Beta Oscillations in Monkey Striatum Encode Reward Prediction Error Signals.

Reward prediction error (RPE) signals are crucial for reinforcement learning and decision-making as they quantify the mismatch between predicted and obtained rewards. RPE signals are encoded in the neural activity of multiple brain areas, such as midbrain dopaminergic neurons, prefrontal cortex, and striatum. However, it remains unclear how these signals are expressed through anatomically and functionally distinct subregions of the striatum. In the current study, we examined to which extent RPE signals are represented across different striatal regions. To do so, we recorded local field potentials (LFPs) in sensorimotor, associative, and limbic striatal territories of two male rhesus monkeys performing a free-choice probabilistic learning task. The trial-by-trial evolution of RPE during task performance was estimated using a reinforcement learning model fitted on monkeys' choice behavior. Overall, we found that changes in beta band oscillations (15-35 Hz), after the outcome of the animal's choice, are consistent with RPE encoding. Moreover, we provide evidence that the signals related to RPE are more strongly represented in the ventral (limbic) than dorsal (sensorimotor and associative) part of the striatum. To conclude, our results suggest a relationship between striatal beta oscillations and the evaluation of outcomes based on RPE signals and highlight a major contribution of the ventral striatum to the updating of learning processes.SIGNIFICANCE STATEMENT Reward prediction error (RPE) signals are crucial for reinforcement learning and decision-making as they quantify the mismatch between predicted and obtained rewards. Current models suggest that RPE signals are encoded in the neural activity of multiple brain areas, including the midbrain dopaminergic neurons, prefrontal cortex and striatum. However, it remains elusive whether RPEs recruit anatomically and functionally distinct subregions of the striatum. Our study provides evidence that RPE-related modulations in local field potential (LFP) power are dominant in the striatum. In particular, they are stronger in the rostro-ventral rather than the caudo-dorsal striatum. Our findings contribute to a better understanding of the role of striatal territories in reward-based learning and may be relevant for neuropsychiatric and neurologic diseases that affect striatal circuits.

Temporal processing in the striatum: Interplay between midbrain dopamine neurons and striatal cholinergic interneurons.

There has been considerable progress in recent years toward understanding the neuronal mechanisms mediating time perception. Notably, the striatum and its dopamine (DA) input from the ventral midbrain are considered to be central for timing on the scale of hundreds of milliseconds and seconds. The cholinergic interneurons (ChIs) of the striatum provide an extensive local innervation, which closely interacts with striatal DA afferents. Both neuronal systems have been shown to influence synaptic plasticity to shape the transfer of information through the striatum. Given their cooperative role in regulating striatal output pathways, DA and cholinergic inputs may have distinct but complementary roles in timing processes. Electrophysiological recordings from behaving animals have provided evidence that responses of midbrain DA neurons and striatal tonically active neurons (TANs), presumed ChIs, to motivationally relevant events are sensitive to the predicted time of these events; namely, changes in neuronal activity are reduced or absent at times when events are more expected, indicating that temporal aspects of prediction play an important role in the responsiveness of these two neuronal systems. Recently, new findings have further suggested that DA neurons and cholinergic TANs are both involved in the ability to keep track of the elapsed time. These two systems appear to work in parallel in initiating the timing process at the beginning of an interval to be timed. It therefore appears that DA and ChI signaling could participate in striatal processing that is crucial for the control of timing behavior.

Activity of fast-spiking interneurons in the monkey striatum during reaching movements guided by external cues or by a free choice.

Parvalbumin-containing GABAergic interneurons in the striatum, electrophysiologically identified as fast-spiking interneurons (FSIs), exert inhibitory control over striatal output to drive appropriate behavior. While a number of studies have emphasized their importance in motor control, it is unknown how these putative interneurons adapt their functional properties to different modes of movement selection. Here, we tested whether FSIs are sensitive to externally versus internally selected movements by recording their activity while two male rhesus monkeys performed reaching movements to visual targets. Two variants were used: an external condition, in which movements were instructed via external cues, and an internal condition, in which movements were guided by an internal representation of the target location. These conditions allowed to contrast the FSI activity associated with either externally cued or internally driven movement selection. After extensive training, reaching performance was only marginally affected by the type of movement, albeit with some differences between the monkeys. Over two-thirds of the FSIs were modulated around movement onset, regardless of the condition, and consisting mostly of increased activity. We found that a subset of FSIs showed stronger activation related to the initiation of movements in the external condition than in the internal condition, suggesting a dependence on movement selection mode. Moreover, this difference in the strength of FSI activation was predominant in the motor striatum. These data indicate that changes in FSI activity carry information that is scaled by constraints on action selection reflecting the involvement of local striatal inhibitory circuits in adaptation of behavior according to task demands.

Targeted Transgene Expression in Cholinergic Interneurons in the Monkey Striatum Using Canine Adenovirus Serotype 2 Vectors.

The striatum, the main input structure of the basal ganglia, is critical for action selection and adaptive motor control. To understand the neuronal mechanisms underlying these functions, an analysis of microcircuits that compose the striatum is necessary. Among these, cholinergic interneurons (ChIs) provide intrinsic striatal innervation whose dysfunction is implicated in neuropsychiatric diseases, such as Parkinson's disease and Tourette syndrome. The ability to experimentally manipulate the activity of ChIs is critical to gain insights into their contribution to the normal function of the striatum and the emergence of behavioral abnormalities in pathological states. In this study, we generated and tested CAV-pChAT-GFP, a replication-defective canine adenovirus type 2 (CAV-2) vector carrying the green fluorescent protein (GFP) sequence under the control of the human choline acetyltransferase (ChAT) promoter. We first tested the potential specificity of CAV-pChAT-GFP to label striatal ChIs in a rat before performing experiments on two macaque monkeys. In the vector-injected rat and monkey striatum, we found that GFP expression preferentially colocalized with ChAT-immunoreactivity throughout the striatum, including those from local circuit interneurons. CAV-2 vectors containing transgene driven by the ChAT promoter provide a powerful tool for investigating ChI contributions to circuit function and behavior in nonhuman primates.

The role of the intrinsic cholinergic system of the striatum: What have we learned from TAN recordings in behaving animals?

Cholinergic interneurons provide rich local innervation of the striatum and play an important role in controlling behavior, as evidenced by the variety of movement and psychiatric disorders linked to disrupted striatal cholinergic transmission. Much progress has been made in recent years regarding our understanding of how these interneurons contribute to the processing of information in the striatum. In particular, investigation of the activity of presumed striatal cholinergic interneurons, identified as tonically active neurons or TANs in behaving animals, has pointed to their role in the signaling and learning of the motivational relevance of environmental stimuli. Although the bulk of this work has been conducted in monkeys, several studies have also been carried out in behaving rats, but information remains rather disparate across studies and it is still questionable whether rodent TANs correspond to TANs described in monkeys. Consequently, our current understanding of the function of cholinergic transmission in the striatum is challenged by the rapidly growing, but often confusing literature on the relationship between TAN activity and specific behaviors. As regards the precise nature of the information conveyed by the cholinergic TANs, a recent influential view emphasized that these local circuit neurons may play a special role in the processing of contextual information that is important for reinforcement learning and selection of appropriate actions. This review provides a summary of recent progress in TAN physiology from which it is proposed that striatal cholinergic interneurons are crucial elements for flexible switching of behaviors under changing environmental conditions.

Differences between Dorsal and Ventral Striatum in the Sensitivity of Tonically Active Neurons to Rewarding Events.

Within the striatum, cholinergic interneurons, electrophysiologically identified as tonically active neurons (TANs), represent a relatively homogeneous group in terms of their functional properties. They display typical pause in tonic firing in response to rewarding events which are of crucial importance for reinforcement learning. These responses are uniformly distributed throughout the dorsal striatum (i.e., motor and associative striatum), but it is unknown, at least in monkeys, whether differences in the modulation of TAN activity exist in the ventral striatum (i.e., limbic striatum), a region specialized for processing of motivational information. To address this issue, we examined the activity of dorsal and ventral TANs in two monkeys trained on a Pavlovian conditioning task in which a visual stimulus preceded the delivery of liquid reward by a fixed time interval. We found that the proportion of TANs responding to the stimulus predictive of reward did not vary significantly across regions (58%-80%), whereas the fraction of TANs responding to reward was higher in the limbic striatum (100%) compared to the motor (65%) and associative striatum (52%). By examining TAN modulation at the level of both the population and the individual neurons, we showed that the duration of pause responses to the stimulus and reward was longer in the ventral than in the dorsal striatal regions. Also, the magnitude of the pause was greater in ventral than dorsal striatum for the stimulus predictive of reward but not for the reward itself. We found similar region-specific differences in pause response duration to the stimulus when the timing of reward was less predictable (fixed replaced by variable time interval). Regional variations in the duration and magnitude of the pause response were transferred from the stimulus to reward when reward was delivered in the absence of any predictive stimulus. It therefore appears that ventral TANs exhibit stronger responses to rewarding stimuli, compared to dorsal TANs. The high proportion of responsive neurons, combined with particular response features, support the notion that the ventral TAN system can be driven by specific synaptic inputs arising from afferent sources distinct from those targeting the dorsal TAN system.

Changes in activity of fast-spiking interneurons of the monkey striatum during reaching at a visual target.

Recent works highlight the importance of local inhibitory interneurons in regulating the function of the striatum. In particular, fast-spiking interneurons (FSIs), which likely correspond to a subgroup of GABAergic interneurons, have been involved in the control of movement by exerting strong inhibition on striatal output pathways. However, little is known about the exact contribution of these presumed interneurons in movement preparation, initiation, and execution. We recorded the activity of FSIs in the striatum of monkeys as they performed reaching movements to a visual target under two task conditions: one in which the movement target was presented at unsignaled left or right locations, and another in which advance information about target location was available, thus allowing monkeys to react faster. Modulations of FSI activity around the initiation of movement (53% of 55 neurons) consisted mostly of increases reaching maximal firing immediately before or, less frequently, after movement onset. Another subset of FSIs showed decreases in activity during movement execution. Rarely did movement-related changes in FSI firing depend on response direction and movement speed. Modulations of FSI activity occurring relatively early in relation to movement initiation were more influenced by the preparation for movement, compared with those occurring later. Conversely, FSI activity remained unaffected, as monkeys were preparing a movement toward a specific location and instead moved to the opposite direction when the trigger occurred. These results provide evidence that changes in activity of presumed GABAergic interneurons of the primate striatum could make distinct contributions to processes involved in movement generation. NEW & NOTEWORTHY: We explored the functional contributions of striatal fast-spiking interneurons (FSIs), presumed GABAergic interneurons, to distinct steps of movement generation in monkeys performing a reaching task. The activity of individual FSIs was modulated before and during the movement, consisting mostly of increased in firing rates. Changes in activity also occurred during movement preparation. We interpret this variety of modulation types at different moments of task performance as reflecting differential FSI control over distinct phases of movement.

Modulation of neuronal activity by reward identity in the monkey subthalamic nucleus.

The subthalamic nucleus (STN) has been argued to be an important component of reward-sensitive basal ganglia circuitry. This view is especially supported by the behavioral changes observed after STN inactivation, which could reflect impairments in the motivational control of action. However, it is still unclear how the STN integrates reward information and to what extent such integration correlates with behavior. In this study, the response properties of STN neurons in monkeys performing reaching movements with a cue predicting the identity of an upcoming liquid reward (juice or water) were investigated. Although the timing of movements reliably indicated that monkeys had greater motivation for juice than water, rarely did task-related changes in neuronal activity depend on the nature of the expected reward. Conversely, when presented with a choice of selecting a response that leads to juice or water delivery, animals showed a clear preference for juice and more than half of the neurons were differentially modulated dependent on the reward obtained, mostly after the monkeys's overt choice of action. Under such circumstances, an increase in activity specifically followed the action outcomes across the population of neurons when monkeys failed to choose the juice reward. These results indicate that STN neurons encode whether or not a preferred reward had been received when a choice between response alternatives is required. This differential neuronal activity might reflect the participation of the STN in evaluating the reward value of chosen actions, thus highlighting its contribution to decision-making processes.

Cortical and thalamic excitation mediate the multiphasic responses of striatal cholinergic interneurons to motivationally salient stimuli.

Cholinergic interneurons are key components of striatal microcircuits. In primates, tonically active neurons (putative cholinergic interneurons) exhibit multiphasic responses to motivationally salient stimuli that mirror those of midbrain dopamine neurons and together these two systems mediate reward-related learning in basal ganglia circuits. Here, we addressed the potential contribution of cortical and thalamic excitatory inputs to the characteristic multiphasic responses of cholinergic interneurons in vivo. We first recorded and labeled individual cholinergic interneurons in anesthetized rats. Electron microscopic analyses of these labeled neurons demonstrated that an individual interneuron could form synapses with cortical and, more commonly, thalamic afferents. Single-pulse electrical stimulation of ipsilateral frontal cortex led to robust short-latency (<20 ms) interneuron spiking, indicating monosynaptic connectivity, but firing probability progressively decreased during high-frequency pulse trains. In contrast, single-pulse thalamic stimulation led to weak short-latency spiking, but firing probability increased during pulse trains. After initial excitation from cortex or thalamus, interneurons displayed a "pause" in firing, followed by a "rebound" increase in firing rate. Across all stimulation protocols, the number of spikes in the initial excitation correlated positively with pause duration and negatively with rebound magnitude. The magnitude of the initial excitation, therefore, partly determined the profile of later components of multiphasic responses. Upon examining the responses of tonically active neurons in behaving primates, we found that these correlations held true for unit responses to a reward-predicting stimulus, but not to the reward alone, delivered outside of any task. We conclude that excitatory inputs determine, at least in part, the multiphasic responses of cholinergic interneurons under specific behavioral conditions.

Linking reward processing to behavioral output: motor and motivational integration in the primate subthalamic nucleus.

The expectation and detection of motivationally relevant events is a major determinant of goal-directed behavior and there is a strong interest in the contribution of basal ganglia in the integration of motivational processes into behavioral output. Recent research has focused on the role of the subthalamic nucleus (STN) in the motivational control of action, but it remains to be determined how information about reward is encoded in this nucleus. We recorded the activity of single neurons in the STN of two behaving monkeys to examine whether activity was influenced by the delivery of reward in an instrumental task, a Pavlovian stimulus-reward association, or outside of a task context. We confirmed preliminary findings indicating that STN neurons were sensitive not only to rewards obtained during task performance, but also to the expectation of reward when its delivery was delayed in time. Most of the modulations at the onset of reaching movement were combined with modulations following reward delivery, suggesting the convergence of signals related to the animal's movement and its outcome in the same neurons. Some neurons were also influenced by the visuomotor contingencies of the task, i.e., target location and/or movement direction. In addition, modulations were observed under conditions where reward delivery was not contingent on an instrumental response, even in the absence of a reward predictive cue. Taken as a whole, these results demonstrate a potential contribution of the STN to motivational control of behavior in the non-human primate, although problems in distinguishing neuronal signals related to reward from those related to motor behavior should be considered. Characterizing the specificity of reward processing in the STN remains challenging and could have important implications for understanding the influence of this key component of basal ganglia circuitry on emotional and motivated behaviors under normal and pathological conditions.

Importance of the temporal structure of movement sequences on the ability of monkeys to use serial order information.

The capacity to acquire motor skills through repeated practice of a sequence of movements underlies many everyday activities. Extensive research in humans has dealt with the importance of spatial and temporal factors on motor sequence learning, standing in contrast to the few studies available in animals, particularly in nonhuman primates. In the present experiments, we studied the effect of the serial order of stimuli and associated movements in macaque monkeys overtrained to make arm-reaching movements in response to spatially distinct visual targets. Under different conditions, the temporal structure of the motor sequence was varied by changing the duration of the interval between successive target stimuli or by adding a cue that reliably signaled the onset time of the forthcoming target stimulus. In each condition, the extent to which the monkeys are sensitive to the spatial regularities was assessed by comparing performance when stimulus locations follow a repeating sequence, as opposed to a random sequence. We observed no improvement in task performance on repeated sequence blocks, compared to random sequence blocks, when target stimuli are relatively distant from each other in time. On the other hand, the shortening of the time interval between successive target stimuli or, more efficiently, the addition of a temporal cue before the target stimulus yielded a performance advantage under repeated sequence, reflected in a decrease in the latency of arm and saccadic eye movements accompanied by an increased tendency for eye movements to occur in an anticipatory manner. Contrary to the effects on movement initiation, the serial order of stimuli and movements did not markedly affect the execution of movement. Moreover, the location of a given target in the random sequence influenced task performance based on the location of the preceding target, monkeys being faster in responding as a result of familiarity caused by extensive practice with some target transitions also used in the repeated sequence. This performance advantage was most prominently detectable when temporal prediction of forthcoming target stimuli was optimized. Taken together, the present findings demonstrate that the monkey's capacity to make use of serial order information to speed task performance was dependent on the temporal structure of the motor sequence.

The role of striatal tonically active neurons in reward prediction error signaling during instrumental task performance.

The detection of differences between predictions and actual outcomes is important for associative learning and for selecting actions according to their potential future reward. There are reports that tonically active neurons (TANs) in the primate striatum may carry information about errors in the prediction of rewards. However, this property seems to be expressed in classical conditioning tasks but not during performance of an instrumental task. To address this issue, we recorded the activity of TANs in the putamen of two monkeys performing an instrumental task in which probabilistic rewarding outcomes were contingent on an action in block-design experiments. Behavioral evidence suggests that animals adjusted their performance according to the level of probability for reward on each trial block. We found that the TAN response to reward was stronger as the reward probability decreased; this effect was especially prominent on the late component of the pause-rebound pattern of typical response seen in these neurons. The responsiveness to reward omission was also increased with increasing reward probability, whereas there were no detectable effects on responses to the stimulus that triggered the movement. Overall, the modulation of TAN responses by reward probability appeared relatively weak compared with that observed previously in a probabilistic classical conditioning task using the same block design. These data indicate that instrumental conditioning was less effective at demonstrating prediction error signaling in TANs. We conclude that the sensitivity of the TAN system to reward probability depends on the specific learning situation in which animals experienced the stimulus-reward associations.

Modulation of neuronal activity in the monkey putamen associated with changes in the habitual order of sequential movements.

The striatum, especially its dorsolateral part, plays a major role in motor skill learning and habit formation, but it is still unclear how this contribution might be mediated at the neuronal level. We recorded single neurons in the posterior putamen of two monkeys performing an overlearned sequence of arm reaching movements to examine whether task-related activities are sensitive to manipulations of the serial order of stimulus-target locations. The monkeys' capacity to learn sequential regularities was assessed by comparing arm movement latencies and saccadic ocular reactions when a fixed repeating sequence was replaced with a random sequence. We examined neurons classified as phasically active projection neurons (PANs) and tonically active presumed cholinergic interneurons (TANs). About one-third of the PANs (35/106, 33%) activated during specific parts of a trial displayed modulations of their level of activation when the sequential structure was changed. This differential activity consisted of either decreases or increases in activity without altering the time period during which task-related activations occurred. In addition, half of the TANs (41/80, 51%) changed their responses to task stimuli with the sequence switch, indicating that the response selectivity of TANs reflects the detection of the context that requires adaptation to changes in the serial order of stimulus presentations. Our findings suggest that task-related changes in activity of projection neurons may be an important factor contributing to the production and adjustment of sequential behavior executed in an automatic fashion, whereas putative interneurons may provide a signal for performance monitoring in specific contexts.

Tonically active neurons in the striatum differentiate between delivery and omission of expected reward in a probabilistic task context.

Tonically active neurons (TANs) in the primate striatum are responsive to rewarding stimuli and they are thought to be involved in the storage of stimulus-reward associations or habits. However, it is unclear whether these neurons may signal the difference between the prediction of reward and its actual outcome as a possible neuronal correlate of reward prediction errors at the striatal level. To address this question, we studied the activity of TANs from three monkeys trained in a classical conditioning task in which a liquid reward was preceded by a visual stimulus and reward probability was systematically varied between blocks of trials. The monkeys' ability to discriminate the conditions according to probability was assessed by monitoring their mouth movements during the stimulus-reward interval. We found that the typical TAN pause responses to the delivery of reward were markedly enhanced as the probability of reward decreased, whereas responses to the predictive stimulus were somewhat stronger for high reward probability. In addition, TAN responses to the omission of reward consisted of either decreases or increases in activity that became stronger with increasing reward probability. It therefore appears that one group of neurons differentially responded to reward delivery and reward omission with changes in activity into opposite directions, while another group responded in the same direction. These data indicate that only a subset of TANs could detect the extent to which reward occurs differently than predicted, thus contributing to the encoding of positive and negative reward prediction errors that is relevant to reinforcement learning.

Leading tonically active neurons of the striatum from reward detection to context recognition.

Tonically active neurons (TANs) in the primate striatum, which are presumed to be cholinergic interneurons, carry signals that are traditionally considered to be important for reward-related learning. Recent studies investigating the functional properties of TANs in behaving monkeys have shown that other factors beyond motivation can affect their responsiveness. There is now evidence that TAN responses reflect stimulus detection, movement control and recognition of a specific context, suggesting that these local circuit neurons contribute to different computations used in learning and action functions of the striatum. This is consistent with the view that TAN responses could represent an important component of the processes that are responsible for the ability to select the appropriate behavioral response to environmental events.

Influence of spatial information on responses of tonically active neurons in the monkey striatum.

Previous studies have demonstrated that tonically active neurons (TANs) in the primate striatum play an important role in the detection of rewarding events. However, the influence of the spatial features of stimuli or actions required to obtain reward remains unclear. Here, we examined the activity of TANs in the striatum of monkeys trained to make spatially directed movements elicited by visual stimuli presented ipsilaterally or contralaterally to the moving arm. Among 181 neurons responding to the trigger stimulus, 127 (70%) were nonselective for stimulus location and 54 (30%) responded to only one location of the stimulus. Most of the selective responses (63%) occurred when the stimulus was presented contralaterally to the moving arm. To examine whether TAN responses are related to the location of the stimulus or to the direction of the movement, we tested a subset of the trigger-responsive neurons (n = 44) in a condition that elicited reaching toward or away from the stimulus. By comparing TAN activity between the two conditions, we found that half of the responses can be interpreted as being related to the location of the stimulus, one quarter to the direction of movement, and one quarter to the context in which stimulus-movement combination occurs. These results demonstrate that TANs are not limited to motivational processing, but may play a role in the processing of spatial attributes of stimulus and/or movement as well. These response properties suggest that TANs are involved in the flexible shifting of motor responses during spatially directed behavior.

Reward-related neuronal activity in the subthalamic nucleus of the monkey.

The subthalamic nucleus is a key structure for motor information processing in the basal ganglia. Little is known about its involvement in other aspects of behavior such as motivation. We investigated neuronal activity in the subthalamic nucleus while a monkey performed arm-reaching movements to obtain a liquid reward. Most neurons were modulated both during the movement and reward phases of the task. The changes in activity occurring after or just before the delivery of reward consisted of either increases or decreases in firing and were not directly related to mouth movements. These findings indicate that STN neurons are involved in the detection and expectation of reward, consistent with a role for these neurons in the processing of motivational information.

Responses of tonically active neurons in the monkey striatum discriminate between motivationally opposing stimuli.

The striatum is involved in the control of appetitively motivated behavior. We found previously that tonically active neurons (TANs) in the monkey striatum show discriminative responses to different stimuli that are appetitive or aversive. However, these differential responses may reflect the sensory qualities of the stimulus rather than its motivational value. In the present study, we sought to define more precisely the relationship between the particular aspect of the response of TANs and the motivational value of stimuli. For this purpose, three monkeys were presented with two types of aversive stimuli (loud sound and air puff) and one appetitive stimulus (fruit juice). In most instances, the TAN responses to the loud sound and the air puff were similar, in terms of response pattern and duration, whereas responses to the liquid reward showed distinct features. Using classical appetitive conditioning, we reversed the motivational value of a stimulus so that a previously aversive stimulus was now associatively paired with a reward and found that this manipulation selectively modifies the expression of TAN responses to the stimulus. These data indicate that the characteristics of neuronal responses undergo modifications when the valence of the stimulus is changed from aversive to appetitive during associative learning, suggesting that TANs may contribute to a form of stimulus encoding that is dependent on motivational attributes. The adaptation of TAN responses such as observed in the present study likewise reflects a neuronal system that adjusts to the motivational information about environmental events.

Tonically active neurons in the primate striatum and their role in the processing of information about motivationally relevant events.

Analysis of recordings of single neuronal activity in the striatum of monkeys engaged in behavioural tasks has shown that tonically active neurons (TANs) can be distinguished by their distinct spontaneous firing and functional properties. As TANs are assumed to be cholinergic interneurons, the study of their physiological characteristics allows us to gain an insight into the role of a particular type of local-circuit neuron in the processing of information at the striatal level. In monkeys performing various behavioural tasks, the change in the activity of TANs, unlike the diversity of task-related activations exhibited by the phasically active population of striatal neurons, involves a transient depression of the tonic firing related to environmental events of motivational significance. Such events include primary rewards and stimuli that have acquired a reward value during associative learning. These neurons also respond to an aversive air puff, indicating that their responsiveness is not restricted to appetitive conditions. Another striking feature of the TANs is that their responses can be modulated by predictions about stimulus timing. Temporal variations in event occurrence have been found to favour the responses of TANs, whereas the responses are diminished or abolished in the presence of external cues that predict the time at which events will occur. These data suggest that the TANs respond as do detectors of motivationally relevant events, but they also demonstrate that these neurons are influenced by predictive information based on past experience with a given temporal context. TANs represent a unique subset of striatal neurons that might serve a modulatory function, monitoring for temporal relationships between environmental events.