territory; Lim, limbic functional territory; CN, caudate nucleus; Put, putamen; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus. Monkeys: A (□), B (graphic), C (△), H (○), N (⋄), and S (graphic). “Filled” symbols represent the microinjections that induced an effect; open symbols correspond to microinjections without an effect. The smaller symbols correspond to the smaller microinjection volume: 1.5–2.0 μL; the larger symbols correspond to a microinjection volume of 2.5–3.0 μL.

Figure 1.

Representation of the functional territories and localization of the microinjection sites within the striatum. (A) Delineation of functional territories according to the topography of corticostriatal projections. (B) An overview of the localization of microinjection sites throughout the striatal functional territories performed on 6 monkeys at 4 levels relative to the AC. SM, sensorimotor functional territory; Ass, associative functional territory; Lim, limbic functional territory; CN, caudate nucleus; Put, putamen; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus. Monkeys: A (□), B (graphic), C (△), H (○), N (⋄), and S (graphic). “Filled” symbols represent the microinjections that induced an effect; open symbols correspond to microinjections without an effect. The smaller symbols correspond to the smaller microinjection volume: 1.5–2.0 μL; the larger symbols correspond to a microinjection volume of 2.5–3.0 μL.

Results

Seventy-one bicuculline microinjections were performed in 62 sites throughout the 4 anteroposterior levels of the striatum: 10, 17, 9, 8, 7, and 11 sites in monkeys A, B, C, H, N, and S, respectively (Fig. 1B and Table 1). Microinjection levels were chosen to investigate the differences of effect induced by bicuculline injection in either the sensorimotor territory (levels: AC 0, AC −2, and AC −4) or the associative and limbic territories (level AC +4). Thus, according to the histological data, 20 microinjections were performed in the sensorimotor, 35 in the associative and the associative–limbic, and 16 in the limbic functional territories.

Two volumes of microinjections were performed. The smaller one (1.5–2.0 μL) was similar to the volume used in a previous study performed in the GPe (Grabli et al. 2004). Compared with the GPe, where all microinjections induced an effect, only 40.0% (6/15) of these small-volume microinjections into the striatum induced an effect. Consequently, the larger microinjection volume (2.5–3.0 μL) was applied and 71.4% (40/56) of microinjections with this volume induced an effect. For both volumes, 65% (46/71) of injections performed in the 3 functional territories of the striatum produced an effect. For 9 injection sites in the striatum, both volumes were applied: the same result was obtained with both volumes in 5 sites and the larger volume induced an effect, whereas the smaller one did not in the 4 other sites.

Abnormal Movements Induced by Bicuculline Microinjections into the Striatum

Two types of abnormal movements were observed after 20 striatal injections in 5 monkeys (A, B, C, H, and S). Both types of abnormal movements primarily occurred contralateral to the injection side.

In the dorsolateral part of the posterior putamen (AC −2 and AC −4), corresponding to the sensorimotor functional territory (Fig. 2A), we observed the first type of dyskinesia after 6 microinjections (30% of all microinjections performed in this territory) in 4 monkeys.

Figure 2.

(A) Distribution of sites in the striatum that induced different types of dyskinesia. (B) Histogram showing an example of a microinjection with dyskinetic effect without behavioral modification. (C) Distribution of latencies. (D) Somatotopic organization of the myoclonic jerks produced by the anterior part of the striatum (AC +4): M, myoclonic jerks; C, chorea; F, face; H, hand; T, tail; L, leg. The dashes (-) indicate the sites where dyskinesias were not induced. Error bars show the standard error of the mean. ***P < 0.001.

Figure 2.

(A) Distribution of sites in the striatum that induced different types of dyskinesia. (B) Histogram showing an example of a microinjection with dyskinetic effect without behavioral modification. (C) Distribution of latencies. (D) Somatotopic organization of the myoclonic jerks produced by the anterior part of the striatum (AC +4): M, myoclonic jerks; C, chorea; F, face; H, hand; T, tail; L, leg. The dashes (-) indicate the sites where dyskinesias were not induced. Error bars show the standard error of the mean. ***P < 0.001.

Dyskinesias had a complex pattern, with an alternation of flexion and extension movements, involving several joints simultaneously. This pattern was reminiscent of the choreic movements described after microinjections into the striatum and GPe in previous studies (Crossman et al. 1984, 1988; Matsumura et al. 1995; Grabli et al. 2004). The latency, namely, the mean delay before the onset of dyskinesia, was 6.6 min (range 4–16) and the mean duration was 107.6 min (range 30–330). Following half of the microinjections, choreic movement was confined to either the upper or the lower limb, whereas following the other half, a rapid progression to the whole hemibody was observed.

The second type of dyskinesia was observed after 14 injections in 4 monkeys. It was characterized by abrupt, brief, rapid, and predictable muscle contractions clearly resembling myoclonic jerks, as previously described by Crossman et al. (1988). Abnormal movements occurred in a repetitive manner, recurring every 3–5 s once the dyskinesia was well developed. After 3 microinjections (8, 9, and 30), the jerks occurred during abnormal posture of limbs or tail. The mean latency of myoclonic jerks was 21.9 min (range 1–50), and the mean duration of this type of dyskinesia was 70.9 min. After a majority of microinjections (10/14), dyskinesias occurred in the face and consisted of exaggerated blinking (4/10), eye deviation (1/10), or lip jerks (5/10) with secondary progression to the upper limb after 2 injections (Fig. 2D). After 4 injections, myoclonic jerks were primarily observed in the upper or lower limb or the tail. In the limbs, myoclonic jerks were visible both at rest and during voluntary movements. Generalized myoclonic seizures developed at the end of the second observational period after 3 injections, even though the primary dyskinetic effect was produced locally and contralateral to the injection side.

Dyskinesias in the upper limb, independently of the type, disturbed the food-retrieving task execution (movement perturbation during the task; see Table 1). The task was performed on both the right and the left side of the board with the unaffected arm, thus including crossover hand errors contralateral to the injection side without any modification in the number of rewards retrieved on each side of the reward board (Fig. 4A). In addition, we observed a slight, nonsignificant increase in the average retrieval time contralateral to the injection side (Fig. 4B).

All injection sites inducing myoclonic jerks were localized in the anterior striatum at level AC +4 (Fig. 2A). The microinjections with the shortest latencies (1–10 min) were predominantly localized in the dorsal part of the anterior putamen, corresponding to the associative territory (Fig. 2C), and the myoclonic jerks occurred alone. By contrast, the injections localized more ventrally in the putamen, within the associative–limbic territory, produced a dyskinetic effect with longer latencies (21–55 min), which was frequently preceded by behavioral modifications (Table 1). Thus, myoclonic jerks were observed after 40% of all injections performed in these territories. Only one microinjection into the purely limbic territory (the most ventral part of the anterior striatum), corresponding to 6% of all injections performed in the limbic territory, induced myoclonias.

Abnormal Behaviors Induced by Bicuculline Microinjections into the Striatum

Four types of abnormal behaviors were observed after 34 striatal injections in the 6 monkeys. Behavioral effects were characterized by a global or a specific perturbation of the monkey's natural behavioral organization. Compared with the control condition, where a resting state was usually accompanied by several types of behavior of low frequency and short duration, one or more behaviors became predominant and abnormal in frequency and/or duration after the microinjection. Abnormal behaviors were not lateralized and could be induced by injections in similar striatal sites in both hemispheres of the brain.

Two behavioral effects, characterized by opposite types of global behavioral modification, were defined as a hyperactive state and a hypoactive state.

The hyperactive state was observed after only 5 injections, but in 4 different monkeys (C, B, N, and S). It was characterized by increased activity with frequent changes in the type of behavior. The most frequent behaviors observed were nongoal-directed arm and leg movements, associated with touching behavior during which the monkey's activity was directed at the closest parts of the experimental setup (Fig. 3A′). The mean latency of this effect was 5 min (range 1–10), and the mean duration of the effect was 48.4 min. After 2 microinjections (18 and 40), the touching behavior was observed without a hyperactive state. In contrast to the hyperactive state after injections into the GPe described in the previous study (Grabli et al. 2004), we did not observe a spatial perturbation of the simple food retrieval task after microinjections into the striatum.

Figure 3.

Latencies and examples of different behavioral manifestations observed after microinjections into the anterior level (AC +4) of the striatum: (A, A′) hypoactivity; (B, B′) hyperactivity; (C, C′) stereotyped behavior; and (D, D′) erection with ejaculation. The numbers represent the latency of the effect of each injection and the dashes (-) indicate the sites where the same effect was not observed. Error bars show the standard error of the mean. ***P < 0.001.

Figure 3.

Latencies and examples of different behavioral manifestations observed after microinjections into the anterior level (AC +4) of the striatum: (A, A′) hypoactivity; (B, B′) hyperactivity; (C, C′) stereotyped behavior; and (D, D′) erection with ejaculation. The numbers represent the latency of the effect of each injection and the dashes (-) indicate the sites where the same effect was not observed. Error bars show the standard error of the mean. ***P < 0.001.

Figure 4.

Two examples of task performance after bicuculline microinjections that induced dyskinesia (A, B) or hypoactivity (C, D). The white bars show the control condition and the black bars the performance after bicuculline injection. Dyskinesia did not produce any effect on the percentage of initiated choices (A) or on retrieval times (B) for either side of the board (ipsilateral or contralateral to the injection site). However, during the hypoactivity effect, the percentage of initiated choices decreased (C) and retrieval times increased (D) for both sides of the board (ipsilateral or contralateral to the injection site). Further analysis of retrieval times showed that the increase in retrieval times during the hypoactivity effect (D) was mainly due to a significant increase in the duration of the interretrieval period between choices and not to a change in the duration of the movement. Error bars show the standard error of the mean. **P < 0.01, ***P < 0.001, NS, no significant effect.

Figure 4.

Two examples of task performance after bicuculline microinjections that induced dyskinesia (A, B) or hypoactivity (C, D). The white bars show the control condition and the black bars the performance after bicuculline injection. Dyskinesia did not produce any effect on the percentage of initiated choices (A) or on retrieval times (B) for either side of the board (ipsilateral or contralateral to the injection site). However, during the hypoactivity effect, the percentage of initiated choices decreased (C) and retrieval times increased (D) for both sides of the board (ipsilateral or contralateral to the injection site). Further analysis of retrieval times showed that the increase in retrieval times during the hypoactivity effect (D) was mainly due to a significant increase in the duration of the interretrieval period between choices and not to a change in the duration of the movement. Error bars show the standard error of the mean. **P < 0.01, ***P < 0.001, NS, no significant effect.

Reconstruction of the microinjection sites showed that the 4 microinjections that induced an effect with the shortest latency were situated in the dorsal part of the anterior putamen (AC +4) (Fig. 3A), corresponding to the associative and associative–limbic territories, and represented 12% of all injections performed in these territories. The fifth site, with the longest latency, was localized in the medial part of the anterior striatum (AC +4), corresponding to the limbic territory, and represented 6% of all injections performed in this territory.

The second global behavioral effect was observed after 11 striatal injections in 5 monkeys (C, H, B, N, and S). We defined this effect as a hypoactive state because it was characterized by a reduction in the duration of all types of the monkey's spontaneous behaviors or even by the disappearance of some of them. Consequently, the duration of resting behavior was considerably longer (Fig. 3B′). The mean latency of the hypoactive state was 16.5 min (range 1–46) and the mean duration 89.2 min (range 42–240). After 6 injections, we observed a progressive perturbation of the simple food retrieval task: the total time to execute the first postinjection trials was increased compared with control conditions and 2 subsequent postinjection tasks were rejected (Table 1). After 5 injections, the rejection of task execution was observed from the first postinjection trial.

The slowness of task performance was not related to executive disorders, such as freezing (sudden blockage during task execution) or hesitation (change of choice during ongoing movement), but to a longer retrieval time. Analysis of the temporal organization showed that the time of movement execution to retrieve the reward did not change, but the interretrieval periods were considerably longer (Fig. 4D).

In addition, the number of rewards taken (Fig. 4C) was considerably diminished for both sides of the board after these injections. No crossover hand errors were observed during this effect. We thus concluded that the monkeys in the hypoactive state preserved their normal capacity for action execution, but spontaneous action initiation was affected.

After 6 injections, the hypoactive state was associated with vomiting. In the majority of injections (5/6), vomiting occurred with a long latency (mean 64.9 min, range 50–82). In the remaining case, vomiting occurred 2 min after the microinjection. Progressively, during the following 2 h, the animals regained their normal behavioral activity and appetite. Reconstruction of the microinjection sites revealed that the majority of them were localized in the ventral striatum (AC +4), either in the ventral putamen (9/11) or in the caudate nucleus (2/11), corresponding, respectively, to the associative and associative–limbic (26% of all injections performed in this territory) and limbic territories (12.5% of all injections performed in this territory) (Fig. 3A).

In contrast to the effects described above, the other 2 observed effects were characterized by abnormal expression of specific behaviors.

Nine injection sites within the striatum in 3 monkeys (N, B, and S) induced an intense expression and persistent repetition of a group of behaviors belonging to the animal's usual repertoire of grooming. At the peak effect, the continuity and duration of these behaviors became clearly abnormal, mostly consisting of licking or biting parts of the body, often the fingers or tail (Fig. 3C). This type of behavioral effect was previously observed after GPe injections (Grabli et al. 2004) and was referred to as stereotyped behavior. Stereotyped behaviors developed rapidly after the microinjection, with a mean latency of 5.6 min (range 1–14), and the mean duration of the effect was 60.1 min. Moreover, they did not perturb the execution of the simple food retrieval task: the spatial strategy was preserved and error frequency remained low. All the injection sites producing stereotyped behaviors were localized in the central part of ventral striatum (AC +4), corresponding to the central part of the associative–limbic (12% of all injections performed in this territory) and limbic territories (30% of all injections performed in this territory) (Fig. 3C).

The last behavioral effect, observed after 9 injections in 4 monkeys, was characterized by sexual behavior manifestations, including erection and ejaculation (Fig. 3D′). Erection was often preceded by a brief period of shivering and accompanied by a backward leaning position. The mean latency of this effect was 5.8 min (range 1–17), and the mean duration was 26.7 min (range 5–60). This effect was also associated with diminished behavioral activity and slow task execution or its rejection (Table 1). The injection sites were localized in the most medial part of the anterior striatum (AC +4), corresponding to the associative–limbic (12% of all injections performed in this territory) and limbic (31% of all injections performed in this territory) functional territories (Fig. 3D). Microinjection 29 was localized in the caudate nucleus at the level of the AC (AC 0) (Fig. 1B), also corresponding to the associative–limbic functional territory.

Electrophysiological Recordings

Thirteen recordings of single-unit activity were performed within the striatum of 2 African green monkeys to identify the local modifications of neuronal activity induced by bicuculline and to determine the speed of bicuculline diffusion around the injection site. All neuronal units were recorded continuously throughout the preinjection, injection, and postinjection periods. Apart from 2 recorded neurons with a high activity rate (>20 spikes/s), the activity rate was low (mean 0.9 spike/s) for the majority of neurons before the injection, suggesting that the majority of recorded neurons were medium spiny projection neurons (MSNs).

For the smaller bicuculline volume of 1.5 μL, the activity of 4 neurons located close (600–700 μm) to the injection site was recorded via an electrode placed in the injection cannula (Fig. 5A). After bicuculline microinjection, the activity rapidly increased (mean 4.6 spike/s, P < 0.001) for all the recorded neurons (Fig. 5B). The increased neuronal activity was mainly due to an increase in the number of spikes during the bursts (Fig. 5C).

Figure 5.

Setup for unit recordings and neuronal modifications observed following injections of bicuculline. (A) Unit recording was obtained from a microelectrode inside the injection cannula or from a second electrode lateral to the injection cannula. Unit recording was done at different distances from the orifice of the injection cannula, depending on the injection volume: 600–700 μm for 1.5 μL of bicuculline (via the first electrode) and 1000 μm for 3.0 μL of bicuculline (via the first or second electrode). (B) Modifications of firing rate for each unit recording were compared between the control period (before injection) and 10 and 30 min after the injection. Error bars show the standard error of the mean. (C) An example of the local effect (<600 μm) observed after 1.5 μL of bicuculline; the numbers represent the mean and the range of the spikes. (D) An example of the distance effect (at 1 mm) after 3.0 μL of bicuculline.

Figure 5.

Setup for unit recordings and neuronal modifications observed following injections of bicuculline. (A) Unit recording was obtained from a microelectrode inside the injection cannula or from a second electrode lateral to the injection cannula. Unit recording was done at different distances from the orifice of the injection cannula, depending on the injection volume: 600–700 μm for 1.5 μL of bicuculline (via the first electrode) and 1000 μm for 3.0 μL of bicuculline (via the first or second electrode). (B) Modifications of firing rate for each unit recording were compared between the control period (before injection) and 10 and 30 min after the injection. Error bars show the standard error of the mean. (C) An example of the local effect (<600 μm) observed after 1.5 μL of bicuculline; the numbers represent the mean and the range of the spikes. (D) An example of the distance effect (at 1 mm) after 3.0 μL of bicuculline.

Figure 6.

(A, B) Summary of the presentation of different behavioral and movement disorders induced through the anterior striatum in the study. CN, caudate nucleus; Put, putamen; Acc, nucleus accumbens; Lim, limbic territory; Ass, associative territory.

Figure 6.

(A, B) Summary of the presentation of different behavioral and movement disorders induced through the anterior striatum in the study. CN, caudate nucleus; Put, putamen; Acc, nucleus accumbens; Lim, limbic territory; Ass, associative territory.

For the bicuculline volume of 3.0 μL, the activity of 9 neurons was recorded at a distance of 1000 μm from the injection site: we recorded 4 neurons situated ventral to the cannula orifice via an electrode placed within it, whereas 5 neurons were recorded via a second electrode positioned laterally (Fig. 5A). For both of the recorded planes, none of the neurons showed an increase in activity immediately after injection. Moreover, during the 10 min immediately after the injection, the majority of recorded neurons (6/9) showed a decrease (P < 0.001) in activity (Fig. 5B). Nevertheless, for all the recorded neurons at this distance, the activity increased a mean 23 min after the injection (range 10–40 min). In the majority of the neurons, activity became higher than before the bicuculline injection. In these neurons, we observed an increase in both burst frequency and spike number during bursts, accompanied by a marked reduction in interspike intervals (Fig. 5D).

Discussion

The results of this study show that the alteration of neuronal activity by bicuculline microinjections in the striatum can produce movement or behavioral disorders depending on the localization of the injections in the different functional territories. Moreover, we have demonstrated that local inhibitory dysfunction results in different functional effects in the dorsal and ventral striatum (Fig. 6).

Bicuculline Microinjections in the Monkey Striatum: A Tool to Study Local Dysfunction of Specific Functional Territories

The ability to reproduce the effects from the same injection site in the same monkey, together with the fact that similar effects were observed after injections in similar sites in several monkeys, provides strong evidence for the consistency of the effects produced in the striatum. However, to induce similar effects with a short delay and to achieve a high percentage of effective injections, we had to use a bigger volume of bicuculline for the striatum (3.0 μL) than that previously used in the GPe (1.5 μL). As the striatum is a more voluminous structure than the Gpe, it is possible that larger populations of neurons have to be activated to produce an equivalent effect. The striatum is also a more complex structure with several neuronal types (Yelnik et al. 1991), including 2 sets of GABAergic neurons—the MSNs—which are submitted to a strong feedforward inhibition due to the fast-spiking interneurons (Koós and Tepper 1999; Plenz 2003).

The bicuculline salts act as an antagonist on the GABAA receptor and block small potassium channels (SKca) channels (Seutin and Johnson 1999), both these mechanisms leading to an increase in the firing rate, as observed in this study with the neuronal recordings close to the injection site. The increase in the firing rate, mainly expressed as an increase in the number of spikes during each burst in the striatum, could be explained by an effect of bicuculline on the inhibitory input provided by the GABAergic interneurons and by collaterals arising from neighboring medium spiny neurons (Shi and Rayport 1994). We also observed biphasic activity changes in neurons 1000 μm from the bicuculline injections. The initial inhibition could be related to the activation of MSNs close to the injection site, acting through their local collaterals. The fact that we observed the increase in neuronal activity at a mean 23 min after the injection for the 1000-μm distance enabled us to evaluate the speed of bicuculline diffusion. Thus, the majority of movement and behavioral effects with a short latency (less than 20 min) were indeed induced by a local effect in the striatum and not by diffusion within or outside the striatum. Consequently, the behavioral effects observed at a long latency (20–40 min) most likely resulted from bicuculline diffusion within other striatal territories around the injection site. The diffusion effect was clearly observed with microinjections into the ventral part of the anterior striatum, where the myoclonias were produced at long latencies (more than 40 min), compared with the injections in the dorsal part, where the same dyskinesia was produced after a short latency (less than 10 min).

Dysfunction of the Dorsal Striatum: Movement Disorders

Dyskinesias of choreic and myoclonic types have already been described following bicuculline microinjections into the monkey striatum and particularly in the posterior putamen (Crossman et al. 1984, 1988). In this study, however, we observed chorea following microinjections in the posterior part (AC −4) of the putamen and myoclonic jerks following bicuculline microinjections in the anterior part (AC +4). This discrepancy may have been due to methodological differences between the 2 studies, as Crossman et al. (1984, 1988) performed the microinjections only in the posterior part of the putamen, whereas in our study, we explored more particularly the anterior part. Nevertheless, according to the data of Crossman et al. (1984, 1988), only a minority of the injections (9/61 or 15%) in the posterior part of the putamen induced myoclonic jerks, whereas in our study, 40% of injections performed in the dorsal part of the anterior striatum induced this type of dyskinesia. Consequently, we suggest that myoclonic jerks are induced preferentially from the anterior part than from the posterior part of the dorsal putamen.

Myoclonic jerks observed in our monkey model were visible at rest and during actions and were localized topographically in the monkey's face and upper limb. These aspects are in common with another type of abnormal movement, namely, simple motor tics. Simple motor tics could be confused with myoclonus because they consist of short-lasting muscle contractions, often producing jerks involving the face, neck, or distal limbs. Tics are also characterized by the possibility of their being temporarily suppressed (Jankovic and Fahn 1986) and are often preceded by premonitory sensations that are relieved by the performance of tics (Leckman et al. 1993; Kwak et al. 2003). In the animal model, the latter 2 aspects of tics are difficult to investigate. Nevertheless, recent neuroimaging studies on patients with tics clearly demonstrate activation of the anterior striatum (Stern et al. 2000; Lerner et al. 2007), corresponding to the region that induced myoclonic jerks in our monkey model. As the anterior striatum receives input from the premotor cortex and the dorsolateral and parietal cortices (Cavada and Goldman-Rakic 1991; Yeterian and Pandya 1991), as does the primary motor area and supplementary motor area (SMA) (Takada et al. 1998a, 1998b; Inase et al. 1999), it could be implicated in motor selection and learning. Indeed, functional studies, including both electrophysiological recordings in awake monkeys and neuroimaging studies in healthy volunteers, have shown that the anterior striatum is involved in the selection and preparation of self-generated movements, whereas the posterior striatum is involved in movement execution (Romo, Scarnati, and Shultz 1992; Schultz and Romo 1992; Gerardin et al. 2004). The suggestion that myoclonic jerks could result from a perturbation of action selection fits well with recent data from patients with tics, showing abnormal activation of the SMA at the onset of tics (Bohlhalter et al. 2006).

Moreover, one hypothesis attributes the expression of tics to an aberrant activation of striatal neurons due to a local release of tonic inhibition (Albin and Mink 2006) that fits well with a focal activation of striatal neurons, as shown by neuronal recordings. Local inhibition in the striatum originates from close axonal collaterals of MSNs and from parvalbumin-positive interneurons, which exert a strong inhibitory effect on a large set of MSNs (Plenz 2003). A recent neuropathological study performed in patients with Tourette's syndrome, the most severe chronic tic disorder, revealed a lower striatal density of the parvalbumin-positive interneurons (Kalanithi et al. 2005). From this point of view, our monkey model fits well not only with some nosological aspects of Tourette's syndrome but also with a pathophysiological mechanism involving dysfunction of the GABAergic system of the BG.

The pharmacological perturbation of the dorsal striatum was also characterized by a behavioral disorder, namely, a hyperactive state, the hallmark of which was the raised motor activity and simultaneous expression of multiple behaviors with a frequent shift from one to another. Despite the similarity in behavioral presentation with the hyperactivity state produced from the GPe (Grabli et al. 2004), the induction of this behavioral effect in the striatum was not characterized by a spatial perturbation of the simple food retrieval task, and probably, consequent to that we did not investigate the whole of the associative territory of the striatum.

In our monkey model, the hyperactive state was often accompanied by touching behavior, which could also be observed independently, in the latter case possibly representing a milder form of hyperactivity. Touching behavior also represents the normal exploration function often observed in monkeys placed in a new environment. The reappearance of this behavior, normally inhibited in the usual environmental context, after bicuculline microinjection may have an alternative explanation, as a deficit in the suppression of the motor response has been described as one dimension of impulsive behaviors (Torregrossa et al. 2008). Together, hyperactivity and impulsivity associated with inattentiveness comprise the core symptoms of ADHD (Sagvolden et al. 2005; Castellanos et al. 2006). Nowadays, ADHDs are considered nosologically heterogeneous disorders with predominantly hyperactive–impulsive, predominantly inattentive, and combined forms (American Psychiatric Association 1994). In addition, in patients with ADHD, the functional brain abnormalities were visualized in the prefrontal cortical areas, but also in the striatum—in both the caudate nucleus and putamen, as well as in the pallidum (Aylward et al. 1996; Castellanos 2001; Spalletta et al. 2001). From this point of view, our study provides interesting insights suggesting that the striatum and GPe could share the different aspects of ADHD.

Dysfunction of the Ventral Striatum: Motivation Disorders

The local inhibitory dysfunction induced by bicuculline microinjections into the ventrolateral putamen produced a hypoactivity characterized by a diminished global behavioral activity associated with a perturbation of the food retrieval task. The diminished frequency of initiated choices for food and the longer periods of interretrieval time were characteristic features of task perturbation and were previously described as behavioral markers of motivation indices in parkinsonian monkeys (Pessiglione et al. 2004). Nevertheless, in contrast to the previously reported findings in parkinsonian monkeys, the development of this behavioral state after bicuculline microinjections into the ventral striatum of normal monkeys was associated neither with executive disorders, such as freezing or hesitation, nor with motor slowness per se or bradykinesia (Fig. 4D).

Motivation can be defined as a driving force of goal-directed behaviors that translates expected reward into action (Dickinson and Balleine 1994; Berridge 2004). In experimental conditions, responses to appetitive stimulation are considered as the classical paradigm to study motivation, as food is a highly salient stimulus because of its biological relevance (Morris and Dolan 2001).

In rats, the ventral striatum, and especially the nucleus accumbens, has been shown to play a specific role in food motivation, food seeking, and intake behavior via a functional link with the lateral hypothalamus and amygdala (Reynolds and Berridge 2001; Kelley 2004; Kelley et al. 2005). In addition, studies in animals (Jean et al. 2007) and humans (Frank et al. 2007) have underlined the role of the ventral striatum in food intake disorders such as anorexia. Nevertheless, in our monkey model, the perturbation of the ventrolateral striatum was restricted not only to a change in food motivation but also to a global paucity of behavioral organization, suggesting a more complex genesis of this effect.

The quantitative reduction of self-generated voluntary behaviors has been ascribed to apathy (Levy and Dubois 2006), which could occur due to a dysfunction of elaboration, execution, or control of goal-directed behaviors (Brown and Pluck 2000). Interestingly, in a recent positron emission tomography (PET) study in Parkinson's disease patients, the binding of both dopamine and noradrenalin transporters in the ventrolateral part of the striatum was inversely correlated with apathy and depression (Remy et al. 2005). Moreover, in a PET study of bipolar II depression, glucose metabolism was shown to be abnormally increased in the anteroventral putamen (Mah et al. 2007), a region similar to the one where we produced a hypoactive state in our monkey model.

Task arrest was also observed after bicuculline microinjections in the most medial part of the ventral striatum, associated with sexual manifestations characterized by erection and ejaculation. Anatomical data in monkeys indicate that the most medial part of the head of the caudate nucleus receives projections from some areas of the orbitofrontal cortex but mostly from the infralimbic and prelimbic parts of the anterior cingulate cortices (Haber et al. 1995; Ferry et al. 2000), as well as from the amygdala and insular cortex (Russchen et al. 1985; Chikama et al. 1997), which have been recognized as a part of the medial prefrontal network (Öngür and Price 2000). The medial prefrontal network appears to function as a sensory–visceromotor link and to be critical for guidance of reward-related behaviors and mood setting (Barbas et al. 2003). If this is indeed the case, our data suggest that the ventromedial striatum, as a part of the medial prefrontal network, could be a breakpoint linking motivational and emotional components of sexual behavior with its peripheral autonomic component. In addition, neuroimaging studies of human sexual behavior have demonstrated its association with limbic brain areas, including the anterior cingulate gyrus, orbitofrontal cortex, and posterior hypothalamus (Redouté et al. 2000; Mouras et al. 2003; Moulier et al. 2006) as well as the ventromedial striatum (Ponseti et al. 2006; Bray and O'Doherty 2007), a subregion similar to the one where we observed the expression of sexual behavior in our monkey model.

Finally, the third behavioral effect, stereotyped behavior, was observed in the central part of the ventral striatum. In primates, the ventral and central part of the striatum receive input from limbic cortical areas, such as the orbitofrontal, anterior cingulate, and insular cortices (Haber et al. 1995; Ferry et al. 2000; Öngür and Price 2000), but also from the amygdala and hippocampus (Fudge and Haber 2002), which are known to process both emotional and motivational information. In accordance with observational studies in monkeys (Lutz et al. 2003), we also suggest that stereotyped behavior could be consequent to the induction of an anxious state. The role of the ventral striatum and particularly that of the nucleus accumbens in the processing of aversive events, such as pain or injections of anxiogenic drugs, has been evidenced both in animal studies (Schoenbaum and Setlow 2003; Yanagimoto and Maeda 2003) and in human functional imaging studies (Becerra et al. 2001; (Jensen et al. 2003; (Tom et al. 2007). Anticipation of a negative event is a key component of anxiety and can lead to behavioral, emotional, and physiological adjustment in preparation for or prevention of aversive outcomes. In monkeys, the ventral striatum and especially the nucleus accumbens have been shown to be implicated in the expression and the contextual regulation of anxiety (Kalin et al. 2005). In humans, dysfunction of the head of the caudate nucleus has also been demonstrated in anxiety spectrum disorders and particularly in OCD (Riffkin et al. 2005). Taken together, these data provide strong evidence for a common neuronal circuit involving part of the ventral striatum and corresponding to the limbic part of the GPe, which could be implicated in the emotional anticipation of an aversive event and its behavioral regulation.

Conclusions

The results of this study together with those of a previous study on the GPe provide further experimental evidence for the implication of different functional territories of the BG in movement and behavioral disorders. These results could help to elucidate the pathophysiology of these disorders, as the spectrum of behavioral disorders observed shares similarities with symptoms such as the simple motor tics, impulsivity, hyperactivity, and anxiety disorders that characterize Tourette's syndrome, ADHD, and OCD (Cath et al. 2001; Jancovic 2001; Diniz et al. 2006). These results may also open the way to study the pathophysiology of other psychiatric disorders, such as sexual, eating, and mood disorders. We hope that this primate model will in future help to evaluate new pharmacological and surgical treatments for neuropsychiatric disorders.

Funding

Agence National de Recherche, France (grant number ANR-05-NEUR-015-01); Association Française du syndrome de Gilles de la Tourette to Y.W.; Lilly Institute to Y.W.

Supplementary Material

Supplementary material can be found at http://www.cercor.oxfordjournals.org/.

We wish to thank Nicholas Barton for checking the English. Conflict of Interest: None declared.

References

Albin
RL
Mink
JW
Recent advances in Tourette syndrome research
Trends Neurosci
 , 
2006
, vol. 
29
 (pg. 
175
-
182
)
Alexander
GE
DeLong
MR
Strick
PL
Parallel organization of functionally segregated circuits linking basal ganglia and cortex
Annu Rev Neurosci
 , 
1986
, vol. 
9
 (pg. 
357
-
381
)
Atallah
HE
Lopez-Paniagua
D
Rudy
JW
O'Reilly
RC
Separate neural substrates for skill learning and performance in the ventral and dorsal striatum
Nat Neurosci
 , 
2007
, vol. 
10
 (pg. 
126
-
131
)
Aylward
EH
Reiss
AL
Reader
MJ
Singer
HS
Brown
JE
Denckla
MB
Basal ganglia volumes in children with attention-deficit hyperactivity disorder
J Child Neurol
 , 
1996
, vol. 
11
 (pg. 
112
-
115
)
Barbas
H
Saha
S
Rempel-Clower
N
Ghashghaei
T
Serial pathways from primate prefrontal cortex to autonomic areas may influence emotional expression
BMC Neurosci
 , 
2003
, vol. 
10
 (pg. 
4
-
25
)
Barnes
TD
Kubota
Y
Hu
D
Jin
DZ
Graybiel
AM
Activity of striatal neurons reflects dynamic encoding and recoding of procedural memories
Nature
 , 
2005
, vol. 
437
 (pg. 
1158
-
1161
)
Becerra
L
Breiter
HC
Wise
R
Gonzalez
RG
Borsook
D
Reward circuitry activation by noxious thermal stimuli
Neuron
 , 
2001
, vol. 
32
 (pg. 
927
-
946
)
Berridge
KC
Motivation concepts in behavioral neuroscience
Physiol Behav
 , 
2004
, vol. 
81
 (pg. 
179
-
209
)
Bohlhalter
S
Goldfine
A
Matteson
S
Garraux
G
Hanakawa
T
Kansaku
K
Wurzman
R
Hallett
M
Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study
Brain
 , 
2006
, vol. 
129
 (pg. 
2029
-
2037
)
Bray
S
O'Doherty
J
Neural coding of reward-prediction error signals during classical conditioning with attractive faces
J Neurophysiol
 , 
2007
, vol. 
97
 (pg. 
3036
-
3045
)
Brown
RG
Pluck
G
Negative symptoms: the ‘pathology’ of motivation and goal-directed behaviour
Trends Neurosci
 , 
2000
, vol. 
23
 (pg. 
412
-
417
)
Castellanos
FX
Neural substrates of attention-deficit hyperactivity disorder
Adv Neurol
 , 
2001
, vol. 
85
 (pg. 
197
-
206
)
Castellanos
FX
Sonuga-Barke
EJ
Milham
MP
Tannock
R
Characterizing cognition in ADHD: beyond executive dysfunction
Trends Cogn Sci
 , 
2006
, vol. 
10
 (pg. 
117
-
123
)
Cath
DC
Spinhoven
P
van Woerkom
TC
van de Wetering
BJ
Hoogduin
CA
Landman
AD
Roos
RA
Rooijmans
HG
Gilles de la Tourette's syndrome with and without obsessive-compulsive disorder compared with obsessive-compulsive disorder without tics: which symptoms discriminate?
J Nerv Ment Dis
 , 
2001
, vol. 
189
 (pg. 
219
-
228
)
Cavada
C
Goldman-Rakic
PS
Topographic segregation of corticostriatal projections from posterior parietal subdivisions in the macaque monkey
Neuroscience
 , 
1991
, vol. 
42
 (pg. 
683
-
696
)
Chikama
M
McFarland
NR
Amaral
DG
Haber
SN
Insular cortical projections to functional regions of the striatum correlate with cortical cytoarchitectonic organization in the primate
J Neurosci
 , 
1997
, vol. 
17
 (pg. 
9686
-
9705
)
Crossman
AR
Mitchell
IJ
Sambrook
MA
Jackson
A
Chorea and myoclonus in the monkey induced by gamma-aminobutyric acid antagonism in the lentiform complex. The site of drug action and a hypothesis for the neural mechanisms of chorea
Brain
 , 
1988
, vol. 
111
 (pg. 
1211
-
1233
)
Crossman
AR
Sambrook
MA
Jackson
A
Experimental hemichorea/hemiballismus in the monkey. Studies on the intracerebral site of action in a drug-induced dyskinesia
Brain
 , 
1984
, vol. 
107
 (pg. 
579
-
596
)
Dickinson
A
Balleine
B
Motivational control of goal-directed action
Anim Learn Behav
 , 
1994
, vol. 
22
 (pg. 
1
-
18
)
Diniz
JB
Rosario-Campos
MC
Hounie
AG
Curi
M
Shavitt
RG
Lopes
AC
Miguel
EC
Chronic tics and Tourette syndrome in patients with obsessive-compulsive disorder
J Psychiatr Res
 , 
2006
, vol. 
40
 (pg. 
487
-
493
)
Ferry
AT
Ongur
D
An
X
Price
JL
Prefrontal cortical projections to the striatum in macaque monkeys: evidence for an organization related to prefrontal networks
J Comp Neurol
 , 
2000
, vol. 
425
 (pg. 
447
-
470
)
Flaherty
AW
Graybiel
AM
Input-output organization of the sensorimotor striatum in the squirrel monkey
J Neurosci
 , 
1994
, vol. 
14
 (pg. 
599
-
610
)
François
C
Grabli
D
McCairn
K
Jan
C
Karachi
C
Hirsch
EC
Féger
J
Tremblay
L
Behavioural disorders induced by external globus pallidus dysfunction in primates II. Anatomical study
Brain
 , 
2004
, vol. 
127
 (pg. 
2055
-
2070
)
François
C
Yelnik
J
Percheron
G
Tande
D
Calbindin D-28k as a marker for the associative cortical territory of the striatum in macaque
Brain Res
 , 
1994
, vol. 
633
 (pg. 
331
-
336
)
Frank
GK
Bailer
UF
Meltzer
CC
Price
JC
Mathis
CA
Wagner
A
Becker
C
Kaye
WH
Regional cerebral blood flow after recovery from anorexia or bulimia nervosa
Int J Eat Disord
 , 
2007
, vol. 
40
 (pg. 
488
-
492
)
Fudge
JL
Haber
SN
Defining the caudal ventral striatum in primates: cellular and histochemical features
J Neurosci
 , 
2002
, vol. 
22
 (pg. 
10078
-
10082
)
Gavazzi
C
Nave
RD
Petrelli
R
Rocca
MA
Tessa
C
Diciotti
S
Filippi
M
Piacentini
S
Mascalchi
M
Combining functional and structural brain magnetic resonance imaging in Huntington disease
J Comput Assist Tomogr
 , 
2007
, vol. 
31
 (pg. 
574
-
580
)
Gerardin
E
Pochon
JB
Poline
JB
Tremblay
L
Van de Moortele
PF
Levy
R
Dubois
B
Le Bihan
D
Lehéricy
S
Distinct striatal regions support movement selection, preparation and execution
Neuroreport
 , 
2004
, vol. 
15
 (pg. 
2327
-
2331
)
Grabli
D
McCairn
K
Hirsch
EC
Agid
Y
Féger
J
François
C
Tremblay
L
Behavioural disorders induced by external globus pallidus dysfunction in primates: I. Behavioural study
Brain
 , 
2004
, vol. 
127
 (pg. 
2039
-
2054
)
Haber
SN
The primate basal ganglia: parallel and integrative networks
J Chem Neuroanat
 , 
2003
, vol. 
26
 (pg. 
317
-
330
)
Haber
SN
Kunishio
K
Mizobuchi
M
Lynd-Balta
E
The orbital and medial prefrontal circuit through the primate basal ganglia
J Neurosci
 , 
1995
, vol. 
15
 (pg. 
4851
-
4867
)
Haber
SN
McFarland
NR
The concept of the ventral striatum in nonhuman primates
Ann N Y Acad Sci
 , 
1999
, vol. 
877
 (pg. 
33
-
48
)
Inase
M
Tokuno
H
Nambu
A
Akazawa
T
Takada
M
Corticostriatal and corticosubthalamic input zones from the presupplementary motor area in the macaque monkey: comparison with the input zones from the supplementary motor area
Brain Res
 , 
1999
, vol. 
833
 (pg. 
191
-
201
)
Jancovic
J
Tourette's syndrome
N Engl J Med
 , 
2001
, vol. 
345
 
16
(pg. 
1184
-
92
)
Jankovic
J
Fahn
S
The phenomenology of tics
Mov Disord
 , 
1986
, vol. 
1
 (pg. 
17
-
26
)
Jean
A
Conductier
G
Manrique
C
Bouras
C
Berta
P
Hen
R
Charnay
Y
Bockaert
J
Compan
V
Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens
Proc Natl Acad Sci USA
 , 
2007
, vol. 
104
 (pg. 
16335
-
16340
)
Jensen
J
McIntosh
AR
Crawley
AP
Mikulis
DJ
Remington
G
Kapur
S
Direct activation of the ventral striatum in anticipation of aversive stimuli
Neuron
 , 
2003
, vol. 
40
 (pg. 
1251
-
1257
)
Johnson
SA
Stout
JC
Solomon
AC
Langbehn
DR
Aylward
EH
Cruce
CB
Ross
CA
Nance
M
Kayson
E
Julian-Baros
E
, et al.  . 
Predict-HD investigators of the Huntington Study Group beyond disgust: impaired recognition of negative emotions prior to diagnosis in Huntington's disease
Brain
 , 
2007
, vol. 
130
 (pg. 
1732
-
1744
)
Kalanithi
PS
Zheng
W
Kataoka
Y
DiFiglia
M
Grantz
H
Saper
CB
Schwartz
ML
Leckman
JF
Vaccarino
FM
Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome
Proc Natl Acad Sci USA
 , 
2005
, vol. 
102
 (pg. 
13307
-
13312
)
Kalin
NH
Shelton
SE
Fox
AS
Oakes
TR
Davidson
RJ
Brain regions associated with the expression and contextual regulation of anxiety in primates
Biol Psychiatry
 , 
2005
, vol. 
58
 (pg. 
796
-
804
)
Kelley
AE
Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning
Neurosci Biobehav Rev
 , 
2004
, vol. 
27
 (pg. 
765
-
776
)
Kelley
AE
Baldo
BA
Pratt
WE
Will
MJ
Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward
Physiol Behav
 , 
2005
, vol. 
86
 (pg. 
773
-
795
)
Koós
T
Tepper
JM
Inhibitory control of neostriatal projection neurons by GABAergic interneurons
Nat Neurosci
 , 
1999
, vol. 
2
 (pg. 
467
-
472
)
Kunishio
K
Haber
SN
Primate cingulostriatal projection: limbic striatal versus sensorimotor striatal input
J Comp Neurol
 , 
1994
, vol. 
350
 (pg. 
337
-
356
)
Kwak
C
Dat Vuong
K
Jankovic
J
Premonitory sensory phenomenon in Tourette's syndrome
Mov Disord
 , 
2003
, vol. 
18
 (pg. 
1530
-
1533
)
Leckman
JF
Walker
DE
Cohen
DJ
Premonitory urges in Tourette's syndrome
Am J Psychiatry
 , 
1993
, vol. 
150
 (pg. 
98
-
102
)
Le Moal
M
Koob
GF
Drug addiction: pathways to the disease and pathophysiological perspectives
Eur Neuropsychopharmacol
 , 
2007
, vol. 
17
 (pg. 
377
-
393
)
Lerner
A
Bagic
A
Boudreau
EA
Hanakawa
T
Pagan
F
Mari
Z
Bara-Jimenez
W
Aksu
M
Garraux
G
Simmons
JM
, et al.  . 
Neuroimaging of neuronal circuits involved in tic generation in patients with Tourette syndrome
Neurology
 , 
2007
, vol. 
68
 
23
(pg. 
1979
-
1987
)
Levy
R
Dubois
B
Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits
Cereb Cortex
 , 
2006
, vol. 
16
 (pg. 
916
-
928
)
Lutz
C
Well
A
Novak
M
Stereotypic and self-injurious behavior in rhesus macaques: a survey and retrospective analysis of environment and early experience
Am J Primatol
 , 
2003
, vol. 
60
 (pg. 
1
-
15
)
Mah
L
Zarate
CA
Jr
Singh
J
Duan
YF
Luckenbaugh
DA
Manji
HK
Drevets
WC
Regional cerebral glucose metabolic abnormalities in bipolar II depression
Biol Psychiatry
 , 
2007
, vol. 
61
 
6
(pg. 
765
-
775
)
Martin
RF
Bowden
DM
Primate brain maps: structure of the macaque brain
 , 
2000
London
Elsevier
Matsumura
M
Tremblay
L
Richard
H
Filion
M
Activity of pallidal neurons in the monkey during dyskinesia induced by injection of bicuculline in the external pallidum
Neuroscience
 , 
1995
, vol. 
65
 (pg. 
59
-
70
)
Middleton
FA
Strick
PL
Basal-ganglia ‘projections’ to the prefrontal cortex of the primate
Cereb Cortex
 , 
2002
, vol. 
12
 (pg. 
926
-
935
)
Morris
JS
Dolan
RJ
Involvement of human amygdala and orbitofrontal cortex in hunger-enhanced memory for food stimuli
J Neurosci
 , 
2001
, vol. 
21
 (pg. 
5304
-
5310
)
Moulier
V
Mouras
H
Pélégrini-Issac
M
Glutron
D
Rouxel
R
Grandjean
B
Bittoun
J
Stoléru
S
Neuroanatomical correlates of penile erection evoked by photographic stimuli in human males
Neuroimage
 , 
2006
, vol. 
33
 (pg. 
689
-
699
)
Mouras
H
Stoléru
S
Bittoun
J
Glutron
D
Pélégrini-Issac
M
Paradis
AL
Burnod
Y
Brain processing of visual sexual stimuli in healthy men: a functional magnetic resonance imaging study
Neuroimage
 , 
2003
, vol. 
20
 (pg. 
855
-
869
)
O'Doherty
JP
Reward representations and reward-related learning in the human brain: insights from neuroimaging
Curr Opin Neurobiol
 , 
2004
, vol. 
14
 (pg. 
769
-
776
)
Öngür
D
Price
JL
The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans
Cereb Cortex
 , 
2000
, vol. 
10
 (pg. 
206
-
219
)
Parent
A
Hazrati
LN
Functional anatomy of the basal ganglia. I. The cortico-basal ganglia–thalamo-cortical loop
Brain Res Rev
 , 
1995
, vol. 
20
 (pg. 
91
-
127
)
Parent
A
Fortin
M
Côté
PY
Cicchetti
F
Calcium-binding proteins in primate basal ganglia
Neurosci Res
 , 
1996
, vol. 
25
 (pg. 
309
-
334
)
Paxinos
G
Huang
X-F
Toga
AW
The rhesus monkey brain in stereotaxic coordinates
 , 
2000
London
Academic Press
Pessiglione
M
Guehl
D
Agid
Y
Hirsch
EC
Féger
J
Tremblay
L
Impairment of context-adapted movement selection in a primate model of presymptomatic Parkinson's disease
Brain
 , 
2003
, vol. 
126
 (pg. 
1392
-
1408
)
Pessiglione
M
Guehl
D
Jan
C
François
C
Hirsch
EC
Féger
J
Tremblay
L
Disruption of self-organized actions in monkeys with progressive MPTP-induced parkinsonism: II. Effects of reward preference
Eur J Neurosci
 , 
2004
, vol. 
19
 (pg. 
437
-
446
)
Peterson
BS
Thomas
P
Kane
MJ
Scahill
L
Zhang
H
Bronen
R
King
RA
Leckman
JF
Staib
L
Basal ganglia volumes in patients with Gilles de la Tourette syndrome
Arch Gen Psychiatry
 , 
2003
, vol. 
60
 (pg. 
415
-
424
)
Plenz
D
When inhibition goes incognito: feedback interaction between spiny projection neurons in striatal function
Trends Neurosci
 , 
2003
, vol. 
26
 (pg. 
436
-
443
)
Ponseti
J
Bosinski
HA
Wolff
S
Peller
M
Jansen
O
Mehdorn
HM
Büchel
C
Siebner
HR
A functional endophenotype for sexual orientation in humans
Neuroimage
 , 
2006
, vol. 
33
 (pg. 
825
-
833
)
Redouté
J
Stoléru
S
Grégoire
MC
Costes
N
Cinotti
L
Lavenne
F
Le Bars
D
Forest
MG
Pujol
JF
Brain processing of visual sexual stimuli in human males
Hum Brain Mapp
 , 
2000
, vol. 
11
 (pg. 
162
-
177
)
Remy
P
Doder
M
Lees
A
Turjanski
N
Brooks
D
Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system
Brain
 , 
2005
, vol. 
128
 (pg. 
1314
-
1322
)
Reynolds
SM
Berridge
KC
Fear and feeding in the nucleus accumbens shell: rostrocaudal segregation of GABA-elicited defensive behavior versus eating behavior
J Neurosci
 , 
2001
, vol. 
21
 (pg. 
3261
-
3270
)
Riffkin
J
Yücel
M
Maruff
P
Wood
SJ
Soulsby
B
Olver
J
Kyrios
M
Velakoulis
D
Pantelis
C
A manual and automated MRI study of anterior cingulate and orbito-frontal cortices, and caudate nucleus in obsessive-compulsive disorder: comparison with healthy controls and patients with schizophrenia
Psychiatry Res
 , 
2005
, vol. 
138
 (pg. 
99
-
113
)
Romo
R
Scarnati
E
Schultz
W
Role of primate basal ganglia and frontal cortex in the internal generation of movements. II. Movement-related activity in the anterior striatum
Exp Brain Res
 , 
1992
, vol. 
91
 (pg. 
385
-
395
)
Russchen
FT
Bakst
I
Amaral
DG
Price
JL
The amygdalostriatal projections in the monkey. An anterograde tracing study
Brain Res
 , 
1985
, vol. 
329
 (pg. 
241
-
257
)
Sagvolden
T
Johansen
EB
Aase
H
Russell
VA
A dynamic developmental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes
Behav Brain Sci
 , 
2005
, vol. 
28
 (pg. 
397
-
419
)
Schoenbaum
G
Setlow
B
Lesions of nucleus accumbens disrupt learning about aversive outcomes
J Neurosci
 , 
2003
, vol. 
23
 (pg. 
9833
-
9841
)
Schultz
W
Romo
R
Role of primate basal ganglia and frontal cortex in the internal generation of movements. I. Preparatory activity in the anterior striatum
Exp Brain Res
 , 
1992
, vol. 
91
 (pg. 
363
-
384
)
Seutin
V
Johnson
SW
Recent advances in the pharmacology of quaternary salts of bicuculline
Trends Pharmacol Sci
 , 
1999
, vol. 
20
 (pg. 
268
-
270
)
Shi
WX
Rayport
S
GABA synapses formed in vitro by local axon collaterals of nucleus accumbens neurons
J Neurosci
 , 
1994
, vol. 
14
 (pg. 
4548
-
4560
)
Spalletta
G
Pasini
A
Pau
F
Guido
G
Menghini
L
Caltagirone
C
Prefrontal blood flow dysregulation in drug naive ADHD children without structural abnormalities
J Neural Transm
 , 
2001
, vol. 
108
 
10
(pg. 
1203
-
1216
)
Stern
E
Silbersweig
DA
Chee
KY
Holmes
A
Robertson
MM
Trimble
M
Frith
CD
Frackowiak
RS
Dolan
RJ
A functional neuroanatomy of tics in Tourette syndrome
Arch Gen Psychiatry
 , 
2000
, vol. 
57
 (pg. 
741
-
748
)
Takada
M
Tokuno
H
Nambu
A
Inase
M
Corticostriatal input zones from the supplementary motor area overlap those from the contra—rather than ipsilateral primary motor cortex
Brain Res
 , 
1998
, vol. 
791
 (pg. 
335
-
340
)
Takada
M
Tokuno
H
Nambu
A
Inase
M
Corticostriatal projections from the somatic motor areas of the frontal cortex in the macaque monkey: segregation versus overlap of input zones from the primary motor cortex, the supplementary motor area, and the premotor cortex
Exp Brain Res
 , 
1998
, vol. 
120
 (pg. 
114
-
128
)
Tom
SM
Fox
CR
Trepel
C
Poldrack
RA
The neural basis of loss aversion in decision-making under risk
Science
 , 
2007
, vol. 
315
 (pg. 
515
-
518
)
Torregrossa
MM
Quinn
JJ
Taylor
JR
Impulsivity, compulsivity, and habit: the role of orbitofrontal cortex revisited
Biol Psychiatry
 , 
2008
, vol. 
63
 (pg. 
253
-
255
)
Tremblay
L
Hollerman
JR
Schultz
W
Modifications of reward expectation-related neuronal activity during learning in primate striatum
J Neurophysiol
 , 
1998
, vol. 
80
 (pg. 
964
-
977
)
Williams
ZM
Eskandar
EN
Selective enhancement of associative learning by microstimulation of the anterior caudate
Nat Neurosci
 , 
2006
, vol. 
9
 (pg. 
562
-
568
)
Yanagimoto
K
Maeda
H
The nucleus accumbens unit activities related to the emotional significance of complex environmental stimuli in freely moving cats
Neurosci Res
 , 
2003
, vol. 
46
 (pg. 
183
-
189
)
Yelnik
J
François
C
Percheron
G
Tandé
D
Morphological taxonomy of the neurons of the primate striatum
J Comp Neurol
 , 
1991
, vol. 
313
 (pg. 
273
-
294
)
Yeterian
EH
Pandya
DN
Prefrontostriatal connections in relation to cortical architectonic organization in rhesus monkeys
J Comp Neurol
 , 
1991
, vol. 
312
 (pg. 
43
-
67
)