Striatal dopamine D1 receptors control motivation to respond, but not interval timing, during the timing task.

Dopamine plays a critical role in behavioral tasks requiring interval timing (time perception in a seconds-to-minutes range). Although some studies demonstrate the role of dopamine receptors as a controller of the speed of the internal clock, other studies demonstrate their role as a controller of motivation. Both D1 dopamine receptors (D1DRs) and D2 dopamine receptors (D2DRs) within the dorsal striatum may play a role in interval timing because the dorsal striatum contains rich D1DRs and D2DRs. However, relative to D2DRs, the precise role of D1DRs within the dorsal striatum in interval timing is unclear. To address this issue, rats were trained on the peak-interval 20-sec procedure, and D1DR antagonist SCH23390 was infused into the bilateral dorsocentral striatum before behavioral sessions. Our results showed that the D1DR blockade drastically reduced the maximum response rate and increased the time to start responses with no effects on the time to terminate responses. These findings suggest that the D1DRs within the dorsal striatum are required for motivation to respond, but not for modulation of the internal clock speed.

Mediodorsal Thalamus Contributes to the Timing of Instrumental Actions.

The perception of time is critical to adaptive behavior. While prefrontal cortex and basal ganglia have been implicated in interval timing in the seconds to minutes range, little is known about the role of the mediodorsal thalamus (MD), which is a key component of the limbic cortico-basal ganglia-thalamocortical loop. In this study, we tested the role of the MD in timing, using an operant temporal production task in male mice. In this task, that the expected timing of available rewards is indicated by lever pressing. Inactivation of the MD with muscimol produced rightward shifts in peak pressing on probe trials as well as increases in peak spread, thus significantly altering both temporal accuracy and precision. Optogenetic inhibition of glutamatergic projection neurons in the MD also resulted in similar changes in timing. The observed effects were found to be independent of significant changes in movement. Our findings suggest that the MD is a critical component of the neural circuit for interval timing, without playing a direct role in regulating ongoing performance.SIGNIFICANCE STATEMENT The mediodorsal nucleus (MD) of the thalamus is strongly connected with the prefrontal cortex and basal ganglia, areas which have been implicated in interval timing. Previous work has shown that the MD contributes to working memory and learning of action-outcome contingencies, but its role in behavioral timing is poorly understood. Using an operant temporal production task, we showed that inactivation of the MD significantly impaired timing behavior.

Bidirectional role of microtubule dynamics in the acquisition and maintenance of temporal information in dorsolateral striatum.

Accurate and precise timing is crucial for complex and purposeful behaviors, such as foraging for food or playing a musical instrument. The brain is capable of processing temporal information in a coordinated manner, as if it contains an 'internal clock'. Similar to the need for the brain to orient itself in space in order to understand its surroundings, temporal orientation and tracking is an essential component of cognition as well. While there have been multiple models explaining the neural correlates of timing, independent lines of research appear to converge on the conclusion that populations of neurons in the dorsal striatum encode information relating to where a subject is in time relative to an anticipated goal. Similar to other learning processes, acquisition and maintenance of this temporal information is dependent on synaptic plasticity. Microtubules are cytoskeletal proteins that have been implicated in synaptic plasticity mechanisms and therefore are considered key elements in learning and memory. In this study, we investigated the role of microtubule dynamics in temporal learning by local infusions of microtubule stabilizing and destabilizing agents into the dorsolateral striatum. Our results suggested a bidirectional role for microtubules in timing, such that microtubule stabilization improves the maintenance of learned target durations, but impairs the acquisition of a novel duration. On the other hand, microtubule destabilization enhances the acquisition of novel target durations, while compromising the maintenance of previously learned durations. These findings suggest that microtubule dynamics plays an important role in synaptic plasticity mechanisms in the dorsolateral striatum, which in turn modulates temporal learning and time perception.

Methylphenidate modifies activity in the prefrontal and parietal cortex accelerating the time judgment.

Methylphenidate produces its effects via actions on cortical areas involved with attention and working memory, which have a direct role in time estimation judgment tasks. In particular, the prefrontal and parietal cortex has been the target of several studies to understand the effect of methylphenidate on executive functions and time interval perception. However, it has not yet been studied whether acute administration of methylphenidate influences performance in time estimation task and the changes in alpha band absolute power in the prefrontal and parietal cortex. The current study investigates the influence of the acute use of methylphenidate in both performance and judgment in the time estimation interpretation through the alpha band absolute power activity in the prefrontal and parietal cortex. This is a double-blind, crossover study with a sample of 32 subjects under control (placebo) and experimental (methylphenidate) conditions with absolute alpha band power analysis during a time estimation task. We observed that methylphenidate does not influence task performance (p > 0.05), but it increases the time interval underestimation by over 7 s (p < 0.001) with a concomitant decrease in absolute alpha band power in the ventrolateral prefrontal cortex and dorsolateral prefrontal cortex and parietal cortex (p < 0.001). Acute use of methylphenidate increases the time interval underestimation, consistent with reduced accuracy of the internal clock mechanisms. Furthermore, acute use of methylphenidate influences the absolute alpha band power over the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, and parietal cortex.

Dopamine dependent setting of a circadian oscillator underlying the memory for time of day.

Animals learn and remember the time of day that significant conditions occur, and anticipate recurrence at 24-h intervals, even after only one exposure to the condition. On several place-conditioning tasks, animals show context avoidance or preference only near the time of day of the experience. The memory for time of day is registered by a circadian oscillator that is set at the time of the training. We show that manipulations of dopamine (DA) neurotransmission can set a time memory in place preference and avoidance tasks, indicating that time of day is part of the context that is learned. Single injections of the DA agonist, d-amphetamine sulfate given without further exposure to the conditioning apparatus, can reset the timing of anticipatory behavior evoked by previously acquired place-event associations. The data support a model for time memory in which DA signaling sets the phase of a circadian oscillator, which returns to the same state at regular 24-h intervals. The data also raise the possibility that some apparent impairments of memory formation or retention could reflect post-experience resetting of the optimal retrieval time rather than impairment of memory or retrieval per se.

Aberrant connections between climbing fibres and Purkinje cells induce alterations in the timing of an instrumental response in the rat.

Cerebellar participation in timing and sensory-motor sequences has been supported by several experimental and clinical studies. A relevant role of the cerebellum in timing of conditioned responses in the range of milliseconds has been demonstrated, but less is known regarding the role of the cerebellum in supra-second timing of operant responses. A dissociated role of the cerebellum and striatum in timing in the millisecond and second range had been reported, respectively. The climbing fibre-Purkinje cell synapse is crucial in timing models; thus, the aberrant connection between these cellular elements is a suitable model for evaluating the contribution of the cerebellum in timing in the supra-second range. The aberrant connection between climbing fibres and Purkinje cells was induced by administration of the antagonist of NMDA receptors MK-801 to Sprague-Dawley rats at postnatal days 7-14. The timing of an operant response with two fixed intervals (5 and 8 s) and egocentric sequential learning was evaluated in 60-day-old adult rats. The aberrant connections caused a reduced accuracy in the timing of the instrumental response that was more evident in the 8-s interval and a reduced number of successive correct responses (responses emitted in the correct second without any other response between them) in the 8-s interval. In addition, an inability to incorporate new information in a sequence previously learned in egocentric-based sequence learning was apparent in rats with aberrant CF-PC synapses. These results support a relevant role for the cerebellum in the fine-tuning of the timing of operant responses in the supra-second range.

Evidence for a Specific Integrative Mechanism for Episodic Memory Mediated by AMPA/kainate Receptors in a Circuit Involving Medial Prefrontal Cortex and Hippocampal CA3 Region.

We asked whether episodic-like memory requires neural mechanisms independent of those that mediate its component memories for "what," "when," and "where," and if neuronal connectivity between the medial prefrontal cortex (mPFC) and the hippocampus (HPC) CA3 subregion is essential for episodic-like memory. Unilateral lesion of the mPFC was combined with unilateral lesion of the CA3 in the ipsi- or contralateral hemispheres in rats. Episodic-like memory was tested using a task, which assesses the integration of memories for "what, where, and when" concomitantly. Tests for novel object recognition (what), object place (where), and temporal order memory (when) were also applied. Bilateral disconnection of the mPFC-CA3 circuit by N-methyl-d-aspartate (NMDA) lesions disrupted episodic-like memory, but left the component memories for object, place, and temporal order, per se, intact. Furthermore, unilateral NMDA lesion of the CA3 plus injection of (6-cyano-7-nitroquinoxaline-2,3-dione) (CNQX) (AMPA/kainate receptor antagonist), but not AP-5 (NMDA receptor antagonist), into the contralateral mPFC also disrupted episodic-like memory, indicating the mPFC AMPA/kainate receptors as critical for this circuit. These results argue for a selective neural system that specifically subserves episodic memory, as it is not critically involved in the control of its component memories for object, place, and time.

The Role of Dopamine in Temporal Uncertainty.

The temporal preparation of motor responses to external events (temporal preparation) relies on internal representations of the accumulated elapsed time (temporal representations) before an event occurs and on estimates about its most likely time of occurrence (temporal expectations). The precision (inverse of uncertainty) of temporal preparation, however, is limited by two sources of uncertainty. One is intrinsic to the nervous system and scales with the length of elapsed time such that temporal representations are least precise for longest time durations. The other is external and arises from temporal variability of events in the outside world. The precision of temporal expectations thus decreases if events become more variable in time. It has long been recognized that the processing of time durations within the range of hundreds of milliseconds (interval timing) strongly depends on dopaminergic (DA) transmission. The role of DA for the precision of temporal preparation in humans, however, remains unclear. This study therefore directly assesses the role of DA in the precision of temporal preparation of motor responses in healthy humans. In a placebo-controlled double-blind design using a selective D2-receptor antagonist (sulpiride) and D1/D2 receptor antagonist (haloperidol), participants performed a variable foreperiod reaching task, under different conditions of internal and external temporal uncertainty. DA blockade produced a striking impairment in the ability of extracting temporal expectations across trials and on the precision of temporal representations within a trial. Large Weber fractions for interval timing, estimated by fitting subjective hazard functions, confirmed that this effect was driven by an increased uncertainty in the way participants were experiencing time. This provides novel evidence that DA regulates the precision with which we process time when preparing for an action.

Acute ethanol effects on neural encoding of reward size and delay in the nucleus accumbens.

Acute ethanol administration can cause impulsivity, resulting in increased preference for immediately available rewards over delayed but more valuable alternatives. The manner in which reward size and delay are represented in neural firing is not fully understood, and very little is known about ethanol effects on this encoding. To address this issue, we used in vivo electrophysiology to characterize neural firing in the core of the nucleus accumbens (NAcc) in rats responding for rewards that varied in size or delay after vehicle or ethanol administration. The NAcc is a central element in the circuit that governs decision-making and importantly, promotes choice of delayed rewards. We found that NAcc firing in response to reward-predictive cues encoded anticipated reward value after vehicle administration, but ethanol administration disrupted this encoding, resulting in a loss of discrimination between immediate and delayed rewards in cue-evoked neural responses. In addition, NAcc firing occurring at the time of the operant response (lever pressing) was inversely correlated with behavioral response latency, such that increased firing rates were associated with decreased latencies to lever press. Ethanol administration selectively attenuated this lever press-evoked firing when delayed but not immediate rewards were expected. These effects on neural firing were accompanied by increased behavioral latencies to respond for delayed rewards. Our results suggest that ethanol effects on NAcc cue- and lever press-evoked encoding may contribute to ethanol-induced impulsivity.

Time on timing: Dissociating premature responding from interval sensitivity in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) can cause impulsivity with premature responses, but there are several potential mechanisms. We proposed a distinction between poor decision-making and the distortion of temporal perception. Both effects may be present and interact, but with different clinical and pharmacological correlates. OBJECTIVES: This study assessed premature responding during time perception in PD. METHODS: In this study, 18 PD patients and 19 age-matched controls completed 2 temporal discrimination tasks (bisection and trisection) and a baseline reaction-time task. Timing sensitivity and decision-making processes were quantified by response and response time. An extended version of the modified difference model was used to examine the precision of time representation and the modulation of response time by stimulus ambiguity. RESULTS: In the bisection task, patients had a lower bisection point (P < .05) and reduced timing sensitivity when compared with controls (P < .001). In the trisection task, patients showed lower sensitivity in discriminating between short and medium standards (P < .05). The impairment in timing sensitivity correlated positively with patients' levodopa dose equivalent (P < .05). Critically, patients had disproportionately faster response times when compared with controls in more ambiguous conditions, and the degree of acceleration of response time increased with disease severity (P < .05). Computational modeling indicated that patients had poorer precision in time representation and stronger modulation of response time by task ambiguity, leading to smaller scaling of the decision latency (P < .05). CONCLUSIONS: These findings suggest that timing deficits in PD cannot be solely attributed to perceptual distortions, but are also associated with impulsive decision strategies that bias patients toward premature responses. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Effects of alcohol intake on time-based event expectations.

Previous evidence suggests that alcohol affects various forms of temporal cognition. However, there are presently no studies investigating whether and how alcohol affects on time-based event expectations. Here, we investigated the effects of alcohol on time-based event expectations. Seventeen healthy volunteers, aged between 19 and 36 years, participated. We employed a variable foreperiod paradigm with temporally predictable events, mimicking a computer game. Error rate and reaction time were analyzed in placebo (0 g/kg), low dose (0.2 g/kg) and high dose (0.6 g/kg) conditions. We found that alcohol intake did not eliminate, but substantially reduced, the formation of time-based expectancy. This effect was stronger for high doses, than for low doses, of alcohol. As a result of our studies, we have evidence that alcohol intake impairs time-based event expectations. The mechanism by which the level of alcohol impairs time-based event expectations needs to be clarified by future research.

Using fMRI to compare the effects of benzylpiperazine with dexamphetamine - Their differences during the Stroop paradigm.

RATIONALE: Benzylpiperazine (BZP) has been found to increase neural activation in the dorsal striatum when compared to placebo in response to a Stroop paradigm, in addition, subjective effects have been compared to dexamphetamine (DEX). Despite their similarities, the two have not been directly compared in respect to their effects on selective attention and inhibition. OBJECTIVES: To use a double-blind placebo-controlled crossover study to compare the acute effects of BZP and DEX on executive function using functional magnetic resonance imaging (fMRI) and an event-related Stroop task. METHODS: Eleven healthy participants aged 18-40 years undertook the Stroop task 90[Formula: see text]min after taking an oral dose of either BZP (200[Formula: see text]mg), DEX (20[Formula: see text]mg) or placebo. RESULTS: BZP induced a greater increase in activation than DEX in the inferior frontal gyrus (IFG) during the Stroop task. DEX increased BOLD signal in the thalamus and decreased it in the IFG in comparison to placebo. CONCLUSION: Despite BZP and DEX reportedly inducing similar subjective effects, there are different patterns of neural activation. We believe this differential activity is due to pharmacological differences in their receptor binding profiles and that subsequent inhibitory effects might be due to their direct effect on dopaminergic activity.

General anesthesia alters time perception by phase shifting the circadian clock.

Following general anesthesia, people are often confused about the time of day and experience sleep disruption and fatigue. It has been hypothesized that these symptoms may be caused by general anesthesia affecting the circadian clock. The circadian clock is fundamental to our well-being because it regulates almost all aspects of our daily biochemistry, physiology, and behavior. Here, we investigated the effects of the most common general anesthetic, isoflurane, on time perception and the circadian clock using the honeybee (Apis mellifera) as a model. A 6-h daytime anesthetic systematically altered the time-compensated sun compass orientation of the bees, with a mean anticlockwise shift in vanishing bearing of 87° in the Southern Hemisphere and a clockwise shift in flight direction of 58° in the Northern Hemisphere. Using the same 6-h anesthetic treatment, time-trained bees showed a delay in the start of foraging of 3.3 h, and whole-hive locomotor-activity rhythms were delayed by an average of 4.3 h. We show that these effects are all attributable to a phase delay in the core molecular clockwork. mRNA oscillations of the central clock genes cryptochrome-m and period were delayed by 4.9 and 4.3 h, respectively. However, this effect is dependent on the time of day of administration, as is common for clock effects, and nighttime anesthesia did not shift the clock. Taken together, our results suggest that general anesthesia during the day causes a persistent and marked shift of the clock effectively inducing "jet lag" and causing impaired time perception. Managing this effect in humans is likely to help expedite postoperative recovery.

Involvement of dopamine signaling in the circadian modulation of interval timing.

Duration discrimination within the seconds-to-minutes range, known as interval timing, involves the interaction of cortico-striatal circuits via dopaminergic-glutamatergic pathways. Besides interval timing, most (if not all) organisms exhibit circadian rhythms in physiological, metabolic and behavioral functions with periods close to 24 h. We have previously reported that both circadian disruption and desynchronization impaired interval timing in mice. In this work we studied the involvement of dopamine (DA) signaling in the interaction between circadian and interval timing. We report that daily injections of levodopa improved timing performance in the peak-interval procedure in C57BL/6 mice with circadian disruptions, suggesting that a daily increase of DA is necessary for an accurate performance in the timing task. Moreover, striatal DA levels measured by reverse-phase high-pressure liquid chromatography indicated a daily rhythm under light/dark conditions. This daily variation was affected by inducing circadian disruption under constant light (LL). We also demonstrated a daily oscillation in tyrosine hydroxylase levels, DA turnover (3,4-dihydroxyphenylacetic acid/DA levels), and both mRNA and protein levels of the circadian component Period2 (Per2) in the striatum and substantia nigra, two brain areas relevant for interval timing. None of these oscillations persisted under LL conditions. We suggest that the lack of DA rhythmicity in the striatum under LL - probably regulated by Per2 - could be responsible for impaired performance in the timing task. Our findings add further support to the notion that circadian and interval timing share some common processes, interacting at the level of the dopaminergic system.

Temporal and visual source memory deficits among ecstasy/polydrug users.

OBJECTIVES: We wished to investigate whether source memory judgements are adversely affected by recreational illicit drug use. METHOD: Sixty-two ecstasy/polydrug users and 75 non ecstasy users completed a source memory task, in which they tried to determine whether or not a word had been previously presented and if so, attempted to recall the format, location and temporal position in which the word had occurred. RESULTS: While not differing in terms of the number of hits and false positive responses, ecstasy/polydrug users adopted a more liberal decision criterion when judging if a word had been presented previously. With regard to source memory, users were less able to determine the format in which words had been presented (upper versus lower case). Female users did worse than female nonusers in determining which list (first or second) a word was from. Unexpectedly, the current frequency of cocaine use was negative associated with list and case source memory performance. CONCLUSIONS: Given the role that source memory plays in everyday cognition, those who use cocaine more frequently might have more difficulty in everyday tasks such as recalling the sources of crucial information or making use of contextual information as an aid to learning.

Getting the timing right: experimental protocols for investigating time with functional neuroimaging and psychopharmacology.

Functional Magnetic Resonance Imaging (fMRI) is an effective tool for identifying brain areas and networks implicated in human timing. But fMRI is not just a phrenological tool: by careful design, fMRI can be used to disentangle discrete components of a timing task and control for the underlying cognitive processes (e.g. sustained attention and WM updating) that are critical for estimating stimulus duration in the range of hundreds of milliseconds to seconds. Moreover, the use of parametric designs and correlational analyses allows us to better understand not just where, but also how, the brain processes temporal information. In addition, by combining fMRI with psychopharmacological manipulation, we can begin to uncover the complex relationship between cognition, neurochemistry and anatomy in the healthy human brain. This chapter provides an overview of some of the key findings in the functional imaging literature of both duration estimation and temporal prediction, and outlines techniques that can be used to allow timing-related activations to be interpreted more unambiguously. In our own studies, we have found that estimating event duration, whether that estimate is provided by a motor response or a perceptual discrimination, typically recruits basal ganglia, SMA and right inferior frontal cortex, and can be modulated by dopaminergic activity in these areas. By contrast, orienting attention to predictable moments in time in order to optimize behaviour, whether that is to speed motor responding or improve perceptual accuracy, recruits left inferior parietal cortex.

Effects of caffeine on temporal perception in Rattus norvegicus.

We report two studies that tested the effects of caffeine, the world's most widely used psychoactive drug, on temporal perception. We trained Wistar rats using the Bisection Procedure (Experiment 1) or the Stubbs' Procedure (Experiment 2) to discriminate between short and long light stimuli. Once training finished, we administered caffeine orally (0, 9.6, and 96.0 mg/kg for Experiment 1 and 0, 9.6, 19.2, and 38.4 mg/kg for Experiment 2) 15 minutes prior to testing. Relative to the control condition, the 9.6 mg/kg condition (Experiments 1 and 2) and the 19.2 mg/kg condition (Experiment 2) resulted in an increase in proportion of choosing the long response. Meanwhile, overall accuracy was not affected by any condition in both experiments. Taken together, these results are consistent with the notion that caffeine, at some doses, speeds up temporal perception. However, it is not clear why the effect disappears at higher doses.

Sex similarities and dopaminergic differences in interval timing.

Rodent behavioral studies have largely focused on male animals, which has limited the generalizability and conclusions of neuroscience research. Working with humans and rodents, we studied sex effects during interval timing that requires participants to estimate an interval of several seconds by making motor responses. Interval timing requires attention to the passage of time and working memory for temporal rules. We found no differences between human females and males in interval timing response times (timing accuracy) or the coefficient of variance of response times (timing precision). Consistent with prior work, we also found no differences between female and male rodents in timing accuracy or precision. In female rodents, there was no difference in interval timing between estrus and diestrus cycle stages. Because dopamine powerfully affects interval timing, we also examined sex differences with drugs targeting dopaminergic receptors. In both female and male rodents, interval timing was delayed after administration of sulpiride (D2-receptor antagonist), quinpirole (D2-receptor agonist), and SCH-23390 (D1-receptor antagonist). By contrast, after administration of SKF-81297 (D1-receptor agonist), interval timing shifted earlier only in male rodents. These data illuminate sex similarities and differences in interval timing. Our results have relevance for rodent models of both cognitive function and brain disease by increasing representation in behavioral neuroscience. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Effects of dopaminergic and subthalamic stimulation on musical performance.

Although subthalamic-deep brain stimulation (STN-DBS) is an efficient treatment for Parkinson's disease (PD), its effects on fine motor functions are not clear. We present the case of a professional violinist with PD treated with STN-DBS. DBS improved musical articulation, intonation and emotional expression and worsened timing relative to a timekeeper (metronome). The same effects were found for dopaminergic treatment. These results suggest that STN-DBS, mimicking the effects of dopaminergic stimulation, improves fine-tuned motor behaviour whilst impairing timing precision.

Striatal dopamine modulates song spectral but not temporal features through D1 receptors.

The activity of midbrain dopaminergic neurons and their projection to the basal ganglia (BG) are thought to play a critical role in the acquisition of motor skills through reinforcement learning, as well as in the expression of learned motor behaviors. The precise role of BG dopamine (DA) in mediating and modulating motor performance and learning, however, remains unclear. In songbirds, a specialized portion of the BG is responsible for song learning and plasticity. Previously we found that DA acts on D1 receptors in Area X to modulate the BG output signal and thereby trigger changes in song variability. Here, we investigate the effect of D1 receptor blockade in the BG on song behavior in the zebra finch. We report that this manipulation abolishes social context-dependent changes in variability not only in harmonic stacks, but also in other types of syllables. However, song timing seems not to be modulated by this BG DA signal. Indeed, injections of a D1 antagonist in the BG altered neither song duration nor the change of song duration with social context. Finally, D1 receptor activation in the BG was not necessary for the modulation of other features of song, such as the number of introductory notes or motif repetitions. Together, our results suggest that activation of D1 receptors in the BG is necessary for the modulation of fine acoustic features of song with social context, while it is not involved in the regulation of song timing and structure at a larger time scale.