Not All Mice Are Created Equal: Interval Timing Accuracy and Scalar Timing in 129, Swiss-Webster, and C57Bl/6 Mice.

Many species, including humans, show both accurate timing-appropriate time estimation in the seconds to minutes range-and scalar timing-time estimation error varies linearly with estimated duration. Behavioral paradigms aimed at investigating interval timing are expected to evaluate these dissociable characteristics of timing. However, when evaluating interval timing in models of neuropsychiatric disease, researchers are confronted with a lack of adequate studies about the parent (background) strains, since accuracy and scalar timing have only been demonstrated for the C57Bl/6 strain of mice (Buhusi et al., 2009). We used a peak-interval procedure with three intervals-a protocol in which other species, including humans, demonstrate accurate, scalar timing-to evaluate timing accuracy and scalar timing in three strains of mice frequently used in genetic and behavioral studies: 129, Swiss-Webster, and C57Bl/6. C57Bl/6 mice showed accurate, scalar timing, while 129 and Swiss-Webster mice showed departures from accuracy and/or scalar timing. Results suggest that the genetic background / strain of the mouse is a critical variable for studies investigating interval timing in genetically-engineered mice. Our study validates the PI procedure with multiple intervals as a proper technique, and the C57Bl/6 strain as the most suitable genetic background to date for behavioral investigations of interval timing in genetically engineered mice modeling human disorders. In contrast, studies using mice in 129, Swiss-Webster, or mixed-background strains should be interpreted with caution, and thorough investigations of accuracy and scalar timing should be conducted before a less studied strain of mouse is considered for use in timing studies.

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.

Timing behavior in genetic murine models of neurological and psychiatric diseases.

How timing behavior is altered in different neurodevelopmental and neurodegenerative disorders is a contemporary research question. Genetic murine models (GMM) that offer high construct validity also serve as useful tools to investigate this question. But the literature on timing behavior of different GMMs largely remains to be consolidated. The current paper addresses this gap by reviewing studies that have been conducted with GMMs of neurodevelopmental (e.g. ADHD, schizophrenia, autism spectrum disorder), neurodegenerative disorders (e.g., Alzheimer's disease, Huntington's disease) as well as circadian and other mutant lines. The review focuses on those studies that specifically utilized the peak interval procedure to improve the comparability of findings both within and between different disease models. The reviewed studies revealed timing deficits that are characteristic of different disorders. Specifically, Huntington's disease models had weaker temporal control over the termination of their anticipatory responses, Alzheimer's disease models had earlier timed responses, schizophrenia models had weaker temporal control, circadian mutants had shifted timed responses consistent with shifts in the circadian periods. The differences in timing behavior were less consistent for other conditions such as attention deficit and hyperactivity disorder and mutations related to intellectual disability. We discuss the implications of these findings for the neural basis of an internal stopwatch. Finally, we make methodological recommendations for future research for improving the comparability of the timing behavior across different murine models.

Selective attention in pigeon temporal discrimination.

Cues can vary in how informative they are about when specific outcomes, such as food availability, will occur. This study was an experimental investigation of the functional relation between cue informativeness and temporal discrimination in a peak-interval (PI) procedure. Each session consisted of fixed-interval (FI) 2- and 4-s schedules of food and occasional, 12-s PI trials during which pecks had no programmed consequences. Across conditions, the phi (ϕ) correlation between key light color and FI schedule value was manipulated. Red and green key lights signaled the onset of either or both FI schedules. Different colors were either predictive (ϕ = 1), moderately predictive (ϕ = 0.2-0.8) or not predictive (ϕ = 0) of a specific FI schedule. This study tested the hypothesis that temporal discrimination is a function of the momentary conditional probability of food; that is, pigeons peck the most at either 2 s or 4 s when ϕ = 1 and peck at both intervals when ϕ < 1. Response distributions were bimodal Gaussian curves; distributions from red- and green-key PI trials converged when ϕ ≤ 0.6. Peak times estimated by summed Gaussian functions, averaged across conditions and pigeons, were 1.85 and 3.87 s; however, pigeons did not always maximize the momentary probability of food. When key light color was highly correlated with FI schedules (ϕ ≥ 0.6), estimates of peak times indicated that temporal discrimination accuracy was reduced at the unlikely interval, but not the likely interval. The mechanism of this reduced temporal discrimination accuracy could be interpreted as an attentional process.

Recalibrating timing behavior via expected covariance between temporal cues.

Individuals must predict future events to proactively guide their behavior. Predicting when events will occur is a critical component of these expectations. Temporal expectations are often generated based on individual cue-duration relationships. However, the durations associated with different environmental cues will often co-vary due to a common cause. We show that timing behavior may be calibrated based on this expected covariance, which we refer to as the 'common cause hypothesis'. In five experiments using rats, we found that when the duration associated with one temporal cue changes, timed-responding to other cues shift in the same direction. Furthermore, training subjects that expecting covariance is not appropriate in a given situation blocks this effect. Finally, we confirmed that this transfer is context-dependent. These results reveal a novel principle that modulates timing behavior, which we predict will apply across a variety of magnitude-expectations.

From minutes to days-The ability of sows (Sus scrofa) to estimate time intervals.

Time estimation helps allocating time to different tasks and to plan behavioural sequences. It may also be relevant to animal welfare if it enables animals assessing the duration of a negative situation. Here, we investigated the ability of dry sows to estimate short and long time periods. We used a variant of the peak-interval procedure and the choice between 2 resources of different quality and replenishment rates to assess time periods in the order of minutes and days, respectively. In the minute-experiment, the sows were trained to expect an interruption while feeding at the end of an interval. Heart rate and heart rate variability slightly and continuously increased and decreased, respectively, towards the end of that interval. In the day-experiment, lasting about 60days, the sows were increasingly more likely to open the door to a high food reward on the correct day when this food reward was presented every fifth day. We conclude that the sows learnt to estimate time intervals of 5days after lengthy training but did not accurately learn intervals in the range of minutes. Therefore, they might re-visit replenishing resources after several days, but may not base short-term decisions solely on the passing of time.

6-Hydroxydopamine lesions in the medial prefrontal cortex of rats exposed to a peak-interval procedure

Impaired temporal control is symptomatic of several neurological disorders; recently, it has been implicated in schizophrenia. An animal model of schizophrenia using 6-hydroxydopamine (6-OHDA) infused to the medial pre-frontal cortex (mPFC) was employed to examine its effects on temporal control. Twelve rats were trained on a peak-interval procedure (PIP) until stable patterns of behavior were obtained. Rats infused with 6-OHDA responded less during peak trials and their peak functions were flatter than sham rats. These results are consistent with similar studies with transgenic mice with increased striatal dopamine D2 receptor activity. Lesions in the mPFC decreased motivation to respond in a PIP. These effects may be considered analogous to negative symptoms of schizophrenia...

6-Hydroxydopamine lesions in the medial prefrontal cortex of rats exposed to a peak-interval procedure

Impaired temporal control is symptomatic of several neurological disorders; recently, it has been implicated in schizophrenia. An animal model of schizophrenia using 6-hydroxydopamine (6-OHDA) infused to the medial pre-frontal cortex (mPFC) was employed to examine its effects on temporal control. Twelve rats were trained on a peak-interval procedure (PIP) until stable patterns of behavior were obtained. Rats infused with 6-OHDA responded less during peak trials and their peak functions were flatter than sham rats. These results are consistent with similar studies with transgenic mice with increased striatal dopamine D2 receptor activity. Lesions in the mPFC decreased motivation to respond in a PIP. These effects may be considered analogous to negative symptoms of schizophrenia.(AU)

Effect of distracter preexposure on the reset of an internal clock.

Interruptions and unfamiliar events (distracters) during a timed signal disrupt (delay) timing in humans and other animals. We hypothesized that repeated exposure to a stimulus may reduce its subsequent time-disrupting properties. To test this hypothesis rats were trained in a reversed peak-interval (RPI) procedure, in which dark timing trials were separated by illuminated inter-trial intervals. Rats were then repeatedly exposed to an auditory stimulus (noise) in either dark (DARK group), or illuminated chambers (LIGHT group); control rats were not exposed to the noise (NOVEL group). Afterwards, the time-resetting properties of the noise were tested by presenting it unexpectedly during the (dark) RPI trials. The noise reset timing in NOVEL rats, but stopped timing in DARK rats, suggesting that preexposure reduces the time-resetting effects of distracters. However, in LIGHT rats, the noise stopped timing when the presented early in the RPI trial, but reset when presented late, suggesting that exposure to noise was only partly effective in overriding other relevant variables, such as distracter location. These results suggest that the effect of distracter preexposure on the reset of an internal clock depends on complex associative and temporal interactions which require further investigations. This article is part of a Special Issue entitled: Associative and Temporal Learning.