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The Journal of Neuroscience, February 1, 2003, 23(3):1041
Selective Disruption of Stimulus-Reward Learning in Glutamate Receptor gria1 Knock-Out Mice
Andy N. Mead and David N. Stephens Laboratory of Experimental Psychology, University of Sussex, Brighton BN1 9QG, United Kingdom
ABSTRACT
TOP
ABSTRACT
Introduction
Glutamatergic neurotransmission via AMPA receptors has been an important focus of studies investigating neuronal plasticity. AMPA receptor glutamate receptor 1 (GluR1) subunits play a critical role in long-term potentiation (LTP). Because LTP is thought to be the cellular substrate for learning, we investigated whether mice lacking the GluR1 subunit [gria1 knock-outs (KO)] were capable of learning a simple cue-reward association, and whether such cues were able to influence motivated behavior. Both gria1 KO and wild-type mice learned to associate a light/tone stimulus with food delivery, as evidenced by their approaching the reward after presentation of the cue. During subsequent testing phases, gria1 KO mice also displayed normal approach to the cue in the absence of the reward (Pavlovian approach) and normal enhanced responding for the reward during cue presentations (Pavlovian to instrumental transfer). However, the cue did not act as a reward for learning a new behavior in the KO mice (conditioned reinforcement). This pattern of behavior is similar to that seen with lesions of the basolateral nucleus of the amygdala (BLA), and correspondingly, gria1 KO mice displayed impaired acquisition of responding under a second-order schedule. Thus, mice lacking the GluR1 receptor displayed a specific deficit in conditioned reward, suggesting that GluR1-containing AMPA receptors are important in the synaptic plasticity in the BLA that underlies conditioned reinforcement. Immunostaining for GluR2/3 subunits revealed changes in GluR2/3 expression in the gria1 KOs in the BLA but not the central nucleus of the amygdala (CA), consistent with the behavioral correlates of BLA but not CA function.
Key words: learning; Pavlovian association; conditioned reinforcement; second order conditioning; Pavlovian to instrumental transfer; Pavlovian approach; AMPA receptor; GluR-A subunit; GluR1 subunit; GluR2 subunit; amygdala
Introduction
The ability of environmental cues associated with rewarding events to influence or maintain behavior in the absence of the primary reward is important in many aspects of motivated behavior. Thus, cues associated with drug taking may play important roles in initiating drug craving or drug seeking in the abstaining addict, and treatments for drug abuse recommend removing the individual from environments associated with drug use (O'Brien et al., 1998
). Understanding the neural mechanisms underlying the response of organisms to reward-paired cues is thus of practical as well as theoretical interest.
In rodent models, stimuli paired with food have been shown to influence behavior in a number of different ways. First, cues conditioned to primary rewards are typically approached when presented (Pavlovian approach) (Tomie et al., 1999
Synaptic plasticity underlying the formation of Pavlovian conditioned associations depends on increased expression and/or redistribution of glutamatergic AMPA receptors (Lledo et al., 1998
Considerably less is understood about the functional significance of GluR1 subunits in the amygdala. GluR1 subunits are richly represented in amygdala nuclei, although the mechanisms of synaptic plasticity in the amygdala do not always resemble those in the hippocampus and may differ among different amygdala nuclei. In particular, different mechanisms underlie synaptic plasticity in the BLA and CA (Chapman and Chattarji, 2000
Therefore, we have examined the formation of a Pavlovian association, and its consequences for motivated behavior, in mice with targeted deletions of the gria1 gene; we also studied the extent to which such mutations affect the distribution of GluR2 subunits in amygdala nuclei.
Materials and Methods
Animals. gria1 Ko and wild-type (WT) littermates were bred at the University of Sussex from heterozygous parents obtained from P. H. Seeburg (MaxPlanck Institut für Molecular Biologie, Heidelberg, Germany) (Zamanillo et al., 1999
Pavlovian conditioning. Mice were food-restricted to ~85% of baseline body weight. During 16 hr sessions, mice were placed into mouse-operant chambers (MedAssociates, Georgia, VT) with the levers removed, and food was delivered at random intervals [mean, 2 min; variable interval (VI)120 sec schedule], preceded by the cue, which consisted of the illumination of two flashing lights (1 Hz) located above each lever, and the onset of a tone (2.9 kHz; 5 dB above background). The cue was presented for 10 sec, and the associated reward, consisting of 0.01 ml of 30% condensed milk solution, was presented for the final 5 sec of this period. Training consisted of 12 sessions, each of which was split into eight 1 hr training blocks with intervening 1 hr pauses. Infrared detectors across the entrance to the food magazine allowed the latency between cue onset and reward retrieval to be measured.
Pavlovian approach. To assess the ability of the cue to elicit conditioned approach, one of the lights was removed from the chamber, and infrared detectors were placed across the entrance to the remaining light, which was relocated beneath the tone source. During a 1 hr test session, the light cue was presented every 2 min for 60 sec, and nose-pokes toward the cue were recorded.
Conditioned reinforcement. To assess the ability of the cue to act as a conditioned reward, two levers were introduced into the operant chambers. Responding on one lever (CR lever) resulted in a brief 1 sec presentation of the cue (cue locations and conditions exactly as during Pavlovian conditioning phase), whereas responding on the alternative lever [nonconditioned reinforcement (NCR) lever] had no consequences. Responses on each lever were recorded during a 15 hr session.
Instrumental responding. A separate group of mice was trained to respond for 15% condensed milk solution on a fixed rate (FR)1 schedule. After acquisition, mice were tested on four additional concentrations of condensed milk for 3 d each. The order of testing was randomized, and all sessions lasted for 180 min.
PIT. To assess PIT, mice were retrained to respond for 30% condensed milk solution on a variable-interval 120 sec schedule, in which the activation of a lever led to the delivery of a reward at random intervals of 120 sec mean duration; the first lever press after the random interval had elapsed produced a reward. This provided a stable, low rate of responding from which to assess the effects of cue presentation. Both WT and KO mice responded at stable rates on this schedule, although the overall rate of responding was higher in KO mice. Subsequently, during a 60 min test session using the VI120 sec schedule, the cue was presented at 300 sec intervals for 60 sec (cue locations and conditions exactly as during the Pavlovian conditioning phase). The rate of responding was then compared during the presence of the cue [conditioned stimulus-positive (CS+)] and the absence of the cue (CS
).
Second-order operant responding. Mice were trained to perform an operant lever-pressing task to obtain 30% condensed milk solution. Initially, food was delivered for each lever press, and then for every 2nd, 4th, and 10th lever press. Each food delivery was preceded and accompanied by presentation of the cue (cue locations and conditions exactly as during the Pavlovian conditioning phase). At this point, the schedule was advanced to a second-order schedule in which every xth lever press resulted in the presentation of the cue (FRx:S); every 10th cue presentation was accompanied by food delivery, a so-called FR10(FRx:S) schedule. Initially, mice were tested on consecutive days with x increasing daily according to the schedule: 1, 2, 4, 8, 16, 32, and 64. Subsequently, x was reduced to 4, and mice were allowed up to 10 sessions to reach a criterion. Animals that succeeded in reaching a criterion of obtaining the first reward within 5 min on each schedule then progressed to an FR10(FR8:S) schedule, subsequently to an FR10(FR16:S) schedule, and finally an FR10(FR32:S) schedule, in which 320 lever presses were required to obtain a single food delivery.
Immunohistochemistry. For immunohistochemical analysis of GluR2/3, adult mice were anesthetized with Avertin (20 mg/kg) and transcardially perfused with 4% paraformaldehyde. Brains were removed and stored in 4% paraformaldehyde for 24 hr, before placement in 0.1 M phosphate buffer containing 30% sucrose for 48 hr. Brains were then frozen in isopentane at
Statistical analysis. Two measures were analyzed for Pavlovian conditioning. First, the latency between cue onset and reward retrieval was compared between genotypes; second, the percentage of total food magazine entries occurring during the CS presentation was compared. Two-way ANOVA was performed, with training session (within subjects) and genotype (between subjects) as factors. Post hoc analysis was performed using independent-samples t tests. For analysis of Pavlovian approach, nose-poke rates toward the CS were assessed during the CS (CS+) and compared with rates when the CS was not presented (CS
Response rates during the test for PIT were collapsed into 10 sec time bins, and the rates were compared for the 60 sec before and after the CS with the rates during the 60 sec CS presentation. Additional comparisons were performed using one-way ANOVA, with response rates during the 60 sec CS being compared with response rates during the 60 sec periods before and after the CS presentation. Responding on a second-order schedule was initially analyzed using the time to obtain the first reinforcer, and total reinforcers obtained, as the dependent variables. The cumulative percentage of mice reaching a criterion of obtaining the first reinforcer within 5 min was also examined for each session; however, because of the relatively low subject numbers (n = 7 and 6 for WT and gria1 KOs, respectively), nonparametric analysis on contingency tables was not performed on these data.
Analysis of GluR2/3 immunoreactivity was performed by counting the number of GluR2/3-positive soma within a 130 × 170 µm region of the BLA and CA. The regions selected are indicated in Figure 5C, and represent regions from within the basolateral amygdaloid nucleus and the central amygdaloid nucleus, respectively, as defined by Franklin and Paxinos (1997)
Results
Pavlovian conditioning
Figure 1A indicates that when trained to associate a tone/light cue with delivery of a food reward, by presenting the cue immediately before the randomly timed delivery of reward, both WT and KO mice learned the association between cue presentation and food delivery, as indicated by a reduction over the first six training sessions in the latency with which they approached the food source when the cue was presented (main effect of session; F(5,70) = 42.9; p < 0.01). Although KO mice appeared to acquire the association more rapidly, as evidenced by a decreased latency in session 1 (session × genotype interaction: F(5,70) = 9.38; p < 0.01; t test for session 1: t(14) = 2.88; p < 0.05), this may be attributable to the general tendency of KO mice to nose-poke at faster rates than WTs (data not shown, but see results from Pavlovian approach for similar effect). Analysis of the percentage of total nose-pokes into the food magazine during the CS presentation (Fig. 1B) also indicated acquisition of the CS-US association, with a main effect of session (F(5,70) = 104.8; p < 0.01). There was also a significant session × genotype interaction (F(5,70) = 5.41; p < 0.01), although post hoc tests for each session indicated no significant between-genotype differences.
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Figure 1. Pavlovian conditioning and Pavlovian approach in WT(+/+) and gria1 KO(
Pavlovian approach
That conditioning itself was unimpaired in the KOs was confirmed by the animal's normal approach to the cue when its source was relocated in the wall opposite the food magazine, within a recess whose entrance was fitted with infrared beams to detect head entries. Figure 1C shows that illumination of the cue light resulted in an increased approach to the cue (Pavlovian approach) in both WT and KO mice (main effect of CS presentation; F(1,14) = 8.76; p < 0.01). Rates of entry remained constant across the session (data not shown). Consistent with the heightened activity in gria1 KO mice (Vekovischeva et al., 2001
Conditioned reinforcement
Despite similarities in conditioning in the WT and gria1 KO mice, a clear difference was seen when levers were introduced into the cage and the mice were able to activate the cue by operating one of the levers. Figure 2A shows that WT mice performed a greater number of lever presses on the lever programmed to deliver the cue than on an alternative lever whose activation was not reinforced (t(7) = 8.69; p < 0.01), indicating that the cue had acquired conditioned rewarding properties as a result of being paired with the food primary reward. However, the gria1 KO mutants operated both levers at low rates, comparable with the rate at which the WT mice operated the ineffective lever (genotype × lever interaction: F(1,14) = 27.57; p < 0.01; t test for KOs: t(7) = 1.72; NS). This low rate was not attributable simply to impaired lever-pressing ability per se in the KO mice because in a separate experiment WT and KO mice responded on a lever at similar rates to obtain a food reward (Fig. 2B) (no main effect of genotype or concentration × genotype interaction).
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Figure 2. Ability of the cue to act as a conditioned reinforcer in WT(+/+) and gria1 KO(
PIT
Stimuli conditioned to primary rewards are also known for a third property, their ability to energize behavior directed toward obtaining the primary reward (PIT) (Dickinson, 1994
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Figure 3. PIT in WT(+/+) and gria1 KO(
Second-order operant responding
To test whether deletion of the gria1 gene impairs this behavior, we trained KO and WT mice to perform an operant lever-pressing task to obtain food on a second-order schedule. When tested on increasing second-order schedules on consecutive days, KO mice took longer to obtain the first reinforcer than WT controls (Fig. 4B) (main effect of genotype: F(1,9) = 5.70; p < 0.05) but showed no deficit in total reinforcers obtained in the 60 min session (Fig. 4A) (main effect of genotype: F(1,9) = 2.62; NS). Gria1 KO mice performed the operant response to obtain food at rates comparable with those seen for WT mice during initial training. However, when allowed up to 10 sessions to reach the criterion of obtaining the first reinforcer within 5 min, Figure 4C shows that they were less competent in acquiring responding on the second-order schedule, with only 50% of the mice reaching the criterion within five sessions when four responses were required for each cue presentation (FR4:S phase) and only 33% reaching the criterion when eight responses were required for each cue presentation (FR8:S phase).
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Figure 4. Responding under a second-order schedule of reinforcement in WT(+/+) and gria1 KO(
Immunohistochemistry
Figure 5A,B shows the distribution of staining for GluR2/3 protein in the hippocampus. Figure 5A illustrates the distribution of GluR2/3 immunostaining in a WT mouse; Figure 5B illustrates staining in the gria1 KO. In the WT mouse, there is only faint staining in the granule cell body layer of the CA1 region, but there is denser immunoreactivity in areas containing dendrites. In contrast, the gria1 KO mouse shows dense staining of GluR2/3 in the cell body layer but poor staining in non-cell body areas. These patterns suggest that in the absence of GluR1 subunits, GluR2/3 protein is not transported away from the cell body, so gria1 KOs may have deficits in AMPA receptors as a result of both the absence of GluR1 and the failure of GluR2/3 to be inserted into functional receptors.
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Figure 5. GluR2/3 immunoreactivity in WT(+/+) and gria1 KO(
In the BLA, the gria1 KOs showed more GluR2/3-containing cell bodies (Fig. 5E) than the WTs (Fig. 5D), although there were no similar changes in the CA (Fig. 5G,H). Quantification of GluR2/3-positive soma in the BLA and CA confirmed these observations (Figs. 5F,I) (region × genotype interaction: F(1,8) = 13.67; p < 0.01; t test on BLA staining; t(8) = 8.99; p < 0.01).
Discussion
In the present experiments, we demonstrate that targeted deletion of the gria1 gene encoding GluR1 subunits of AMPA receptors leads to a subtle deficit in Pavlovian appetitive conditioning. Although gria1 KO mice showed an unaltered ability to associate a tone/light cue with food delivery, the CS retained its ability to act as a conditional stimulus for approach to the food cup (Pavlovian conditioning), to elicit approach (Pavlovian approach), and to facilitate instrumental responding to obtain food reward (PIT); in contrast to their WT littermates, the KO mice did not learn a novel response to obtain presentations of the conditioned cue (conditioned reinforcement). Failure to learn to respond to obtain a cue previously paired with a primary reward might be attributable to the animal's failure to form an association between the two events or to a failure of the animal to attribute incentive properties to the cue. Because the KOs were unimpaired in other measures of Pavlovian association and in their ability to learn the same instrumental response to obtain a milk reward, their failure to perform for a conditioned reinforcer indicates that in these animals, the cue had not acquired reinforcing properties of its own. Thus, the deficit in responding for the cue (conditioned reinforcer) is attributable to the gria1 KO mice not having attributed affective properties to the cue.
This pattern of results, with deficits in conditioned reward but not in discriminated approach, Pavlovian approach, or PIT, is similar to that found in rats with excitotoxic lesions of the BLA (Everitt et al., 2000
In the BLA, AMPA receptors mediate fast EPSPs in response to the activation of glutamatergic inputs from both cortical and subcortical regions (Rainnie et al., 1991
In the absence of GluR2 subunits in most receptors, the high calcium permeability of AMPA receptors in synaptic contacts onto BLA interneurons may make such synapses especially sensitive to plastic modification. Tetanic stimulation of inputs to BLA inhibitory neurons results in increased synaptic efficacy, which is independent of NMDA receptor activation and is reflected in an increase in GABAergic inhibitory currents in pyramidal neurons (Mahanty and Sah, 1998
Current theories hold that the BLA functions to allow animals to use cues associated with primary reinforcers to assess the current motivational properties of the primary reinforcer and to use that representation to alter their behavioral response (Baxter and Murray, 2002
The gria1 KOs showed intact Pavlovian approach and PIT, behaviors that are disrupted by lesions of the CA (Gallagher et al., 1990
In the present experiments, evidence that gria1 deletion does indeed have different consequences for the function of BLA and CA is provided by immunostaining for GluR2/3 protein in the gria1 KOs. In the BLA, the gria1 KOs showed an increased number of GluR2/3-positive neuronal cell bodies, whereas there were no changes in the CA. It is very likely that the increases observed in the BLA are attributable to increased staining in interneurons, because GluR2 subunits in pyramidal cells are associated with dendritic processes rather than cell bodies (He et al., 1999
Our results have interesting implications for understanding the mechanisms underlying drug addiction and relapse to drug abuse. The BLA is thought to influence goal-directed instrumental behavior through its projections to the orbital prefrontal cortex and ventral striatum (Pitkanen, 2000
FOOTNOTES Received Sept. 3, 2002; revised Oct. 31, 2002; accepted Nov. 12, 2002.
This work was supported by funding from the United Kingdom Biotechnology and Biological Sciences Research Council. We thank Dr. S. Rulten and Dr. L. Mayne for genotyping and Prof. Peter Seeburg and Dr. Rolf Sprengel for donating gria1 breeding stock.
Correspondence should be addressed to Dr. David N. Stephens, Laboratory of Experimental Psychology, University of Sussex, Brighton BN1 9QG, UK. E-mail: dns{at}biols.susx.ac.uk.
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