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Dorsolateral striatum and dorsal hippocampus: A serial contribution to acquisition of cue-reward associations in rats
Behavioural Brain Research 239 (2013) 94–103
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Dorsolateral striatum and dorsal hippocampus: A serial contribution to acquisition of cue-reward associations in rats M. Jacquet a,1 , L. Lecourtier b,1 , R. Cassel b , M. Loureiro b , B. Cosquer b , G. Escoffier a , M. Migliorati a , J.-C. Cassel b , F.S. Roman a , E. Marchetti a,∗ a b
Aix-Marseille University, CNRS, NICN, UMR7259, 13344 Marseille, France Laboratoire d’Imagerie et de Neurosciences Cognitives, UMR7237 Université de Strasbourg-CNRS, Faculté de Psychologie, 12 rue Goethe, F-67000 Strasbourg, France
h i g h l i g h t s
Rats with dorsolateral striatum lesions were impaired in procedural and declarative-like memories. Rats with dorsal hippocampal lesions were impaired in declarative-like memory. Rats with dorsal hippocampal lesions were not impaired procedural memory. Establishment of a procedural may be a prerequisite for a declarative-like memory.
a r t i c l e
i n f o
Article history: Received 6 August 2012 Received in revised form 25 October 2012 Accepted 29 October 2012 Available online 9 November 2012 Keywords: Dorsolateral striatum Dorsal hippocampus Procedural memory Reference memory Learning
a b s t r a c t In laboratory rodents, procedural and declarative-like memory processes are often considered operating in dual, sometimes even competing with each other. There is evidence that the initial approach of a repetitive task first engages a hippocampus-dependent declarative-like memory system acquiring knowledge. Over repetition, there is a gradual shift towards a striatum-dependent response memory system. In the current experiment, Long-Evans male rats with bilateral, fiber-sparing ibotenic acidinduced lesions of the dorsolateral striatum or the dorsal hippocampus were trained in an olfactory associative task requiring the acquisition of both a procedural and a declarative-like memory. Rats with dorsolateral striatum lesions, and thus an intact hippocampus, were impaired on both sub-categories of memory performance. Rats with dorsal hippocampal lesions exhibited a substantial deficit in learning the declarative-like cue-reward associations, while the acquisition of the procedural memory component of the task was not affected. These data suggest that the dorsolateral striatum is required to acquire the task rule while the dorsal hippocampus is required to acquire the association between a given stimulus and its associated outcome. The finding is that the dorsolateral striatum and the dorsal hippocampus most probably contribute to successful learning of cue-reward associations in a sequential (from procedural to declarative-like memory) order using this olfactory associative learning task. © 2012 Published by Elsevier B.V.
1. Introduction Damage to hippocampal and retrohippocampal structures in rodents causes selective impairments in a variety of spatial and non spatial declarative-like learning tasks [1–4]. Such damage, however, was also shown to have little or no effects on other types of learning [5,6], including olfactory associative learning [7–10]. An example is provided by the effects of such lesions in the successive
∗ Corresponding author at: Aix-Marseille Université, CNRS, UMR7259, NICN, Centre St Charles-3, Place Victor Hugo, 13331 Marseille Cedex 03, France. Tel.: +33 4 13 55 08 53; fax: +33 4 13 55 08 58. E-mail address: [email protected] (E. Marchetti). 1 Contributed equivalently to this work. 0166-4328/$ – see front matter © 2012 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.bbr.2012.10.061
go/no go olfactory discrimination task [11]. In this task, animals are successively presented with individual odor stimuli, which are paired (i.e., indicative of go trials) or not (i.e., indicative of no go trials) with reinforcement. The prerequisite for successful learning of go/no go tasks after hippocampal damage is that the cues are presented with a short inter-trial interval. Indeed, when rats with hippocampal damage have to manage the successive odor presentations with long inter-trial intervals (>15 s), the odor-reward association is not acquired [9,10]. These observations confirmed earlier findings in both rats and monkeys subjected to fornix or hippocampal lesions [12]. Surprisingly, there are only a few studies which aimed at identifying the brain regions involved in this type of hippocampus-independent learning [13]. One candidate structure is the striatum, the rodent equivalent of the caudate–putamen in primates. In rats, lesions of the striatum,
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Table 1 Coordinates and injection volumes for ibotenate lesions of the dorsolateral striatum or the dorsal hippocampus. Coordinates are given in mm anterior and lateral to Bregma (Paxinos and Watson, 1998) and from the skull surface in depth. Structure
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Laterality
Depth
Volume (L)
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+0.5 +1.2
± 3.9 ± 3.6
−5.2 −5.2
0.4 0.4
Dorsal hippocampus
−2.6 −3.1 −3.0 −3.8 −3.8 −4.1 −4.1
± 1.0 ± 3.0 ± 1.4 ± 3.7 ± 2.6 ± 4.0 ± 2.5
−3.8 −2.8 −3.2; −2.4 −2.8 −3.0; −2.5 −3.2 −2.5
0.06 0.06 0.06 each 0.06 0.06 each 0.08 0.08
and more specifically of its dorsal regions, impair the acquisition or/and retrieval of several operant tasks that are not or only poorly affected by hippocampal lesions [2]. These include tasks based on avoidance responses [14–19], brightness discrimination [20], processing of visual cues in the Morris water maze [21,22], and visual/olfactory conditioning of emotional responses [23]. Our associative olfactory task [9] enables separate assessment of performance linked to procedural or declarative-like memory contributions. Using this task, a first experiment assessed performance after fiber-sparing lesions of the dorsolateral striatum. Given the outcome of this experiment (i.e., the impairment of procedural learning prevented acquisition of the hippocampusdependent declarative-like component of the task), we performed a complementary experiment in which the effects of dorsal hippocampus lesions were assessed according to exactly the same protocol. Following hippocampal lesions, we expected normal procedural learning but no acquisition of the hippocampus-dependent, declarative-like component of the task. Our results suggest a serial implication of the striatum and the hippocampus in cue-reward associations learning.
light–dark cycle (lights on at 7:00 am and off at 7:00 pm) in a room held at a constant temperature (22◦ ). After surgery and before testing, each animal was first handled (10 min) daily for three consecutive days. Then it was deprived of water 48 h before the beginning of training. During training of the following days, the rats were given water ad libitum for 30 min per day at 6:30 pm. European guidelines on procedures for animal experimentation were followed, and all efforts were made to minimize the animals’ suffering and to reduce the number of animals used while complying with statistical constraints. 2.2. Lesion surgeries All rats were anaesthetized with an intraperitoneal (ip) administration of pentobarbital (60 mg/kg, i.p.). Once anaesthetized, they were given an intramuscular injection of an antibiotic (Extencilline; 0.3 mL/kg) and were subsequently placed on a stereotaxic apparatus. Their scalp was opened longitudinally with a scalpel and little holes were drilled in the skull at locations where a needle had to be introduced into the brain to perform the ibotenate infusions. The ibotenate solution (5 g/L) was infused at the coordinates indicated in Table 1 at a speed of 0.25 L/min. After each infusion, the needle was left in place for 4 min before being slowly retracted. In the sham-operated rats, the needle was descended into the brain at each of the coordinates used for the lesion, but no infusion was performed. After surgery, the scalp was sutured and all rats were placed in a heated cage until complete recovery from anesthesia. Behavioral training was started 4 weeks after surgery. 2.3. Apparatus and training procedure
2. Material and methods 2.1. Animals Fifty two young adult Long-Evans rats (R. Janvier, France) weighing 250–275 g at the time of surgery were used. They were individually housed and kept on a 24 h
The olfactory training apparatus was a rectangular box made of wire mesh (30 cm × 30 cm × 50 cm). A conical odor port (1.5 cm in diameter, 0.5 cm above the floor) was drilled horizontally through a triangular wedge of Plexiglas, mounted in one corner of the cage. A circular (1 cm diameter) water port in the shape of a well was placed directly above the odor port. Responses to the odor presentation
Fig. 1. Representative photographs illustrating lesions following NeuN staining in the groups of SHAM (A, C, E) and lesioned (B, D, F) rats. B and D show typical examples of lesions in the dorsolateral striatum and in the dorsal hippocampus, respectively. Dashed lines indicate the limits of the damaged area. E and F indicate that rostral regions of the hippocampus were not damaged after lesions of the dorsal hippocampus (F) as compared to a sham-operated rat (E). Scale bars at the bottom right of photos B, D and F correspond to 1 M.
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Fig. 2. Schematic representation of the smallest (light gray) and largest (dark gray) extent of dorsal hippocampal (left) and dorsolateral striatal (right) lesions in the rats kept for statistical analyses. Numbers above the drawings indicate the distance (in mm) of each section from Bregma (according to Paxinos and Watson, 1998).
were monitored by a photoelectric circuit. Two flashlight bulbs which could be turned on and off, as the testing conditions required, were placed outside the cage, one on each side of the odor and water ports, 10 cm above the floor. Individual odors were delivered by forcing clean air (0.7 bars) through one of two 1 L Erlenmeyer flasks that contained 500 mL of water mixed with 0.2% of chemical odorants (jasmine vs. strawberry) from Sigma Inc. Non-odorized air, between each odor presentation, was delivered by sending air through a flask that contained only water. Odorized and clean air streams were passed individually through tubes that were put through the back of the sound-attenuating chamber and attached to the odor port. Water was delivered using a gravity-fed system, and passed through
a valve which, when opened, allowed 0.1 mL of water to be released into the water port. All experiments were conducted simultaneously in four olfactory cages to ensure that, in each experiment, representatives from each group were trained at the same time, and thus under identical conditions [10,24]. Animals were trained to make two odor-reward associations. Each odor had to be associated with a specific reward, one arbitrarily designated as positive and the other as negative. One session was made of 60 trials using a successive Go or No-Go paradigm. Individual trials (S+ or S− ) were run in a quasi-random fashion (no more than 3 consecutive trials with the same valence). When the odor (S+ ) was delivered into the cage, if rat
responded by going to the water port a reward of 0.l mL of water was obtained. The same response to delivery of the other odor (S− ) resulted in no water and activation of an error light. The maximum duration of odor presentation (S+ or S− ) was 10 s. Correct responses, therefore, corresponded to Go before the 10 s presentation for one odor had elapsed (S+ ) and No-Go to the other (S− ). Once responded or not to the odor presentation (the trial) a fixed inter-trial interval (ITI) of 15 seconds with clean air was started. If a response was given during the last second of the ITI, the next trial was delayed by 10 s and delayed by additional 10 s fractions as long as the rat was still present during the last second of each fraction in the corner where the reward is delivered. Consequently, the duration between two trials could last longer than 15 s and constituted the cumulative time to the minimum ITI. Animals were tested every day between 08:00 am and 02:00 pm. Then, all animals were trained to make associations with the odor pair for six sessions at a pace of one session per day.
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3. Results 3.1. Histological analysis Typical examples of lesion extents and placements are shown in Fig. 1. Lesion extent and location are further illustrated in Fig. 2. Histological verifications showed that 6 rats which had received ibotenate into the dorsolateral striatum (DL STRIATUM; Experiment 1) and 7 rats which had received ibotenate into the dorsal hippocampus (D HIPP; Experiment 2) had lesions that were either partly misplaced (e.g., encroaching too much onto the dorsomedial striatum, being slightly too dorsal, or showing asymmetry) or of insufficient extent. These rats were withdrawn from statistical analyses. Consequently, rats with dorsal hippocampus lesions constituted a group of 9, those with dorsolateral striatum lesions a group of 10. The respective groups of sham-operated rats (SHAM) comprised 10 subjects. 3.2. Behavioral studies 3.2.1. Experiment 1: lesions of the dorsolateral striatum Analyses of the percentage of correct responses (Fig. 3A) showed that only rats of the SHAM group improved their overall
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Correct responses were characterized as Go for the positive odor and No-Go for the negative one. Incorrect responses were Go for the negative odor and NoGo for the positive one. The number of correct responses for both positive and negative odors was expressed as a percentage of the total number of odor presentations (60 per session), thereby providing a global estimate of performance for all groups (global memory). Training continued until a criterion of 80 ± 5% correct responses was reached by the control groups. This level of performance is required to ensure that all animals have learned both associations. Latencies for positive (S+ ) and negative (S− ) odors were recorded and represented the time elapsed between the beginning of a trial and its end (10 s), when the rat responded to the odor (reference memory, which is presumed to correspond by some aspects to declarative memory in humans; [24]. When a rat did not respond, a latency of 10 s was scored. The median cumulative time (accounting for the efficiency of some aspects of procedural memory; [24]) was the number of seconds above the fixed 15 s ITI, divided by the number of ITIs, which in this experiment amounted to 59. All behavorial events were controlled and recorded by a computer. Statistical analyses were performed with SPSS/PC+ statistics 11.0 software marketed by SPSS, Inc. All data are presented as means ± SEM. Performance was analyzed using a repeated-measure MANOVA. Then, subsequent ANOVAs for each session were computed. The threshold for significance was set at p ≤ 0.05. (on graphs: *p ≤ 0.05; **p ≤ 0.01; p*** ≤ 0.001). Percentage of correct responses in comparison to chance level (50%) was analyzed using a one-sample t-test.
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2.4. Histological verifications Upon termination of the behavioral experiments, all rats were deeply anesthetized with an overdose of pentobarbital (150 mg/kg i.p.). They were transcardially perfused with 60 mL of phosphate-buffered 4% paraformaldehyde (pH 7.4; 4 ◦ C) over 5 min. The brains were extracted, postfixed for 2 h in the same fixative (4 ◦ C), and transferred into a 0.1 M phosphate-buffered 20% sucrose solution for about 48 h (4 ◦ C). Brains were subsequently frozen in isopentane (−30 ◦ C) and 40 m-thick sections were cut in the coronal plane at 21 ◦ C using a freezing microtome and placed in phosphate buffer saline. NeuN-staining was performed using a mouse polyclonal antibody directed against NeuN (1/2000; Millipore, MAB377) as primary antibody and a horse anti-mouse biotinylated antibody (1/500; Vector, BA 2001) as secondary antibody.
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SESSION (Day) Fig. 3. Mean performance (±SEM) obtained across the five sessions of 60 trials in control (SHAM) (N = 10), and bilaterally dorsolateral STRIATUM lesioned rats (DL STRIATUM) (N = 10). (A) Mean percentage of correct responses. The difference between the SHAM and DL STRIATUM groups was significant from the fourth session onward. (B) Mean cumulative time (in seconds). Significant statistical difference was observed between the two groups on session 5. (C) Mean latencies (in seconds), S+ are the latencies for the positive odor and S− the latencies for the negative odor one. Only the SHAM group started to make significant associations from session 4 onward.
performance across the five sessions (MANOVA, Group × Session interaction: [F(4,68) = 6.09; p < 0.001]; the overall Group effect was significant [F(1,17) = 9.18 p < 0.01]. Subsequent ANOVAs revealed a clear-cut difference between the two groups from the fourth session onwards [F(1,17) = 6.84 p < 0.01]. In the DL STRIATUM group, the percent correct responses was never different from chance level, whatever the session (t ≤ 1.10, NS). The cumulative time (Fig. 3B) decreased across sessions in the SHAM group, whereas the DL STRIATUM group performed at a constant level throughout all five training sessions. Consequently, a significant difference was observed between the performance of these two groups across the five successive sessions [F(1,17) = 10.79 p < 0.01]; the Group × Session interaction was
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significant (F(4,68) = 6.02 p < 0.001), most probably because of the substantial inter-group difference found on session 5 [(ANOVA, F(1,17) = 5.52 p < 0.05]. Training performance analyzed in terms of S+ and S− latencies (Fig. 3C) showed a dramatic impairment in the DL STRIATUM group. Indeed, conversely to their SHAM counterparts, lesioned rats were unable to make correct associations on S+ and S− stimuli. In the SHAM group, correct associations were observed from the fourth session onwards [F(1,18) ≥ 15.39; p < 0.001]. The DL STRIATUM group also showed a slight gradual decrease in the time taken to respond to both stimuli across the five sessions. SHAM rats showed a continuous decrease in latencies of response to S+ stimuli throughout the training session while for S− stimuli a decrease was observed during session 2 and 3, but then the rats began to withhold their responses (and therefore, started to exhibit correct behavior). Consequently, a significant difference between the groups was observed on S+ [F(1,17) = 10.05; p < 0.01, but not across the five sessions [F(4.68) = 0.65; NS], and not on S− stimuli [F(1,17) = 0.26; NS], but with a significant difference across sessions [F(4,68) = 3.97; p < 0.01]. We additionally performed a detailed analysis considering performance in blocks of 10 trials within each of the 5 sessions (S1-S5; Fig. 4). From S1 to S3 a slight difference between groups was observed on cumulative time. This difference did not reach the level of significance. On S4, the difference was more pronounced, yet
not significant. On S5, however, the difference was dramatic and significant [F(1,17) ≥ 5.55; p ≤ 0.05]. Similarly, in terms of latencies (Fig. 5), a deficit between the two groups appeared on S4 and S5 (Fig. 5) and only the SHAM group made constant correct associations between S+ and S− latencies on all blocks on S4 and S5 [F(1,18) ≥ 4.62; p ≤ 0.05]; lesioned rats showed correct associations only during one single block (block3) on session 5, [F(1,16) = 4.73; p < 0.05]. 3.2.2. Experiment 2: lesions of the dorsal hippocampus The performance of SHAM rats improved across sessions, reaching a correct response score of 80 ± 5% on session 5. This improvement was not observed in D HIPP rats (Fig. 6A). MANOVAs indicated a group difference across the five sessions [F(1,17) = 11.2; p < 0.01] and even over sessions (group × session interaction, [F(4,68) = 28.42; p < 0.001]. Subsequent ANOVAs revealed that this difference appeared from the third session onwards [F(1,17) ≥ 5.64; p ≤ 0.05]. Only on session 5, D HIPP rats performed above chance level (t = 3.57; p < 0.01). The cumulative time decreased over the sessions [F(4,68) = 11.89; p < 0.001] but similarly [F(4,68) = 0.52; NS] in both groups (Fig. 6B), and there was no significant group effect [F(1,17) = 0.51; NS]. Training performance analyzed by S+ and S− latencies for the two groups is presented in Fig. 6C. While correct associations on
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BLOCK OF TRIALS Fig. 5. Mean latencies by block of 10 trials (±SEM) recorded during sessions S1 to S5. S+ are the latencies for the positive odor and S− the latencies for the negative one. SHAM rats started to make constant significant odor-reward associations from the first block of the fourth session onwards. Only a transient significant association was observed for STRIATUM rats during the third block of the fifth session, indicating absence of consistency. See also legend to Fig. 3.
S+ and S− stimuli started to be significant from the third session onwards in the SHAM group [F(1,18) ≥ 4.74 p ≤ 0.05], D HIPP rats responded to S+ or S− trials without discernment [F(1,16) ≤ 1.6; NS]. This difference came as well over the sessions from the S+ [F(4,68) = 14.87; p < 0.001] as the S− stimuli [F(4,68) = 11.89; p < 0.001] A more detailed analysis considered changes in cumulative time over blocks of 10 trials within each of the 5 sessions (S1–S5; Fig. 7). It showed that no scores, even during one single block, were significantly different between SHAM and D HIPP rats. Inversely, on latencies, a profound difference between the two groups appeared from the fourth session onwards (Fig. 8), where a significant odorreward association appeared from the first block of S4 in the SHAM group [F(1,18) ≥ 9.52 p ≤ 0.01]. In D HIPP rats, such an effect was never observed whatever the session [F(1,16) ≤ 1.5; NS]. 4. Discussion In this operant task, when a response is given during the last second of the ITI, the start of the next trial is delayed by 10 s, and additional 10 s delay are added as long as, on the last second of an ongoing delay, the rat is still present in the corner where the reward is delivered. Thus, the duration between two trials could last longer
than 15 s and constituted the cumulative time added to the 15 s of the fixed ITI time. A behavioral inhibition deficit, once the rats have learned that they can get the positive reward in the corner, should be followed by a substantial increase of the cumulative time in all sessions. In fact, such behavior is observed only during the first and the second sessions (Figs. 4 and 7) for both sham groups and hippocampal lesioned rats. Afterwards, one observes a significant decrease. On the contrary, the rats with lesions of the dorsolateral striatum did not increase or even decreased their cumulative time across sessions; they responded randomly during the last second of the ITI and occasionally delayed the next trial. Consequently, the mean of the cumulative time was constant throughout the sessions and did not seem to be related to an alteration of behavioral inhibition capacities. An alternative explanation could be that the lesions of the dorsolateral structure disrupted the timing ability, in agreement with the scalar timing theory developed by Meck and Church [25]. In fact, as demonstrated previously in this task [26], improved performance is observed despite altered timing ability. Indeed, the disruption of the ability to manage the timing as seen after lesions of the dorsomedial prefrontal cortex led rats to respond only when the olfactory cue was presented, thereby facilitating the odor-reward association due to the absence of extra time added to the fixed ITI. A third possibility would be that the dorsolateral striatum lesions
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SESSION (Day) Fig. 6. Mean performance (±SEM) obtained across the five sessions of 60 trials in control rats (SHAM) (N = 10) and rats with bilateral dorsal hippocampus lesions (D HIPP) (N = 9). (A) Mean percentage of correct responses. The difference between the SHAM and D HIPP groups was significant from the third session onwards. (B) Mean cumulative time (in seconds); no statistical difference was observed between the two groups. (C) Mean latencies (in seconds); S+ are the latencies for the positive odor and S− the latencies for the negative odor. Only the SHAM group started to make significant associations from session 3 onwards.
disrupted the establishment of stimulus-response associations [13,27] or altered the habit-based memory system [28]. However, in agreement with these authors, dorsal striatum lesions marginally impair the initial learning of odor discrimination. Furthermore, before a deficit became apparent, the presentation of three successive discrimination problems was required. Compton [29] suggested that the dorsal striatum is necessary for the mediation of stimulus-response learning while the hippocampus is necessary to mediate expression of place learning (in their experiments); these processes can occur simultaneously and in parallel. In our current experiment, dorsolateral striatum lesioned rats were both impaired in cumulative time and in odor-reward associations, whereas hippocampal lesioned rats were able to withhold a response during the ITI but showed unable to make correct stimulus-response associations. To master the timing in this task a stimulus-elicited response is not required and the dorsolateral striatum rats were impaired by responding randomly during the
ITI. So, in addition to stimulus-response impairments, it seems that striatum lesioned rats did not figure out how to use the task to get only the positive reward and to get it rapidly. This deficit might be interpreted as consequent to an impairment of suppressing automatic responding. In rodents, lesions altering the medial part of the dorsal striatum usually impair goal-directed learning. Damage to the dorsolateral striatum is described as impacting habit learning (for a review, see [30]). Research on skill learning and cognitive control is often guided by a ‘multiple memory systems’ framework. This framework usually contrasts declarative memory, which provides flexible and explicite access to semantic and episodic content and requires conscious awareness, with memory for how to implement procedures (i.e., how to perform a sequence of actions). These procedures can become automatic and subconscious [31]. Based on the recent review by Liljeholm and O’Doherty [30], the impairments reported herein after lesions of the dorsolateral striatum could be the result of impaired procedure learning and consequently reflect a procedural memory dysfunction. Although several studies show a dissociation between the forms of memory related to the striatum (procedural) and those related to the hippocampus (declarative), there is also evidence pointing to the involvement of the caudate nucleus in declarative memory [32,33]. For instance, Ben Yakov and Dudai [34] performed fMRI experiments in humans in which they measured brain activity time-locked to the offset of short narrative audiovisual episodes. They found that a set of brain regions, most prominently the hippocampus and the caudate nucleus, both bilaterally exhibited memory-predictive activity that was time-locked to the stimulus offset. The hippocampus and caudate nucleus are involved in registering integrated episodes to memory as cohesive internal representations. It cannot be excluded that in our rats the lesions of the dorsolateral striatum disabled a similar process and thus prevented learning by affecting also the declarative-like component of the task. We would nevertheless privilege an alternative explanation. The fact that procedural memory deficits prevented the acquisition of the association, and thus a declarative-like item, could be questioned from a view considering encoding in the SPI system proposed by Tulving in humans [35]. This system places procedural memory at the lowest hierarchical level, semantic memory above, the highest level being that of episodic memory. From this functional hierarchy of encoding processes, it can be derived that, in tasks requiring a serial engagement of procedural and declarativelike memory processes, as seems to be the case for the task used in the current study, a deficit affecting the lowest system should have consequences on the efficiency of the higher one. This is one possible interpretation of our observations in rats with lesions of the dorsolateral striatum. In our study both the hippocampus and striatum were involved in learning and memorizing the meaning of each olfactory cue. It is thus possible, given the type of task which we used, that the dorsolateral striatum and the dorsal hippocampus had to contribute to task acquisition in a sequential order. First the dorsolateral striatum might have been required to master the procedural component of the task, mainly during the two first sessions. Then, the hippocampus might have taken over the acquisition of the odor-reward associations, and thus the declarative-like items. In other words, before being able to make correct associations engaging the hippocampus, rats had to learn the timing sequence of the task, for which the engagement of the dorsolateral striatum might be crucial. Indeed, learning to respond only when an olfactory cue is presented and not to respond during the inter-trial delay (when only a neutral air is on) required a tuned control of the locomotor neural system to engage into going or refrain from going (engage into No-Go behavior). Then, in a second phase, a choice has to be made in order to respond only to the positively-rewarded
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BLOCK OF TRIALS Fig. 7. Mean cumulative time in blocks of 10 trials (±SE) recorded during sessions S1 to S5. Both groups showed a time decreasing over sessions. No significant difference was observed between SHAM and D HIPP groups. See also legend to Fig. 6.
cue. When the striatum-dependent learning is prevented by striatal lesions, the acquisition of the hippocampus-dependent selection of the correct odor to engage in an appropriate response might become impossible. Previous results using this olfactory associative task showed that 5-HT4 receptors are substantially involved in the modulation of learning and memory processes [24]. Prior to the first training session, the injection of a selective 5-HT4 receptor antagonist (RS 67532) was followed by an increase in cumulative time, demonstrating that treated rats were more active at figuring out how to get the reward and delayed the upcoming trial by responding during the ITIs on the first session. This behavior allowed them to learn the protocol timing faster and consequently, once the procedural aspect of the task was acquired, treated rats started to make consistent cue–reward associations during the second session while control rats did not start until the third one. The injections of the partial agonist (RS 67333) prior to the first session had no significant effect, whether on the first or subsequent sessions, and only a learning deficit was observed. One interesting point, in this study, was that injections administered prior to the first or third training session gave rise to opposite effects. A facilitating effect on learning and memory was found on session 3 when RS 67333 had been injected prior to this session, and an opposite effect when the injection occurred prior to the first session. The same procedure with antagonist RS 67532 injections was followed by a learning and memory performance deficit on session 4 when the injection occurred before the third session, and a facilitatory effect on session 2 when it occurred before the first session. The opposite
effects obtained in these experiments with the partial agonist and antagonist can be related to the sub-categories of memory involved in this task. Decreasing the activation of the hippocampal system by the use of a 5-HT4 receptor antagonist at the onset of training facilitates procedural memory, and the inverse seems true for the partial agonist. By contrast, once the timing component of the task (procedural memory) has been learned (after the first two sessions), the injection of the partial agonist facilitates hippocampal processing and consequently improves memory for the associations (reference memory, related to declarative memory in humans); the opposite reasoning applies to the antagonist. As a whole, from these experiments, it seems that procedural learning comes first in this task and is crucial for acquiring subsequent declarative-like learning. When declarative-like and procedural memory processes are investigated in laboratory rodents, they are often considered as operating in dual and sometimes even competing memory systems. In rats trained for response learning in the cross-maze task, Packard and McGaugh [36] showed that the initial approach of the task engaged a hippocampus-dependent declarative-like memory system acquiring knowledge about place. Only over task repetition was there a gradual shift towards a striatum-dependent response memory system. Approaches and tasks such as the ones used by Packard and McGaugh posit the declarative-like memory as a prerequisite for response memory to be established over behavior repeats (see also [37,38]). In the test situation used in our current experiments, the cognitive operations required for task acquisition seem to occur according to an inverse schedule: only when
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D HIPP S + D HIPP S SHAM S + SHAM S-
0
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BLOCK OF TRIALS Fig. 8. Mean latencies in block of 10 trials (±SE) recorded during sessions S1 to S5. S+ are the latencies for the positive odor and S− the latencies for the negative one. SHAM rats started to make constant significant odor-rewards associations from the first block of the fourth session onwards. No significant associations were observed in D HIPP rats across the five sessions. See also legend to Fig. 6.
the dorsolateral striatum-dependent component of the task is mastered can the declarative-like, hippocampus-dependent component of the task be learned and memorized, as demonstrated by the consequences of our permanent lesions. This, along with recently published data [37,38], is another example showing that systems driving declarative-like and procedural memories may cooperate for adapting goal-directed behaviors.
5. Conclusion The original contribution of our current study resides in the demonstration that, at least in the olfactory association task we used, the establishment of a procedural memory may be a prerequisite for that of a declarative-like one.
Acknowledgements We are grateful for the expert secretarial assistance of Valerie Demare.
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Research report
Dorsolateral striatum and dorsal hippocampus: A serial contribution to acquisition of cue-reward associations in rats M. Jacquet a,1 , L. Lecourtier b,1 , R. Cassel b , M. Loureiro b , B. Cosquer b , G. Escoffier a , M. Migliorati a , J.-C. Cassel b , F.S. Roman a , E. Marchetti a,∗ a b
Aix-Marseille University, CNRS, NICN, UMR7259, 13344 Marseille, France Laboratoire d’Imagerie et de Neurosciences Cognitives, UMR7237 Université de Strasbourg-CNRS, Faculté de Psychologie, 12 rue Goethe, F-67000 Strasbourg, France
h i g h l i g h t s
Rats with dorsolateral striatum lesions were impaired in procedural and declarative-like memories. Rats with dorsal hippocampal lesions were impaired in declarative-like memory. Rats with dorsal hippocampal lesions were not impaired procedural memory. Establishment of a procedural may be a prerequisite for a declarative-like memory.
a r t i c l e
i n f o
Article history: Received 6 August 2012 Received in revised form 25 October 2012 Accepted 29 October 2012 Available online 9 November 2012 Keywords: Dorsolateral striatum Dorsal hippocampus Procedural memory Reference memory Learning
a b s t r a c t In laboratory rodents, procedural and declarative-like memory processes are often considered operating in dual, sometimes even competing with each other. There is evidence that the initial approach of a repetitive task first engages a hippocampus-dependent declarative-like memory system acquiring knowledge. Over repetition, there is a gradual shift towards a striatum-dependent response memory system. In the current experiment, Long-Evans male rats with bilateral, fiber-sparing ibotenic acidinduced lesions of the dorsolateral striatum or the dorsal hippocampus were trained in an olfactory associative task requiring the acquisition of both a procedural and a declarative-like memory. Rats with dorsolateral striatum lesions, and thus an intact hippocampus, were impaired on both sub-categories of memory performance. Rats with dorsal hippocampal lesions exhibited a substantial deficit in learning the declarative-like cue-reward associations, while the acquisition of the procedural memory component of the task was not affected. These data suggest that the dorsolateral striatum is required to acquire the task rule while the dorsal hippocampus is required to acquire the association between a given stimulus and its associated outcome. The finding is that the dorsolateral striatum and the dorsal hippocampus most probably contribute to successful learning of cue-reward associations in a sequential (from procedural to declarative-like memory) order using this olfactory associative learning task. © 2012 Published by Elsevier B.V.
1. Introduction Damage to hippocampal and retrohippocampal structures in rodents causes selective impairments in a variety of spatial and non spatial declarative-like learning tasks [1–4]. Such damage, however, was also shown to have little or no effects on other types of learning [5,6], including olfactory associative learning [7–10]. An example is provided by the effects of such lesions in the successive
∗ Corresponding author at: Aix-Marseille Université, CNRS, UMR7259, NICN, Centre St Charles-3, Place Victor Hugo, 13331 Marseille Cedex 03, France. Tel.: +33 4 13 55 08 53; fax: +33 4 13 55 08 58. E-mail address: [email protected] (E. Marchetti). 1 Contributed equivalently to this work. 0166-4328/$ – see front matter © 2012 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.bbr.2012.10.061
go/no go olfactory discrimination task [11]. In this task, animals are successively presented with individual odor stimuli, which are paired (i.e., indicative of go trials) or not (i.e., indicative of no go trials) with reinforcement. The prerequisite for successful learning of go/no go tasks after hippocampal damage is that the cues are presented with a short inter-trial interval. Indeed, when rats with hippocampal damage have to manage the successive odor presentations with long inter-trial intervals (>15 s), the odor-reward association is not acquired [9,10]. These observations confirmed earlier findings in both rats and monkeys subjected to fornix or hippocampal lesions [12]. Surprisingly, there are only a few studies which aimed at identifying the brain regions involved in this type of hippocampus-independent learning [13]. One candidate structure is the striatum, the rodent equivalent of the caudate–putamen in primates. In rats, lesions of the striatum,
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Table 1 Coordinates and injection volumes for ibotenate lesions of the dorsolateral striatum or the dorsal hippocampus. Coordinates are given in mm anterior and lateral to Bregma (Paxinos and Watson, 1998) and from the skull surface in depth. Structure
Anteriority
Laterality
Depth
Volume (L)
Dorsolateral striatum
+0.5 +1.2
± 3.9 ± 3.6
−5.2 −5.2
0.4 0.4
Dorsal hippocampus
−2.6 −3.1 −3.0 −3.8 −3.8 −4.1 −4.1
± 1.0 ± 3.0 ± 1.4 ± 3.7 ± 2.6 ± 4.0 ± 2.5
−3.8 −2.8 −3.2; −2.4 −2.8 −3.0; −2.5 −3.2 −2.5
0.06 0.06 0.06 each 0.06 0.06 each 0.08 0.08
and more specifically of its dorsal regions, impair the acquisition or/and retrieval of several operant tasks that are not or only poorly affected by hippocampal lesions [2]. These include tasks based on avoidance responses [14–19], brightness discrimination [20], processing of visual cues in the Morris water maze [21,22], and visual/olfactory conditioning of emotional responses [23]. Our associative olfactory task [9] enables separate assessment of performance linked to procedural or declarative-like memory contributions. Using this task, a first experiment assessed performance after fiber-sparing lesions of the dorsolateral striatum. Given the outcome of this experiment (i.e., the impairment of procedural learning prevented acquisition of the hippocampusdependent declarative-like component of the task), we performed a complementary experiment in which the effects of dorsal hippocampus lesions were assessed according to exactly the same protocol. Following hippocampal lesions, we expected normal procedural learning but no acquisition of the hippocampus-dependent, declarative-like component of the task. Our results suggest a serial implication of the striatum and the hippocampus in cue-reward associations learning.
light–dark cycle (lights on at 7:00 am and off at 7:00 pm) in a room held at a constant temperature (22◦ ). After surgery and before testing, each animal was first handled (10 min) daily for three consecutive days. Then it was deprived of water 48 h before the beginning of training. During training of the following days, the rats were given water ad libitum for 30 min per day at 6:30 pm. European guidelines on procedures for animal experimentation were followed, and all efforts were made to minimize the animals’ suffering and to reduce the number of animals used while complying with statistical constraints. 2.2. Lesion surgeries All rats were anaesthetized with an intraperitoneal (ip) administration of pentobarbital (60 mg/kg, i.p.). Once anaesthetized, they were given an intramuscular injection of an antibiotic (Extencilline; 0.3 mL/kg) and were subsequently placed on a stereotaxic apparatus. Their scalp was opened longitudinally with a scalpel and little holes were drilled in the skull at locations where a needle had to be introduced into the brain to perform the ibotenate infusions. The ibotenate solution (5 g/L) was infused at the coordinates indicated in Table 1 at a speed of 0.25 L/min. After each infusion, the needle was left in place for 4 min before being slowly retracted. In the sham-operated rats, the needle was descended into the brain at each of the coordinates used for the lesion, but no infusion was performed. After surgery, the scalp was sutured and all rats were placed in a heated cage until complete recovery from anesthesia. Behavioral training was started 4 weeks after surgery. 2.3. Apparatus and training procedure
2. Material and methods 2.1. Animals Fifty two young adult Long-Evans rats (R. Janvier, France) weighing 250–275 g at the time of surgery were used. They were individually housed and kept on a 24 h
The olfactory training apparatus was a rectangular box made of wire mesh (30 cm × 30 cm × 50 cm). A conical odor port (1.5 cm in diameter, 0.5 cm above the floor) was drilled horizontally through a triangular wedge of Plexiglas, mounted in one corner of the cage. A circular (1 cm diameter) water port in the shape of a well was placed directly above the odor port. Responses to the odor presentation
Fig. 1. Representative photographs illustrating lesions following NeuN staining in the groups of SHAM (A, C, E) and lesioned (B, D, F) rats. B and D show typical examples of lesions in the dorsolateral striatum and in the dorsal hippocampus, respectively. Dashed lines indicate the limits of the damaged area. E and F indicate that rostral regions of the hippocampus were not damaged after lesions of the dorsal hippocampus (F) as compared to a sham-operated rat (E). Scale bars at the bottom right of photos B, D and F correspond to 1 M.
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Fig. 2. Schematic representation of the smallest (light gray) and largest (dark gray) extent of dorsal hippocampal (left) and dorsolateral striatal (right) lesions in the rats kept for statistical analyses. Numbers above the drawings indicate the distance (in mm) of each section from Bregma (according to Paxinos and Watson, 1998).
were monitored by a photoelectric circuit. Two flashlight bulbs which could be turned on and off, as the testing conditions required, were placed outside the cage, one on each side of the odor and water ports, 10 cm above the floor. Individual odors were delivered by forcing clean air (0.7 bars) through one of two 1 L Erlenmeyer flasks that contained 500 mL of water mixed with 0.2% of chemical odorants (jasmine vs. strawberry) from Sigma Inc. Non-odorized air, between each odor presentation, was delivered by sending air through a flask that contained only water. Odorized and clean air streams were passed individually through tubes that were put through the back of the sound-attenuating chamber and attached to the odor port. Water was delivered using a gravity-fed system, and passed through
a valve which, when opened, allowed 0.1 mL of water to be released into the water port. All experiments were conducted simultaneously in four olfactory cages to ensure that, in each experiment, representatives from each group were trained at the same time, and thus under identical conditions [10,24]. Animals were trained to make two odor-reward associations. Each odor had to be associated with a specific reward, one arbitrarily designated as positive and the other as negative. One session was made of 60 trials using a successive Go or No-Go paradigm. Individual trials (S+ or S− ) were run in a quasi-random fashion (no more than 3 consecutive trials with the same valence). When the odor (S+ ) was delivered into the cage, if rat
responded by going to the water port a reward of 0.l mL of water was obtained. The same response to delivery of the other odor (S− ) resulted in no water and activation of an error light. The maximum duration of odor presentation (S+ or S− ) was 10 s. Correct responses, therefore, corresponded to Go before the 10 s presentation for one odor had elapsed (S+ ) and No-Go to the other (S− ). Once responded or not to the odor presentation (the trial) a fixed inter-trial interval (ITI) of 15 seconds with clean air was started. If a response was given during the last second of the ITI, the next trial was delayed by 10 s and delayed by additional 10 s fractions as long as the rat was still present during the last second of each fraction in the corner where the reward is delivered. Consequently, the duration between two trials could last longer than 15 s and constituted the cumulative time to the minimum ITI. Animals were tested every day between 08:00 am and 02:00 pm. Then, all animals were trained to make associations with the odor pair for six sessions at a pace of one session per day.
A
90
PERCENTAGE OF CORRECT RESPONSES
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DL STRIATUM SHAM
60 50 40 30 0
3. Results 3.1. Histological analysis Typical examples of lesion extents and placements are shown in Fig. 1. Lesion extent and location are further illustrated in Fig. 2. Histological verifications showed that 6 rats which had received ibotenate into the dorsolateral striatum (DL STRIATUM; Experiment 1) and 7 rats which had received ibotenate into the dorsal hippocampus (D HIPP; Experiment 2) had lesions that were either partly misplaced (e.g., encroaching too much onto the dorsomedial striatum, being slightly too dorsal, or showing asymmetry) or of insufficient extent. These rats were withdrawn from statistical analyses. Consequently, rats with dorsal hippocampus lesions constituted a group of 9, those with dorsolateral striatum lesions a group of 10. The respective groups of sham-operated rats (SHAM) comprised 10 subjects. 3.2. Behavioral studies 3.2.1. Experiment 1: lesions of the dorsolateral striatum Analyses of the percentage of correct responses (Fig. 3A) showed that only rats of the SHAM group improved their overall
CUMULATIVE TIME (Sec.)
Correct responses were characterized as Go for the positive odor and No-Go for the negative one. Incorrect responses were Go for the negative odor and NoGo for the positive one. The number of correct responses for both positive and negative odors was expressed as a percentage of the total number of odor presentations (60 per session), thereby providing a global estimate of performance for all groups (global memory). Training continued until a criterion of 80 ± 5% correct responses was reached by the control groups. This level of performance is required to ensure that all animals have learned both associations. Latencies for positive (S+ ) and negative (S− ) odors were recorded and represented the time elapsed between the beginning of a trial and its end (10 s), when the rat responded to the odor (reference memory, which is presumed to correspond by some aspects to declarative memory in humans; [24]. When a rat did not respond, a latency of 10 s was scored. The median cumulative time (accounting for the efficiency of some aspects of procedural memory; [24]) was the number of seconds above the fixed 15 s ITI, divided by the number of ITIs, which in this experiment amounted to 59. All behavorial events were controlled and recorded by a computer. Statistical analyses were performed with SPSS/PC+ statistics 11.0 software marketed by SPSS, Inc. All data are presented as means ± SEM. Performance was analyzed using a repeated-measure MANOVA. Then, subsequent ANOVAs for each session were computed. The threshold for significance was set at p ≤ 0.05. (on graphs: *p ≤ 0.05; **p ≤ 0.01; p*** ≤ 0.001). Percentage of correct responses in comparison to chance level (50%) was analyzed using a one-sample t-test.
C LATENCY (Sec.)
2.5. Data analysis
B
* * *
* *
70
1
2.4. Histological verifications Upon termination of the behavioral experiments, all rats were deeply anesthetized with an overdose of pentobarbital (150 mg/kg i.p.). They were transcardially perfused with 60 mL of phosphate-buffered 4% paraformaldehyde (pH 7.4; 4 ◦ C) over 5 min. The brains were extracted, postfixed for 2 h in the same fixative (4 ◦ C), and transferred into a 0.1 M phosphate-buffered 20% sucrose solution for about 48 h (4 ◦ C). Brains were subsequently frozen in isopentane (−30 ◦ C) and 40 m-thick sections were cut in the coronal plane at 21 ◦ C using a freezing microtome and placed in phosphate buffer saline. NeuN-staining was performed using a mouse polyclonal antibody directed against NeuN (1/2000; Millipore, MAB377) as primary antibody and a horse anti-mouse biotinylated antibody (1/500; Vector, BA 2001) as secondary antibody.
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12 11 10 9 8 7 6 5 4 3 2 1 0
2
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*
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SHAM SSHAM S+ DL STRIATUM SDL STRIATUM S+
3 2 1 0
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SESSION (Day) Fig. 3. Mean performance (±SEM) obtained across the five sessions of 60 trials in control (SHAM) (N = 10), and bilaterally dorsolateral STRIATUM lesioned rats (DL STRIATUM) (N = 10). (A) Mean percentage of correct responses. The difference between the SHAM and DL STRIATUM groups was significant from the fourth session onward. (B) Mean cumulative time (in seconds). Significant statistical difference was observed between the two groups on session 5. (C) Mean latencies (in seconds), S+ are the latencies for the positive odor and S− the latencies for the negative odor one. Only the SHAM group started to make significant associations from session 4 onward.
performance across the five sessions (MANOVA, Group × Session interaction: [F(4,68) = 6.09; p < 0.001]; the overall Group effect was significant [F(1,17) = 9.18 p < 0.01]. Subsequent ANOVAs revealed a clear-cut difference between the two groups from the fourth session onwards [F(1,17) = 6.84 p < 0.01]. In the DL STRIATUM group, the percent correct responses was never different from chance level, whatever the session (t ≤ 1.10, NS). The cumulative time (Fig. 3B) decreased across sessions in the SHAM group, whereas the DL STRIATUM group performed at a constant level throughout all five training sessions. Consequently, a significant difference was observed between the performance of these two groups across the five successive sessions [F(1,17) = 10.79 p < 0.01]; the Group × Session interaction was
M. Jacquet et al. / Behavioural Brain Research 239 (2013) 94–103
CUMULATIVE TIME (sec.)
98
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20
S2
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15
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4 5 0
2 0
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*
*
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2
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BLOCK OF TRIALS Fig. 4. Mean cumulative time by block of 10 trials (±SEM) obtained during sessions S1–S5. Only the SHAM group showed a time that decreased over sessions, inversely to DL STRIATUM group. A significant difference was observed between SHAM and STRIATUM groups in session 5. See also legend to Fig. 3.
significant (F(4,68) = 6.02 p < 0.001), most probably because of the substantial inter-group difference found on session 5 [(ANOVA, F(1,17) = 5.52 p < 0.05]. Training performance analyzed in terms of S+ and S− latencies (Fig. 3C) showed a dramatic impairment in the DL STRIATUM group. Indeed, conversely to their SHAM counterparts, lesioned rats were unable to make correct associations on S+ and S− stimuli. In the SHAM group, correct associations were observed from the fourth session onwards [F(1,18) ≥ 15.39; p < 0.001]. The DL STRIATUM group also showed a slight gradual decrease in the time taken to respond to both stimuli across the five sessions. SHAM rats showed a continuous decrease in latencies of response to S+ stimuli throughout the training session while for S− stimuli a decrease was observed during session 2 and 3, but then the rats began to withhold their responses (and therefore, started to exhibit correct behavior). Consequently, a significant difference between the groups was observed on S+ [F(1,17) = 10.05; p < 0.01, but not across the five sessions [F(4.68) = 0.65; NS], and not on S− stimuli [F(1,17) = 0.26; NS], but with a significant difference across sessions [F(4,68) = 3.97; p < 0.01]. We additionally performed a detailed analysis considering performance in blocks of 10 trials within each of the 5 sessions (S1-S5; Fig. 4). From S1 to S3 a slight difference between groups was observed on cumulative time. This difference did not reach the level of significance. On S4, the difference was more pronounced, yet
not significant. On S5, however, the difference was dramatic and significant [F(1,17) ≥ 5.55; p ≤ 0.05]. Similarly, in terms of latencies (Fig. 5), a deficit between the two groups appeared on S4 and S5 (Fig. 5) and only the SHAM group made constant correct associations between S+ and S− latencies on all blocks on S4 and S5 [F(1,18) ≥ 4.62; p ≤ 0.05]; lesioned rats showed correct associations only during one single block (block3) on session 5, [F(1,16) = 4.73; p < 0.05]. 3.2.2. Experiment 2: lesions of the dorsal hippocampus The performance of SHAM rats improved across sessions, reaching a correct response score of 80 ± 5% on session 5. This improvement was not observed in D HIPP rats (Fig. 6A). MANOVAs indicated a group difference across the five sessions [F(1,17) = 11.2; p < 0.01] and even over sessions (group × session interaction, [F(4,68) = 28.42; p < 0.001]. Subsequent ANOVAs revealed that this difference appeared from the third session onwards [F(1,17) ≥ 5.64; p ≤ 0.05]. Only on session 5, D HIPP rats performed above chance level (t = 3.57; p < 0.01). The cumulative time decreased over the sessions [F(4,68) = 11.89; p < 0.001] but similarly [F(4,68) = 0.52; NS] in both groups (Fig. 6B), and there was no significant group effect [F(1,17) = 0.51; NS]. Training performance analyzed by S+ and S− latencies for the two groups is presented in Fig. 6C. While correct associations on
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S+ and S− stimuli started to be significant from the third session onwards in the SHAM group [F(1,18) ≥ 4.74 p ≤ 0.05], D HIPP rats responded to S+ or S− trials without discernment [F(1,16) ≤ 1.6; NS]. This difference came as well over the sessions from the S+ [F(4,68) = 14.87; p < 0.001] as the S− stimuli [F(4,68) = 11.89; p < 0.001] A more detailed analysis considered changes in cumulative time over blocks of 10 trials within each of the 5 sessions (S1–S5; Fig. 7). It showed that no scores, even during one single block, were significantly different between SHAM and D HIPP rats. Inversely, on latencies, a profound difference between the two groups appeared from the fourth session onwards (Fig. 8), where a significant odorreward association appeared from the first block of S4 in the SHAM group [F(1,18) ≥ 9.52 p ≤ 0.01]. In D HIPP rats, such an effect was never observed whatever the session [F(1,16) ≤ 1.5; NS]. 4. Discussion In this operant task, when a response is given during the last second of the ITI, the start of the next trial is delayed by 10 s, and additional 10 s delay are added as long as, on the last second of an ongoing delay, the rat is still present in the corner where the reward is delivered. Thus, the duration between two trials could last longer
than 15 s and constituted the cumulative time added to the 15 s of the fixed ITI time. A behavioral inhibition deficit, once the rats have learned that they can get the positive reward in the corner, should be followed by a substantial increase of the cumulative time in all sessions. In fact, such behavior is observed only during the first and the second sessions (Figs. 4 and 7) for both sham groups and hippocampal lesioned rats. Afterwards, one observes a significant decrease. On the contrary, the rats with lesions of the dorsolateral striatum did not increase or even decreased their cumulative time across sessions; they responded randomly during the last second of the ITI and occasionally delayed the next trial. Consequently, the mean of the cumulative time was constant throughout the sessions and did not seem to be related to an alteration of behavioral inhibition capacities. An alternative explanation could be that the lesions of the dorsolateral structure disrupted the timing ability, in agreement with the scalar timing theory developed by Meck and Church [25]. In fact, as demonstrated previously in this task [26], improved performance is observed despite altered timing ability. Indeed, the disruption of the ability to manage the timing as seen after lesions of the dorsomedial prefrontal cortex led rats to respond only when the olfactory cue was presented, thereby facilitating the odor-reward association due to the absence of extra time added to the fixed ITI. A third possibility would be that the dorsolateral striatum lesions
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disrupted the establishment of stimulus-response associations [13,27] or altered the habit-based memory system [28]. However, in agreement with these authors, dorsal striatum lesions marginally impair the initial learning of odor discrimination. Furthermore, before a deficit became apparent, the presentation of three successive discrimination problems was required. Compton [29] suggested that the dorsal striatum is necessary for the mediation of stimulus-response learning while the hippocampus is necessary to mediate expression of place learning (in their experiments); these processes can occur simultaneously and in parallel. In our current experiment, dorsolateral striatum lesioned rats were both impaired in cumulative time and in odor-reward associations, whereas hippocampal lesioned rats were able to withhold a response during the ITI but showed unable to make correct stimulus-response associations. To master the timing in this task a stimulus-elicited response is not required and the dorsolateral striatum rats were impaired by responding randomly during the
ITI. So, in addition to stimulus-response impairments, it seems that striatum lesioned rats did not figure out how to use the task to get only the positive reward and to get it rapidly. This deficit might be interpreted as consequent to an impairment of suppressing automatic responding. In rodents, lesions altering the medial part of the dorsal striatum usually impair goal-directed learning. Damage to the dorsolateral striatum is described as impacting habit learning (for a review, see [30]). Research on skill learning and cognitive control is often guided by a ‘multiple memory systems’ framework. This framework usually contrasts declarative memory, which provides flexible and explicite access to semantic and episodic content and requires conscious awareness, with memory for how to implement procedures (i.e., how to perform a sequence of actions). These procedures can become automatic and subconscious [31]. Based on the recent review by Liljeholm and O’Doherty [30], the impairments reported herein after lesions of the dorsolateral striatum could be the result of impaired procedure learning and consequently reflect a procedural memory dysfunction. Although several studies show a dissociation between the forms of memory related to the striatum (procedural) and those related to the hippocampus (declarative), there is also evidence pointing to the involvement of the caudate nucleus in declarative memory [32,33]. For instance, Ben Yakov and Dudai [34] performed fMRI experiments in humans in which they measured brain activity time-locked to the offset of short narrative audiovisual episodes. They found that a set of brain regions, most prominently the hippocampus and the caudate nucleus, both bilaterally exhibited memory-predictive activity that was time-locked to the stimulus offset. The hippocampus and caudate nucleus are involved in registering integrated episodes to memory as cohesive internal representations. It cannot be excluded that in our rats the lesions of the dorsolateral striatum disabled a similar process and thus prevented learning by affecting also the declarative-like component of the task. We would nevertheless privilege an alternative explanation. The fact that procedural memory deficits prevented the acquisition of the association, and thus a declarative-like item, could be questioned from a view considering encoding in the SPI system proposed by Tulving in humans [35]. This system places procedural memory at the lowest hierarchical level, semantic memory above, the highest level being that of episodic memory. From this functional hierarchy of encoding processes, it can be derived that, in tasks requiring a serial engagement of procedural and declarativelike memory processes, as seems to be the case for the task used in the current study, a deficit affecting the lowest system should have consequences on the efficiency of the higher one. This is one possible interpretation of our observations in rats with lesions of the dorsolateral striatum. In our study both the hippocampus and striatum were involved in learning and memorizing the meaning of each olfactory cue. It is thus possible, given the type of task which we used, that the dorsolateral striatum and the dorsal hippocampus had to contribute to task acquisition in a sequential order. First the dorsolateral striatum might have been required to master the procedural component of the task, mainly during the two first sessions. Then, the hippocampus might have taken over the acquisition of the odor-reward associations, and thus the declarative-like items. In other words, before being able to make correct associations engaging the hippocampus, rats had to learn the timing sequence of the task, for which the engagement of the dorsolateral striatum might be crucial. Indeed, learning to respond only when an olfactory cue is presented and not to respond during the inter-trial delay (when only a neutral air is on) required a tuned control of the locomotor neural system to engage into going or refrain from going (engage into No-Go behavior). Then, in a second phase, a choice has to be made in order to respond only to the positively-rewarded
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cue. When the striatum-dependent learning is prevented by striatal lesions, the acquisition of the hippocampus-dependent selection of the correct odor to engage in an appropriate response might become impossible. Previous results using this olfactory associative task showed that 5-HT4 receptors are substantially involved in the modulation of learning and memory processes [24]. Prior to the first training session, the injection of a selective 5-HT4 receptor antagonist (RS 67532) was followed by an increase in cumulative time, demonstrating that treated rats were more active at figuring out how to get the reward and delayed the upcoming trial by responding during the ITIs on the first session. This behavior allowed them to learn the protocol timing faster and consequently, once the procedural aspect of the task was acquired, treated rats started to make consistent cue–reward associations during the second session while control rats did not start until the third one. The injections of the partial agonist (RS 67333) prior to the first session had no significant effect, whether on the first or subsequent sessions, and only a learning deficit was observed. One interesting point, in this study, was that injections administered prior to the first or third training session gave rise to opposite effects. A facilitating effect on learning and memory was found on session 3 when RS 67333 had been injected prior to this session, and an opposite effect when the injection occurred prior to the first session. The same procedure with antagonist RS 67532 injections was followed by a learning and memory performance deficit on session 4 when the injection occurred before the third session, and a facilitatory effect on session 2 when it occurred before the first session. The opposite
effects obtained in these experiments with the partial agonist and antagonist can be related to the sub-categories of memory involved in this task. Decreasing the activation of the hippocampal system by the use of a 5-HT4 receptor antagonist at the onset of training facilitates procedural memory, and the inverse seems true for the partial agonist. By contrast, once the timing component of the task (procedural memory) has been learned (after the first two sessions), the injection of the partial agonist facilitates hippocampal processing and consequently improves memory for the associations (reference memory, related to declarative memory in humans); the opposite reasoning applies to the antagonist. As a whole, from these experiments, it seems that procedural learning comes first in this task and is crucial for acquiring subsequent declarative-like learning. When declarative-like and procedural memory processes are investigated in laboratory rodents, they are often considered as operating in dual and sometimes even competing memory systems. In rats trained for response learning in the cross-maze task, Packard and McGaugh [36] showed that the initial approach of the task engaged a hippocampus-dependent declarative-like memory system acquiring knowledge about place. Only over task repetition was there a gradual shift towards a striatum-dependent response memory system. Approaches and tasks such as the ones used by Packard and McGaugh posit the declarative-like memory as a prerequisite for response memory to be established over behavior repeats (see also [37,38]). In the test situation used in our current experiments, the cognitive operations required for task acquisition seem to occur according to an inverse schedule: only when
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the dorsolateral striatum-dependent component of the task is mastered can the declarative-like, hippocampus-dependent component of the task be learned and memorized, as demonstrated by the consequences of our permanent lesions. This, along with recently published data [37,38], is another example showing that systems driving declarative-like and procedural memories may cooperate for adapting goal-directed behaviors.
5. Conclusion The original contribution of our current study resides in the demonstration that, at least in the olfactory association task we used, the establishment of a procedural memory may be a prerequisite for that of a declarative-like one.
Acknowledgements We are grateful for the expert secretarial assistance of Valerie Demare.
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