The timing database: An open-access, live repository for interval timing studies.

Interval timing refers to the ability to perceive and remember intervals in the seconds to minutes range. Our contemporary understanding of interval timing is derived from relatively small-scale, isolated studies that investigate a limited range of intervals with a small sample size, usually based on a single task. Consequently, the conclusions drawn from individual studies are not readily generalizable to other tasks, conditions, and task parameters. The current paper presents a live database that presents raw data from interval timing studies (currently composed of 68 datasets from eight different tasks incorporating various interval and temporal order judgments) with an online graphical user interface to easily select, compile, and download the data organized in a standard format. The Timing Database aims to promote and cultivate key and novel analyses of our timing ability by making published and future datasets accessible as open-source resources for the entire research community. In the current paper, we showcase the use of the database by testing various core ideas based on data compiled across studies (i.e., temporal accuracy, scalar property, location of the point of subjective equality, malleability of timing precision). The Timing Database will serve as the repository for interval timing studies through the submission of new datasets.

Mice make temporal inferences about novel locations based on previously learned spatiotemporal contingencies.

Animals learn multiple spatiotemporal contingencies and organize their anticipatory responses accordingly. The representational/computational capacity that underlies such spatiotemporally guided behaviors is not fully understood. To this end, we investigated whether mice make temporal inferences of novel locations based on previously learned spatiotemporal contingencies. We trained 18 C57BL/6J mice to anticipate reward after three different intervals at three different locations and tested their temporal expectations of a reward at five locations simultaneously, including two locations that were not previously associated with reward delivery but adjacent to the previously trained locations. If mice made spatiotemporal inferences, they were expected to interpolate between duration pairs associated with previously reinforced hoppers surrounding the novel hopper. We found that the maximal response rate at the novel locations indeed fell between the two intervals reinforced at the surrounding hoppers. We argue that this pattern of responding might be underlain by spatially constrained Bayesian computations.

Count-based decision-making in mice: numerosity vs. stimulus control.

Numerical and temporal control of behavior is ubiquitous across many species of animals. Recent studies showed that in the presence of reliable discriminative stimuli, mice ignore temporal relations and probabilistic information but when discriminative stimuli become non-informative, the same mice can spontaneously start relying on previously experienced time intervals and probabilities. Similar dynamics do not readily generalize to counting behavior since the response-outcome contingency functions differ when reinforcement depends on the number vs. timing of responding. In the current study, mice (N = 32) learned to press two different levers 10 (few) or 20 (many) times, while the active lever was signaled by a light stimulus. The probability of the few/many trials was manipulated between groups. During testing, the informative value of light stimulus was eliminated by signaling both few- and many-levers. In a quarter of training trials, mice ignored the discriminative stimulus and adopted a numerical decision strategy (starting to respond on the few-option and then switching to the many-option in many trials) that was sensitive to probabilistic information. The frequency but not the probability-sensitive parametrization of switching behavior changed when the discriminative stimulus became non-informative in testing. These findings suggest that there is a relatively strong representational control over counting behavior even in conditions that afford strong stimulus control.

Testing the memory reconsolidation hypothesis in a fear extinction paradigm: The effects of ecological and arbitrary stimuli.

Various studies demonstrated that extinction training taking place shortly after the activation of the acquired fear could weaken the conditioned fear. The procedure is called post-retrieval extinction (PRE). However, from the time it emerged, it has suffered from inconsistencies in the ability of researchers to replicate the seemingly established effects. Extant literature implies that conditioned fear might be differentially sensitive to the nature of conditioned stimuli (CS) used. The aim of the present study, therefore, is threefold. First, we aimed to replicate Schiller et al. (Nature, 463, 49-53. 2010) procedure in which the PRE had produced positive results with arbitrary CSs only. Also, we examined the PRE as a function of CS type (ecological-fear-relevant (images of spider and snake) vs. arbitrary (images of yellow and blue circles)). Finally, we aimed to investigate the long-term effects of the PRE (i.e., 24 h, 15 d, and 3 mo). The study consisted of acquisition, re-activation and extinction, and re-extinction phases. Dependent measure was the recovery of fear responses as indexed by the skin conductance responses (SCRs) and arousal ratings of the participants at the last trial of the extinction and the first trial of the re-extinction. All groups showed significant acquisition and extinction patterns, compared to the other two groups (i.e., 6 h after the activating CS and without an activating stimulus) only the group that undertook extinction trials 10 min after the activating CS showed a sustained extinction. Thus, our findings provided further evidence for the robustness of the PRE paradigm in preventing the recovery of extinguished fears behaviorally, both with ecological and arbitrary stimuli.

Numerical averaging in mice.

Rodents can be trained to associate different durations with different stimuli (e.g., light/sound). When the associated stimuli are presented together, maximal responding is observed around the average of individual durations (akin to averaging). The current study investigated whether mice can also average independently trained numerosities. Mice were initially trained to make 10 or 20 lever presses on a single (run) lever to obtain a reward and each fixed-ratio schedule was signaled either with an auditory or visual stimulus. Then, mice were trained to press another lever to obtain the reward after they responded on the run lever for the minimum number of presses [Fixed Consecutive Number (FCN)-10 or -20 trials] signaled by the corresponding discriminative stimulus. Following this training, FCN trials with the compound stimulus were introduced to test the counting behavior of mice when they encountered conflicting information regarding the number of responses required to obtain the reward. Our results showed that the numbers of responses on these compound test trials were around the average of the number of responses in FCN-10 and FCN-20 trials particularly when the auditory stimulus was associated with a fewer number of required responses. The counting strategy explained the behavior of the majority of the mice in the FCN-Compound test trials (as opposed to the timing strategy). The number of responses in FCN-Compound trials was accounted for equally well by the arithmetic, geometric, and Bayesian averages of the number of responses observed in FCN-10 and FCN-20 trials.

Aging impairs perceptual decision-making in mice: integrating computational and neurobiological approaches.

Decision-making is one of the cognitive domains which has been under-investigated in animal models of cognitive aging along with its neurobiological correlates. This study investigated the latent variables of the decision process using the hierarchical drift-diffusion model (HDDM). Neurobiological correlates of these processes were examined via immunohistochemistry. Young (n = 11, 4 months old), adult (n = 10, 10 months old), and old (n = 10, 18 months old) mice were tested in a perceptual decision-making task (i.e. two-alternative forced-choice; 2AFC). Observed data showed that there was an age-dependent decrease in the accuracy rate of old mice while response times were comparable between age groups. HDDM results revealed that age-dependent accuracy difference was a result of a decrease in the quality of evidence integration during decision-making. Significant positive correlations observed between evidence integration rate and the number of tyrosine hydroxylase positive (TH+) neurons in the ventral tegmental area (VTA) and axon terminals in dorsomedial striatum (DMS) suggest that decrease in the quality of evidence integration in aging is related to decreased function of mesocortical and nigrostriatal dopamine.

Interval timing deficits and their neurobiological correlates in aging mice.

Age-related neurobiological and cognitive alterations suggest that interval timing (as a related function) is also altered in aging, which can, in turn, disrupt timing-dependent functions. We investigated alterations in interval timing with aging and accompanying neurobiological changes. We tested 4-6, 10-12, and 18-20 month-old mice on the dual peak interval procedure. Results revealed a specific deficit in the termination of timed responses (stop-times). The decision processes contributed more to timing variability (vs. clock/memory process) in the aged mice. We observed age-dependent reductions in the number of dopaminergic neurons in the VTA and SNc, cholinergic neurons in the medial septum/diagonal band (MS/DB) complex, and density of dopaminergic axon terminals in the DLS/DMS. Negative correlations were found between the number of dopaminergic neurons in the VTA and stop times, and the number of cholinergic neurons in MS/DB complex and the acquisition of stop times. Our results point at age-dependent changes in the decisional components of interval timing and the role of dopaminergic and cholinergic functions in these behavioral alterations.

Probabilistic Information Modulates the Timed Response Inhibition Deficit in Aging Mice.

How interval timing is affected by aging constitutes one of the contemporary research questions. There is however a limited number of studies that investigate this research question in animal models of aging. The current study investigated how temporal decision-making is affected by aging. Initially, we trained young (2-3 month-old) and old C57BL/6J male mice (18-19 month-old) independently with short (3 s) and long (9 s) intervals by signaling, in each trial, the hopper associated with the interval that is in effect in that trial. The probability of short and long trials was manipulated (0.25 or 0.75) for different animals in each age group. During testing, both hoppers were illuminated, and thus active trial type was not differentiated. We expected mice to spontaneously combine the independently acquired time interval-location-probability information to adaptively guide their timing behavior in test trials. This adaptive ability and the resultant timing behavior were analyzed and compared between the age groups. Both young and old mice indeed adjusted their timing behavior in an abrupt fashion based on the independently acquired temporal-spatial-probabilistic information. The core timing ability of old mice was also intact. However, old mice had difficulty in terminating an ongoing timed response when the probability for the short trial was higher and this difference disappeared in the group that was exposed to a lower probability of short trials. These results suggest an inhibition problem in old mice as reflected through the threshold modulation process in timed decisions, which is cognitively penetrable to the probabilistic information.

Interval timing is disrupted in female 5xFAD mice: An indication of altered memory processes.

Temporal information processing in the seconds-to-minutes range is disrupted in patients with Alzheimer's disease (AD). In this study, we investigated the timing behavior of the 5xFAD mouse model of AD in the peak interval (PI) procedure. Nine-month-old female mice were trained with sucrose solution reinforcement for their first response after a fixed-interval (FI) and tested in the inter-mixed non-reinforced PI trials that lasted longer than FI. Timing performance indices were estimated from steady-state timed anticipatory nose-poking responses in the PI trials. We found that the time of maximal reward expectancy (peak time) of the 5xFAD mice was significantly earlier than that of the wild-type (WT) controls with no differences in other indices of timing performance. These behavioral differences corroborate the findings of previous studies on the disruption of temporal associative memory abilities of 5xFAD mice and can be accounted for by the scalar timing theory based on altered long-term memory consolidation of temporal information in the 5xFAD mice. This is the first study to directly show an interval timing phenotype in a genetic mouse model of AD.

Sex differences in the timing behavior performance of 3xTg-AD and wild-type mice in the peak interval procedure.

We investigated interval timing behavior of 10-month-old male and female 3xTg-AD mice compared with their B6129F2/J wild type controls using the peak interval procedure with a 15 s target interval. Multiple parameters reflecting different aspects of timing performance were extracted from steady-state anticipatory nose-poking behavior using two different approaches: single trial analyses and average response curve analyses. These measures can dissociate the differences in performance due to distortions in the interval timing ability or to motivational decline (i.e. apathy); both of which have been reported in Alzheimer patients. We found that the interval timing ability of male and female 3xTg-AD mice did not differ from wild-type controls. However, in measures reflecting motivational state, we found significant sex differences regardless of genotype. Specifically, female mice initiated anticipatory responding later in the trial and had lower response amplitudes than males. Although our findings can also be interpreted in terms of differences in temporal control for response initiation, they more strongly suggest the effect of differential incentive motivation between sexes on timing behavior in these mice.

Spontaneous integration of temporal information: implications for representational/computational capacity of animals.

How do animals adapt their behaviors to changing conditions? This question relates to the debate between associative versus representational/computational approaches in cognitive science. An influential line of research that has significantly shaped the conceptual development of animal learning over decades has primarily focused on the role of associative dynamics with little-to-no ascription of representational/combinatorial capacities. The common assumption of these models is that behavioral adjustments are incremental and they result from updating of associations based on actions and their outcomes, without encoding the critical information serving as the determinant(s) of such contingencies (e.g., time in interval schedules, number in ratio schedules). On the other hand, an independent line of research provides evidence for behavioral phenomena that cannot be readily accounted for by the conventional associationist approach. In this paper, we will review different sets of findings particularly in the area of interval timing that suggest the ability of animals to make swift spontaneous computations on subjective quantities and incorporate them into their behavior. Findings of these studies constitute empirical challenges for the associationist approaches to behavioral flexibility. We argue that interval timing is a fertile ground for the formulation of critical tests of different theoretical approaches to animal behavior.

Mice optimize timed decisions about probabilistic outcomes under deadlines.

Optimal performance in temporal decisions requires the integration of timing uncertainty with environmental statistics such as probability or cost functions. Reward maximization under response deadlines constitutes one of the most stringent examples of these problems. The current study investigated whether and how mice can optimize their timing behavior in a complex experimental setting under a response deadline in which reward maximization required the integration of timing uncertainty with a geometrically increasing probability/decreasing cost function. Mice optimized their performance under seconds-long response deadlines when the underlying function was reward probability but approached this level of performance when the underlying function was reward cost, only under the assumption of logarithmically scaled subjective costs. The same subjects were then tested in a timed response inhibition task characterized by response rules that conflicted with the initial task, not responding earlier than a schedule as opposed to not missing the deadline. Irrespective of original test groups, mice optimized the timing of their inhibitory control in the second experiment. These results provide strong support for the ubiquity of optimal temporal risk assessment in mice.

Mice plan decision strategies based on previously learned time intervals, locations, and probabilities.

Animals can shape their timed behaviors based on experienced probabilistic relations in a nearly optimal fashion. On the other hand, it is not clear if they adopt these timed decisions by making computations based on previously learnt task parameters (time intervals, locations, and probabilities) or if they gradually develop their decisions based on trial and error. To address this question, we tested mice in the timed-switching task, which required them to anticipate when (after a short or long delay) and at which of the two delay locations a reward would be presented. The probability of short trials differed between test groups in two experiments. Critically, we first trained mice on relevant task parameters by signaling the active trial with a discriminative stimulus and delivered the corresponding reward after the associated delay without any response requirement (without inducing switching behavior). During the test phase, both options were presented simultaneously to characterize the emergence and temporal characteristics of the switching behavior. Mice exhibited timed-switching behavior starting from the first few test trials, and their performance remained stable throughout testing in the majority of the conditions. Furthermore, as the probability of the short trial increased, mice waited longer before switching from the short to long location (experiment 1). These behavioral adjustments were in directions predicted by reward maximization. These results suggest that rather than gradually adjusting their time-dependent choice behavior, mice abruptly adopted temporal decision strategies by directly integrating their previous knowledge of task parameters into their timed behavior, supporting the model-based representational account of temporal risk assessment.