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. Author manuscript; available in PMC: 2011 Sep 16.
Published in final edited form as: J Neurosci. 2011 Mar 16;31(11):4290–4297. doi: 10.1523/JNEUROSCI.5066-10.2011

Dopamine, but not serotonin, regulates reversal learning in the marmoset caudate nucleus

H F Clarke 1,3,*, G J Hill 1,3, T W Robbins 1,3, A C Roberts 2,3
PMCID: PMC3083841  EMSID: UKMS34709  PMID: 21411670

Abstract

Studies of visual discrimination reversal learning have revealed striking neurochemical dissociations at the level of the orbitofrontal cortex (OFC) with serotoninergic, but not dopaminergic integrity being important for successful reversal learning. These findings have considerable implications for disorders such as obsessive compulsive disorder and schizophrenia in which reversal learning is impaired, and are primarily treated with drugs targeting the dopaminergic and serotoninergic systems. Dysfunction in such disorders however, is not limited to the OFC and extends subcortically to other structures implicated in reversal learning, such as the medial caudate nucleus. Therefore, because the roles of the serotonin and dopamine within the caudate nucleus are poorly understood, this study compared the effects of selective serotoninergic or selective dopaminergic depletions of the marmoset medial caudate nucleus on serial discrimination reversal learning.

All monkeys were able to learn novel stimulus-reward associations, but unlike control monkeys and monkeys with selective serotoninergic medial caudate depletions, dopamine-depleted monkeys were markedly impaired in their ability to reverse this association. This impairment was not perseverative in nature. These findings are the opposite of those seen in the OFC and provide evidence for a neurochemical double dissociation between the OFC and medial caudate in the regulation of reversal learning. Whilst the specific contributions of these monoamines within the OFC-striatal circuit remain to be elucidated, these findings have profound implications for the development of drugs designed to remediate some of the cognitive processes underlying impaired reversal learning.

Introduction

Visual discrimination reversal learning is commonly used to investigate the neurobiological mechanisms underlying the ability of animals to adapt their behavior to changes in the motivational significance of environmental stimuli. Studies using this paradigm have focussed on the fronto-striatal ‘loops’ and the relative contributions of different nodes of these circuits to adaptive behavior. Damage to both the orbitofrontal cortex (OFC) and the medial caudate nucleus (the region that receives OFC input, Haber et al., 1995; Roberts et al., 2007; Schilman et al., 2008) impairs reversal learning performance in primates and rodents (Divac et al., 1967; Butter, 1969; McEnaney and Butter, 1969; Jones and Mishkin, 1972; Dias et al., 1996; McAlonan and Brown, 2003; Hornak et al., 2004; Clarke et al., 2008).

During reversal learning, subjects associate cues with the presence or absence of reward or punishment, adapting their behavior when those contingencies change. Computational models postulate that reward and error prediction signals are generated from the mismatch between observed and expected outcomes, and used to match behaviour to the current contingency (Sutton and Barto, 1998; Schultz and Dickinson, 2000; Daw et al., 2002; Frank and Claus, 2006). Serotoninergic dorsal raphé neurons may encode the expectation and delivery of reward (Nakamura et al., 2008; Bromberg-Martin et al., 2010), while error signals are generated by phasic mesolimbic dopaminergic neuron firing (Montague et al., 1996; Schultz et al., 1997; Schultz et al., 1998). Both the dorsal raphé serotonin and mesocortical/mesolimbic dopamine neurons project to the OFC and striatum (van der Kooy and Hattori, 1980; Oades and Halliday, 1987; Corvaja et al., 1993) suggesting that their integrity may be important for reversal learning; however, their specific contributions remain uncertain.

Genetic and systemic manipulations targeting both serotonin and dopamine modulate reversal learning (Mehta et al., 2001; Kruzich and Grandy, 2004; Izquierdo et al., 2006; 2007; Lee et al., 2007; Lapiz-Bluhm et al., 2009; Brigman et al., 2010), but the localization of these effects are unknown. Within the OFC of marmoset monkeys, anatomically and neurochemically selective depletions of serotonin, but not dopamine, severely impairs reversal learning performance (Clarke et al., 2006). In contrast, some studies suggest a critical role for striatal dopamine in reversal learning. For example, methylphenidate-induced dopamine release in the human medial striatum correlates with reversal learning performance (Clatworthy et al., 2009), and those humans carrying a polymorphism that reduces striatal dopamine D2 receptor expression show reduced ventral striatal activation during probabilistic reversals (Jocham et al., 2009). In addition, dopamine depletion of the rat dorsomedial striatum impaired reversal learning in one study (O’Neill and Brown, 2007), although selective catecholaminergic lesions of the marmoset caudate nucleus were without effect (Collins et al., 2000; Crofts et al., 2001). However, whether serotonin at the level of the striatum contributes to reversal learning is unknown.

We therefore sought to compare directly the roles of striatal serotonin and dopamine in serial visual discrimination reversal learning by investigating the behavioral effects of selective dopaminergic and serotonergic depletions of the marmoset medial caudate nucleus.

Materials and Methods

Subjects and housing

Ten common marmosets (Callithrix jacchus; 5 females, 5 males) bred on site at the University of Cambridge Marmoset Breeding Colony were housed in pairs. All monkeys were fed 20 g of MP.E1 primate diet (Special Diet Services/SDS, Withams, Essex, UK) and two pieces of carrot five days a week after the daily behavioral testing session, with simultaneous access to water for two hours. At weekends, their diet was supplemented with fruit, rusk, malt loaf, eggs, treats and marmoset jelly (SDS) and they had free access to water. Their cages contained a variety of environmental enrichment aids that were regularly varied and all procedures were performed in accordance with the UK Animals (Scientific Procedures) Act 1986.

Apparatus

Behavioral testing took place within a sound-attenuated box in a dark room. As described previously (Clarke et al., 2008), the animal sat in a clear, plastic transport box, one side of which was removed to reveal a colour computer monitor (Samsung, Surrey, UK). The marmoset reached through an array of vertical metal bars to touch stimuli presented on the monitor and these responses were detected by an array of infra-red beams (Intasolve Ltd, Interact 415, Colchester, UK) attached to the screen. A reward of cooled banana milkshake (Nestlé, York, UK) was delivered to a centrally placed spout for 5 s. Presentation of reward was signalled by a 4 kHz tone played through loudspeakers located to the left and right of the monitor and was dependent upon the marmoset licking the spout to trigger a peristaltic pump that delivered the milkshake. The test chamber was lit with a 3 W bulb. The stimuli presented on the monitor were abstract, multicoloured visual patterns (32 mm wide × 50 mm high) which were displayed to the left and right of the central spout. The stimuli were presented using the Whisker control system (Cardinal and Aitken, 2001) running MonkeyCantab (designed by Roberts and Robbins, version 3.6; Cardinal, 2007) which also controlled the apparatus and recorded responding.

Behavioral Training and Testing

All monkeys were trained initially to enter a clear plastic transport box for marshmallow reward and familiarised with the testing apparatus. Monkeys then received the following sequence of training: familiarization of a milkshake reward, learning a tone-reward contingency, and responding on the touchscreen until they were reliably and accurately making 30 responses or more to a square stimulus presented to the left and right of the licker in 20 minutes. (For full experimental details, see Roberts et al., 1988). After behavioral training, the marmosets proceeded onto serial visual discrimination reversal learning.

Serial Reversal Learning

As described previously (2004; Clarke et al., 2008), this consisted of two-choice discriminations between abstract, coloured patterns (See Figure 1). For all discriminations, two stimuli were presented to the left and right of the centre of the screen. A response to the ‘correct’ stimulus resulted in the ‘incorrect’ stimulus disappearing from the screen, and the ‘correct’ stimulus remaining present for the duration of a 5 s tone that signalled the availability of 5 s of reinforcement. Failure to collect the reward was scored as a missed reinforcement. Following a response to the ‘incorrect’ stimulus both stimuli disappeared from the screen, and a 5 s timeout period ensued during which the houselight was extinguished. The intertrial interval was 3 s and, within a session, the stimuli were presented equally to the left and right sides of the screen. Each monkey was presented with 30 trials per day, five days a week and progressed to the next discrimination (described in detail below) after attaining a criterion of 90% correct in the immediately preceding session. If a monkey showed a significant side bias (10 consecutive responses to one side), a rolling correction procedure was implemented whereby the correct stimulus was presented on the non-preferred side until the monkey had made a total of three correct responses.

Figure 1.

Figure 1

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A schematic diagram illustrating the sequence of visual discriminations presented during the study and their occurrence relative to surgery. For each discrimination, ‘correct’ and ‘incorrect’ exemplars are indicated by the ‘+’ and ‘−’ respectively. Actual stimuli were multicoloured.

All animals received the following series of discriminations:

  • 1)

    Acquisition of a novel discrimination (D1).

  • 2)

    Acquisition of a second novel discrimination (D2).

After attainment of criterion on D2, animals were separated into groups. They then received infusions of a dopaminergic (n = 4), or serotoninergic (n = 3) neurotoxin into the medial head of the caudate nucleus or a sham-operated control procedure (n = 3). After two weeks’ recovery, they received the following series of discriminations;

  • 3)

    Retention of D2.

  • 4)

    Acquisition of a third novel discrimination (D3). From this stage onwards the stimulus contingencies were counterbalanced to prevent differences in performance being an artefact of any innate biases in stimulus preference.

  • 5)

    A series of 7 discrimination reversals, whereupon on each reversal, the previously ‘correct’ stimulus became ‘incorrect’ and the previously ‘incorrect’ stimulus became ‘correct’ (Reversals 1-7).

Behavioral Measures

The main measure of the monkeys’ performance on the visual discriminations was the total number of errors made prior to achieving the criterion of ≥ 90% correct in one session (excluding the criterion session) on each discrimination. Additional measures recorded for each trial were the latency to respond to the stimuli presented on the monitor (response latency), the latency to collect the reward from the spout (lick latency) and the left/right location of the response. In addition, the type of errors that were made during the reversal were classified as perseverative (where responding to the previously-correct stimulus was significantly above chance), chance, or learning (where responding to the newly-correct stimulus was at, or above chance respectively). Signal detection theory (see Macmillan and Creelman, 1991) was used to establish subjects’ ability to discriminate correct from incorrect stimuli independently of any side bias that might have been present. The discrimination measure d′ and the bias measure c were calculated and the normal cumulative distribution function (CDF) compared to the criterion values of a two-tailed Z test (each tail p = 0.05) to determine the classification of each 15 trial half session (perseveration, chance or learning). Sessions where CDF(d′) < 0.05 were classified as perseverative; sessions where CDF(d′) > 0.95 were classified as learning, and sessions where 0.05 ≤ CDF(d′) ≤ 0.95 were classified as chance. Sessions where CDF(c) < 0.025 or CDF(c) > 0.975 were considered biased, but were not excluded as d′ is still a valid measure of discrimination (Clarke et al., 2004). Days on which subjects attained criterion were excluded, as were the errors from half sessions in which the monkey was on the same correction procedure trial for the entire block of trials and d′ could not be calculated. However the numbers of errors that were excluded across the 7 reversals was equivalent for all three groups (square root transformed data. Group, F(2,7) = 2.013, P = 0.204; Reversal × group, F(12,42) = 1.578, P = 0.136).

Statistics

The behavioral results were subjected to ANOVA using SPSS v16 (SPSS, Chicago, USA). ANOVA models are in the form A3 × (C3 × S), where A is a between-subject factor with three levels (lesion group) and C is a within-subjects factor of error type with three levels (perseveration/chance/learning); S represents subjects (Keppel, 1991). Where raw data did not display homogeneity of variance, it was transformed appropriately (see Howell, 1997). A Huynh–Feldt correction was used to adjust the degrees of freedom if sphericity could not be assumed and post hoc comparisons were made using Fisher’s protected Least Significant Differences test (LSD; performing three uncorrected pairwise tests following a significant one-way ANOVA with three groups), the most powerful test in this context (Howell, 1997). Behavioral data was analysed in the following blocks: i) pre-surgical discriminations (D1 and D2), ii) post-surgical discriminations (D2 ret and D3 acq) and iii) the serial reversals (reversals 1-7). For the lesion data, depletion levels were analysed using two-tailed one sample t-tests (comparing the percentage depletion to zero/no depletion).

Surgical Procedure

Subjects were pre-medicated with ketamine hydrochloride (Pharmacia and Upjohn, 0.05ml of a 100mg/ml solution, i.m.), given a 24–hour prophylactic analgesic (Rimadyl; 0.03ml of 50mg/ml carprofen, s.c.; Pfizer, Kent, UK), and then intubated and maintained on isoflurane gas anaesthetic (flow rate: 2.5% isoflurane in 0.2 l/min O2; Novartis Animal Health UK, Herts, UK), prior to being placed in a stereotaxic frame especially modified for the marmoset (David Kopf, Tujanga, CA, USA). Anaesthesia was closely monitored clinically and by pulse oximetry.

Anatomically defined lesions of the caudate nucleus were targeted towards the medial head of the caudate nucleus (the area that preferentially receives input from the orbitofrontal cortex in the marmoset, Roberts et al., 2007), and achieved using stereotaxic injections of dopaminergic or serotoninergic neurotoxins (Sigma, Poole, UK) at carefully defined co-ordinates (see Table 1). These co-ordinates were individually adjusted where necessary in situ to take into account the individual differences in brain size as described previously (see Dias et al., 1996). All injections were made in one stage of surgery using a pulled glass cannula attached to a 2 μl Hamilton syringe (Hamilton, Bonaduz, Switzerland) at the rate of 0.04 μl/20 s. Sham surgery (n = 3) was identical except for the omission of any toxin from the infusion.

Table 1.

Lesion parameters including the stereotaxic co-ordinates of each injection (based on the inter-aural plane), the injection volume and toxin details.

Lesion type No. injections per side toxin concentration Co-ordinates (mm) Volume injected (μl)
AP LM V
DA:5-HT medial caudate 4 6μg/μl: 4μg/μl 12.5 ± 2.3 10.6 0.30
11.9 0.30
11.5 ± 2.3 11.5 0.25
12.5 0.25
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Lesions of the serotoninergic innervation of the medial head of the caudate nucleus were made using 5,7-dihydroxytryptamine (5,7-DHT, Sigma, UK; 4μg/μl) in saline/0.1% L-ascorbic acid. To protect the noradrenaline (NA) and dopamine (DA) innervation respectively, the NA uptake blocker nisoxetine (50 mM; Sigma) and the DA uptake blocker GBR-12909 (2.0 mM; Sigma) were administered concomitantly in the infusate. Lesions of the dopaminergic innervation of the medial caudate were made using 6-hydroxydopamine (6-OHDA, Sigma;6μg/μl) in saline/0.1% L-ascorbic acid. To protect the serotoninergic innervation of the medial caudate from the 6-OHDA the selective serotonin reuptake inhibitor citalopram (Lundbeck; 5mg/kg s.c.) was administered concomitantly in the infusate. Pilot lesion data (not shown) suggested that NA protection was not necessary, partly because of the very sparse noradrenergic innervation of the caudate (Arakawa et al., 2008). Post-operatively, all monkeys received the analgesic Metacam (meloxicam, 0.1 ml of a 1.5 mg/ml oral suspension; Boehringer Ingelheim, Germany), and complete recovery was assured, before being returned to their home cage for 10 days of ‘weekend diet’ and water ad libitum before returning to experimental testing.

Post mortem neurochemical assessment

The specificity and extent of the selective serotonin (5-HT) and DA depletions of the caudate nucleus were assessed by post mortem tissue analysis of monoamine levels in cortical and subcortical regions 218-335 days after administration of the neurotoxin as described previously (Clarke et al., 2004). As we have previously shown that 6-OHDA lesions of the striatum show considerable recovery over time, three additional animals received unilateral DA lesions using the same surgical procedures as described earlier, and were assessed for post mortem cortical and subcortical monoamine levels at 10 days, 95 days and 141 days post-operatively. Tissue samples were homogenised in 200μl 0.2M perchloric acid for 1.5 mins and centrifuged at 6000 rpm for 20 mins at 4°C. The supernatant (75 μl) was subsequently analysed using reversed phase high-performance liquid chromatography (HPLC) and electrochemical detection as described previously (Clarke et al., 2005).

Results

Neurochemical analysis of post mortem tissue from monkeys with DA or 5-HT medial striatal depletions

Striatal DA depletion

Our previous work has shown that 6-OHDA-induced dopaminergic depletions in the striatum do show recovery across time. Therefore, for long term studies such as this, it was important to obtain the time-course of DA depletion including the timepoint that corresponds to when the major behavioural deficits were observed. Consequently, the dopamine depletion resulting from injections of 6-OHDA into the medial head of the caudate nucleus of marmosets was assessed at 10 days, 95 days and 141 days post-surgery. This revealed substantial, selective, dopaminergic depletions of 79% (10 days), 98.94% (95 days) and 44.54% (141 days) in the medial head of the caudate These findings confirm that the levels of DA were indeed starting to recover at 141 days, but more importantly clearly indicate that the period when the main behavioural observations of this study were made (i.e. reversals 1-3) coincides with very high, sustained levels of medial caudate dopamine depletion (see Figure 2). As predicted by the partial recovery of the dopamine depletion seen at 141 days, injections of 6-OHDA into the medial head of the caudate nucleus did not result in a significant reduction of medial caudate dopamine when measured an average of 271 days after surgery (14.67% ± 11.34; Table 2). Despite this, significant dopaminergic decreases were seen in the anterior cingulate (44.87% ± 12.5; t(3) = 3.578, P = 0.037), mid cingulate (35.86 ± 7.29; t(2) = 4.921, P = 0.039) and anterior parietal cortices (41.63% ± 0.51; t(2) = 81.409, P < 0.001) at this timepoint. However, this is probably due to regional variation in recovery from the effects of the neurotoxin and is considered further in the Discussion.

Figure 2.

Figure 2

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Post mortem depletions of DA in the medial head of the caudate as a function of time since surgery in DA-depleted monkeys. The grey region indicates the time period in which reversals one, two and three were completed by the dopamine-depleted monkeys. The horizontal lines represent the maximum duration of each reversal, (extending from the earliest starting point to the latest endpoint and thus reflecting the quickest and slowest learning monkeys respectively), while the vertical marks on the lines represent the mean time points for the beginning and end of the reversal. Thus, the periods where the maximal behavioral impairment is seen corresponds to high levels of medial caudate dopamine depletion. a, b, c, pilot lesions; 10, 95 and 141 days post-surgery respectively; d, termination of current behavioural study. Inset; dopamine depletions in all striatal regions for monkeys a, b and c.

Table 2.

Mean percentage depletions of 5-HT, DA and NA (± standard error of the mean) in the striatum and anterior cortices of marmosets with 5,7-DHT or 6-OHDA infusions into the caudate nucleus. Significant percentage changes are highlighted in bold and ‘−‘ indicates a percentage increase.

Caudate Dopamine depletions Caudate 5-HT depletions
DA 5-HT NA 5-HT DA NA
Medial head of
caudate 		14.67 ± 11.34 24.91 ± 20.21 −3.99 ± 43.04 66.68 ± 12.1 * −16.73 ± 5.58 7.57 ± 40.38
Lateral head of
caudate 		−35.94 ± 25.15 −2.15 ± 28.94 33.17 ± 27.42 29.50 ± 9.89 −41.6 ± 6.95 * 60.36 ± 11.9 *
Caudate body −5.73 ± 6.19 38.55 ±16.73 −0.77 ± 35.65 34.98 ± 3.43 * −11.54 ± 12.41 51.36 ± 25.67
Nucleus
Accumbens 		5.72 ± 22.17 10.63 ± 33.01 2.77 ± 27.13 1.69 ± 34.26 −4.51 ± 11.69 −8.90 ± 28.22
Putamen −1.02 ± 22.17 25.02 ± 23.53 19.03 ± 27.18 −14.92 ± 33.76 −19.03 ± 17.12 1.48 ± 13.82
Lateral PFC 15.02 ± 12.03 33.67 ± 27.15 14.86 ± 19.49 22.49 ± 18.05 5.29 ± 13.68 −19.1 ± 14.67
OFC −7.31 ± 26.41 14.96 ± 21.14 4.86 ± 10.04 −7.30 ± 22.28 14.14 ± 18.58 −23.79 ± 21.14
Medial PFC 25.92 ± 9.11 36.87 ± 14.57 11.39 ± 22.40 −29.08 ± 24.19 24.80 ± 13.32 −36.63 ± 23.04
Dorsal PFC 11.68 ± 4.80 45.57 ± 19.25 30.90 ± 22.29 14.08 ± 20.28 3.45 ± 16.88 −23.72 ± 23.33
Motor cortex 18.65 ± 10.93 39.11 ± 24.88 25.18 ± 11.89 21.93 ± 11.30 −4.02 ± 3.13 −19.62 ± 14.49
Anterior
cingulate 		44.87 ± 12.5 * 41.08 ± 18.45 25.38 ± 15.76 3.81 ± 31.46 11.11 ± 8.22 −25.48 ± 15.88
Mid ingulate 35.86 ± 7.29 * 35.88 ± 25.95 20.85 ± 21.62 58.07 ± 11.7 * −5.87 ± 10.32 −4.06 ± 13.95
Anterior
Parietal 		41.63 ± 0.51 * 46.21 ± 26.64 43.39 ± 15.27 53.08 ± 13.68 9.39 ± 12.23 −15.07 ± 6.74
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PFC, prefrontal cortex; OFC, orbitofrontal cortex

*

P < 0.05.

No significant depletions were observed in serotonin, indicating that citalopram was successful at protecting 5-HT.

Striatal 5-HT depletions

Infusions of 5,7-DHT into the marmoset medial caudate nucleus resulted in a significant decrease in the levels of 5-HT in both the medial head (66.68% ± 12.1; t(2) = 5.529, P = 0.031) and body of the caudate nucleus (34.98% ± 3.43; t(2) = 10.185, P = 0.010) an average of 252 days after surgery (Table 2). The DA and NA reuptake blockers GBR12909 and nisoxetine successfully prevented any alterations in DA and NA within these regions. No other regions showed alterations in 5-HT levels apart from the medial cingulate (58.07% ± 11.7; t(2) = 0.121, P = 0.037). Whilst the adjacent lateral head of the caudate nucleus showed no depletions of 5-HT there was a significant increase in DA levels (41.6% ± 6.95; t(2) = 5.985, P = 0.027) and a significant decrease in NA (60.36% ± 11.9; t(2) = 5.071, P = 0.037).

Behavioral results: Effects of striatal DA and 5-HT depletion on serial reversal learning

Pre-operative discrimination behavior

Pre-operatively, the three groups of monkeys did not differ in their ability to learn two novel visual discriminations (D1 and D2; group and group × discrimination, F values < 1, see Table 3).

Table 3.

Pre-reversal discrimination performance. Number of errors made before reaching the performance criterion on all pre-reversal discriminations for monkeys with 5,7-DHT or 6-OHDA medial caudate infusions and controls.

Errors (± SEM)
Group D1 D2 S
U
R
G
E
R
Y 		D2
retention 		D3
acquisition
Controls 49.67 ± 13.32 50.33 ± 13.38 7.33 ± 3.84 45.67 ± 12.99
DA medial
caudate depletions 		51.0 ± 10.13 57.5 ± 11.98 3.75 ± 3.12 74.75 ± 17.69
5-HT medial
caudate depletions 		38.0 ± 12.86 54.0 ± 19.98 1.33 ± 1.33 42.33 ± 26.96
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Post-operative discrimination behavior

Post-operatively, there were no significant differences in the ability of the three groups of monkeys to remember a previously learnt discrimination, or to learn a third novel discrimination (D2 retention and D3 acquisition; group and group × discrimination, F values < 1). However, there was a main effect of discrimination (F(1,7) = 20.379, P = 0.003) representing the ease with which all monkeys performed D2 retention compared to D3 acquisition.

Serial Reversals

It can be seen in Fig 3a that DA medial caudate-depleted monkeys made many more errors across the series of seven reversals than both 5-HT medial caudate-depleted monkeys and control monkeys. Repeated measures ANOVA on the overall (total) errors to criterion across reversals (1-7) revealed significant main effects of group (F(2,7) = 7.005, P = 0.021) and reversal (F(3.8,26.7) = 7.091, ε̃ = 0.634, P = 0.001) but no reversal × group interaction (F(7.6,26.7) = 1.736, ε̃ = 0.634, P = 0.139). Post hoc analysis using Fishers LSD test showed that control monkeys did not differ from 5-HT-depleted monkeys (P = 0.893), while dopamine-depleted monkeys showed significantly worse performance than both controls (P = 0.014) and 5-HT-depleted monkeys (P = 0.018). See figure 3b. Analysis of reversal 1 independently revealed a main effect of group (F(2,9) = 4.974, P = 0.045) that was due to monkeys with DA medial caudate depletions making significantly more errors than control monkeys (P = 0.017) but not 5-HT depleted monkeys (P = 0.118), the latter not differing from controls (P = 0.252).

Figure 3.

Figure 3

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Serial discrimination reversal performance. A, total errors to criterion for each reversal. Repeated measures ANOVA revealed a main effect of group (P = 0.025) attributable to an increased number of errors in the dopamine-depleted group. B, Total errors, collapsed across reversals. *P < 0.05. C, Mean perseveration, chance and learning errors, showing that the increase in errors shown by the dopamine-depleted monkeys was not due to a specific error type (error type × group interaction, F<1).

As described previously, such a gross analysis can be insensitive to changes within reversals, and can fail to detect more subtle changes, such as the perseverative responding seen after excitotoxic lesions of the medial caudate/nucleus accumbens in marmosets (Clarke et al., 2008). We therefore used signal detection theory to classify errors as either perseverative, random chance, or learning (see Materials and Methods), and performed additional analyses to investigate whether the different lesions preferentially caused distinct error types.

Despite their overall reversal impairment, monkeys with dopamine depletions in the medial caudate did not show a preponderance of any particular error type. Their impairment was due to an overall increase in all three error types (see figure 3c). Repeated measures ANOVA revealed main effects of reversal (F(6,42) = 6.945, P < 0.001), error type (F(2,14) = 12.604, P = 0.001) and group (F(2,7) = 6.638, P = 0.024) but no reversal × group (F(12,42) = 1.780, P = 0.084) or error type × group (F<1) interactions. Post hoc analysis of this group effect confirms the findings of the total error analysis (controls vs 5-HT lesions, P = 0.899; controls vs dopamine lesions, P = 0.016; 5-HT lesions vs dopamine lesions, P = 0.020). Independent analysis of reversal one revealed no group interaction with error type (F<1).

Latencies

At no point during the serial reversal paradigm were there any group differences in the latencies to make correct or incorrect responses (correct/incorrect × group, reversal × group, correct/incorrect × reversal × group, all Fs < 1). Although a trend towards a main effect of group was seen (F2,7 = 3.768, P = 0.077), posthoc LSD analysis revealed that this was due to a significant difference between the 5-HT and DA-depleted animals (P = 0.031), but not to any significant differences between depleted animals and controls (5-HT vs controls P = 0.105; DA vs controls P = 0.502). Moreover, this effect is due to just one 5-HT depleted animal who uniformly responded very slowly, and given that the group n =3, has a disproportionate effect on the group mean.

Discussion

This study provides insights into the neurochemical modulation of circuits subserving the behavioral flexibility inherent in discrimination reversal tasks. Selective dopamine depletion from the medial head of the marmoset caudate nucleus resulted in significantly more errors whilst performing a series of reversals. In contrast, selective serotoninergic depletion from this region had no effect on performance.

This neurochemical dissociation between the roles of serotonin and dopamine within the medial head of the caudate nucleus is the opposite to that seen in the OFC. The marmoset OFC has extensive connections with this striatal region (Roberts et al., 2007) and like the caudate nucleus, contributes to successful discrimination reversal performance. However, within the OFC, selective dopaminergic depletions had no effect on reversal learning, while selective serotonergic depletions caused marked impairment (Clarke et al., 2004; 2007).

The current finding of a profound non-perseverative reversal learning deficit after caudate dopamine depletion is consistent with previous findings in rodents and humans that implicate striatal dopamine in reversal learning (Lee et al., 2007; O’Neill and Brown, 2007; Dodds et al., 2008; Clatworthy et al., 2009). In contrast to the current findings, previous marmoset striatal dopaminergic depletions had no effect on individual reversals embedded in an attentional set-shifting task (Collins et al., 2000). However, although non-significant when compared against controls and subjects with prefrontal dopaminergic lesions (Crofts et al., 2001), such subjects nevertheless displayed the most errors when reversing a simple discrimination (square-root transformed data ± SEM: controls, 11.96 ± 1.58; caudate DA depletions, 17.54 ± 2.3; prefrontal DA depletions, 14.3 ± 1.47).

Intriguingly, the impairments seen after dopamine striatal depletion in marmosets (current study) and rats (O’Neill and Brown, 2007) were not due to perseveration. This contrasts strongly with the perseveration seen after OFC 5-HT manipulations (Clarke et al., 2004; 2005; 2007), excitotoxic striatal lesions (Clarke et al., 2008) and systemic administration of amphetamine (Ridley et al., 1981b, a), in marmosets performing reversal learning. We speculate that striatal dopaminergic inactivation (pharmacologically or via selective dopaminergic lesions) causes non-perseverative impairments, while excessive dopaminergic activation may lead to perseveration (but see Ersche et al., 2008). Indeed activation of the caudate nucleus, and specifically caudate dopamine D2/3 receptors, is associated with perseverative responding after contingency change (Clatworthy et al., 2009; Jocham et al., 2009; Ersche et al., personal communication), and variations in baseline striatal dopamine synthesis capacity can modulate the outcome of dopaminergic manipulations on probabilistic reversal learning. Thus, Cools et al. (2009) have shown that the D2 agonist bromocriptine has beneficial effects in subjects with low compared to high baseline striatal dopamine synthesis, raising the possibility that activation of striatal D2 receptors may have ameliorated the current reversal deficits. However, blockade, deletion and activation of D2-like receptors have all been shown to impair reversal learning (Ridley et al., 1981a; Smith et al., 1999; Mehta et al., 2001; Izquierdo et al., 2006; Lee et al., 2007; Cools et al., 2009), and complex interactions between the heterogenous striatal distribution of dopamine receptors, the tonic and phasic release of dopamine, baseline dopamine levels at the striatal synapse, and serotonergic modulation of dopamine release via 5-HT1c, 2a/c, 3 and 4 receptor subtypes, may all determine the contribution of striatal dopamine to behavioral flexibility (Porras et al., 2002; Alex et al., 2005; Goto and Grace, 2007; Goto et al., 2007; Lee et al., 2007; Cools et al., 2009; Navailles and De Deurwaerdere, 2010).

There is also extensive evidence linking serotonin to behavioural flexibility processes. A variety of chemical agents that reduce neural 5-HT, including 5,7-DHT (Clarke et al., 2004), PCA (Masaki et al., 2006) and PCPA (Lapiz-Bluhm et al., 2009; but see Brigman et al., 2010) disrupt reversal learning, as does chronic cold stress (Lapiz-Bluhm et al., 2009) and sub-chronic PCP (Abdul-Monim et al., 2003). Furthermore, the reversal learning impairments induced by chronic cold stress and sub-chronic PCP can be ameliorated by systemic drugs that increase serotonergic function (Abdul-Monim et al., 2003; McLean et al., 2009; Danet et al., 2010). In addition, pharmacological or genetic inactivation of the 5-HT transporter, as well as polymorphisms in the promoter (5-HTTLPR) and the 3′ untranslated regions all modulate reversal learning (Izquierdo et al., 2007; Vallender et al., 2009; Brigman et al., 2010). The particular importance of the OFC in 5-HT’s modulatory effects on reversal learning is illustrated by the perseverative reversal impairments that follow local OFC 5-HT depletion in marmosets (Clarke et al., 2004; 2007), the correlations between 5-HT levels in the OFC and reversal performance (Masaki et al., 2006), and the rise of extracellular 5-HT during reversal performance in rats (Lapiz-Bluhm et al., 2009). Neuroimaging studies of acutely tryptophan-depleted humans during reversal learning also implicate regions of the medial and orbitofrontal PFC (Cools et al., 2005; Evers et al., 2005; Cools et al., 2008; van der Veen et al., 2007; Evers et al., 2010). Together with the present findings, these results suggest that the ventromedial PFC, but not the caudate nucleus, is implicated in the serotonergic modulation of reversal learning.

The role of fronto-striatal 5-HT is clinically relevant. Functional imaging studies typically show increased OFC metabolism in obsessive-compulsive disorder (OCD) patients compared to healthy controls, which normalises after successful selective serotonergic reuptake inhibitor (SSRI) treatment (Saxena et al., 1998; Brody et al., 1999; Saxena and Rauch, 2000). In addition, patients and their first degree relatives both show reversal learning-related OFC hypofunction, suggesting that OFC activity may represent an endophenotype for individuals at increased genetic risk of OCD (Chamberlain et al., 2008). Despite this, there is limited evidence for reversal learning deficits per se in OCD patients (Remijnse et al., 2006; 2009), although evidence that the OFC and 5-HT are implicated in some forms of compulsive behaviour can be found in the signal attenuation paradigm, a proposed model of OCD (Joel and Avisar, 2001; Joel et al., 2005; Flaisher-Grinberg et al., 2008). In this model, compulsive responding induced by excitotoxic OFC lesions is accompanied by a decreased density of striatal 5-HT and the presynaptic striatal 5-HT transporter (Joel et al., 2005; Schilman et al., 2010). Altered striatal, specifically caudate, activity is well documented in OCD (Saxena et al., 1998; 1999; Remijnse et al., 2006) and it was speculated that decreased striatal 5-HT may mediate the increased compulsive-like behavior seen after OFC lesions (Schilman et al., 2010), perhaps due to striatal serotonergic (or dopaminergic, Joel and Doljansky, 2003; Denys et al., 2004) receptor up-regulation, e.g. 5-HT2a (Adams et al., 2005). The present findings that caudate 5-HT depletion had no effect on reversal learning do not support this hypothesis. However, it remains possible that striatal 5-HT assumes a greater role when the OFC is compromised, a premise supported by evidence that striatal SSRI infusion abolishes the increased compulsivity seen in OFC-lesioned rats, but has no effect in controls (Joel et al., 2005).

Whilst we conclude that dopamine rather than serotonin is important for mediating reversal learning in the caudate nucleus, an important caveat in the present study is the depletion observed in the cingulate cortex and the anterior parietal cortex in monkeys receiving intra-caudate 6-OHDA. However, evidence for a role of the anterior cingulate cortex in reversal learning is inconsistent (Bussey et al., 1997; Meunier et al., 1997; Schweimer and Hauber, 2005; Ragozzino and Rozman, 2007), while evidence concerning the parietal cortex is scant (Fox et al., 2003; Chamberlain et al., 2008). It should also be noted that the unilaterally-lesioned monkeys used for the timeline analysis (Figure 2) showed nucleus accumbens dopamine depletions ranging from 25-60%. However, there is little evidence for nucleus accumbens involvement in serial visual reversal learning (see Clarke et al., 2008), and we think it unlikely that this contributed to the current behavioral deficits. Nevertheless, the impact of selective dopaminergic depletions of these areas on serial reversal learning performance needs to be evaluated before the possibility of their involvement is excluded.

To conclude, these data suggest that reversal learning, at the level of the caudate nucleus and OFC, is differentially regulated by dopamine and serotonin, respectively. These data are not easily explained by existing reinforcement models of dopamine and 5-HT (Boureau and Dayan, 2011; Cools et al., 2011), which do not account for the actions of these neuromodulators at different levels of the neural hierarchy. However, we and others have shown the differential contribution of dopamine to cognition within the PFC and caudate nucleus (Collins et al., 2000; Crofts et al., 2001; Cools, 2008; Dodds et al., 2008), which is consistent with proposals that prefrontal dopamine stabilises goal-relevant representations (Cohen and Servan-Schreiber, 1993; Durstewitz et al., 2000; Robbins and Roberts, 2007), while caudate dopamine promotes cognitive switching (see van Schouwenburg et al., 2010 for review). We would argue that simple discrimination reversal learning only taxes the latter. In contrast, whilst we have shown that orbitofrontal 5-HT contributes to attentional saliency (Walker et al., 2008), its role at the striatal level is poorly understood, and its overall contribution to the OFC-striatal circuit requires further investigation.

Acknowledgements

Supported by a Wellcome Trust programme grant to TWR, JW Dalley, B.J. Everitt, ACR, and B.J. Sahakian and conducted within the University of Cambridge Behavioural and Clinical Neuroscience Institute, supported by a joint award from the Medical Research Council and the Wellcome Trust. HFC is supported by a Network Grant from the J. McDonnell Foundation and a Junior Research Fellowship from Newnham College, Cambridge. Funding to pay the open access publication charges for this article was provided by the Wellcome Trust. We thank Jing Xia for the HPLC analysis.

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