The dorsal hippocampus' role in context-based timing in rodents.

To act proactively, we must predict when future events will occur. Individuals generate temporal predictions using cues that indicate an event will happen after a certain duration elapses. Neural models of timing focus on how the brain represents these cue-duration associations. However, these models often overlook the fact that situational factors frequently modulate temporal expectations. For example, in realistic environments, the intervals associated with different cues will often covary due to a common underlying cause. According to the 'common cause hypothesis,' observers anticipate this covariance such that, when one cue's interval changes, temporal expectations for other cues shift in the same direction. Furthermore, as conditions will often differ across environments, the same cue can mean different things in different contexts. Therefore, updates to temporal expectations should be context-specific. Behavioral work supports these predictions, yet their underlying neural mechanisms are unclear. Here, we asked whether the dorsal hippocampus mediates context-based timing, given its broad role in context-conditioning. Specifically, we trained rats with either hippocampal or sham lesions that two cues predicted reward after either a short or long duration elapsed (e.g., tone-8 s/light-16 s). Then, we moved rats to a new context and extended the long cue's interval (e.g., light-32 s). This caused rats to respond later to the short cue, despite never being trained to do so. Importantly, when returned to the initial training context, sham rats shifted back toward both cues' original intervals. In contrast, lesion rats continued to respond at the long cue's newer interval. Surprisingly, they still showed contextual modulation for the short cue, responding earlier like shams. These data suggest the hippocampus only mediates context-based timing if a cue is explicitly paired and/or rewarded across distinct contexts. Furthermore, as lesions did not impact timing measures at baseline or acquisition for the long cue's new interval, our data suggests that the hippocampus only modulates timing when context is relevant.

Cerebellar D1DR-expressing neurons modulate the frontal cortex during timing tasks.

Converging lines of evidence suggest that the cerebellum plays an integral role in cognitive function through its interactions with association cortices like the medial frontal cortex (MFC). It is unknown precisely how the cerebellum influences the frontal cortex and what type of information is reciprocally relayed between these two regions. A subset of neurons in the cerebellar dentate nuclei, or the homologous lateral cerebellar nuclei (LCN) in rodents, express D1 dopamine receptors (D1DRs) and may play a role in cognitive processes. We investigated how pharmacologically blocking LCN D1DRs influences performance in an interval timing task and impacts neuronal activity in the frontal cortex. Interval timing requires executive processes such as working memory, attention, and planning and is known to rely on both the frontal cortex and cerebellum. In our interval timing task, male rats indicated their estimates of the passage of a period of several seconds by making lever presses for a water reward. We have shown that a cue-evoked burst of low-frequency activity in the MFC initiates ramping activity (i.e., monotonic increases or decreases of firing rate over time) in single MFC neurons. These patterns of activity are associated with successful interval timing performance. Here we explored how blocking right LCN D1DRs with the D1DR antagonist SCH23390 influences timing performance and neural activity in the contralateral (left) MFC. Our results indicate that blocking LCN D1DRs impaired some measures of interval timing performance. Additionally, ramping activity of MFC single units was significantly attenuated. These data provide insight into how catecholamines in the LCN may drive MFC neuronal dynamics to influence cognitive function.

Nonhuman sequence learning findings argue against Hoerl and McCormack's two systems of temporal cognition.

Hoerl & McCormack propose that animals learn sequences through an entrainment-like process, rather than tracking the temporal addresses of each event in a given sequence. However, past research suggests that animals form "temporal maps" of sequential events and also comprehend the concept of ordinal position. These findings suggest that a clarification or qualification of the authors' hypothesis is needed.

Rodent Medial Frontal Control of Temporal Processing in the Dorsomedial Striatum.

Although frontostriatal circuits are critical for the temporal control of action, how time is encoded in frontostriatal circuits is unknown. We recorded from frontal and striatal neurons while rats engaged in interval timing, an elementary cognitive function that engages both areas. We report four main results. First, "ramping" activity, a monotonic change in neuronal firing rate across time, is observed throughout frontostriatal ensembles. Second, frontostriatal activity scales across multiple intervals. Third, striatal ramping neurons are correlated with activity of the medial frontal cortex. Finally, interval timing and striatal ramping activity are disrupted when the medial frontal cortex is inactivated. Our results support the view that striatal neurons integrate medial frontal activity and are consistent with drift-diffusion models of interval timing. This principle elucidates temporal processing in frontostriatal circuits and provides insight into how the medial frontal cortex exerts top-down control of cognitive processing in the striatum.SIGNIFICANCE STATEMENT The ability to guide actions in time is essential to mammalian behavior from rodents to humans. The prefrontal cortex and striatum are critically involved in temporal processing and share extensive neuronal connections, yet it remains unclear how these structures represent time. We studied these two brain areas in rodents performing interval-timing tasks and found that time-dependent "ramping" activity, a monotonic increase or decrease in neuronal activity, was a key temporal signal. Furthermore, we found that striatal ramping activity was correlated with and dependent upon medial frontal activity. These results provide insight into information-processing principles in frontostriatal circuits.

Amygdala central nucleus modulation of cerebellar learning with a visual conditioned stimulus.

Previous studies found that reversible inactivation of the central amygdala (CeA) severely impairs acquisition and retention of cerebellum-dependent eye-blink conditioning (EBC) with an auditory conditioned stimulus (CS). A monosynaptic pathway between the CeA and basilar pontine nuclei (BPN) may be capable of facilitating cerebellar learning. However, given that the CeA projects to the medial auditory thalamus, a critical part of the auditory CS pathway in EBC, the CeA influence on cerebellar learning could be specific to auditory stimuli. Here we examined the generality of CeA facilitation of EBC acquisition and retention in rats using a visual CS. As in our previous studies using an auditory CS, inactivation of the CeA with muscimol severely impaired acquisition and retention of EBC with a visual CS. Extending training to 15 100-trial sessions resulted in acquisition of EBC, indicating that the CeA plays a modulatory role in cerebellar learning and is not part of the necessary neural circuitry for EBC. Tract-tracing experiments verified that axons from the CeA reach both the BPN and medial auditory thalamus (part of the necessary auditory CS pathway), but were not found in the ventral lateral geniculate (part of the necessary visual CS pathway). The neuroanatomical results suggest that the CeA most likely modulates cerebellar learning through its projection to the BPN. The findings of the current study are consistent with the hypothesis that the CeA modulates cerebellar learning by increasing CS-related sensory input to the cerebellar cortex and interpositus nucleus via the BPN. This increase in CS-related input is thought to constitute an increase in attention to the CS during EBC.

Temporal averaging across multiple response options: insight into the mechanisms underlying integration.

Rats trained on a dual-duration, dual-modality peak-interval procedure (e.g., tone = 10 s/light = 20 s) often show unimodal response distributions with peaks that fall in between the anchor durations when both cues are presented as a simultaneous compound. Two hypotheses can explain this finding. According to the averaging hypothesis, rats integrate the anchor durations into an average during compound trials, with each duration being weighted by its respective reinforcement probability. According to the simultaneous temporal processing hypothesis, rats time both durations veridically and simultaneously during compound trials and respond continuously across both durations, thereby producing a unimodal response distribution with a peak falling in between the anchor durations. In the present compounding experiment, rats were trained to associate a tone and light with two different durations (e.g., 5 and 20 s, respectively). However, in contrast to previous experiments, each cue was also associated with a distinct response requirement (e.g., left nosepoke for tone/right nosepoke for light). On the majority of compound trials, responding on a given nosepoke fell close to its respective duration, but was shifted in the direction of the other cue's duration, suggesting rats timed an average of the two durations. However, more weight appeared to be given to the duration associated with the manipulandum on which the rat responded, rather than the duration associated with a higher reinforcement probability as predicted by the averaging hypothesis. Group differences were also observed, with rats trained to associate the tone and light with the short and long durations, respectively, being more likely to show these shifts than the counterbalanced modality-duration group (i.e., light-short/tone-long). This parallels group differences observed in past studies and suggest that cue weighting in response to stimulus compounds is influenced by the modality-duration relationship of the anchor cues. The current results suggest that temporal averaging is a more flexible process than previously theorized and provide novel insight into the mechanisms that affect cue weighting.

Temporal scaling and computing time in neural circuits: Should we stop watching the clock and look for its gears?

Timing underlies a variety of functions, from walking to perceiving causality. Neural timing models typically fall into one of two categories-"ramping" and "population-clock" theories. According to ramping models, individual neurons track time by gradually increasing or decreasing their activity as an event approaches. To time different intervals, ramping neurons adjust their slopes, ramping steeply for short intervals and vice versa. In contrast, according to "population-clock" models, multiple neurons track time as a group, and each neuron can fire nonlinearly. As each neuron changes its rate at each point in time, a distinct pattern of activity emerges across the population. To time different intervals, the brain learns the population patterns that coincide with key events. Both model categories have empirical support. However, they often differ in plausibility when applied to certain behavioral effects. Specifically, behavioral data indicate that the timing system has a rich computational capacity, allowing observers to spontaneously compute novel intervals from previously learned ones. In population-clock theories, population patterns map to time arbitrarily, making it difficult to explain how different patterns can be computationally combined. Ramping models are viewed as more plausible, assuming upstream circuits can set the slope of ramping neurons according to a given computation. Critically, recent studies suggest that neurons with nonlinear firing profiles often scale to time different intervals-compressing for shorter intervals and stretching for longer ones. This "temporal scaling" effect has led to a hybrid-theory where, like a population-clock model, population patterns encode time, yet like a ramping neuron adjusting its slope, the speed of each neuron's firing adapts to different intervals. Here, we argue that these "relative" population-clock models are as computationally plausible as ramping theories, viewing population-speed and ramp-slope adjustments as equivalent. Therefore, we view identifying these "speed-control" circuits as a key direction for evaluating how the timing system performs computations. Furthermore, temporal scaling highlights that a key distinction between different neural models is whether they propose an absolute or relative time-representation. However, we note that several behavioral studies suggest the brain processes both scales, cautioning against a dichotomy.

A limited cerebellar contribution to suprasecond timing across differing task demands.

The involvement of the cerebellum in suprasecond interval timing (i.e., timing in the seconds to minutes range) is controversial. A limited amount of evidence from humans, nonhuman primates, and rodents has shown that the lateral cerebellum, including the lateral cerebellar nucleus (LCN), may be necessary for successful suprasecond timing performance. However, many existing studies have pitfalls, such as limited timing outcome measures and confounded task demands. In addition, many existing studies relied on well-trained subjects. This approach may be a drawback, as the cerebellum is hypothesized to carry out ongoing error correction to limit timing variability. By using only experienced subjects, past timing studies may have missed a critical window of cerebellar involvement. In the experiments described here, we pharmacologically inactivated the rat LCN across three different peak interval timing tasks. We structured our tasks to address past confounds, collect timing variability measures, and characterize performance during target duration acquisition. Across these various tasks, we did not find strong support for cerebellar involvement in suprasecond interval timing. Our findings support the existing distinction of the cerebellum as a subsecond interval timing brain region. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Striatal dopamine and the temporal control of behavior.

Striatal dopamine strongly regulates how individuals use time to guide behavior. Dopamine acts on D1- and D2- dopamine receptors in the striatum. However, the relative role of these receptors in the temporal control of behavior is unclear. To assess this, we trained rats on a task in which they decided to start and stop a series of responses based on the passage of time and evaluated how blocking D1 or D2-dopamine receptors in the dorsomedial or dorsolateral striatum impacted performance. D2 blockade delayed the decision to start and stop responding in both regions, and this effect was larger in the dorsomedial striatum. By contrast, dorsomedial D1 blockade delayed stop times, without significantly delaying start times, whereas dorsolateral D1 blockade produced no detectable effects. These findings suggest that striatal dopamine may tune decision thresholds during timing tasks. Furthermore, our data indicate that the dorsomedial striatum plays a key role in temporal control, which may be useful for localizing neural circuits that mediate the temporal control of action.

Attenuation of cocaine seeking in rats via enhancement of infralimbic cortical activity using stable step-function opsins.

RATIONALE: The infralimbic cortex (IL) and its downstream projection target the nucleus accumbens shell (NAshell) mediate the active suppression of cocaine-seeking behavior. Although an optogenetic approach would be beneficial for stimulating the IL and its efferents to study their role during reinstatement of cocaine seeking, the use of channelrhodopsin introduces significant difficulties, as optimal stimulation parameters are not known. OBJECTIVES: The present experiments utilized a stable step-function opsin (SSFO) to potentiate endogenous activity in the IL and in IL terminals in the NAshell during cocaine-seeking tests to determine how these manipulations affect cocaine-seeking behaviors. METHODS: Rats first underwent 6-h access cocaine self-administration followed by 21-27 days in the homecage. Rats then underwent cue-induced and cocaine-primed drug-seeking tests during which the optogenetic manipulation was given. The same rats then underwent extinction training, followed by cue-induced and cocaine-primed reinstatements. RESULTS: Potentiation of endogenous IL activity did not significantly alter cue-induced or cocaine-primed drug seeking following the homecage period. However, following extinction training, enhancement of endogenous IL activity attenuated cue-induced reinstatement by 35% and cocaine-primed reinstatement by 53%. Stimulation of IL terminals in the NAshell did not consistently alter cocaine-seeking behavior. CONCLUSION: These results suggest the utility of an SSFO-based approach for enhancing activity in a structure without driving specific patterns of neuronal firing. However, the utility of an SSFO-based approach for axon terminal stimulation remains unclear. Moreover, these results suggest that the ability of the IL to reduce cocaine seeking depends, at least in part, on rats first having undergone extinction training.

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.

Non-cortical magnitude coding of space and time by pigeons.

Considerable research in cognitive science, neuroscience, and developmental science has revealed that the temporal, spatial, and numerical features of a stimulus can interact with one another [1,2], as when larger stimuli are perceived as lasting longer than smaller stimuli. These findings have inspired the prominent hypothesis that time, space, and number are processed by a 'common magnitude system', which represents these dimensions via the same unit of magnitude [3,4]. According to current theorizing, the parietal cortex mediates this system [4]. To test the species generality and neuroanatomical foundations of this hypothesis, we asked whether space-time interactions can be observed in birds. Unlike mammals, birds lack a cortex [5,6]; rather, they possess a neuron-dense pallium that is organized in clusters, in contrast to the laminar structure of the mammalian cortex [7]. Despite these striking neuroanatomical disparities, we observed reliable space-time interactions in pigeons. Our findings suggest that common magnitude systems are more widespread among animals than previously believed and need not be cortically dependent in all species.

Interval timing, temporal averaging, and cue integration.

In a series of recent experiments, we found that if rats are presented with two temporal cues, each signifying that reward will be delivered after a different duration elapses (e.g., tone-10 seconds / light-20 seconds), they will behave as if they have computed a weighted average of these respective durations. In the current article, we argue that this effect, referred to as "temporal averaging", can be understood within the context of Bayesian Decision Theory. Specifically, we propose and provide preliminary data showing that, when averaging, rats weight different durations based on the relative variability of the information their respective cues provide.