Temporal specificity in Pavlovian-to-instrumental transfer.

Presentation of a previously trained Pavlovian conditioned stimulus while an organism is engaged in operant responding can moderate the rate of responding, a phenomenon known as Pavlovian-to-instrumental transfer. Although it is well known that Pavlovian contingencies will generate conditioned behavior that is temporally organized with respect to the arrival of the predicted outcome, little work has examined the temporal dynamics of responding during Pavlovian-instrumental transfer. We trained rats using a fixed time 60-sec, fixed time 120-sec, or random time 60-sec schedule in an appetitive Pavlovian task, and found that presentation of the conditioned stimulus potentiated operant responding in a manner that reflected these previously established temporal expectancies. Further, this temporal specificity conformed to the scalar property as seen with other forms of interval timing behavior. Surprisingly, this effect was only seen when the conditioned stimulus was a visual cue, but not when it was an auditory cue. These data suggest that the motivational processes triggered by Pavlovian cues are not static, but fluctuate in strength as a function of temporally specific expectations of reward.

Rodent Medial Frontal Control of Temporal Processing in the Dorsomedial Striatum.

Although frontostriatal circuits are critical for the temporal control of action, how time is encoded in frontostriatal circuits is unknown. We recorded from frontal and striatal neurons while rats engaged in interval timing, an elementary cognitive function that engages both areas. We report four main results. First, "ramping" activity, a monotonic change in neuronal firing rate across time, is observed throughout frontostriatal ensembles. Second, frontostriatal activity scales across multiple intervals. Third, striatal ramping neurons are correlated with activity of the medial frontal cortex. Finally, interval timing and striatal ramping activity are disrupted when the medial frontal cortex is inactivated. Our results support the view that striatal neurons integrate medial frontal activity and are consistent with drift-diffusion models of interval timing. This principle elucidates temporal processing in frontostriatal circuits and provides insight into how the medial frontal cortex exerts top-down control of cognitive processing in the striatum.SIGNIFICANCE STATEMENT The ability to guide actions in time is essential to mammalian behavior from rodents to humans. The prefrontal cortex and striatum are critically involved in temporal processing and share extensive neuronal connections, yet it remains unclear how these structures represent time. We studied these two brain areas in rodents performing interval-timing tasks and found that time-dependent "ramping" activity, a monotonic increase or decrease in neuronal activity, was a key temporal signal. Furthermore, we found that striatal ramping activity was correlated with and dependent upon medial frontal activity. These results provide insight into information-processing principles in frontostriatal circuits.

Temporal averaging across multiple response options: insight into the mechanisms underlying integration.

Rats trained on a dual-duration, dual-modality peak-interval procedure (e.g., tone = 10 s/light = 20 s) often show unimodal response distributions with peaks that fall in between the anchor durations when both cues are presented as a simultaneous compound. Two hypotheses can explain this finding. According to the averaging hypothesis, rats integrate the anchor durations into an average during compound trials, with each duration being weighted by its respective reinforcement probability. According to the simultaneous temporal processing hypothesis, rats time both durations veridically and simultaneously during compound trials and respond continuously across both durations, thereby producing a unimodal response distribution with a peak falling in between the anchor durations. In the present compounding experiment, rats were trained to associate a tone and light with two different durations (e.g., 5 and 20 s, respectively). However, in contrast to previous experiments, each cue was also associated with a distinct response requirement (e.g., left nosepoke for tone/right nosepoke for light). On the majority of compound trials, responding on a given nosepoke fell close to its respective duration, but was shifted in the direction of the other cue's duration, suggesting rats timed an average of the two durations. However, more weight appeared to be given to the duration associated with the manipulandum on which the rat responded, rather than the duration associated with a higher reinforcement probability as predicted by the averaging hypothesis. Group differences were also observed, with rats trained to associate the tone and light with the short and long durations, respectively, being more likely to show these shifts than the counterbalanced modality-duration group (i.e., light-short/tone-long). This parallels group differences observed in past studies and suggest that cue weighting in response to stimulus compounds is influenced by the modality-duration relationship of the anchor cues. The current results suggest that temporal averaging is a more flexible process than previously theorized and provide novel insight into the mechanisms that affect cue weighting.

The influence of multiple temporal memories in the peak-interval procedure.

Memories for when an event has occurred are used to anticipate future occurrences of the event, but what happens when the event is equally likely to occur at two different times? In this study, one group of rats was always reinforced at 21 s on the peak-interval procedure (21-only group), whereas another group of rats was reinforced at either 8 or 21 s, which varied daily (8-21 group). At the beginning of each session, the behavior of the 8-21 group largely lacked temporal control, but by the end of the session, temporal control was reestablished. When both groups were reinforced at 21 s, the patterns of responding were indistinguishable after subjects in the 8-21 group had experienced 13 reinforcement trials. Finally, the reinforcement times of previous sessions affected the 8-21 group, such that subjects were biased depending on the reinforcement time of the prior session. These results show that when the reinforcement time is initially ambiguous, rats respond in a way that combines their expectations of both possibilities; then they incrementally adjust their responding as they receive more information, but still information from prior sessions biases their initial expectation for the reinforcement time. Combined, these results imply that rats are sensitive to the age of encoded temporal memories in an environment in which the reinforcement time is variable. How these results inform the scalar expectancy theory, the currently accepted model of interval-timing behavior, is discussed.

Searching for the holy grail: temporally informative firing patterns in the rat.

This chapter reviews our work from the past decade investigating cortical and striatal firing patterns in rats while they time intervals in the multi-seconds range. We have found that both cortical and striatal firing rates contain information that the rat can use to identify how much time has elapsed both from trial onset and from the onset of an active response state. I describe findings showing that the striatal neurons that are modulated by time are also modulated by overt behaviors, suggesting that time modulates the strength of motor coding in the striatum, rather than being represented as an abstract quantity in isolation. I also describe work showing that there are a variety of temporally informative activity patterns in pre-motor cortex, and argue that the heterogeneity of these patterns can enhance an organism's temporal estimate. Finally, I describe recent behavioral work from my lab in which the simultaneous cueing of multiple durations leads to a scalar temporal expectation at an intermediate time, providing strong support for a monotonic representation of time.

Fast forward: supramarginal gyrus stimulation alters time measurement.

The neural basis of temporal processing is unclear. We addressed this important issue by performing two experiments in which repetitive transcranial magnetic stimulation (rTMS) was administered in different sessions to the left or right supramarginal gyrus (SMG) or vertex; in both tasks, two visual stimuli were presented serially and subjects were asked to judge if the second stimulus was longer than the first (standard) stimulus. rTMS was presented on 50% of trials. Consistent with a previous literature demonstrating the effect of auditory clicks on temporal judgment, rTMS was associated with a tendency to perceive the paired visual stimulus as longer in all conditions. Crucially, rTMS to the right SMG was associated with a significantly greater subjective prolongation of the associated visual stimulus in both experiments. These findings demonstrate that the right SMG is an important element of the neural system underlying temporal processing and, as discussed, have implications for neural and cognitive models of temporal perception and attention.

Averaging of temporal memories by rats.

Rats were trained on a mixed fixed-interval schedule in which stimulus A (tone or light) indicated food availability after 10 s and stimulus B (the other stimulus) indicated food availability after 20 s. Testing consisted of nonreinforced probe trials in which the stimulus was A, B, or the compound AB. On single-stimulus trials, rats responded with a peak of activity around the programmed reinforced time. On compound-stimulus trials, rats showed a single scalar peak of responding at a time midway between those for stimulus A and B. These results suggest that when provided with discrepant information regarding the temporal predictability of reinforcement, rats compute an average of the scheduled reinforcement times for the A and B stimuli and use this average to generate an expectation of reward for the compound stimuli.

Striatal dopamine and the temporal control of behavior.

Striatal dopamine strongly regulates how individuals use time to guide behavior. Dopamine acts on D1- and D2- dopamine receptors in the striatum. However, the relative role of these receptors in the temporal control of behavior is unclear. To assess this, we trained rats on a task in which they decided to start and stop a series of responses based on the passage of time and evaluated how blocking D1 or D2-dopamine receptors in the dorsomedial or dorsolateral striatum impacted performance. D2 blockade delayed the decision to start and stop responding in both regions, and this effect was larger in the dorsomedial striatum. By contrast, dorsomedial D1 blockade delayed stop times, without significantly delaying start times, whereas dorsolateral D1 blockade produced no detectable effects. These findings suggest that striatal dopamine may tune decision thresholds during timing tasks. Furthermore, our data indicate that the dorsomedial striatum plays a key role in temporal control, which may be useful for localizing neural circuits that mediate the temporal control of action.

Accurate timing but increased impulsivity following excitotoxic lesions of the subthalamic nucleus.

Several lines of evidence have implicated the subthalamic nucleus (STN) in behaviors that require precise temporal control. In order to investigate this possibility further, we trained rats to perform a peak-interval (PI) timing task [S. Roberts, Isolation of an internal clock, J. Exp. Psychol. Anim. B 7 (1981) 242-268] with two durations (10 s and 40 s), and then lesioned the STN by microinjection of ibotenic acid. Lesioned animals were able to maintain precise temporal control, yet were unable to inhibit operant responses late in the trial, at times that were unlikely to yield reinforcement. These results indicate the involvement of the STN in impulsive or perseverative response inhibition, but not in temporal processing.

5-HT1a Receptor Involvement in Temporal Memory and the Response to Temporal Ambiguity.

It has previously been demonstrated that rats trained on the peak-interval procedure to associate two different cues with two different fixed interval schedules will generate a scalar peak function at an intermediate time when presented with the compound cue. This response pattern has been interpreted as resulting from the simultaneous retrieval of different temporal memories, and a consequential averaging process to resolve the ambiguity. In the present set of studies, we investigated the role that serotonin 1a receptors play in this process. In Experiment 1, rats were trained on a peak-interval procedure to associate the interoceptive states induced by saline and the 5-HT1a agonist, 8-OH-DPAT, with a 5 s or 20 s fixed-interval schedule signaled by the same tone cue (counter-balanced). While peak functions following administration of saline were centered at the appropriate time (5 s or 20 s), peak functions following administration of the agonist were centered around 7 s, irrespective of the reinforced time during training, suggesting agonist-induced disruption in selective temporal memory retrieval, resulting in increased ambiguity regarding the appropriate time at which to respond. In Experiment 2, rats were trained in a peak-interval procedure to associate a tone cue with a 10 s fixed interval and a light cue with a 20 s fixed interval. Administration of the 5-HT1a antagonist, WAY-100635, had no impact on timing when single cues were presented, but altered the intermediate, scalar, response to the stimulus compound, suggesting antagonist-induced disruption in the processes used to deal with temporal memory ambiguity. Together, these data suggest that manipulations of 5HT transmission at the 5-HT1a receptor cause changes in the temporal pattern of responding that are consistent with alterations in temporal memory processes and responses to temporal ambiguity.

Recalibrating timing behavior via expected covariance between temporal cues.

Individuals must predict future events to proactively guide their behavior. Predicting when events will occur is a critical component of these expectations. Temporal expectations are often generated based on individual cue-duration relationships. However, the durations associated with different environmental cues will often co-vary due to a common cause. We show that timing behavior may be calibrated based on this expected covariance, which we refer to as the 'common cause hypothesis'. In five experiments using rats, we found that when the duration associated with one temporal cue changes, timed-responding to other cues shift in the same direction. Furthermore, training subjects that expecting covariance is not appropriate in a given situation blocks this effect. Finally, we confirmed that this transfer is context-dependent. These results reveal a novel principle that modulates timing behavior, which we predict will apply across a variety of magnitude-expectations.

Evidence for separate neural mechanisms for the timing of discrete and sustained responses.

Methamphetamine (MAP), an indirect dopamine agonist, has been shown to produce a leftward shift in the time of responding under operant response protocols that encourage repetitive responding (e.g., lever pressing). Given the involvement of striatal dopamine activity in the control of discrete motor behavior, as well as in the timing of these responses, an important question arises as to whether a dissociation is possible between changes in the timing of discrete responding and timing of other behaviors. Rats were trained on a modified peak-interval (PI) procedure such that reward was contingent upon the presence of the animal's snout in a nosepoke apparatus at the target time, as an alternative to the typical requirement of a discrete head entry response. Thus spatial selection, but not necessarily motor behavior, at the appropriate time was required to receive a reward. Rats were given MAP in one of 3 doses (0.5, 1.0, or 1.5 mg/kg), or a saline control injection before PI sessions to determine whether the drug elicits a dose-dependent effect on timing of spatial position, as it has been shown to do for discrete behaviors. Following administration of MAP, the peak time of the proportion of time spent in the nosepoke did not change, while the peak time of the rate of response shifted to the left. Single-trial analysis revealed a similar pattern: Position of response step functions defined by being in the nosepoke did not shift, but step functions based on response rate changed with increasing doses of MAP. These data support a model of multiple timing processes controlling different behaviors, at least one of which is specific to discrete motor behavior and is modifiable by dopamine.

Impulsive responding on the peak-interval procedure.

The pattern of responding on a peak-interval timing task allows one to make inferences regarding the sources of variation that contribute to interval timing behavior. Non-temporal factors such as impulsivity may impact the validity of these inferences. Rats were trained on a 15s peak-interval procedure (PI) or a mixed 15s behaviorally dependent variable-interval, 15s peak-interval procedure (bdVIPI) for an extended number of sessions. Extended training on the PI revealed a bi-modal distribution in the times at which subjects started responding for temporally predictable reinforcement, suggesting that multiple processes contribute to the behavioral pattern obtained in this procedure. Training on the bdVIPI eliminated the early mode of this bi-modal distribution, thereby decreasing the variation in start times. These results suggest that alternative response options can modulate the influence of impulsivity in timing tasks.

Single-trials analyses demonstrate that increases in clock speed contribute to the methamphetamine-induced horizontal shifts in peak-interval timing functions.

INTRODUCTION: Drugs that increase dopamine (DA) transmission have been shown to produce an overestimation of time in duration production procedures as exhibited by horizontal leftward shifts of the psychophysical functions. However, the generality of these results has been inconsistent in the literature. MATERIALS AND METHODS: The present report evaluates the effects of five doses of methamphetamine (MAP) (0.5-1.5 mg/kg, i.p.) on two duration production procedures, the single duration peak-interval (PI) procedure and the multiduration tri-peak procedure in rats. RESULTS: We replicated and extended prior results by showing a dose-dependent proportional overestimation of time that was equivalent on both procedures (i.e., subjects behaved as though they expected reinforcement to be available earlier in real time). Single-trials analyses demonstrated that the reduction in peak rate that is often observed after MAP administration is due to an increase in the proportion of trials in which responding occurred at very low rates and without temporal control. However, these low-rate trials were not the source of the leftward shift in the temporal estimates. Rather, we found that the leftward shift of the PI functions was due to proportional changes in the placement of temporally controlled high-rate responding, which is consistent with a DA-mediated alteration in clock speed.

Dopamine D1 activation shortens the duration of phases in stereotyped grooming sequences.

Rats frequently emit grooming actions in a highly stereotyped, syntactic chain in which three distinct phases of facially directed forearm movements are sequentially emitted in a rule-governed pattern and followed by body-directed licking. The present study evaluated the effects of the full dopamine D1 agonist, SKF 81297, and the partial dopamine D1 agonist, SKF 38393, on the duration of individual phases of stereotyped grooming chains. We found that systemic administration of SKF 81297 significantly shortened grooming chain duration. An examination of the fine temporal structure of syntactic grooming chain actions showed that duration changes were correlated with decreased numbers of actions in phases I and IV of the chain. Phases II and III were not changed in duration, although there were some structural distortions introduced. The partial D1 agonist, SKF 38393, had no effect on duration or number of component actions in the grooming chain. Based on these results, we hypothesize that the timing of syntactic grooming phase transitions may involve a D1-mediated internal clock process that is altered by full D1 agonist activation. By this model, SKF 81297 increases the speed of the clock used for the temporal control of grooming actions, and thus shortens phase durations.

Interval timing, temporal averaging, and cue integration.

In a series of recent experiments, we found that if rats are presented with two temporal cues, each signifying that reward will be delivered after a different duration elapses (e.g., tone-10 seconds / light-20 seconds), they will behave as if they have computed a weighted average of these respective durations. In the current article, we argue that this effect, referred to as "temporal averaging", can be understood within the context of Bayesian Decision Theory. Specifically, we propose and provide preliminary data showing that, when averaging, rats weight different durations based on the relative variability of the information their respective cues provide.

Interval timing and the encoding of signal duration by ensembles of cortical and striatal neurons.

This study investigated the firing patterns of striatal and cortical neurons in rats in a temporal generalization task. Striatal and cortical ensembles were recorded in rats trained to lever press at 2 possible criterion durations (10 s or 40 s from tone onset). Twenty-two percent of striatal and 15% of cortical cells had temporally specific modulations in their firing rate, firing at a significantly different rate around 10 s compared with 40 s. On 80% of trials, a post hoc analysis of the trial-by-trial consistency of the firing rates of an ensemble of neurons predicted whether a spike train came from a time window around 10 s versus around 40 s. Results suggest that striatal and cortical neurons encode specific durations in their firing rate and thereby serve as components of a neural circuit used to represent duration.

Differential modulation of clock speed by the administration of intermittent versus continuous cocaine.

The roles that psychostimulant sensitization and tolerance play in temporal perception in the seconds-to-minutes range were assessed in rats. Cocaine (20 mg/kg/day) was administered for 2 weeks either intermittently via daily injections (induces sensitization) or continuously via an osmotic minipump (induces tolerance). Interval timing was evaluated throughout administration and withdrawal. Injections of cocaine caused immediate, proportional, leftward shifts in peak times, indicating an increase in the speed of an internal clock. These shifts grew progressively larger with repeated administration, indicating that stimulant-induced increases in clock speed can be sensitized. Continuous cocaine administration produced no reliable effects. These results suggest that the mechanisms of sensitization may play a considerable role in drug-induced alterations of the perception of time.

Cortico-striatal circuits and interval timing: coincidence detection of oscillatory processes.

Humans and other animals demonstrate the ability to perceive and respond to temporally relevant information with characteristic behavioral properties. For example, the response time distributions in peak-interval timing tasks are well described by Gaussian functions, and superimpose when scaled by the criterion duration. This superimposition has been referred to as the scalar property and results from the fact that the standard deviation of a temporal estimate is proportional to the duration being timed. Various psychological models have been proposed to account for such responding. These models vary in their success in predicting the temporal control of behavior as well as in the neurobiological feasibility of the mechanisms they postulate. A review of the major interval timing models reveals that no current model is successful on both counts. The neurobiological properties of the basal ganglia, an area known to be necessary for interval timing and motor control, suggests that this set of structures act as a coincidence detector of cortical and thalamic input. The hypothesized functioning of the basal ganglia is similar to the mechanisms proposed in the beat frequency timing model [R.C. Miall, Neural Computation 1 (1989) 359-371], leading to a reevaluation of its capabilities in terms of behavioral prediction. By implementing a probabilistic firing rule, a dynamic response threshold, and adding variance to a number of its components, simulations of the striatal beat frequency model were able to produce output that is functionally equivalent to the expected behavioral response form of peak-interval timing procedures.

Reinforcement probability modulates temporal memory selection and integration processes.

We have previously shown that rats trained in a mixed-interval peak procedure (tone=4s, light=12s) respond in a scalar manner at a time in between the trained peak times when presented with the stimulus compound (Swanton & Matell, 2011). In our previous work, the two component cues were reinforced with different probabilities (short=20%, long=80%) to equate response rates, and we found that the compound peak time was biased toward the cue with the higher reinforcement probability. Here, we examined the influence that different reinforcement probabilities have on the temporal location and shape of the compound response function. We found that the time of peak responding shifted as a function of the relative reinforcement probability of the component cues, becoming earlier as the relative likelihood of reinforcement associated with the short cue increased. However, as the relative probabilities of the component cues grew dissimilar, the compound peak became non-scalar, suggesting that the temporal control of behavior shifted from a process of integration to one of selection. As our previous work has utilized durations and reinforcement probabilities more discrepant than those used here, these data suggest that the processes underlying the integration/selection decision for time are based on cue value.