Timing Behavior

Catalin V. Buhusi1, Warren H. Meck2

department of Neurosciences, Medical University of

South Carolina, Charleston, SC, USA

2Center for Behavioral Neuroscience and Genomics,

Duke University, Durham, NC, USA

Synonyms

Interval timing; Temporal processing; Timing conditioning; Temporal

Definition

Timing accuracy refers to the estimated duration. Timing accuracy is estimated by the mean or peak time of the response distribution (see Gibbon et al., 1997).

Definition

Timing behavior refers to the capacity of subjects to perceive, estimate, and discriminate time intervals (e.g., durations of and between events), to emit (or avoid emitting) behavioral responses at appropriate time intervals, and more generally, to modulate their behavior in time (Buhusi and Meck 2005; Gibbon et al. 1997). Timing behavior includes millisecond timing, ► interval timing, and circadian timing. Millisecond timing refers to the perception, estimation, and discrimination of durations in the subsecond range, crucial for motor control, speech generation and recognition, and music production and perception. Disorders of millisecond timing may result in disorders of motor control (see ► motor activity and stereotypy). Circadian timing (see ► circadian rhythms) refers to repetition of certain phenomena at about the same time each day as a function of the light/dark cycle. The most studied circadian rhythm is sleep, but other examples include body temperature, blood pressure, production of hormones, and digestive secretions. Here, we discuss the effect of psychoactive drugs on timing behavior in the seconds-to-minutes range (interval timing) which is considered crucial to learning and cognition (Gallistel and Gibbon 2000; Williamson et al. 2008).

Impact of Psychoactive Drugs

Protocols Used to Investigate the Neuropharmacology of Interval Timing

The most reliable approach to investigate the neurophar-macology of interval timing in humans and animals is to use a ► reproduction protocol, such as the ► peak-interval (PI) procedure (Matell et al. 2006) although a variety of different timing procedures can be used (see Paule et al. 1999). Idealized data from a PI procedure in two groups of subjects trained to time different durations are shown in Fig. 1. The subject's responses distribute normally around the criterion duration, and the width of this distribution is proportional to the criterion. The way in which the mean and standard deviation of the response distribution covary is typically referred to as the ► scalar property (Gibbon et al. 1997), a strong form of Weber's Law, which is obeyed by most sensory dimensions. The scalar property applies not only to behavioral responses, but also to neural activity as measured by electrophysio-logical recordings as well as the hemodynamic response

Timing Behavior. Fig. 1. The scalar property is a hallmark of interval timing at both the behavioral and neural levels. In a typical duration reproduction procedure called the PI procedure, subjects receive training trials, during which they are presented with target stimuli of specific durations (here, panel A: 8 s, panel C: 21 s), and test trials, in which the subjects are asked to reproduce the criterion duration. Typically, in peak trials the responses distribute normally around the criterion duration with a width that is proportional to the criterion. When the response distributions are scaled both in amplitude and duration they superimpose, thus demonstrating the scalar property at the behavioral level. (Redrawn from Buhusi and Meck 2005.)

Timing Behavior. Fig. 1. The scalar property is a hallmark of interval timing at both the behavioral and neural levels. In a typical duration reproduction procedure called the PI procedure, subjects receive training trials, during which they are presented with target stimuli of specific durations (here, panel A: 8 s, panel C: 21 s), and test trials, in which the subjects are asked to reproduce the criterion duration. Typically, in peak trials the responses distribute normally around the criterion duration with a width that is proportional to the criterion. When the response distributions are scaled both in amplitude and duration they superimpose, thus demonstrating the scalar property at the behavioral level. (Redrawn from Buhusi and Meck 2005.)

associated with a subject's active reproduction of a timed interval, but not for passive responses triggered at the untimed interval (Buhusi and Meck 2005).

Estimating the Effect of Psychoactive Drugs

The PI procedure with gaps allows the independent assessment of the effect of psychoactive drugs on timing (► timing accuracy and ► timing precision), as well as their ► attentional effect, and allows the dissociation of these effects from motor/motivational effects as illustrated in Fig. 2. Generally speaking motor/motivational effects of drugs are observed as shifts in the amplitude of the response functions along the vertical axis, while effects on timing are observed as leftward or rightward shifts in the response function along the horizontal axis. Timing accuracy is estimated by the peak of the response function in ► peak trials (Fig. 2 - left panel). Timing precision is estimated by the width of the response function in peak trials (Fig. 2 - left panel). ► Attentional effects are estimated by inserting gaps (e.g., retention intervals) in a subset of peak trials (Fig. 2 - right panel). For illustrative purposes, Fig. 2 shows the effect of systemic administration of the dopamine D2 antagonist ► haloperidol in the PI procedure with gaps. Haloperidol has both motor/ motivational and timing effects: It not only reduces the amplitude of the response function (Fig. 2 - left and right panels), but also produces an immediate proportional rightward shift in the peak function (e.g., slows down the speed of the clock as shown in Fig. 2 - left panel).

When retention intervals are inserted in the to-be-timed duration, haloperidol also increases the attention to time (attentional effect): It diminishes the resetting effect of the retention intervals as shown in Fig. 2 (rightpanel) (Buhusi 2003).

Dopaminergic Drugs: The Clock-Speed Effect

Dopaminergic drugs selectively affect the subjective speed of an internal clock in a variety of animals (Buhusi and Meck 2005; Meck 1996) (Fig. 3). More specifically, when timing is evaluated in the PI procedure, dopamine agonists produce an immediate leftward shift of response function in proportion to the to-be-timed criterion, indicative of an increase of the speed of an internal clock. In contrast, dopamine antagonists produce an immediate rightward shift of response function in proportion to the to-be-timed criterion, indicative of a decrease in the speed of an internal clock (Fig. 3a) (Meck 1996). Repeated administration of dopaminergic drugs is followed by a characteristic decrease in the effect of the drug (Fig. 3a), which is not interpreted as desensitization but rather as recalibration of the timer. The interruption of the drug regimen results in a rebound in the opposite direction (Meck 1996). Dopamine antagonists were shown to produce a deceleration of the subjective clock speed in proportion to their affinity to dopamine D2 receptor (Fig. 3b) (Meck 1996). The effects of dopamine drugs on clock speed are diminished as a function of experience with the timing task (habit formation) prior to drug administration which

Timing Behavior. Fig. 2. The PI procedure with gaps allows the independent assessment of the effect of a drug on timing accuracy, timing precision, and attention to timing. Here are data from groups of subjects trained to time a 30-s PI procedure, tested under systemic administration of saline and the dopamine D2 antagonist haloperidol (0.04-0.06 mg/kg i.p). Timing accuracy is estimated by the peak response rate, timing precision by the width of the response function, and attentional effect by the delay of the response function in trials with gaps (right) relative to trials without gaps (left). Left panel (peak trials): Motor/ motivational effects are observed as changes on the vertical axis, while timing effects are observed as proportional changes on the horizontal axis. Here, haloperidol has both motor/motivational effect as well as effect on timing: It slows down timing (rightward shift relative to saline control). Right panel (gap trials): Attentional effects are evaluated by introducing a gap (retention interval) on a subset of peak trials, which delays the response function. Motor/motivational effects are observed as changes on the vertical axis, while attentional effects are observed as absolute changes on the horizontal axis. Here, haloperidol has both a motor/motivational effect and an attentional effect: It reduces the delay following a retention interval, suggesting that subjects are paying more attention to the task. (Adapted from Buhusi 2003.)

Timing Behavior. Fig. 3. The effects of the dopamine D2 antagonist haloperidol on interval timing are consistent with the slowing down of time accumulation. Panel A: Two groups of subjects were trained to time two durations, using 20-s and 40-s PI procedures. Afterward, in test sessions, subjects received systemic administration of vehicle (VEH), then five consecutive sessions with systemic administration of haloperidol. Acute administration of haloperidol results in a sudden rightward shift that is proportional to the estimated durations, whereas its repeated administration results in a gradual return of the estimated time to the criterion duration. Panel B: The rightward shift of the estimated time is proportional to the affinity of the drug for the D2 dopamine receptor. (Adapted from Buhusi and Meck 2005.)

may reflect a change in the balance between dopamine-glutamate interactions (Williamson et al. 2008).

Cholinergic Drugs: The Memory-Storage Effect

When initially administered, cholinergic drugs have no immediate effects on interval timing. However, repeated administration of cholinergic agonists results in a gradual decrease of the estimated duration, while cholinergic antagonists result in a gradual increase of the estimated duration (Fig. 4a). Discontinuing the drug administration results in a gradual return to the baseline. These results are interpreted as alteration of memory storage of duration. More specifically, reference memory error was found to vary in proportion to cholinergic activity in frontal cortex (Buhusi and Meck 2005; Meck 1996) (Fig. 4b).

Serotonergic Drugs: The Attentional Effect

Time accumulation and attention to the timing task can be dissociated pharmacologically, and they depend on the dopamine and serotonin systems in the cortex and ► striatum (Buhusi and Meck 2009; Ho et al. 2002). Administration of the indirect dopamine agonist ► meth-amphetamine shortens estimated durations, and decreases attention to timing (Buhusi 2003). In turn, the dopamine D2 receptor blocker haloperidol lengthens estimated durations, but facilitates the maintenance in temporal information in working memory (Buhusi 2003). However, the effect of methamphetamine to shorten estimated durations is blocked by depletion of serotonin, suggesting that an intact serotonergic system is required for interval timing. Indeed, specific stimulation of either 5-HT1A or 5-HT2A receptors shortens estimated durations in qualitatively similar ways, an effect antagonized by specific blockade of these receptors. Interestingly, ► clozapine - a drug acting on both dopamine and serotonin systems - not only shortens the estimated durations but also facilitates the attention to time (attentional effect) during retention intervals (Buhusi and Meck 2009). Clozapine is reported to have differential effects on dopamine levels in the frontal cortex and striatum: It serves as a dopamine receptor antagonist in the mesolimbic dopaminergic system and as an indirect dopamine agonist in the frontal cortex by its activation of the serotonin 5-HT2A receptors on dopamine neurons. This pattern of pharmacological results is consistent with the hypothesis that the effect of clozapine on time estimation is due to an increase in dopamine neurotransmission in frontal cortex, but not in the dorsal striatum. Together, these data suggest that drug effects on time accumulation and attention to time rely on the interaction between the dopaminergic and serotonergic activation in frontal cortex and striatum (Buhusi and Meck 2009; Ho et al. 2002).

Drugs of Addiction

Acute exposure to ► psychostimulants, e.g., ► cocaine, ► methamphetamine, ► nicotine, etc., produces results compatible with the speeding up of an internal clock (Matell et al. 2006; Meck 1996; Paule et al. 1999). These

Acetylcholine and Ihe memory paltern

Timing Behavior. Fig. 4. The effects of cholinergic drugs are consistent with effects on reference memory. Panel A: Two groups of subjects were trained to time two durations, using 20-s and 40-s PI procedures. Afterward, in test sessions, subjects received systemic administration of VEH, then five consecutive sessions with systemic administration of the muscarinic cholinergic receptor atropine. Acute administration of atropine results in a gradual scalar (proportional to the timed criterion) rightward shift of the estimated time. Panel B: The effect is correlated with the activity of cholinergic neurons in the frontal cortex as measured by sodium-dependent high-affinity choline uptake (SDHACU). (Redrawn from Buhusi and Meck 2005.)

effects are believed to be linked to the addictive and rewarding properties of psychostimulants (see ► self-administration of drugs, ► addictive disorder, animal model), and are susceptible to the effects of overtraining and habit formation. In addition, repetitive, high-dose exposure to psychostimulants such as methamphetamine produces deficits in time perception, possibly due to neu-rotoxic effects on the dopaminergic system. Of particular interest is the observation that stimulant-dependent individuals exhibit impaired timing and time perception. Taken together, these findings may help to explain why human subjects that abuse methamphetamine or cocaine show more ► impulsivity and less self-control in decision making due to greater discounting of delayed rewards (Williamson et al. 2008).

A Model of Drug Action on Interval Timing

The striatal beat frequency (SBF) model of interval timing ascribes a mechanism for detecting event durations to medium spiny neurons within the dorsal striatum (Buhusi and Meck 2005). These striatal neurons have a set of functional properties that place them in an ideal position to detect behaviorally relevant patterns of afferent cortical input. Briefly, the SBF model posits that medium spiny neurons in the dorsal striatum become entrained to fire in response to oscillating, coincident cortical inputs that become active at a previously trained event duration. In the context of this model, the clock effect of dopaminergic drugs is interpreted as reflecting tonic dopamine levels within the striatum, modulating the oscillatory frequency within the cortex through corticostriato-thalamo-cortical feedback mechanisms. Similarly, the memory effect of cholinergic drugs is interpreted as affecting the synaptic weights of striatal median spiny neurons and tonically active interneurons (Buhusi and Meck 2009; Matell et al. 2006; Williamson et al. 2008).

Cross-References

► Addictive Disorder: Animal Models

► Behavioral Economics

► Circadian Rhythms

► Motor Activity and Stereotypy

► Self-Administration of Drugs

References

Buhusi CV (2003) Dopaminergic mechanisms of interval timing and attention. In: Meck WH (ed) Functional and neural mechanisms of interval timing. CRC Press, Boca Raton, pp 317-338 Buhusi CV, Meck WH (2005) What makes us tick? Functional and neural mechanisms of interval timing. Nat Rev Neurosci 6:755-765

Buhusi CV, Meck WH (2009) Relative time sharing: new findings and an extension of the resource allocation model of temporal processing. Philos Trans R Soc B 364(1525):1875-1885 Gallistel CR, Gibbon J (2000) Time, rate, and conditoning. Psychol Rev 107:289-344

Gibbon J, Malapani C, Dale CL, Gallistel CR (1997) Toward a neurobiol-ogy of temporal cognition: advances and challenges. Curr Opin Neurobiol 7:170-184 Ho MY, Velazquez-Martinez DN, Bradshaw CM, Szabadi E (2002) 5-Hydroxytryptamine and interval timing behaviour. Pharmacol Biochem Behav 71:773-785 Matell MS, Bateson M, Meck WH (2006) Single-trials analyses demonstrate that increases in clock speed contribute to the methamphetamine-induced horizontal shifts in peak-interval timing functions. Psycho-pharmacology 188:201-212 Meck WH (1996) Neuropharmacology of timing and time perception.

Cogn Brain Res 3:227-242 Paule MG, Meck WH, McMillan DE, McClure GYH, Bateson M, Popke EJ, Chelonis JJ, Hinton SC (1999) The use of timing behaviors in animals and humans to detect drug and/or toxicant effects. Neuro-toxicol Teratol 21:491-502 Williamson LL, Cheng RK, Etchegaray M, Meck WH (2008) ''Speed'' warps time: methamphetamine's interactive roles in drug abuse, habit formation, and the biological clocks of circadian and interval timing. Curr Drug Abuse Rev 1:203-212

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