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1 Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville 94608 2 Graduate Program in Neuroscience, University of California, San Francisco 94143 3 Departments of Neurology and Physiology, and Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, California 94143
Submitted 9 July 2003; accepted in final form 20 November 2003
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ABSTRACT |
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INTRODUCTION |
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) suggested that the NAc functions as a limbic-motor interface. The evidence in favor of this idea was that the NAc receives projections from limbic structures (basolateral amygdala, prefrontal cortex, hippocampus), and projects primarily to the ventral pallidum, a major output nucleus of the basal ganglia. In addition, midbrain dopamine neurons project to the NAc, and injections of dopamine agonists into the NAc increased locomotion (Mogenson et al. 1980). Later investigations led to several more specific theories regarding the precise role played by the NAc in behavior. Among these are that the NAc neurons (and particularly dopamine acting on these neurons) contribute to an assessment of the "incentive salience" of environmental cues (Berridge and Robinson 1998)—that is, NAc neurons determine the likelihood of a motor response to a cue based on the animal's motivational state and the predictive information of the cue. Another theory suggests that NAc neurons perform a cost/benefit computation (based on environmental information, the animal's motivational state, and the amount of work required to obtain a reward) that influences the animal's choice among different possible motor behaviors (Salamone and Correa 2002). Yet another theory proposes that the NAc is essential for mediating the influence of Pavlovian conditioned stimuli (which do not require specific action by the animal to obtain reward or avoid punishment) on the animal's instrumental or other motor behavior (Cardinal et al. 2002a).
Common to all of these proposals is the idea that the activity of NAc neurons encodes sensory information relevant to the potential consequences of different behaviors and that this activity promotes actions that will maximize reward. A number of experiments have provided specific support for this hypothesis. One example comes from the study of Pavlovian-instrumental transfer. In these experiments, an animal is first trained to associate a conditioned stimulus (CS) with a food reward. The animal is then trained to perform an instrumental action (lever press) to obtain the same reward in the absence of the CS. In the test session, the animal is allowed to press the lever under extinction conditions. Intermittent presentation of the CS during the test session potentiates responding on the lever (Dickinson and Dawson 1987; Lovibond 1983). Lesions of the NAc block the potentiation of responding by the CS (Corbit et al. 2001; de Borchgrave et al. 2002; Hall et al. 2001), and injection of amphetamine (a drug that increases extracellular dopamine) into the NAc enhances the CS-induced potentiation of responding (Wyvell and Berridge 2000, 2001), suggesting a critical role for NAc neurons in promoting behavior in response to goal-associated cues.
Another line of evidence that NAc neurons facilitate the behavioral response to reward-predictive cues comes from studies of conditioned reinforcement in which animals lever-press to obtain a cue that has previously been associated with reward (Robbins 1975). NAc amphetamine injections potentiate responding for the cue by a mechanism dependent on dopamine receptors (Wolterink et al. 1993). Furthermore, approach to a CS that predicts reward is reduced by manipulations that impair NAc function (reviewed in Cardinal et al. 2002a). Also, NAc lesions disrupt the processing of predictive cues, biasing the animal toward smaller rewards that require less effort (Cardinal et al. 2001). This effect is consistent with studies showing that an action of dopamine on NAc neurons increases the effort animals will put forth to obtain reward (Salamone and Correa 2002), possibly by modulating NAc neurons that process the cues that guide the animal to reward. Thus taken together, the available behavioral evidence points strongly toward a role for NAc neurons in promoting behavioral responses to cues that possess incentive value.
Despite the growing evidence that NAc neurons contribute to the motor response to incentive cues, relatively little is known about how they encode information about environmental cues. Recordings from the primate striatum (including the ventral striatum, which includes the NAc) have revealed excitations in response to cues that predict reward (Bowman et al. 1996; Cromwell and Schultz 2003; Hassani et al. 2001; Hollerman et al. 1998; Schultz et al. 1992; Shidara et al. 1998). These excitations depend strongly on the predictive value of the cue because the type of reward predicted (Hassani et al. 2001), the magnitude of the predicted reward (Cromwell and Schultz 2003; Hollerman et al. 1998), and the temporal proximity of the reward (Shidara et al. 1998) all affect the magnitude of excitation when the behavior required to obtain reward is held constant. In subpopulations of cue-responsive neurons, the magnitude of the excitation evoked by predictive cues is also correlated with the specific motor activity required to obtain the reward (Cromwell and Schultz 2003; Hassani et al. 2001; Hollerman et al. 1998).
Although recordings from primate striatum are consistent with the behavioral evidence that NAc neurons encode incentive cue information, it has been difficult to relate this information directly to the large body of behavioral pharmacology, which is primarily based on rodent experiments. Primate recordings are usually made in the striatum, although the rodent literature suggests quite different roles for the dorsal striatum and NAc in behavior (Parkinson et al. 2000a; Reading et al. 1991). In addition, in rodent behavioral tasks, animals are free to locomote, whereas, during recording experiments in primates, the monkey is immobilized and free only to make arm or eye movements. Because the NAc is an important regulator of locomotion (Mogenson et al. 1993; Tzschentke and Schmidt 2000), the difference between whole body locomotor and more restricted movements could be reflected in the firing patterns of NAc neurons.
The firing of NAc neurons in rats during drug self-administration has been extensively studied using simple operant tasks such as fixed ratio (Carelli 2000, 2002; Carelli and Deadwyler 1994, 1996a,b; Carelli and Ijames 2000, 2001; Carelli et al. 1993, 1999, 2000; Chang et al. 1998, 2000; Chang et al. 1996, 1997a,b; Janak et al. 1999; Lee et al. 1999; Nicola and Deadwyler 2000; Peoples and West 1996; Peoples et al. 1997, 1998a,b, 1999a,b; Uzwiak et al. 1997). These studies report brief excitations and inhibitions just before, during, and after operant responses as well as changes in firing that appear to correlate with the level of drug in the brain. In addition, several studies have found excitations and inhibitions just before and after operant responses for natural reward (Carelli and Ijames 2001; Carelli et al. 2000; Hollander et al. 2002; Roop et al. 2002), reporting firing patterns generally similar to those found during operant responding for drug reward. CS's associated with cocaine (Carelli 2000; Carelli and Ijames 2001), and stimuli that predict cocaine (Ghitza et al. 2003) can excite and inhibit NAc neurons. However, the firing changes of rat NAc neurons in response to stimuli that predict natural reward have not been reported.
In this study, we use a discriminative stimulus (DS) task to explore how NAc neurons encode predicted outcomes and the behavioral responses required to obtain the outcome. The DS is a sensory cue that directs the animal to perform an operant response (in this case, a nose-poke into a hole equipped with a photobeam) to obtain a sucrose reward. Because the same behavior can be elicited repeatedly by presentation of the cue, the task is well suited to the correlation of behavioral events with the activity of single units. In trained animals, DSs elicit robust reward-seeking and may be involved in cue-induced relapse to drug-seeking behavior (Berridge and Robinson 1998; Kantak et al. 2002; Weiss et al. 2000; Yun and Fields 2003). Furthermore, several studies have suggested a role for the NAc in DS-controlled responding. The human NAc is activated during DS-based tasks (Breiter et al. 2001; Knutson et al. 2001), dopamine is released in the NAc of rats after DS presentation (Bassareo and Di Chiara 1999; Weiss et al. 2000), and activation of NAc dopamine receptors is essential for animals to respond to DSs at least under some circumstances (Yun et al. 2004). Here, to more fully understand how NAc neurons contribute to cue-mediated behavioral responding, we characterize the cue-evoked and operant responses of NAc neurons as rats perform a DS task.
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METHODS |
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Male Long-Evans rats (Harlan or Charles River) were used in this study (n = 21). Animals (
350 g) were individually housed on a 12-h light/dark cycle, and experiments were performed during the light phase. After receipt, rats were allowed 
1 wk of ad lib food and water, followed by 1 wk of restricted food and water prior to training. Throughout all experiments, restriction was accomplished by allowing the animals 1 h of free access to food and water per day at the end of experimental manipulations. Animal handling and experiments conformed to National Institutes of Health and Ernest Gallo Clinic and Research Center animal care and use policies.
Apparatus
Animals were trained in custom-built Lucite operant chambers contained within light- and sound-insulated boxes. Chambers were 40.6 x 40.6 cm and were equipped, on one wall, with two nose-pokes (Med Associates) and a reward receptacle located between them. Liquid reward (50 µl of a 10% sucrose solution) was delivered by a dipper (Coulbourne Instruments) in most experiments; in some experiments, a syringe pump was used to deliver the solution into a small well inside the receptacle. Receptacles were equipped with photobeams to determine the times at which the animal's head entered and exited the receptacle. Operant chambers also contained two white houselights, a white-noise speaker, and a loudspeaker for delivering auditory stimuli (Med Associates). White noise (65 dB) was present throughout all experiments. Each box was equipped with a video camera and monitor to allow experimenters to observe animals inside the behavior chambers as they performed the task.
Training and behavioral task
The firing patterns described in this work were observed during a DS task. Animals progressed through several stages of training before undergoing surgical implantation of electrodes in the NAc and subsequent recording of neural activity. In the first stage, food-restricted animals were introduced to the chamber. Entry into the reward receptacle triggered delivery of the sucrose reward and dimming of houselights (by turning off 1 of the 2) for 20 s, during which subsequent entries had no effect. After animals learned to obtain all 100 available rewards in <1 h (usually this took only 1 or 2 days), animals were advanced to a fixed ratio (FR) task in which a single nose-poke in either of the two nose-poke holes resulted in reward delivery, accompanied by the 20-s dimmed houselights and time-out. After animals learned to obtain 100 rewards in <2 h (1–3 days), they were advanced to a cue-response task in which a compound cue (an intermittent tone and dimmed houselights) was presented every 60 s. In this task, the left or the right nose-poke was chosen to be the "active" nose-poke, and thereafter all rewards were contingent on responses in the active nose-poke during presentation of the cue. The tone was either 6 kHz (12 rats) or 4 kHz (9 rats). This and all other tones presented in this study were intermittent, cycling between a 200-ms tone-on pulse and a 550-ms tone-off period prior to the next tone-on; all tones were 85 dB. The tone/dimmed lights lasted for 
60 s, and a single nose-poke in the active nose-poke hole during cue presentation terminated the cue, caused the delivery of the sucrose reward, and triggered a 20-s conditioned stimulus (CS) consisting of continued dimmed houselights and an 8-kHz intermittent tone. Nose-pokes in the absence of the cue and during the CS were not rewarded. Animals were advanced to the DS task when they received >60 rewards in 2 h (2–3 days).
In the DS task (Fig. 1A), the cue that, in the previous stage of training, signaled contingent reward availability was presented for 20 s with an average frequency of once every 2 min (variable interval 2-min schedule). Actual intervals between DS presentation were randomly selected by the computer from the following list: 60, 90, 104, 112, 116, 118, 119, 119.5, 120, 120.5, 121, 122, 124, 128, 136, 150, and 180 s. A response on the active nose-poke during DS presentation terminated the DS and resulted in delivery of the sucrose reward in the receptacle, accompanied by a 20-s CS (8-kHz intermittent tone/dimmed houselights). In addition to the DS, a nonrewarded stimulus (NS) was presented on an independent variable interval 2-min schedule. The NS was always 20 s long and consisted of an intermittent tone of either 6 kHz (9 rats) or 4 kHz (12 rats); the frequency that was not used for the DS was chosen to be the NS for each rat. To prevent overlap, DSs and NSs whose onset times were scheduled to occur during the other cue (or CS) were delayed by 40 s. Nose-pokes during the NS or CS were not rewarded nor were nose-pokes at any time during the session other than during DS presentation. Nose-pokes in the inactive nose-poke hole were never rewarded. Animals were run once per day, 5 days/wk. Animals usually learned to respond to >90% of DSs within one week of training. However, surgery was often not performed for 2 or more weeks after the beginning of this training phase, during which animals were run every day (5 days/wk).
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Anesthesia was induced with ketamine/xylazine and maintained with either subsequent ketamine injections or isoflurane. One array consisting of eight 50-µm-diam Teflon-insulated wires (NB Labs, Denison, TX) was chronically implanted into the NAc of each hemisphere as previously described (Nicola and Deadwyler 2000). Target coordinates (Paxinos and Watson 1998) were (in mm) AP, +1.0 to +2.5; ML, ±0.5 to ±1.5; DV, –6.5 to 8. Electrodes were fixed to the skull with acrylic dental cement secured with stainless steel bone screws. A silver wire implanted into the cortex caudal to the NAc was used as a ground electrode, and a miniature connector wired to the electrodes was exposed at the top of the implant. Animals were allowed to recover for one week prior to beginning experiments.
Electrophysiology
Prior to each session, a headstage containing unity gain field-effect transistors (NB Labs) was connected to the animal's implanted electrodes. A cable transmitted the voltage signals to a multichannel commutator (NB Labs) that allowed the rat free movement within the behavioral chamber. The signals were then amplified and spikes were sorted with a Multiunit Acquisition Processor (Plexon). To reduce noise, the signal from a reference electrode (without identifiable spike waveforms) was usually subtracted from each individual wire's signal. Templates of waveforms that appeared to be action potentials were computed by averaging together waveforms selected by the experimenter, and spikes recorded during the experiment were matched to these templates by the computer. All waveforms that exceeded an amplitude threshold were saved to disk for later analysis whether they were assigned to a template or not. Templates were adjusted by the experimenter prior to each recording session to capture waveforms that changed amplitude or shape from the previous session. After each session, spikes on each wire were re-sorted to eliminate noise and to capture waveforms not previously assigned to the appropriate template. Waveforms <75 µV peak to peak were rejected; typical noise levels were 25–50 µV. In many cases, more than one waveform shape, corresponding to more than one unit, could be isolated on a single wire. In most instances, the shapes of these waveforms could be clearly separated. When there was overlap, waveforms that could not be definitively assigned to one unit were rejected from the analysis. When spike re-sorting was complete, autocorrelograms were constructed for each unit; units without well-defined refractory periods were either rejected or re-sorted. Crosscorrelograms were constructed for units on the same wire. If two units exhibited a common refractory period, the waveforms were re-sorted again or combined if the waveforms could not be definitively distinguished.
Data analysis
Each unit was assigned, based on its firing pattern, to at least one of the subsets of neurons exhibiting the response types described in Table 1. To do this, units were first prescreened with a series of paired t-tests that compared the baseline (precue) firing rate with the firing rate during each event (DS, NS, nose-poke, receptacle entry, receptacle exit). Table 1 shows the peri-event windows from which the event-associated firing was obtained. The data used for each paired t-test was the set of all instances of the event in question (e.g., nose-pokes). A low stringency significance level (P < 0.05) was deliberately chosen so that units with peak firing changes that occurred slightly outside the time ranges shown in Table 1 would be included. Next, peri-event histograms (PEHs) from all the prescreened units with significant firing changes were examined and scored independently by two investigators as either exhibiting or not exhibiting the response type in question. If both investigators agreed that the unit exhibited the firing pattern, it was classified as such; if one or both scored the unit as not exhibiting the firing pattern, it was classified as nonphasic with respect to the event in question.
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For Table 2 (which shows the proportion of neurons showing each response type), we limited the neuronal population to that obtained from the first recording session from each animal. For Table 3 (which shows the proportion of neurons exhibiting a given response type that also exhibited any other response type), we found the first session during which the response type listed in the first column (response type 1) was observed to arise from an electrode. This may or may not have been on the animal's first recording day. This was repeated for each electrode in each rat. We then asked whether, during the recording session, the neuron exhibited any of the other response types (response type 2), and in Table 3 we expressed the number of neurons displaying both response types 1 and 2 as the percentage of neurons with response type 1. For any electrode, this analysis uses only the first recording session during which response type 1 was observed to arise from a neuron on the electrode; subsequent recording sessions were not analyzed.
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) also uses data from the experiments described in this paper, but examines firing related to other task events than those described in detail here. Histology
After completion of experiments, electrode positions were marked and the animals were perfused. Histology methods and results are reported in the companion paper (Nicola et al. 2004).
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RESULTS |
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Electrophysiological recordings were taken from 21 rats that were fully trained on the DS task. In this task, a DS was presented to the animals at random intervals (mean: 2 min); performing a nose-poke response during the DS resulted in delivery of a 10% sucrose solution into a reward receptacle located next to the nose-poke hole. In addition to a DS, an NS was also randomly presented; responding to the NS was not rewarded (Fig. 1A). Typical performance on the DS task is shown in Fig. 1B. General behavioral performance was monitored by the experimenters with a video camera, and animals were observed to performed the task without superstitious learning effects. Specifically, rats responded on the active nose-poke at short latency after onset of the DS without performing other behaviors such as responding in the inactive nose-poke or checking the reward receptacle before making the nose-poke. Animals usually made a number of uncued responses (in the absence of DS, NS, and CS) in the active and, less frequently, inactive nose-poke holes. Averaged across 184 sessions, the rate of uncued responses in the active nose-poke was 0.0061 ± 0.0005 (SE) Hz, whereas the uncued response rate in the inactive nose-poke was one-tenth as fast (0.00056 ± 0.00013 Hz). These rates were significantly different (t183 = 11.3, P < 0.001), indicating that animals differentiated between inactive and active nose-poke holes in the absence of explicitly presented cues. The animals' responding was under control of the DS because the average latency to respond (2.9 s) corresponds to an instantaneous response rate of 0.35 Hz; because this is much larger than the uncued response rate in the active nose-poke (0.006 Hz), the rate of uncued responding cannot account for the high DS response ratio or the low latency to respond to the DS.
Animals responded to >90% of DS presentations (DS response ratio) while responding to only half of NS presentations, a difference that was highly significant (t183 = 25.9, P < 0.001; Fig. 1C). In addition, the latency to respond to the NS was significantly higher than the DS response latency (t182 = 11.7, P < 0.001; Fig. 1D). Therefore animals clearly differentiated between the DS and NS. The response ratio for the NS was higher than would be expected given that responding to the NS did not result in reward delivery. In our hands, rats are capable of differentiating between two dissimilar cues such that response ratios are >90% for rewarded DSs and <20% for NSs (Nicola, unpublished observations), consistent with previous studies (e.g., Robbins et al. 1990). The 49% NS response ratio is therefore likely a result of generalization between the DS and NS (Hull 1943; Tarpy 1982), which were physically very similar (both were compound stimuli, with intermittent tones of slightly different frequency and dimmed houselights). The DS can be thought of as a cue that is more reward-predictive than the NS, and this is reflected in the animals' behavioral performance. Thus the high NS response ratio allowed us to compare the firing rate of NAc neurons to cues that differed in their reward-predictive value when the behavioral responses to the cues were similar.
Neurons
A total of 211 behavioral sessions were used to obtain electrophysiological recordings during the DS task; of these, 27 were the "random withholding" sessions described in the companion paper (Nicola et al. 2004). Neurons were classified according to whether there was an increase or decrease in the neuron's firing in the peri-event windows listed in Table 1, relative to the precue baseline. Subpopulations of NAc neurons responded phasically to each obvious component of the DS task (Table 2): cue presentation, operant response, entry into the reward receptacle, reward consumption, and exit from the receptacle. The proportion of neurons exhibiting each response type is shown in Table 2. To avoid the complication that the same or different neurons can be recorded on an individual microwire electrode across several sessions (see METHODS), we used only the first recording session from each animal to construct Table 2. Of the 217 neurons recorded, 105 (48.4%) exhibited at least one response type. Many neurons were phasic with respect to more than one event; the proportion of neurons displaying each response type that also displayed the other response types is shown in Table 3. Only the first session during which each response type was recorded on an electrode was used to construct Table 3. This prevents neurons recorded subsequently on the same wire (which may or may not have been the same neurons as those recorded initially) from affecting the calculated proportions. In this paper, we examine the first eight response types: phasic firing in response to one or both of the cues, and phasic firing in relation to the operant response. The remaining cell types are examined in the companion paper (Nicola et al. 2004).
Interestingly, in neurons with more than one type of phasic response, certain combinations occurred at greater than chance levels. For example, 53.5% of neurons with incentive cue excitations were also inhibited during reward consumption ("sustained receptacle inhibition" in Table 3), and 39.1% of operant-excited neurons exhibited this inhibition as well. The overall proportion of neurons showing this type of inhibition was estimated to be 18.9% (Table 2), significantly lower than the proportion in incentive-cue-excited neurons (
2 = 21.3, P < 0.001) and in operant-excited neurons (2 = 10.7, P < 0.002). Similarly, proportionally more incentive-cue-inhibited neurons exhibited excitation during reward consumption ("sustained receptacle excitation") than did neurons in the overall population (20.0 vs. 2.8%; 2 = 16.3, P < 0.001); also, more operant-inhibited neurons displayed sustained receptacle excitation than did neurons overall (9.0 vs. 2.8%; 2 = 4.6, P < 0.04). Thus there is an enriched representation of phasic firing during reward consumption in neurons active during reward-seeking behavior. These examples of overrepresentation support the validity of our system of waveform sorting. The clustering of specific firing patterns in single neurons is unlikely to be explained by the systematic misclassification of the waveforms from two or more neurons (with potentially different firing patterns) as a single neuron because such an error should result in combinations of different response types that reflect their overall proportions.
Incentive cue excitations
Six different firing responses to cue presentation were observed. Figure 2 shows four examples of the first of these (incentive cue excitations), each recorded from a different rat. The firing response of these neurons was much greater to the DS (Fig. 2, A1–D1) than to the NS (A2–D2), was often sustained throughout the interval between DS and nose-poke response and usually continued until the animal received the reward (Figs. 2, A1, C1, and D1, and 3, A and B). A smaller proportion of these neurons (the 44.2% that were not also classified as operant excited; see Table 3) exhibited firing increases that lasted for several seconds after DS presentation but were reduced just before the nose-poke (Fig. 2B1). The majority (53.5%) of incentive-cue-excited neurons were inhibited while the animal was in the reward receptacle (Table 3). These inhibitions can be clearly seen in the examples in Fig. 3, which show rasters and histograms time-locked to DS onset and receptacle entry.
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The difference in DS- and NS-evoked excitation may have been due to the difference in latency to respond to the cues because animals were slower to respond to the NS than to the DS (Fig. 1D). However, the average excitation in response to the cues did not depend on response latencies. Figure 4F shows the excitation from 0 to 1 s after each cue for nose-poke response latencies in 1-s bins between 0 and 4 s. In this analysis, only the 25 incentive-cue-excited neurons that were recorded during sessions with at least one behavioral response to both DS and NS in each latency range were included. Two-way within-subjects ANOVA on the firing rate increases of the 25 neurons showed an overall effect of the cue [F(1,24) = 5.2, P < 0.04] but no effect of latency [F(3,72) = 0.5, P > 0.6] and no interaction between cue and latency [F(3,72) = 0.2, P > 0.8; post hoc tests were not done because of the lack of latency effects]. Therefore the firing response of incentive-cue-excited neurons was not affected by latency in the range 0–4 s but was significantly smaller across these latencies for the NS in comparison with the DS. Thus incentive cue excitation encodes information about the cue (the response is greater to the more reward-predictive cue than the less-predictive cue, even if the motor response is equivalent) and is correlated with the animal's motor response (the firing response is greater when the animal subsequently makes an operant response to the cue than when the animal does not respond).
Transient incentive cue excitations
In contrast to neurons with sustained excitations in response to the DS, some neurons exhibited brief DS-evoked excitations lasting no more than 0.5 s (Fig. 5, A1 and B). The excitation clearly did not extend until the nose-poke because firing was not increased prior to the response (P < 0.001 for overall ANOVA, P < 0.05 for SNK comparison of the post-DS firing increase vs. the preresponse increase; n = 19; Fig. 5, D and E). Furthermore, unlike the sustained incentive cue excitations that were sensitive to the information contained by the cue, firing did not differ in response to DSs and NSs (P > 0.05, SNK; Fig. 5, B, C, and E; only DSs and NSs followed by nose-pokes were used for analysis). Because few of these neurons were recorded during sessions in which animals failed to respond to at least some DSs, it was not possible to determine whether the DS-evoked excitation was different if the animal did not make an operant response. The similar response to the DS and NS, however, indicates that these neurons may encode only the information that a prominent sensory stimulus has begun, but not its predictive value.
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Incentive-cue-inhibited neurons were similar to incentive-cue-excited neurons in most respects except for the sign of the firing change. First, similar proportions of all neurons were classified as each cell type (5.1% were incentive cue excited and 2.8% were incentive-cue-inhibited; Table 2). Second, the inhibitions usually lasted for several seconds, often continuing throughout the operant response and even reward consumption (Fig. 6, A1 and B1). This is reflected in the large proportion of incentive-cue-inhibited neurons that were also classified as operant inhibited (62.5%). Third, the NS-evoked inhibition was less than the DS-evoked inhibition (Fig. 6, A2 and B2); only 37.5% of incentive-cue-inhibited neurons were also classified as NS inhibited. Fourth, as for incentive-cue-excited neurons, the difference in the firing response to DS and NS cannot simply be attributed to the fact that the animal responded less to the NS (Fig. 7). In the 31 incentive-cue-inhibited neurons that were present in sessions in which the animal failed to respond to at least one DS and responded to at least one NS, the median DS-evoked inhibition was smaller when the animal did not respond to the cue (ANOVA P < 0.005, P < 0.05 for SNK; Fig. 7, A, C, and E). There was no significant difference in the inhibition evoked by NSs to which the animal responded and did not respond (Fig. 7, B, D, and E); however, inhibition evoked by NSs with behavioral responses was very small (median: 0.28 Hz), which would make it difficult to observe any significant reduction in this inhibition. Indeed, the inhibition evoked by NSs with behavioral responses was significantly smaller than the inhibition evoked by DSs with responses (Fig. 7, A, B, and E). These results suggest that, similar to incentive-cue-excited neurons, the inhibition in response to the DS was greater than in response to the NS, especially when the animal responded to the cues.
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Excitations and inhibitions in response to the NS
As shown in Table 2, we found analogs of incentive-cue-excited, transient incentive-cue-excited, and incentive-cue-inhibited neurons that showed these firing patterns in response to the NS. However, it is unlikely that the NS-evoked firing patterns represent distinct populations of neurons from those exhibiting DS-evoked firing patterns. This is because the majority of NS responses occurred in neurons that also responded to the DS. Specifically, 75% of NS-excited neurons were also incentive cue excited (either transient or sustained), 71% of NS transiently excited neurons also had transient or sustained incentive cue-excitations, and 56% of NS-inhibited neurons were inhibited by the DS as well. The number of NS-responsive neurons that remained after excluding DS-responsive neurons was too small (n = 7 for NS excitation, n = 5 for transient NS excitation, and n = 12 for NS inhibition) to perform the same analyses that were done for the incentive cue-responsive neurons. Therefore although very small subpopulations of cue-responsive neurons may have larger responses to the NS than to the DS, the data support the hypothesis that NAc neuronal responses that preferentially encode reward-predictive cues are represented with much greater frequency than responses that preferentially encode less predictive stimuli.
Operant excitations
Operant excitations were defined by a significant increase in firing either just before or surrounding the DS-evoked nose-poke response (Table 1). Many incentive-cue-excited neurons were also classified as operant excited (56%) because incentive cue excitations tended to last throughout the nose-poke response. Representative examples of operant-excited neurons are shown in Fig. 8, demonstrating the tight coupling between nose-poke response and the peak of the excitation. These examples also show substantial inhibition during reward consumption (that is, after reward receptacle entry), an attribute shared by 39% of operant-excited neurons.
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The substantial overlap between incentive-cue- and operant-excited subpopulations raises the question of how different is the information encoded by these two firing patterns. To address this issue, we first divided neurons with incentive cue excitations and operant excitations into three nonoverlapping classes: neurons with incentive cue excitations only (IC+; example shown in Fig. 2B; n = 21), those with both incentive cue and operant excitations (IC+Op+; Fig. 2, A, C, and D; n = 27), and those with operant excitations only (Op+; Fig. 8, A and B; n = 48). We then asked whether the operant-related firing of these neurons was affected by the cue being presented when the animal responded: DS, NS, or none. The latter category was comprised of nose-pokes made in the absence of stimuli; these were present in almost every session and were not rewarded. Often, animals made a series of such nose-pokes in rapid succession; therefore to avoid including data from overlapping time windows, uncued nose-pokes that followed a previous uncued nose-poke by <10 s were excluded from the analysis. In addition, neurons that were recorded only in sessions in which animals failed to make uncued nose-pokes or to respond to the NS were excluded.
The operant-related firing of IC+Op+ neurons was greater in the presence of the cue, but the firing of IC+ and Op+ neurons was not. The excitation of IC+ neurons in the 0.5 s just prior to the nose-poke was not significantly different for nose-pokes elicited by the DS than for nose-pokes elicited by the NS or uncued nose-pokes (P > 0.1 for ANOVA, n = 19; Fig. 9, A and D). The baseline firing rate also did not differ (P > 0.1). In contrast, the operant-related firing of IC+Op+ neurons was greatest for the nose-pokes during the DS, smaller for nose-pokes during the NS, and smallest for uncued nose-pokes (P < 0.001, P < 0.05 for SNKs, n = 26; Fig. 9, B and D). The baseline firing rates also differed slightly but significantly under the three conditions (median: 3.7 Hz for uncued, 3.9 Hz for NS, and 4.1 Hz for DS; P < 0.02 for ANOVA, with all rates significantly different by SNK test). However, these differences are small and unlikely to account for the differences in operant-associated firing. In contrast to the differences in operant firing in IC+Op+ neurons, Op+ cells exhibited the same degree of excitation no matter whether the nose-poke was a response to the DS, NS, or uncued (P > 0.06, n = 45; Fig. 9, C and D), as suggested by the examples shown in Fig. 8. Baseline firing rates did not differ (P > 0.1). Therefore IC+Op+ differ from IC+ and Op+ neurons in that their operant-related firing depends on whether the nose-poke is a response to a cue and whether the cue is reward-predictive. One reason why differences in the operant-related firing of IC+ neurons were not obviously greater than differences in baseline rate may be that IC+ neurons by definition do not have large operant-related responses. In contrast, Op+ neurons are defined by their operant excitation. These results suggest that Op+ neurons encode information about the subsequent or ongoing behavior but not about the predictive information contained by the preceding sensory cue, whereas IC+Op+ neurons encode predictive information immediately after cue presentation and continue to encode this information at least until the animal makes the operant response.
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The fact that many incentive-cue-excited neurons also show operant excitation (IC+Op+) raises the question of whether DS-evoked excitation is sustained at the same level throughout the DS-nose-poke interval or if, instead, transient changes occur just before the nose-poke or just before reward receptacle entry. To answer this question, we first constructed PEHs for IC+, IC+Op+, and Op+ neurons, aligned with each of three different events: the DS (only DSs followed by a nose-poke response were used), the nose-poke response to the DS, and the reward receptacle entry after a successful nose-poke response to the DS (Fig. 10). The histogram bars are median firing rate across all neurons in the class. Particularly for IC+Op+ neurons, two peaks are present: one immediately after the DS (Fig. 10D) and another immediately prior to the nose-poke response (Fig. 10E). For IC+ neurons, the operant-associated peak is somewhat more diffuse than the DS-evoked peak (Fig. 10, A and B).
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0.5 s prior to the nose-poke response, whereas the time course of the IC+Op+ peak prior to the nose-poke was much slower (Fig. 11B) and IC+ neurons showed no excitation tightly coupled to the operant response (Fig. 11B). These results indicate that the firing of IC+ neurons remains elevated at a low constant level until just before the nose-poke. They also support the idea that IC+Op+ neurons may have a second peak (operant excitation) just prior to the nose-poke.
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1–1.5 s before the response, no matter whether the DS was presented a short (e.g., <2 s) or long time (>6 s) before the operant response. Accordingly, when the firing of these neurons was aligned to the DS onset, the excitation was delayed until just before the nose-poke response (Fig. 12C, left). Substantially different results were obtained with IC+ neurons (Fig. 12A). For these neurons, the firing rate was increased immediately after the DS and remained significantly increased until the nose-poke for DS-nose-poke latencies that were <2 and 2–4 s (Fig. 12A, left). At longer latencies (4–6 and >6 s), IC+ neurons were not significantly excited above baseline at any time point. At short latencies, the excitation remained significant and pronounced until the operant response (Fig. 12A, right). The excitation of IC+ neurons is therefore tightly locked to the DS and is sustained throughout DS-nose-poke latencies <4 s. These results differ from Op+ neurons in that Op+ firing is not tightly coupled to DS onset and is not sustained throughout the DS-nose-poke intervals of any length.
IC+Op+ neurons exhibited time courses of excitation that appeared to be hybrid between IC+ and Op+ neurons (Fig. 12B). Like IC+ neurons, these neurons were almost always significantly excited immediately after DS presentation (Fig. 12B, left), but the excitation was clearly smaller at longer (>4 s) than shorter latencies (<4 s). The smaller excitation at longer latencies can be seen in the examples in Fig. 2, C1 and D1. Also like IC+ neurons, the excitation of IC+Op+ neurons remained sustained throughout DS-nose-poke intervals <4 s, until the animal performed the nose-poke (Fig. 12B, right). However, unlike IC+ neurons and like Op+ neurons, at longer latencies (>4 s), IC+Op+ neurons exhibited a rapid increase in excitation beginning 1–2 s before the nose-poke (Fig. 12B, right) which was significant for the longest latencies (>6 s). Therefore at shorter DS-nose-poke latencies, IC+Op+ neurons exhibit the properties of IC+ neurons, whereas at longer latencies, IC+Op+ neurons exhibit the properties of Op+ neurons.
In summary, the excitation of Op+ neurons is tightly coupled to the operant response, whereas IC+ and IC+Op+ neurons show abrupt increases in firing time-locked to DS onset that are sustained throughout DS-response intervals that are <4 s. IC+Op+ neurons also show excitation time-locked to the operant response when the DS-nose-poke latency is >4 s. Therefore the operant-associated firing peak of IC+ and IC+Op+ neurons in the histograms in Figs. 10B and 9E (which included all DS-nose-poke latencies) can be explained by two factors. For IC+ neurons, the peak is due only to the sustained firing at shorter latencies. For IC+Op+ neurons, the peak is due to both sustained firing between the DS and nose-poke at shorter latencies, and a prominent, independent operant-associated peak at longer latencies. In contrast, the time course of Op+ neuron firing is independent of the DS-nose-poke latency. The excitation always begins 1–2 s before the operant response, whether the latency is long or short. This means that the apparent DS-evoked peak in Op+ neuron firing (Fig. 10G) is not a true DS-evoked peak but rather a consequence of many excitations tightly time-locked to the operant response, which occurs at variable times after DS presentation.
According to Fig. 4F, the incentive cue excitation is not dependent on the behavioral response latency. Although this result appears to conflict with the data shown in Fig. 12, A and B, showing that sustained excitation is less pronounced at longer latencies, Fig. 12 shows a greater range of latencies and time points. In Fig. 4F, only latencies in the range 0–4 s were considered, and the firing rate only in the 1 s after the DS was analyzed. Comparison of the firing rates in Fig. 12, A and B, for the <2- and 2- to 4-s latency ranges reveals that the excitation in the 0- to 0.5-s and 0.5- to 1-s bins after the DS was similar for the two latency ranges, consistent with Fig. 4F. Therefore the firing of IC+ and IC+Op+ neurons does depend on latency in that the sustained excitation during latencies >4 s is smaller or less consistent than during latencies <4 s; however, as shown in Fig. 4F, the excitation is invariant across a range of latencies <4 s.
Although all three neuron classes (IC+, IC+Op+, Op+) exhibited increased firing prior to the operant response, firing was not reduced to baseline levels until after the animal's entry into the reward receptacle (Figs. 10, C, F, and I, and 11C). Therefore in the majority of cases (when the DS-nose-poke latency was <4 s), incentive-cue-excited neurons maintain an elevated firing rate from 200 ms after DS onset until entry into the reward receptacle. In contrast, operant-excited neurons exhibit rapidly increasing excitation that is independent of the time at which the DS occurs, beginning 1.5 s prior to the operant response and lasting until receptacle entry.
Operant inhibitions
Operant inhibitions were defined by significant inhibition between the nose-poke and entry into the reward receptacle (Table 1). Similar to the overlap of incentive-cue- and operant-excited neurons, many incentive-cue-inhibited neurons were also classified as operant inhibited (62.5%) because incentive cue inhibitions tended to last at least until and often beyond the nose-poke response (Table 3). Representative examples of operant inhibitions are shown in Fig. 13. These examples show that the inhibition typically began just before the nose-poke response and lasted at least until the receptacle entry. Many (32.0%) operant-inhibited neurons were also inhibited during reward consumption (e.g., Fig. 13B1), significantly more than would be expected from the overall proportion of reward inhibitions (18.9%; 2 = 5.9, P < 0.02).
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To determine whether the operant inhibitions and incentive cue inhibitions were affected by the cue being presented, we first divided neurons with these firing patterns into three nonoverlapping classes for analysis: incentive cue inhibited only (IC–, n = 18), incentive cue inhibited and operant inhibited (IC–Op–, n = 29), and operant inhibited only (Op–, n = 87). For IC– neurons, the operant-related inhibition (from the nose-poke to 0.5 s after the nose-poke) was very small (median: 0.37 Hz after the DS), and therefore, not surprisingly, there were no significant differences in the degree of this inhibition when the nose-poke was a response to the DS or to the NS or was uncued (P > 0.2, n = 17; Fig. 14, A and D). Although the baseline firing rates shown in Fig. 14A appear to differ, in fact they were not significantly different (P > 0.25). For IC–Op– neurons, the operant inhibition was greatest if the response was made to the DS, intermediate if the response was to the NS, and smallest when it was uncued (P < 0.003 for ANOVA, P < 0.05 for SNKs, n = 28; Fig. 14, B and D). Baseline firing rates did not differ (P > 0.25). For Op– neurons, the operant inhibition was greater if the nose-poke response was made to the DS than to the NS or if the response was uncued (P < 0.02 for ANOVA, P < 0.05 for SNKs, n = 85; Fig. 14, C and D); again, baseline firing rates did not differ (P > 0.7). Therefore operant-related inhibition encodes the predictive information of the cue whether or not the neurons were also classified as incentive cue inhibited. Operant-inhibited neurons are thus unlike operant-excited neurons, which do not encode the predictive value of cues unless the neuron also responds to the DS.
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To examine more closely the time course of incentive cue and operant inhibition, we constructed median PEHs for IC–, IC–Op–, and Op– neurons that were aligned with the DS (only DSs followed by a nose-poke response were included), the nose-poke response to the DS, and the reward receptacle entry (Figs. 15 and 16). IC–Op– neurons showed inhibition that began within 100 ms after the DS (Figs. 15D and 16A), continued throughout the nose-poke response (Figs. 15E and 16B) and receptacle entry (Figs. 15F and 16C) and began to recover 1 s after the reward receptacle entry (Fig. 15F). The DS-evoked inhibition of IC– neurons was similar to that of IC–Op– neurons in its early onset and magnitude (Figs. 15A and 16A), but was less pronounced when measured at the nose-poke (Figs. 15B and 16B) and receptacle entry (Figs. 15C and 16C). In contrast, Op– neurons were not substantially inhibited until >1 s after the DS (Figs. 15G and 16A). Op– inhibition was most pronounced immediately after the nose-poke (Figs. 15H and 16B) and did not begin to recover until 1 s after reward receptacle entry (Fig. 15I). These results suggest that incentive-cue-inhibited neurons remain inhibited throughout the operant response until shortly after reward receptacle entry, whereas operant inhibitions begin just before the nose-poke and continue until after receptacle entry.
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DISCUSSION |
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Neuron classification
The firing patterns described here are similar to those found in primate ventral striatum (Bowman et al. 1996; Cromwell and Schultz 2003; Hassani et al. 2001; Hollerman et al. 1998; Schultz et al. 1992; Shidara et al. 1998; Tremblay et al. 1998; Williams et al. 1993), and thus our results provide an important bridge between the primate electrophysiology literature and the large body of research into the behavioral function of the rodent NAc using lesions and pharmacological manipulations. One striking difference between our results and the firing patterns described in primates is that in the primate literature there are very few reports of inhibitions of ventral striatal neurons in relation to task events, whereas we found both phasic inhibitions and excitations associated with nearly every task event. Reports of inhibitions in monkey striatum have been largely limited to "tonically active neurons" (TANs), which fire at higher baseline rates and are not as easily identifiable in rats as in primates (Apicella 2002). Indeed, the presence of inhibition has been used as a criterion for distinguishing TANs from phasically active neurons in recordings of primate striatal neurons (Apicella 2002), potentially explaining the paucity of reported inhibitions in studies of phasically active neurons in the monkey. Interestingly, we observed inhibitions even in neurons with very low baseline firing rates (the median firing rate of every class of inhibited neuron was <2 Hz; see median histograms), and inhibitions were at least as common as excitations. These findings argue against the possibility that our inhibited neurons were TANs because TANs fire more rapidly and are reported to be sparsely distributed.
Our observation of task-related inhibitions is consistent with other studies of rat NAc during fixed ratio responding for water, sucrose, and drug reward in which both excitations and inhibitions time-locked to the operant response have been observed (Carelli and Deadwyler 1994; Chang et al. 1998; Janak et al. 1999; Peoples and West 1996; Roop et al. 2002). In rats, however, few studies have addressed whether subpopulations of NAc neurons might be excited or inhibited by cues. Both excitations and inhibitions observed during cocaine self-administration can be evoked in the same neurons by cocaine-associated stimuli in the absence of operant behavior (Carelli 2000), and a recent study described excitations and inhibitions during extinction in response to DSs that had previously indicated the opportunity to obtain cocaine (Ghitza et al. 2003). In contrast, a recent study of NAc core and ventral caudate/putamen neurons in rats performing an olfactory discrimination task did not report cue-evoked inhibitions (Setlow et al. 2003). However, in that study, firing rates in relation to task events were apparently not systematically compared with baseline. Although differences in the task, the requirement for locomotion, the locations of the recorded neurons, or the subject species may account for differences in the frequency of inhibitions found by different investigators, another possibility is simply that in some studies inhibitions were not explicitly investigated. This work therefore provides novel descriptions of excitation and inhibition of rat NAc neurons by cues predictive of natural reward.
Although studies of the primate ventral striatum have not reported task-related inhibitions in phasically active neurons, the proportion of neurons in the present study that displayed cue-evoked and operant-related excitations is similar to that observed in primate striatal recordings during go-no-go tasks (Apicella et al. 1992; Cromwell and Schultz 2003; Hassani et al. 2001; Hollerman et al. 1998; Inase et al. 1997; Schultz et al. 1992): 5–10% of neurons are excited by cues and a somewhat greater proportion responds just prior to or during operant behavior. These proportions are, however, smaller than those reported by other investigators in cue-responding tasks. For instance, Shidara et al. (1998) reported that about one-third of monkey ventral striatal neurons were excited by cues, and Setlow et al. (2003) found that 40% of rat ventral striatal neurons displayed different firing rates during presentation of two different odor cues. Although some of these differences may be due to the use of different species, behavioral tasks, recording techniques, and electrode positions, a major factor may also be the criteria used to classify neural firing as phasic. For instance, Shidara et al. (1998) assumed a neuron was phasic if its firing rate was significantly different from baseline using a paired t-test with P < 0.05, and Setlow et al. (2003) did not classify neurons as phasic with respect to baseline firing (instead, they found that the absolute firing rate during odor sampling was significantly different for different odor cues in 40% of their neurons). In contrast, the Schultz lab used nonparametric Wilcoxon tests with P < 0.01 to judge whether a neuron is phasic, a procedure that is likely to result in fewer phasic neurons (e.g., Cromwell and Schultz 2003; Hassani et al. 2001). In this study, we used a two-step classification procedure that involved both statistical comparison and visual inspection by two independent investigators. This resulted in proportions of phasic neurons similar to those found by Schultz and colleagues. Our criteria therefore allowed only the most strongly phasic responses to be classified as phasic and would therefore have caused us to miss the contribution of weaker responses to firing changes. Thus our numbers almost certainly represent an underestimate of the total number of neurons with each firing pattern.
Information encoded by incentive cue responses
To determine whether NAc neurons encode the predictive value of the cue independent of motor behavior, two cues were presented to our animals: a DS, which predicted that a sucrose reward would be available after an operant response and entry into the reward receptacle, and an NS (nonrewarded stimulus). We intentionally made these cues similar so that animals would respond to a large proportion of NSs, a phenomenon known as stimulus generalization (Hull 1943; Tarpy 1982). Rats responded more often to the DS than the NS, indicating that the stimulus generalization was only partial. The relatively high NS response ratio allowed us to compare the firing of cueresponsive neurons to the DS and NS when the animal's behavioral responses were similar, a comparison that is essential to determine whether the neurons encode the predictive value of the cue independent of the execution of motor behavior. The magnitude of both cue-evoked excitations and inhibitions depended on both the presence of an operant response to the cue and on the predictive value of the cue. Specifically, the firing increase or decrease after cue presentation was larger for both DS and NS if the animal exhibited an appropriate behavioral response than if he did not. This indicates that the firing correlates, at least in part, with the animal's motor behavior. In addition, when the animals did make a response, the firing clearly encoded the predictive value of the cues: excitations and inhibitions were greater in response to the DS than in response to the NS, even when the animal's motor responses to the two cues occurred at identical latencies.
Although there were some transient cue-evoked excitations that appeared to be specified by the sensory features of the cue, regardless of its predictive value, the majority of cue-evoked excitations and inhibitions were larger for the DS than for the NS, particularly when the animal responded to the cues. Very few neurons responded preferentially to the NS. This result is consistent with previous studies in which monkeys responded both to reward-predictive cues and to cues that predicted no reward delivery (but had to be responded to in order to advance to the next, potentially rewarded, trial). These studies found that more dorsal and ventral striatal neurons fired, with greater excitation, when the cue predicted immediate reward after the operant response than when the cue signaled that an unrewarded operant response had to be made (Hollerman et al. 1998; Kawagoe et al. 1998; Shidara et al. 1998). Cue-evoked excitations were often strongly modulated by the specific reward predicted by the cue (Hassani et al. 2001) and by the magnitude of the predicted reward (Cromwell and Schultz 2003), suggesting that our cue-responsive neurons may have encoded similar information about the forthcoming reward. Our findings of greater firing changes in response to the DS than the NS are also consistent with a recent report showing that in extinction, NAc neuronal activity is greater in response to DSs that previously predicted cocaine reward than in response to a nonpredictive stimulus (Ghitza et al. 2003).
Our finding that incentive cue excitations and inhibitions are larger when the animal makes an outcome-appropriate response indicates that these firing patterns also encode information about motor behavior. The specific information encoded is unknown; there are several possibilities. First, the firing patterns could be influenced by collaterals from neurons in upstream nuclei that also project (directly or indirectly) to the NAc and that control the motor behavior without a contribution from NAc neurons. Second, the firing patterns could facilitate a behavioral response nonspecifically, for instance, by increasing the probability of a behavioral response without specifying what that response should be. Third, the firing patterns could encode the likelihood of achieving the goal (sucrose) in the presence of the cue and thus increase the probability of several motor behaviors that had previously been associated with the goal. Fourth, the firing patterns could increase the probability of the specific behavior that is the best response to the cue.
Although our experiments do not distinguish among these possibilities, both behavioral and electrophysiological evidence from previous studies argues in favor of the third or fourth hypotheses (that the firing encodes behavioral responses with some specificity). For instance, Pavlovian-instrumental transfer, the behavioral phenomenon in which instrumental responding is increased in the presence of cues that have been associated with reward, is both blocked by NAc lesions (Corbit et al. 2001; de Borchgrave et al. 2002; Hall et al. 2001) and potentiated by NAc amphetamine microinjections (Wyvell and Berridge 2000). Similarly, Pavlovian approach behavior, in which an animal approaches a CS that has been paired with reward, requires the NAc (Cardinal et al. 2002b; Di Ciano et al. 2001; Parkinson et al. 1999, 2000b, 2002). Conditioned reinforcement, in which animals preferentially respond on a lever that delivers reward-associated stimuli (but not reward itself), is potentiated by the increased NAc dopamine resulting from amphetamine injections (Taylor and Robbins 1986; Wolterink et al. 1993). The NAc amphetamine-induced effects on conditioned reinforcement have been interpreted to mean that the amphetamine potentiates the ability of the stimulus produced by the operant response to promote further operant responding (Cardinal et al. 2002a). In all of these experiments, the effects of NAc manipulations on cue responding are specific to reward-associated cues and to the trained reward-directed instrumental behavior; cues and behaviors that are not reward-associated are less affected. It follows from these behavioral studies that there must be a population of NAc neurons that responds differently to predictive and nonpredictive cues and that may also encode the specific motor behavior appropriate to the cue. Incentive-cue-excited and -inhibited neurons are a likely substrate for the NAc's role in cue-mediated behaviors. Because many of the cue-mediated behaviors described in the preceding text depend on NAc dopamine, the hypothesis that incentive cue excitations and inhibitions are required for these behaviors is strongly supported by our findings that responding to the DS requires activation of dopamine receptors within the NAc and that incentive cue excitations and inhibitions are likely to be dopamine dependent because they are reduced by inactivation of the VTA dopaminergic neurons that project to the NAc (Yun et al. 2004). Although the results of behavioral studies are consistent with a role for cue-evoked excitations and inhibitions of NAc neurons in promoting specific behavioral responses, more experiments are required to confirm the properties of NAc cue-responsive neurons during different behaviors involving cues and to determine whether specific motor behaviors are in fact encoded by such neurons.
Further support for a role for NAc cue-responsive neurons in promoting specific behavioral responses comes from studies of primate dorsal and ventral striatal neurons, which have found excitations in response to reward-predictive cues (Bowman et al. 1996; Cromwell and Schultz 2003; Hassani et al. 2001; Hollerman et al. 1998; Itoh et al. 2003; Kawagoe et al. 1998; Lauwereyns et al. 2002; Schultz et al. 1992; Shidara et al. 1998; Williams et al. 1993). Although some neurons in both dorsal and ventral striatum encode the reward-predictive value of the cue, and not the anticipation of a particular movement (Hollerman et al. 1998; Schultz et al. 1992), other neurons exhibit responses to cues that vary depending on whether a behavioral response is required to obtain reward (Hollerman et al. 1998) or on the direction of the required response (Hassani et al. 2001; Itoh et al. 2003; Kawagoe et al. 1998; Lauwereyns et al. 2002). Because the tasks used for the primate studies usually involved a delay between cue presentation and motor action, the excitation in response to cues that is not attributable to the reward predictive value of the cue may encode either motor planning or the suppression of a behavioral response until the end of the delay. In our task, there was no required delay, and therefore our results demonstrate that the cue-evoked activity of rat NAc neurons correlates with both reward prediction and the ongoing motor activity instigated by the cue. The degree to which the firing of NAc neurons during cue-evoked motor activity encodes specific movements remains to be determined.
The hypothesis that the firing of subpopulations of cue-responsive neurons increases the probability of the specific motor behavior required to obtain the predicted reward is analogous to the conclusions drawn from recordings of primate caudate neurons during saccadic eye movement tasks. Many caudate neurons are excited by cues that both instruct the direction of the saccade and predict the reward to be obtained. The excitations are strongly modulated by the predicted reward but are also specific for particular saccade directions (Itoh et al. 2003; Kawagoe et al. 1998). These reward- and direction-dependent excitations are proposed to bias the direction of the saccade toward the direction that will maximize reward (Lauwereyns et al. 2002). The circuit by which caudate neurons ultimately influence the firing of brain stem neurons that control specific movements is relatively well understood (Hikosaka et al. 2000); NAc neurons may play a similar role in the circuits that control the direction of locomotion in response to cues, perhaps by means of its direct and indirect projections to the pedunculopontine tegmental nucleus (Winn et al. 1997) and ventral pallidum (Zahm 1999). Consistent with this idea, preliminary findings from our laboratory suggest that the firing rate of some NAc neurons depends strongly on the specific movement required to obtain reward (Taha and Fields 2003).
Because we presented animals with only two explicit cues, we do not know whether other NAc neurons would respond to other cues that predict different rewards or that direct the animal to perform a different motor behavior to obtain the predicted reward. On the assumption that at least some other NAc neurons each connect one predictive stimulus (or a few predictive stimuli) with the specific response required to take advantage of it, incentive cue-responsive NAc neurons could play an important role in the selection of appropriate behavior in response to environmental stimuli. As others have proposed (Pennartz et al. 1994), reciprocal inhibition between spiny neurons, as has been described in dorsal striatum (Czubayko and Plenz 2002; Plenz 2003; Tunstall et al. 2002), could allow for different stimuli to compete for motor resources, with the strongest (most predictive) stimuli "winning" by promoting the specific behavior associated with the stimulus. The behavioral evidence in favor of this idea has been described for both dorsal and ventral striatal circuits (Oades 1985; Parkinson et al. 2000a; Redgrave et al. 1999). Our finding of cue-responsive neurons whose firing is correlated with both the predictive value of the cue and the animal's motor response provides a potential substrate for response selection. Because cue-evoked responses are dynamic as animals learn the meaning of cues (Setlow et al. 2003; Tremblay et al. 1998), the association encoded by individual neurons may contribute to the learned behavioral response to cues. A network of competing subpopulations of cue- and motor-encoding NAc neurons could help explain how the NAc functions as a cost/benefit calculator (Salamone and Correa 2002), as a judge of the incentive salience of environmental stimuli (Berridge and Robinson 1998), and as a facilitator of instrumental behavior by Pavlovian-conditioned cues associated with the outcome of an instrumental response (Cardinal et al. 2002a).
Although the competitive network model awaits further testing, previous electrophysiological studies provide some support. One prediction of the model is that the firing of the neurons that drive an operant response should be time-locked to the onset of locomotion toward the operandum. Consistent with this prediction, the operant-related firing of NAc neurons during cocaine self-administration has been shown to begin at the time animals make the initial motor response (orienting or raising the head toward the lever) that precedes the operant response itself (Chang et al. 1994, 2000); cue-evoked NAc firing responses also appear to begin just prior to the behavioral response (Ghitza et al. 2003).
Information encoded by operant-related neuronal responses
We observed two types of phasic firing change in relation to the operant response: an excitation surrounding the response and an inhibition that began just before the response and continued until just past reward receptacle entry. Many operant-excited and -inhibited neurons were also classified as incentive cue excited and inhibited, respectively, because the cue-evoked firing changes tended to last until the animal obtained the reward. Operant excitations in neurons that were not also excited by the DS (Op+) were found to be the same amplitude whether the nose-poke was a response to the DS, the NS or uncued; furthermore, the latency to respond to the DS did not affect the timing and amplitude of the operant-related excitation. In contrast, operant inhibitions (whether or not the neurons were also classified as incentive cue inhibited) were found to be largest if the nose-poke was a DS response, intermediate if it was an NS response, and smallest if it was uncued. Therefore operant inhibitions encode the predictive value of the cue as well as the operant behavior, whereas operant excitations encode only the operant behavior. [Given the relatively small size of the difference in operant-inhibited neurons (Fig. 14D, right), another possibility is that a substantial subpopulation of operant-inhibited neurons is not modulated by the presence of a cue.] The specific aspect of operant behavior encoded by these firing patterns is not known; however, primate striatal recordings found that movement-related excitations often depended on the specific parameters (e.g., direction) of the movement required to obtain the reward (Alexander 1987; Alexander and Crutcher 1990; Cromwell and Schultz 2003; Crutcher and Alexander 1990; Hassani et al. 2001; Hikosaka et al. 1989; Hollerman et al. 1998; Jaeger et al. 1993; Schultz et al. 1992). Interestingly, the firing of some NAc neurons is known to be modulated by the animal's location (Lavoie and Mizumori 1994; Martin and Ono 2000; Shibata et al. 2001), and therefore operant excitation and inhibition may also depend in part on location (which is necessarily the same during all operant responses on the same operandum).
An intriguing hypothesis is that the phasic firing of operant-excited and -inhibited neurons (and perhaps all NAc neurons) is in fact driven by specific environmental cues, only a small subset of which is under experimenter control. So, for instance, visual or olfactory cues provided by the nose-poke hole itself could drive operant-excited neurons to fire, whereas the cue that best drives incentive cue excitations is the DS. Because animals always sense the nose-poke hole as they approach it, the firing of operant neurons appears to be time-locked to the motor action of reaching the nose-poke hole but may in fact have a sensory component (i.e., the firing may be driven by the stimulus of the nose-poke hole itself or by the predictive value of the nose-poke hole cue). This is supported by the findings from self-administering animals that operant responses begin when the animal orients toward the operandum (Chang et al. 1994, 2000); after orienting, the sensory stimulus associated with the operandum is likely to be greatest. The fact that operant excitation is independent of the explicit cue (DS or NS) being presented indicates that, if operant excitations are indeed driven by cues, the effective cues for driving these excitations do not include the DS or NS. If cue-evoked excitations and inhibitions (including those classified as operant-related) reflect a specific motor sequence that has an increased probability of resulting in the reward predicted by the cue, this hypothesis provides a simplification of the findings, common to almost all studies of the responses of NAc neurons during behavior, that small subpopulations of these neurons respond phasically to each event in the task. It is not that some NAc neurons are "sensory" and some are "motor" but rather that each NAc neuron encodes a specific motor response driven by a sensory cue that indicates that the motor response is likely to result in reward. This hypothesis is similar to previously proposed ideas that NAc neuronal firing participates in planning and executing behavior in response to continually changing environmental stimuli (Chang et al. 1994; Mizumori et al. 1999; Shidara et al. 1998). Further experiments are required to address the extent to which the operant-related firing of NAc neurons is controlled by cues and to which such firing facilitates specific motor behaviors.
One piece of evidence in support of the hypothesis that both cue- and operant-responsive neurons encode similar classes of information comes from comparison of their encoding of reward. If operant-excited neurons receive inputs that are similar to those of incentive-cue-excited neurons, then their responses should be similar not just during cue presentation and the operant response but during other task events as well. Consistent with this, about half of incentive-cue-excited neurons are inhibited during reward consumption, and a similar proportion (39%) of operant-excited neurons also display reward-related inhibitions. These proportions are significantly greater than the proportion of reward-inhibited neurons in the general population (19%; these are the neurons with sustained receptacle inhibition in Tables 2 and 3). Similarly, 20% of incentive-cue-inhibited neurons and 9% of operant-inhibited neurons were excited during reward consumption (sustained receptacle excitation in Table 2), proportions significantly greater than the overall proportion of reward-excited neurons (2.8%). (However, 32% of operant-inhibited neurons also exhibited sustained receptacle inhibitions, which may be due to the receptacle inhibitions beginning before actual entry into the receptacle. Because operant inhibitions were defined by their inhibition between the nose-poke and the receptacle entry, some overlap between receptacle- and operant-related inhibitions would be expected.) Thus both incentive cue and operant neurons display a tendency toward phasic modulation of their firing during reward consumption in the opposite direction from that displayed during reward seeking, consistent with the idea that inputs encoding the same class of information drive the firing changes in cue- and operant-responsive neurons.
Opposite modulation of NAc neuronal firing during operant responding for reward and during (or after) reward delivery has also been observed during cocaine self-administration (Nicola and Deadwyler 2000; Peoples and West 1996; Peoples et al. 1998b). A potential explanation for why cue- and operant-responsive neurons display firing changes during reward consumption that are opposite to those before and during operant responding is that the phasic firing that drives a particular behavior is actively terminated when the goal has been achieved, and the transition from excitation to inhibition (or vice versa) serves as a signal to the animal to cease the appetitive behavior and begin consumption. Such an explanation is consistent with the large literature implicating the NAc in consummatory behavior; in particular, nonselective pharmacological inhibition of NAc neurons increases consumption (Kelley et al. 2002; Saper et al. 2002). This explanation is consistent with the larger proportion of reward-inhibited than reward-excited NAc neurons and with the idea that the basal ganglia, including the NAc, is involved in the suppression and activation of behaviors that need to occur in a specific sequence (Aldridge and Berridge 1998; Hikosaka et al. 1999, 2000). For instance, neurons that are excited during appetitive behavior might suppress consummatory behavior, and inhibition in these neurons during consumption might suppress appetitive behavior.
Origin of excitations and inhibitions
Because NAc projection neurons require glutamatergic input to fire and because glutamatergic neurons are absent within the NAc (reviewed in Nicola et al. 2000; Wilson 1998), excitatory firing patterns probably result from glutamatergic projections to the NAc. The majority of excitatory input to the NAc arises from limbic structures such as the prefrontal cortex, basolateral amygdala, and hippocampal formation (Zahm 2000). Interestingly, all of these brain areas contain neurons that respond to predictive cues in ways that are not purely sensory but instead depend on the information conveyed by the cue. For instance, amygdala neurons respond to cues, and a subset of these responses depend on the reward predicted by the cue (Nishijo et al. 1988; Sanghera et al. 1979). Neurons in the basolateral amygdala respond with different firing rates during sampling of odor cues that predict reward and those that do not (Schoenbaum et al. 1998, 1999). Similarly, excitations in the orbitofrontal cortex in response to task events, including cues, are greater if the operant behavior instructed by the cue is rewarded (Critchley and Rolls 1996b; Tremblay and Schultz 2000a,b). Also, orbitofrontal cortical neuron responses to cues associated with specific foods are smaller after feeding to satiety on the food (Critchley and Rolls 1996a). Neurons in the perirhinal cortex respond to predictive cues but not other task events, and these responses are strongly modulated by the temporal proximity of reward (Liu and Richmond 2000). Neurons in several areas of the prefrontal cortex show sustained activation during working memory tasks (Miller 2000; Watanabe 1996). Because these nuclei project to the NAc and excitatory afferents from at least some of them converge onto single NAc neurons (Mulder et al. 1998; O'Donnell and Grace 1995), a suggestive hypothesis is that the properties of NAc incentive-cue-excited neurons are a direct consequence of these convergent inputs. Specifically, the fact that cue-evoked excitations are often sustained until reward is received, and reflect both the predicted reward and motor behavior, may result from the integration of the cue-related information from these NAc-projecting cortical and limbic areas.
The origin of inhibitions is less clear. In the striatum, inhibitory input onto spiny neurons appears to result primarily from within the striatum, either from inhibitory interneurons (Koos and Tepper 1999) or from other spiny projection neurons, which are GABAergic and reciprocally connected in both dorsal striatum (Czubayko and Plenz 2002; Plenz 2003; Tunstall et al. 2002) and NAc (Chang and Kitai 1985). Other potential sources of inhibition include the GABAergic projection from the VTA (Van Bockstaele and Pickel 1995), the GABAergic projection from ventral pallidum (the major output nucleus of the NAc) back to the NAc (Zahm 2000), or peptidergic projections. One argument in favor of the hypothesis that task-related inhibition arises from reciprocal connections between NAc neurons is the balanced proportion of neurons showing excitation and inhibition. If every excited NAc neuron succeeds in inhibiting at least one other NAc neuron, the result should be approximately as many inhibitions as excitations. Consistent with this, 5.1 and 2.8% of neurons were excited and inhibited by cues, respectively. Operant-excited neurons comprised 11.1% of the population and operant-inhibited neurons comprised 15.2%; however, operant inhibitions were defined somewhat more broadly than excitations (see Table 1). Another possibility is simply that some neurons in NAc afferent structures that maintain the tonic firing of NAc neurons are themselves inhibited, resulting in reduced firing in subpopulations of NAc neurons.
Summary
Our findings indicate that subpopulations of NAc neurons are excited and inhibited by cues that predict reward delivery after a specific operant behavior. These cue-elicited responses are often maintained throughout the DS-nose-poke interval until the beginning of reward consumption. They are larger if the animal responds to the cue and larger for the reward-predictive DS than for the less-predictive NS, suggesting that these firing patterns reflect information related to the motor response elicited by the cue as well as the predictive value of the cue. Operant excitations did not depend on the cue being presented, whereas operant inhibitions were largest if the response was made during the DS. The encoding of both cue predictive and motor information is consistent with the idea that NAc neurons promote behavioral responses appropriate to predictive cues, perhaps by means of competition among NAc neurons.
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ACKNOWLEDGMENTS |
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GRANTS
This work was supported by funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco; by the Wheeler Center for the Neurobiology of Addiction; by the Ernest Gallo Clinic and Research Center; by National Institute on Drug Abuse grants to S. M. Nicola and H. L. Fields; and by a National Science Foundation Predoctoral Training Consortium in Affective Science fellowship to I. A. Yun.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. Nicola, Ernest Gallo Clinic and Research Center, University of California, San Francisco, 5858 Horton St., Ste. 200, Emeryville, CA 94608 (E-mail: nicola{at}phy.ucsf.edu).
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indicates the median, and the lower and upper edges of the box show the 1st and 3rd quartiles, respectively, of the distribution of firing rate increases. *, P < 0.05. F: the mean firing rate increase in response to cues does not depend on the latency to respond. The firing rate increase in the 1st 1 s after the DS is significantly greater than after the NS, with no effect of latency. Post hoc comparisons were not performed because of the absence of latency effects. Error bars represent SE.
