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The overlap of neural circuits involved in episodic memory, relational learning, trace conditioning, and interval timing suggests the importance of hippocampal-dependent processes. Identifying the functional and neural mechanisms whereby the hippocampus plays a role in timing and decision-making, however, has been elusive. In this article we describe recent neurobiological findings, including the discovery of hippocampal 'time cells', dependency of duration discriminations in the minutes range on hippocampal function, and the correlation of hippocampal theta rhythm with specific features of temporal processing. These results provide novel insights into the ways in which the hippocampus might interact with the striatum in order to support both retrospective and prospective timing. Suggestions are also provided for future research on the role of the hippocampus in memory for elapsed time.

The perception of time is heavily influenced by attention and memory, both of which change over the lifespan. In the current study, children (8yrs), young adults (18-25yrs), and older adults (60-75yrs) were tested on a duration bisection procedure using 3 and 6-s auditory and visual signals as anchor durations. During test, participants were exposed to a range of intermediate durations, and the task was to indicate whether test durations were closer to the 'short' or 'long' anchor. All groups reproduced the classic finding that 'sounds are judged longer than lights'. This effect was greater for older adults and children than for young adults, but for different reasons. Replicating previous results, older adults made similar auditory judgments as young adults, but underestimated the duration of visual test stimuli. Children showed the opposite pattern, with similar visual judgments as young adults but overestimation of auditory stimuli. Psychometric functions were analyzed using the Sample Known Exactly-Mixed Memory quantitative model of the Scalar Timing Theory of interval timing. Results indicate that children show an auditory-specific deficit in reference memory for the anchors, rather than a general bias to overestimate time and that aged adults show an exaggerated tendency to judge visual stimuli as 'short' due to a reduction in the availability of controlled attention. [ABSTRACT FROM AUTHOR]

Animals can learn to repeat behaviors to earn desired rewards, a process commonly known as reinforcement learning. While previous work has implicated the ascending dopaminergic projections to the basal ganglia in reinforcement learning, little is known about the role of the hippocampus. Here, we report that a specific population of hippocampal neurons and their dopaminergic innervation contribute to operant self-stimulation. These neurons are located in the dentate gyrus, receive dopaminergic projections from the locus coeruleus, and express D1 dopamine receptors. Activation of D1 + dentate neurons is sufficient for self-stimulation: mice will press a lever to earn optogenetic activation of these neurons. A similar effect is also observed with selective activation of the locus coeruleus projections to the dentate gyrus, and blocked by D1 receptor antagonism. Calcium imaging of D1 + dentate neurons revealed significant activity at the time of action selection, but not during passive reward delivery. These results reveal the role of dopaminergic innervation of the dentate gyrus in supporting operant reinforcement., Competing Interests: EP, IF, RH, GW, WM, FU, HY No competing interests declared, (© 2023, Petter et al.)

Durations are defined by a beginning and an end, and a major distinction is drawn between durations that start in the present and end in the future ('prospective timing') and durations that start in the past and end either in the past or the present ('retrospective timing'). Different psychological processes are thought to be engaged in each of these cases. The former is thought to engage a clock-like mechanism that accurately tracks the continuing passage of time, whereas the latter is thought to engage a reconstructive process that utilizes both temporal and non-temporal information from the memory of past events. We propose that, from a biological perspective, these two forms of duration estimation are supported by computational processes that are both reliant on population state dynamics but are nevertheless distinct. Prospective timing is effectively carried out in a single step where the ongoing dynamics of population activity directly serve as the computation of duration, whereas retrospective timing is carried out in two steps: the initial generation of population state dynamics through the process of event segmentation and the subsequent computation of duration utilizing the memory of those dynamics., (© 2022. Springer Nature Limited.)

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., (Published by Elsevier Inc.)

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., (Copyright © 2020 the authors.)

A robust adaptation to environmental changes is vital for survival. Almost all living organisms have a circadian timing system that allows adjusting their physiology to cyclic variations in the surrounding environment. Among vertebrates, many birds are also seasonal species, adapting their physiology to annual changes in photoperiod (amplitude, length and duration). Tawny Owls (Strix aluco) are nocturnal birds of prey that use vocalization as their principal mechanism of communication. Diurnal and seasonal changes in vocalization have been described for several vocal species, including songbirds. Comparable studies are lacking for owls. In the present work, we show that male Tawny Owls present a periodic vocalization pattern in the seconds-to-minutes range that is subject to both daily (early vs. late night) and seasonal (spring vs. summer) rhythmicity. These novel theory-generating findings appear to extend the role of the circadian system in regulating temporal events in the seconds-to-minutes range to other species., Competing Interests: The authors have declared that no competing interests exist.

The majority of studies in the field of timing and time perception have generally focused on sub- and supra-second time scales, specific behavioral processes, and/or discrete neuronal circuits. In an attempt to find common elements of interval timing from a broader perspective, we review the literature and highlight the need for cell and molecular studies that can delineate the neural mechanisms underlying temporal processing. Moreover, given the recent attention to the function of microtubule proteins and their potential contributions to learning and memory consolidation/re-consolidation, we propose that these proteins play key roles in coding temporal information in cerebellar Purkinje cells (PCs) and striatal medium spiny neurons (MSNs). The presence of microtubules at relevant neuronal sites, as well as their adaptability, dynamic structure, and longevity, makes them a suitable candidate for neural plasticity at both intra- and inter-cellular levels. As a consequence, microtubules appear capable of maintaining a temporal code or engram and thereby regulate the firing patterns of PCs and MSNs known to be involved in interval timing. This proposed mechanism would control the storage of temporal information triggered by postsynaptic activation of mGluR7. This, in turn, leads to alterations in microtubule dynamics through a "read-write" memory process involving alterations in microtubule dynamics and their hexagonal lattice structures involved in the molecular basis of temporal memory., (Copyright © 2020 Yousefzadeh, Hesslow, Shumyatsky and Meck.)

Time perception is an essential element of conscious and subconscious experience, coordinating our perception and interaction with the surrounding environment. In recent years, major technological advances in the field of neuroscience have helped foster new insights into the processing of temporal information, including extending our knowledge of the role of the cerebellum as one of the key nodes in the brain for this function. This consensus paper provides a state-of-the-art picture from the experts in the field of the cerebellar research on a variety of crucial issues related to temporal processing, drawing on recent anatomical, neurophysiological, behavioral, and clinical research.The cerebellar granular layer appears especially well-suited for timing operations required to confer millisecond precision for cerebellar computations. This may be most evident in the manner the cerebellum controls the duration of the timing of agonist-antagonist EMG bursts associated with fast goal-directed voluntary movements. In concert with adaptive processes, interactions within the cerebellar cortex are sufficient to support sub-second timing. However, supra-second timing seems to require cortical and basal ganglia networks, perhaps operating in concert with cerebellum. Additionally, sensory information such as an unexpected stimulus can be forwarded to the cerebellum via the climbing fiber system, providing a temporally constrained mechanism to adjust ongoing behavior and modify future processing. Patients with cerebellar disorders exhibit impairments on a range of tasks that require precise timing, and recent evidence suggest that timing problems observed in other neurological conditions such as Parkinson's disease, essential tremor, and dystonia may reflect disrupted interactions between the basal ganglia and cerebellum.The complex concepts emerging from this consensus paper should provide a foundation for further discussion, helping identify basic research questions required to understand how the brain represents and utilizes time, as well as delineating ways in which this knowledge can help improve the lives of those with neurological conditions that disrupt this most elemental sense. The panel of experts agrees that timing control in the brain is a complex concept in whom cerebellar circuitry is deeply involved. The concept of a timing machine has now expanded to clinical disorders.

We present an integrated view of interval timing and reinforcement learning (RL) in the brain. The computational goal of RL is to maximize future rewards, and this depends crucially on a representation of time. Different RL systems in the brain process time in distinct ways. A model-based system learns 'what happens when', employing this internal model to generate action plans, while a model-free system learns to predict reward directly from a set of temporal basis functions. We describe how these systems are subserved by a computational division of labor between several brain regions, with a focus on the basal ganglia and the hippocampus, as well as how these regions are influenced by the neuromodulator dopamine., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Ordinal comparison of successively presented signal durations requires (a) the encoding of the first signal duration (standard), (b) maintenance of temporal information specific to the standard duration in memory, and (c) timing of the second signal duration (comparison) during which a comparison is made of the first and second durations. Rats were first trained to make ordinal comparisons of signal durations within three time ranges using 0.5, 1.0, and 3.0-s standard durations. Local field potentials were then recorded from the dorsal striatum and sensorimotor cortex in order to investigate the pattern of neural oscillations during each phase of the ordinal-comparison process. Increased power in delta and theta frequency ranges was observed during both the encoding and comparison stages. Active maintenance of a selected response, "shorter" or "longer" (counter-balanced across left and right levers), was represented by an increase of theta and delta oscillations in the contralateral striatum and cortex. Taken together, these data suggest that neural oscillations in the delta-theta range play an important role in the encoding, maintenance, and comparison of signal durations., (Copyright © 2018. Published by Elsevier Inc.)

Considerable evidence implicates the basal ganglia in interval timing, yet the underlying mechanisms remain poorly understood. Using a novel behavioral task, we demonstrate that head-fixed mice can be trained to show the key features of timing behavior within a few sessions. Single-trial analysis of licking behavior reveals stepping dynamics with variable onset times, which is responsible for the canonical Gaussian distribution of timing behavior. Moreover, the duration of licking bouts decreased as mice became sated, showing a strong motivational modulation of licking bout initiation and termination. Using optogenetics, we examined the role of the basal ganglia output in interval timing. We stimulated a pathway important for licking behavior, the GABAergic output projections from the substantia nigra pars reticulata to the deep layers of the superior colliculus. We found that stimulation of this pathway not only cancelled licking but also delayed the initiation of anticipatory licking for the next interval in a frequency-dependent manner. By combining quantitative behavioral analysis with optogenetics in the head-fixed setup, we established a new approach for studying the neural basis of interval timing., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Time and memory are inextricably linked, but it is far from clear how event durations and temporal sequences are encoded in memory. In this review, we focus on resource allocation models of working memory which suggest that memory resources can be flexibly distributed amongst several items such that the precision of working memory decreases with the number of items to be encoded. This type of model is consistent with human performance in working memory tasks based on visual, auditory as well as temporal stimulus patterns. At the neural-network level, we focus on excitatory-inhibitory oscillatary processes that are able to encode both interval timing and working memory in a coupled excitatory-inhibitory network. This modification of the striatal beat-frequency model of interval timing shows how memories for multiple time intervals are represented by neural oscillations and can also be used to explain the mechanisms of resource allocation in working memory.

The contributions of cortico-cerebellar and cortico-striatal circuits to timing and time perception have often been a point of contention. In this review we propose that the cerebellum principally functions to reduce variability, through the detection of stimulus onsets and the sub-division of longer durations, thus contributing to both sub-second and supra-second timing. This sensitivity of the cerebellum to stimulus dynamics and subsequent integration with motor control allows it to accurately measure intervals within a range of 100-2000ms. For intervals in the supra-second range (e.g., >2000ms), we propose that cerebellar output signals from the dentate nucleus pass through thalamic connections to the striatum, where cortico-thalamic-striatal circuits supporting higher-level cognitive functions take over. Moreover, the importance of intrinsic circuit dynamics as well as behavioral, neuroimaging, and lesion studies of the cerebellum and striatum are discussed in terms of a framework positing initiation, continuation, adjustment, and termination phases of temporal processing., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Temporal and social processing are intricately linked. The temporal extent and organization of interactional behaviors both within and between individuals critically determine interaction success. Conversely, social signals and social context influence time perception by, for example, altering subjective duration and making an event seem 'out of sync'. An 'internal clock' involving subcortically orchestrated cortical oscillations that represent temporal information, such as duration and rhythm, as well as insular projections linking temporal information with internal and external experiences is proposed as the core of these reciprocal interactions. The timing of social relative to non-social stimuli augments right insular activity and recruits right superior temporal cortex. Together, these reciprocal pathways may enable the exchange and respective modulation of temporal and social computations., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Time is a universal psychological dimension, but time perception has often been studied and discussed in relative isolation. Increasingly, researchers are searching for unifying principles and integrated models that link time perception to other domains. In this review, we survey the links between temporal cognition and other psychological processes. Specifically, we describe how subjective duration is affected by nontemporal stimulus properties (perception), the allocation of processing resources (attention), and past experience with the stimulus (memory). We show that many of these connections instantiate a "processing principle," according to which perceived time is positively related to perceptual vividity and the ease of extracting information from the stimulus. This empirical generalization generates testable predictions and provides a starting-point for integrated theoretical frameworks. By outlining some of the links between temporal cognition and other domains, and by providing a unifying principle for understanding these effects, we hope to encourage time-perception researchers to situate their work within broader theoretical frameworks, and that researchers from other fields will be inspired to apply their insights, techniques, and theorizing to improve our understanding of the representation and judgment of time. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

This review outlines the basic psychological and neurobiological processes associated with age-related distortions in timing and time perception in the hundredths of milliseconds-to-minutes range. The difficulty in separating indirect effects of impairments in attention and memory from direct effects on timing mechanisms is addressed. The main premise is that normal aging is commonly associated with increased noise and temporal uncertainty as a result of impairments in attention and memory as well as the possible reduction in the accuracy and precision of a central timing mechanism supported by dopamine-glutamate interactions in cortico-striatal circuits. Pertinent to these findings, potential interventions that may reduce the likelihood of observing age-related declines in timing are discussed. Bayesian optimization models are able to account for the adaptive changes observed in time perception by assuming that older adults are more likely to base their temporal judgments on statistical inferences derived from multiple trials than on a single trial's clock reading, which is more susceptible to distortion. We propose that the timing functions assigned to the age-sensitive fronto-striatal network can be subserved by other neural networks typically associated with finely-tuned perceptuo-motor adjustments, through degeneracy principles (different structures serving a common function).

Like other senses, our perception of time is not veridical, but rather, is modulated by changes in environmental context. Anecdotal experiences suggest that emotions can be powerful modulators of time perception; nevertheless, the functional and neural mechanisms underlying emotion-induced temporal distortions remain unclear. Widely accepted pacemaker-accumulator models of time perception suggest that changes in arousal and attention have unique influences on temporal judgments and contribute to emotional distortions of time perception. However, such models conflict with current views of arousal and attention suggesting that current models of time perception do not adequately explain the variability in emotion-induced temporal distortions. Instead, findings provide support for a new perspective of emotion-induced temporal distortions that emphasizes both the unique and interactive influences of arousal and attention on time perception over time. Using this framework, we discuss plausible functional and neural mechanisms of emotion-induced temporal distortions and how these temporal distortions may have important implications for our understanding of how emotions modulate our perceptual experiences in service of adaptive responding to biologically relevant stimuli., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Discriminative fear conditioning requires learning to dissociate between safety cues and cues that predict negative outcomes yet little is known about what processes contribute to discriminative fear learning. According to attentional models of time perception, processes that distract from timing result in temporal underestimation. If discriminative fear learning only requires learning what cues predict what outcomes, and threatening stimuli distract attention from timing, then better discriminative fear learning should predict greater temporal distortion on threat trials. Alternatively, if discriminative fear learning also reflects a more accurate perceptual experience of time in threatening contexts, discriminative fear learning scores would predict less temporal distortion on threat trials, as time is perceived more veridically. Healthy young adults completed discriminative fear conditioning in which they learned to associate one stimulus (CS+) with aversive electrical stimulation and another stimulus (CS-) with non-aversive tactile stimulation and then an ordinal comparison timing task during which CSs were presented as task-irrelevant distractors Consistent with predictions, we found an overall temporal underestimation bias on CS+ relative to CS- trials. Differential skin conductance responses to the CS+ versus the CS- during conditioning served as a physiological index of discriminative fear conditioning and this measure predicted the magnitude of the underestimation bias, such that individuals exhibiting greater discriminative fear conditioning showed less underestimation on CS+ versus CS- trials. These results are discussed with respect to the nature of discriminative fear learning and the relationship between temporal distortions and maladaptive threat processing in anxiety.

Performance on different psychophysical tasks measuring the sense of time indicates a large amount of individual variation in the accuracy and precision of timing in the hundredths of milliseconds-to-minutes range. Quantifying factors with an influence on timing is essential to isolating a biological (genetic) contribution to the perception and estimation of time. In the largest timing study to date, 647 participants completed a duration-discrimination task in the sub-second range and a time-production task in the supra-second range. We confirm the stability of a participant's time sense across multiple sessions and substantiate a modest sex difference on time production. Moreover, we demonstrate a strong correlation between performance on a standardized cognitive battery and performance in both duration-discrimination and time-production tasks; we further show that performance is uncorrelated with age after controlling for general intelligence. Additionally, we find an effect of ethnicity on time sense, with African Americans and possibly Hispanics in our cohort differing in accuracy and precision from other ethnic groups. Finally, a preliminary genome-wide association and exome chip study was performed on 148 of the participants, ruling out the possibility for a single common variant or groups of low-frequency coding variants within a single gene to explain more than ~18% of the variation in the sense of time.

Interval timing and working memory are critical components of cognition that are supported by neural oscillations in prefrontal-striatal-hippocampal circuits. In this review, the properties of interval timing and working memory are explored in terms of behavioral, anatomical, pharmacological, and neurophysiological findings. We then describe the various neurobiological theories that have been developed to explain these cognitive processes - largely independent of each other. Following this, a coupled excitatory - inhibitory oscillation (EIO) model of temporal processing is proposed to address the shared oscillatory properties of interval timing and working memory. Using this integrative approach, we describe a hybrid model explaining how interval timing and working memory can originate from the same oscillatory processes, but differ in terms of which dimension of the neural oscillation is utilized for the extraction of item, temporal order, and duration information. This extension of the striatal beat-frequency (SBF) model of interval timing (Matell and Meck, 2000, 2004) is based on prefrontal-striatal-hippocampal circuit dynamics and has direct relevance to the pathophysiological distortions observed in time perception and working memory in a variety of psychiatric and neurological conditions., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Time perception is fundamental and heavily researched, but the field faces a number of obstacles to theoretical progress. In this advanced review, we focus on three pieces of 'bad news' for time perception research: temporal perception is highly labile across changes in experimental context and task; there are pronounced individual differences not just in overall performance but in the use of different timing strategies and the effect of key variables; and laboratory studies typically bear little relation to timing in the 'real world'. We describe recent examples of these issues and in each case offer some 'good news' by showing how new research is addressing these challenges to provide rich insights into the neural and information-processing bases of timing and time perception. WIREs Cogn Sci 2014, 5:429-446. doi: 10.1002/wcs.1298 This article is categorized under: Psychology > Perception and Psychophysics Neuroscience > Cognition., (© 2014 The Authors. WIREs Cognitive Science published by John Wiley & Sons, Ltd.)

Variations in both pitch and time are important in conveying meaning through speech and music, however, research is scant on perceptual interactions between these two domains. Using an ordinal comparison procedure, we explored how different pitch levels of flanker tones influenced the perceived duration of empty interstimulus intervals (ISIs). Participants heard monotonic, isochronous tone sequences (ISIs of 300, 600, or 1200 ms) composed of either one or five standard ISIs flanked by 500 Hz tones, followed by a final interval (FI) flanked by tones of either the same (500 Hz), higher (625 Hz), or lower (400 Hz) pitch. The FI varied in duration around the standard ISI duration. Participants were asked to determine if the FI was longer or shorter in duration than the preceding intervals. We found that an increase in FI flanker tone pitch level led to the underestimation of FI durations while a decrease in FI flanker tone pitch led to the overestimation of FI durations. The magnitude of these pitch-level effects decreased as the duration of the standard interval was increased, suggesting that the effect was driven by differences in mode-switch latencies to start/stop timing. Temporal context (One vs. Five Standard ISIs) did not have a consistent effect on performance. We propose that the interaction between pitch and time may have important consequences in understanding the ways in which meaning and emotion are communicated., (Copyright © 2014 Elsevier B.V. All rights reserved.)

An emerging corpus of clinical and neuroimaging data suggests that subsecond and suprasecond durations are represented via 2 distinct mechanisms in humans; however, surprisingly, behavioral data to this effect are lacking. In our first experiment, we perform the first systematic exploration of subsecond and suprasecond timing within the same session in nonhuman subjects. Rats were trained to judge the relative duration of 2 sequential stimuli, responding on one lever if the first stimulus was longer or on a second lever if the converse was true. Our data provide strong evidence of an abstract understanding of longer and shorter for durations in the suprasecond range, whereas responding was at chance levels for durations in the subsecond range. Data from a second experiment reveal that this pattern is not due to an inability to time subsecond signals, as rats respond systematically in subsecond and suprasecond bisection tasks. Together, our results provide the first clear behavioral evidence of a discontinuity in the mental time line. These data from rats are discussed in light of similar findings of a discontinuity in the mental number line in human infants.

Mice with cytotoxic lesions of the dorsal hippocampus (DH) underestimated 15 s and 45 s target durations in a bi-peak procedure as evidenced by proportional leftward shifts of the peak functions that emerged during training as a result of decreases in both 'start' and 'stop' times. In contrast, mice with lesions of the ventral hippocampus (VH) displayed rightward shifts that were immediately present and were largely limited to increases in the 'stop' time for the 45 s target duration. Moreover, the effects of the DH lesions were congruent with the scalar property of interval timing in that the 15 s and 45 s functions superimposed when plotted on a relative timescale, whereas the effects of the VH lesions violated the scalar property. Mice with DH lesions also showed enhanced reversal learning in comparison to control and VH lesioned mice. These results are compared with the timing distortions observed in mice lacking δ-opioid receptors (Oprd1(-/-)) which were similar to mice with DH lesions. Taken together, these results suggest a balance between hippocampal-striatal interactions for interval timing and demonstrate possible functional dissociations along the septotemporal axis of the hippocampus in terms of motivation, timed response thresholds and encoding in temporal memory.

Humans share with other animals an ability to measure the passage of physical time and subjectively experience a sense of time passing. Subjective time has hallmark qualities, akin to other senses, which can be accounted for by formal, psychological, and neurobiological models of the internal clock. These include first-order principles, such as changes in clock speed and how temporal memories are stored, and second-order principles, including timescale invariance, multisensory integration, rhythmical structure, and attentional time-sharing. Within these principles there are both typical individual differences--influences of emotionality, thought speed, and psychoactive drugs--and atypical differences in individuals affected with certain clinical disorders (e.g., autism, Parkinson's disease, and schizophrenia). This review summarizes recent behavioral and neurobiological findings and provides a theoretical framework for considering how changes in the properties of the internal clock impact time perception and other psychological domains.

Scalar Timing Theory (an information-processing version of Scalar Expectancy Theory) and its evolution into the neurobiologically plausible Striatal Beat-Frequency (SBF) theory of interval timing are reviewed. These pacemaker/accumulator or oscillation/coincidence detection models are then integrated with the Adaptive Control of Thought-Rational (ACT-R) cognitive architecture as dedicated timing modules that are able to make use of the memory and decision-making mechanisms contained in ACT-R. The different predictions made by the incorporation of these timing modules into ACT-R are discussed as well as the potential limitations. Novel implementations of the original SBF model that allow it to be incorporated into ACT-R in a more fundamental fashion than the earlier simulations of Scalar Timing Theory are also considered in conjunction with the proposed properties and neural correlates of the "internal clock".

The goal of our study was to characterize the relationship between intertemporal choice and interval timing, including determining how drugs that modulate brain serotonin and dopamine levels influence these two processes. In Experiment 1, rats were tested on a standard 40-s peak-interval procedure following administration of fluoxetine (3, 5, or 8 mg/kg) or vehicle to assess basic effects on interval timing. In Experiment 2, rats were tested in a novel behavioral paradigm intended to simultaneously examine interval timing and impulsivity. Rats performed a variant of the bi-peak procedure using 10-s and 40-s target durations with an additional "defection" lever that provided the possibility of a small, immediate reward. Timing functions remained relatively intact, and 'patience' across subjects correlated with peak times, indicating a negative relationship between 'patience' and clock speed. We next examined the effects of fluoxetine (5 mg/kg), cocaine (15 mg/kg), or methamphetamine (1 mg/kg) on task performance. Fluoxetine reduced impulsivity as measured by defection time without corresponding changes in clock speed. In contrast, cocaine and methamphetamine both increased impulsivity and clock speed. Thus, variations in timing may mediate intertemporal choice via dopaminergic inputs. However, a separate, serotonergic system can affect intertemporal choice without affecting interval timing directly. This article is part of a Special Issue entitled: Associative and Temporal Learning., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Precise timing is crucial to decision-making and behavioral control, yet subjective time can be easily distorted by various temporal contexts. Application of a Bayesian framework to various forms of contextual calibration reveals that, contrary to popular belief, contextual biases in timing help to optimize overall performance under noisy conditions. Here, we review recent progress in understanding these forms of temporal calibration, and integrate a Bayesian framework with information-processing models of timing. We show that the essential components of a Bayesian framework are closely related to the clock, memory, and decision stages used by these models, and that such an integrated framework offers a new perspective on distortions in timing and time perception that are otherwise difficult to explain., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Five experiments were conducted to determine the effects of hippocampal damage on timing and the memory for temporal events. In Experiments 1-3, rats were trained to discriminate between auditory signals that differed in both duration (2 or 8 s) and rate (2 or 16 cycles/s). Half of the rats were trained to discriminate duration, and half were trained to discriminate rate. After rats acquired the relevant discrimination, signals with intermediate durations and rates were presented to obtain psychophysical functions that related signal duration and/or rate to response choice. Rats then received either lesions of the fimbria-fornix or control operations. Postoperatively, the accuracy of duration and rate discriminations as measured by the difference limen (DL) was unaffected by the lesion, but the point of subjective equality (PSE) was shifted to a shorter duration and a slower rate by the lesion in Experiment 1. Both rats with lesions and rats with control operations showed cross-modal transfer of duration and rate from the auditory signals used in training to visual signals used in testing in Experiment 2. A 5-s delay was imposed between the end of a signal and the opportunity to respond in Experiment 3. The delay served as a retention interval for the rats trained in the rate discrimination, and the rats with fimbria-fornix lesions were selectively impaired by the addition of the delay as measured by an increase in the DL. The delay did not serve as a retention interval for rats trained in the duration discrimination because they were able to continue timing through the delay. A peak procedure was employed in Experiment 4. The maximum response rate of control rats was approximately at the time of scheduled reinforcement (20 s), but the maximum response rate of rats with fimbria-fornix lesions was reliably earlier than the time of scheduled reinforcement. When a 5-s gap was imposed in the signal, control rats summed the signal durations before and after the gap, whereas rats with fimbria-fornix lesions showed no retention of the signal duration prior to the gap. Experiment 5 continued the testing of the rats used in Experiments 1-4 and showed that rats with lesions had an impairment in a test of spatial working memory in an eight-arm radial maze. Taken together, these results demonstrate that a fimbria-fornix lesion interferes with temporal and spatial working memory, reduces the remembered time of reinforcement stored in reference memory, and has no effect on the animal's sensitivity to stimulus duration., (2013 APA, all rights reserved)

Interval timing within the seconds-to-minutes range involves the interaction of the prefrontal cortex and basal ganglia via dopaminergic-glutamatergic pathways. Because the secreted protein brain-derived neurotrophic factor (BDNF) is able to modulate dopamine release as well as glutamatergic activity, we hypothesized that BDNF may be important for these timing mechanisms. Recently, the calcium-responsive transcription factor (CaRF) was identified as an important modulator of BDNF expression in the cerebral cortex. In this study, a strain of Carf knockout mice was evaluated for their ability to acquire the 'Start' and 'Stop' response thresholds under sequential and simultaneous training conditions, using multiple (15-second and 45-second) or single (30-second) target durations in the peak-interval procedure. Both Carf(+/-) and Carf(-/-) mice were impaired in their ability to acquire timed response thresholds relative to Carf(+/+) mice. Additionally, control mice given microinjections of BDNF antisense oligodeoxynucleotide to inhibit protein expression in the prefrontal cortex showed timing impairments during acquisition similar to Carf mice. Together, these results suggest that the inhibitory processes required to update response thresholds and exert temporal control of behavior during acquisition may be dependent on CaRF regulation of genes including Bdnf in cortico-striatal circuits., (© 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Understanding how sensory and motor processes are temporally integrated to control behavior in the hundredths of milliseconds-to-minutes range is a fascinating problem given that the basic electrophysiological properties of neurons operate on a millisecond timescale. Single-unit recording studies in monkeys have identified localized timing circuits, whereas neuropsychological studies of humans who have damage to the basal ganglia have indicated that core structures, such as the cortico-thalamic-basal ganglia circuit, play an important role in timing and time perception. Taken together, these data suggest that a core timing mechanism interacts with context-dependent areas. This idea of a temporal hub with a distributed network is used to investigate the abstract properties of interval tuning as well as temporal illusions and intersensory timing. We conclude by proposing that the interconnections built into this core timing mechanism are designed to provide a form of degeneracy as protection against injury, disease, or age-related decline.

Healthy volunteers were tested on 7-s and 17-s peak-interval timing procedures following d-amphetamine (20mg-oral), haloperidol (2mg-oral), and placebo treatments in order to assess the dopaminergic regulation of temporal processing. Individual differences were observed in the drug effects such that two different patterns of timing behavior emerged. In the first pattern, d-amphetamine produced proportional leftward shifts of the timing functions while haloperidol produced proportional rightward shifts. This symmetrical pattern of results suggests that clock speed is regulated by the effective level of dopamine, i.e., d-amphetamine increases clock speed and haloperidol decreases clock speed. The second pattern was the opposite of the first pattern and was revealed by d-amphetamine producing proportional rightward shifts of the timing functions while haloperidol produced no reliable effect. This asymmetrical pattern of results is consistent with an explanation in which attention toward the stimulant-induced euphoria produced by d-amphetamine diminishes the attentional resources available for temporal processing, thereby diluting any drug-induced changes in clock speed. The result of increased competition and time-sharing between these two dimensions (e.g., attention towards feelings of euphoria versus attention towards the passage of time) leads to the underestimation/overproduction of temporal intervals. Interestingly, participants that displayed the 'clock-speed' pattern liked d-amphetamine significantly less than participants that displayed the 'attention' pattern and were more variable in a simple reaction time task than other participants. These results suggest that individuals with a higher degree of sensitivity to time are also more sensitive to their feelings of stimulant-induced euphoria and drug liking-suggesting that internal clock and reward pathways share common dopaminergic pathways., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The gustatory cortex (GC) is important for perceiving the intensity of tastants but it remains unclear as to how single neurons in the region carry out this function. Previous studies have shown that taste-evoked activity from single neurons in GC can be correlated or anticorrelated with tastant concentration, yet whether one or both neural responses signal intensity is poorly characterized because animals from these studies were not trained to report the intensity of the concentration that they tasted. To address this issue, we designed a two-alternative forced choice (2-AFC) task in which freely licking rats distinguished among concentrations of NaCl and recorded from ensembles of neurons in the GC. We identified three neural ensembles that rapidly (<300 ms or ∼2 licks) processed NaCl concentration. For two ensembles, their NaCl evoked activity was anticorrelated with NaCl concentration but could be further distinguished by their response to water; in one ensemble, water evoked the greatest response while in the other ensemble the lowest tested NaCl concentration evoked the greatest response. However, the concentration sensitive activity from each of these ensembles did not show a strong association with the behaviour of the rat in the 2-AFC task, suggesting a lesser role for signalling tastant intensity. Conversely, for a third neural ensemble, its neural activity was well correlated with increases in NaCl concentration, and this relationship best matched the intensity perceived by the rat. These results suggest that this neuronal ensemble in GC whose activity monotonically increases with concentration plays an important role in signalling the intensity of the taste of NaCl.

Time-based decision-making in peak-interval timing procedures involves the setting of response thresholds for the initiation ("Start") and termination ("Stop") of a response sequence that is centered on a target duration. Using intracerebral infusions of the protein synthesis inhibitor anisomycin, we report that the acquisition of the "Start" response depends on normal functioning (including protein synthesis) in the dorsal striatum (DS), but not the ventral striatum (VS). Conversely, disruption of the VS, but not the DS, impairs the acquisition of the "Stop" response. We hypothesize that the dorsal and ventral regions of the striatum function as a competitive neural network that encodes the temporal boundaries marking the beginning and end of a timed response sequence.

Estimations of time and number share many similarities in both non-humans and man. The primary focus of this review is on the development of time and number sense across infancy and childhood, and neuropsychological findings as they relate to time and number discrimination in infants and adults. Discussion of these findings is couched within a mode-control model of timing and counting which assumes time and number share a common magnitude representation system. A basic sense of time and number likely serves as the foundation for advanced numerical and temporal competence, and aspects of higher cognition-this will be discussed as it relates to typical childhood, and certain developmental disorders, including autism spectrum disorder. Directions for future research in the developmental neuroscience of time and number (NEUTIN) will also be highlighted.

The dopamine transporter (DAT) is the major regulator of the spatial and temporal resolution of dopaminergic neurotransmission in the brain. Hyperdopaminergic mice with DAT gene deletions were evaluated for their ability to perform duration discriminations in the seconds-to-minutes range. DAT -/- mice were unable to demonstrate temporal control of behavior in either fixed-interval or peak-interval timing procedures, whereas DAT +/- mice were similar to DAT +/+ mice under normal conditions. Low to moderate-dose methamphetamine (MAP) challenges indicated that DAT +/- mice were less sensitive to the clock-speed enhancing effects of MAP compared with DAT +/+ mice. In contrast, DAT +/- mice were more vulnerable than DAT +/+ mice to the disruptive effects of MAP at high doses as revealed by the elevation of response rate in the right hand tail of the Gaussian-shaped timing functions. Moreover, this treatment made DAT +/- mice functionally equivalent to DAT -/- mice in terms of the loss of temporal control. Taken together, these results demonstrate the importance of dopaminergic control of interval timing in cortico-striatal circuits and the potential link of timing dysfunctions to schizophrenia and drug abuse., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Distortions in time perception and timed performance are presented by a number of different neurological and psychiatric conditions (e.g. Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder and autism). As a consequence, the primary focus of this review is on factors that define or produce systematic changes in the attention, clock, memory and decision stages of temporal processing as originally defined by Scalar Expectancy Theory. These findings are used to evaluate the Striatal Beat Frequency Theory, which is a neurobiological model of interval timing based upon the coincidence detection of oscillatory processes in corticostriatal circuits that can be mapped onto the stages of information processing proposed by Scalar Timing Theory.

The relation between the contingent negative variation (CNV) and time estimation is evaluated in terms of temporal accumulation and preparation processes. The conclusion is that the CNV as measured from the electroencephalogram (EEG) recorded at fronto-central and parietal-central areas is not a direct reflection of the underlying interval timing mechanism(s), but more likely represents a time-based response preparation/decision-making process.

Neural timing mechanisms range from the millisecond to diurnal, and possibly annual, frequencies. Two of the main processes under study are the interval timer (seconds-to-minute range) and the circadian clock. The molecular basis of these two mechanisms is the subject of intense research, as well as their possible relationship. This article summarizes data from studies investigating a possible interaction between interval and circadian timing and reviews the molecular basis of both mechanisms, including the discussion of the contribution from studies of genetically modified animal models. While there is currently no common neurochemical substrate for timing mechanisms in the brain, circadian modulation of interval timing suggests an interaction of different frequencies in cerebral temporal processes.

Sex differences in the rapid and acute effects of estradiol on time perception were investigated in adult male and female Sprague-Dawley rats. Because estradiol has been shown to increase striatal dopamine release, it may be able to modify time perception and timed performance by increasing the speed of an internal clock in a manner similar to indirect dopamine agonists such as amphetamine and cocaine. Two groups of females (neonatally estradiol-treated/adult ovariectomized and neonatally oil-treated/adult ovariectomized) and two groups of males (neonatally castrated and adult castrated) were trained in a 2 vs. 8-s duration bisection procedure and tested using intermediate signal durations. After obtaining oil-injected baseline psychometric functions over several days, rats were administered 5 μg of estradiol for 4 days and behaviorally evaluated 30 min following each injection. This oil-estradiol administration cycle was subsequently repeated three times following the re-establishment of baseline training. Results revealed significant sex differences in the initial baseline functions that were not modifiable by organizational hormones, with males' duration bisection functions shifted horizontally to the left of females'. Upon the first administration of estradiol, females, but not males, showed a significant, transient leftward shift in their bisection functions, indicative of an increase in clock speed. After extensive retraining in the duration bisection procedure, rats that were exposed to gonadal hormones during the first week of life showed a significant rightward shift in their bisection functions on the fourth day of estradiol administration during each cycle, suggesting a decrease in clock speed. Taken together, our results support the view that there are multiple mechanisms of estrogens' action in the striatum that modulate dopaminergic activity and are differentially organized by gonadal steroids during early brain development.

Quinpirole-sensitized rats were tested on a discrete-trials 40-s peak-interval procedure using lever pressing as the instrumental response. Although there was no evidence of rhythmical activity in lever pressing, periodic output was observed in a secondary response (food-cup entries) during the inter-trial interval following the delivery of reinforcement on fixed-interval trials, but not during unreinforced probe trials. This repetitive pattern of behavior with a 40-s period points to the primacy of reinforcement as a time marker and an increased tendency to synchronize to noisy and sparse periodic input as a result of reduced inhibitory control in cortico-striatal circuits following chronic quinpirole administration. Parallels between quinpirole-induced rhythmical behavior and the repetitive motor habits frequently observed in obsessive-compulsive disorder are discussed., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

The recombination activating genes (RAGs) encode two enzymes that play key roles in the adaptive immune system. RAG1 and RAG2 mediate VDJ recombination, a process necessary for the maturation of B- and T-cells. Interestingly, RAG1 is also expressed in the brain, particularly in areas of high neural density such as the hippocampus, although its function is unknown. We tested evidence that RAG1 plays a role in brain function using a social recognition memory task, an assessment of the acquisition and retention of conspecific identity. In a first experiment, we found that RAG1-deficient mice show impaired social recognition memory compared to mice wildtype for the RAG1 allele. In a second experiment, by breeding to homogenize background genotype, we found that RAG1-deficient mice show impaired social recognition memory relative to heterozygous or RAG2-deficient littermates. Because RAG1 and RAG2 null mice are both immunodeficient, the results suggest that the memory impairment is not an indirect effect of immunological dysfunction. RAG1-deficient mice show normal habituation to non-socially derived odors and habituation to an open-field, indicating that the observed effect is not likely a result of a general deficit in habituation to novelty. These data trace the origin of the impairment in social recognition memory in RAG1-deficient mice to the RAG1 gene locus and implicate RAG1 in memory formation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Aged male rats at 10, 20, and 30 mo of age were trained on a 2.0 vs. 8.0-s duration bisection procedure using both auditory and visual signals and were then tested with visual signal durations in which the spacing of the intermediate signal durations was held constant as the short (S) and long (L) anchor durations were moved progressively closer to each other across blocks of sessions. Auditory clicks also preceded some trials in order to determine the potential effects of arousal and/or distraction on the timing of visual signals. The consequences of aging, reducing the S:L ratio, and auditory clicks were to increase the likelihood of observing reversals in response classifications around the geometric mean of the anchor durations. Taken together, these results suggest that the bisection "reversal effect" is dependent upon the calculation of the subjective mid-point between the two anchor durations and the differential setting of response thresholds around this category boundary as a function of temporal context., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We all have a sense of time. Yet, there are no sensory receptors specifically dedicated for perceiving time. It is an almost uniquely intangible sensation: we cannot see time in the way that we see color, shape, or even location. So how is time represented in the brain? We explore the neural substrates of metrical representations of time such as duration estimation (explicit timing) or temporal expectation (implicit timing). Basal ganglia (BG), supplementary motor area, cerebellum, and prefrontal cortex have all been linked to the explicit estimation of duration. However, each region may have a functionally discrete role and will be differentially implicated depending upon task context. Among these, the dorsal striatum of the BG and, more specifically, its ascending nigrostriatal dopaminergic pathway seems to be the most crucial of these regions, as shown by converging functional neuroimaging, neuropsychological, and psychopharmacological investigations in humans, as well as lesion and pharmacological studies in animals. Moreover, neuronal firing rates in both striatal and interconnected frontal areas vary as a function of duration, suggesting a neurophysiological mechanism for the representation of time in the brain, with the excitatory-inhibitory balance of interactions among distinct subtypes of striatal neuron serving to fine-tune temporal accuracy and precision.