Elucidating a locus coeruleus-dentate gyrus dopamine pathway for operant reinforcement.

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.

The neural bases for timing of durations.

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.

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.

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.

Daily and seasonal fluctuation in Tawny Owl vocalization timing.

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.

Consensus paper: Decoding the Contributions of the Cerebellum as a Time Machine. From Neurons to Clinical Applications.

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.

Internal Clocks, mGluR7 and Microtubules: A Primer for the Molecular Encoding of Target Durations in Cerebellar Purkinje Cells and Striatal Medium Spiny Neurons.

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.

Integrating Models of Interval Timing and Reinforcement Learning.

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.

Oscillation patterns of local field potentials in the dorsal striatum and sensorimotor cortex during the encoding, maintenance, and decision stages for the ordinal comparison of sub- and supra-second signal durations.

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.

Nigrotectal Stimulation Stops Interval Timing in Mice.

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.

The Persistence of Memory: How the Brain Encodes Time in Memory.

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.

Interactive roles of the cerebellum and striatum in sub-second and supra-second timing: Support for an initiation, continuation, adjustment, and termination (ICAT) model of temporal processing.

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.

The Socio-Temporal Brain: Connecting People in Time.

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.

Discriminative Fear Learners are Resilient to Temporal Distortions during Threat Anticipation.

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.

Cognitive Aging and Time Perception: Roles of Bayesian Optimization and Degeneracy.

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).

Temporal cognition: Connecting subjective time to perception, attention, and memory.

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

Emotional modulation of interval timing and time perception.

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.

Analysis of Genetic and Non-Genetic Factors Influencing Timing and Time Perception.

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.

Oscillatory multiplexing of neural population codes for interval timing and working memory.

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.