Shogo Sakata

Retrospective and Prospective Views on the Role of the Hippocampus in Interval Timing and Memory for Elapsed Time

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.

Enhanced flexibility of place discrimination learning by targeting striatal cholinergic interneurons

Behavioural flexibility is mediated through the neural circuitry linking the prefrontal cortex and basal ganglia. Here we conduct selective elimination of striatal cholinergic interneurons in transgenic rats by immunotoxin-mediated cell targeting. Elimination of cholinergic interneurons from the dorsomedial striatum (DMS), but not from the dorsolateral striatum, results in enhanced reversal and extinction learning, sparing the acquisition of place discrimination. This enhancement is prevented by infusion of a non-selective muscarinic acetylcholine receptor agonist into the DMS either in the acquisition, reversal or extinction phase. In addition, gene-specific silencing of M4 muscarinic receptor by lentiviral expression of short hairpin RNA (shRNA) mimics the place reversal learning promoted by cholinergic elimination, whereas shRNA-mediated gene silencing of M1 muscarinic receptor shows the normal performance of reversal learning. Our data indicate that DMS cholinergic interneurons inhibit behavioural flexibility, mainly through the M4 muscarinic receptor, suggesting that this role is engaged to the stabilization of acquired reward contingency and the suppression of response switch to changed contingency.

Distinct roles of basal forebrain cholinergic neurons in spatial and object recognition memory.

Recognition memory requires processing of various types of information such as objects and locations. Impairment in recognition memory is a prominent feature of amnesia and a symptom of Alzheimer’s disease (AD). Basal forebrain cholinergic neurons contain two major groups, one localized in the medial septum (MS)/vertical diagonal band of Broca (vDB), and the other in the nucleus basalis magnocellularis (NBM). The roles of these cell groups in recognition memory have been debated, and it remains unclear how they contribute to it. We use a genetic cell targeting technique to selectively eliminate cholinergic cell groups and then test spatial and object recognition memory through different behavioural tasks. Eliminating MS/vDB neurons impairs spatial but not object recognition memory in the reference and working memory tasks, whereas NBM elimination undermines only object recognition memory in the working memory task. These impairments are restored by treatment with acetylcholinesterase inhibitors, anti-dementia drugs for AD. Our results highlight that MS/vDB and NBM cholinergic neurons are not only implicated in recognition memory but also have essential roles in different types of recognition memory.

Brain electrophysiological activity correlates with temporal processing in rats

In this study, we present electroencephalographic (EEG) recording data obtained in correlation with timing behavior in rats trained in a 30-s peak interval (PI) procedure. The distribution of lever press responses was found to be Gaussian, peaking at approximately 30s: lever pressing behavior increased for 30s then decreased after the reinforcement time. We recorded EEG activity in the hippocampus (hippocampal theta wave) and striatum during the task, and evaluated whether the EEG power correlated with the behavior pattern. We found that the striatum EEG, but not the hippocampal theta wave, showed a good correlation with the response pattern in the 30-s PI. This result suggests that striatum neurons fired more synchronously at the time of reinforcement, thus supporting a critical role for synchronization of firing of striatal neurons in regulating timing mechanisms. This article is part of a Special Issue entitled: Associative and Temporal Learning.

Change in hippocampal theta activity with transfer from simple discrimination tasks to a simultaneous feature-negative task

It was showed that solving a simple discrimination task (A+, B−) and a simultaneous feature-negative (FN) task (A+, AB−) used the hippocampal-independent strategy. Recently, we showed that the number of sessions required for a rat to completely learn a task differed between the FN and simple discrimination tasks, and there was a difference in hippocampal theta activity between these tasks. These results suggested that solving the FN task relied on a different strategy than the simple discrimination task. In this study, we provided supportive evidence that solving the FN and simple discrimination tasks involved different strategies by examining changes in performance and hippocampal theta activity in the FN task after transfer from the simple discrimination task (A+, B− → A+, AB−). The results of this study showed that performance on the FN task was impaired and there was a difference in hippocampal theta activity between the simple discrimination task and FN task. Thus, we concluded that solving the FN task uses a different strategy than the simple discrimination task.

Hippocampal theta activity during behavioral inhibition for conflicting stimuli

A recent behavioral inhibitory theory proposed that the hippocampus plays an important role in response inhibition to conflicting stimuli composed of simple inhibitory associations between events embedded in concurrent simple excitatory associations. In addition, the theory states that a serial feature negative (FN) task is a hippocampal-dependent task requiring the formation of a simple inhibitory association; on the other hand, a simple discrimination (SD) task is a typical hippocampus-independent task. In the present study, we recorded hippocampal theta activity from rats during FN and SD tasks to identify any potential differences. In the FN (A+, B→A-) task used in this study, rats were required to press a lever to present stimulus A (A+) and avoid pressing a lever to present a serial compound stimulus (B→A-). In the simple discrimination task (A+, B-), rats were required to press a lever to present stimulus A (A+) and avoid pressing a lever to present stimulus B (B-). We observed a transient decline of hippocampal theta power during response inhibition for a serial compound stimulus in the FN task. Thus, we conclude that the transient decline in hippocampal theta power reflects response inhibition for a conflicting stimulus. The results of the present study strongly support the behavioral inhibition theory.

A model of multisecond timing behaviour under peak-interval procedures

In this study, the authors developed a fundamental theory of interval timing behaviour, inspired by the learning-to-time (LeT) model and the scalar expectancy theory (SET) model, and based on quantitative analyses of such timing behaviour. Our experiments used the peak-interval procedure with rats. The proposed model of timing behaviour comprises clocks, a regulator, a mixer, a response, and memory. Using our model, we calculated the basic clock speeds indicated by the subjects’ behaviour under such peak procedures. In this model, the scalar property can be defined as a kind of transposition, which can then be measured quantitatively. The Akaike information criterion (AIC) values indicated that the current model fit the data slightly better than did the SET model. Our model may therefore provide a useful addition to SET for the analysis of timing behaviour.

Change in hippocampal theta activity during behavioral inhibition for a stimulus having an overlapping element

It is believed that a decline in hippocampal theta power is induced by response inhibition for a conflict stimulus having an overlapping element. This study used a simultaneous feature positive (simul FP: A-, AX+) task and a serial FP (A-, X→A+) task. In these tasks, the compound and single stimuli have an overlapping element, and rats are required to exhibit response inhibition for the single stimulus A. We examined hippocampal theta activity during simul FP (A-, AX+), serial FP (A-, X→A+), and simple discrimination (SD; A-, X+) tasks and revealed that the transient decrease in hippocampal theta power occurred during response inhibition for the single stimulus A in simul FP tasks, which provides evidence that a transient decline in hippocampal theta power is induced by behavioral inhibition of conflict stimuli having an overlapping element. Thus, we concluded that the transient decline in hippocampal theta power was induced by behavioral inhibition for the conflict stimulus having an overlapping element.

Behavioral inhibition during a conflict state elicits a transient decline in hippocampal theta power

Although it has been shown that hippocampal theta power transiently declines during response inhibition in a simultaneous feature negative (FN: A+, AB-) task, observations of additional changes after this initial decline have been inconsistent across subjects. We hypothesized that the cause of these inconsistencies might be that variations in the learning speed for the FN task differentially affect the changes in hippocampal theta activity observed during the task. In this study, we classified rats into three groups (fast, intermediate, and slow FN-learning groups) based on the number of sessions required to complete learning of the FN task. We then examined whether there was a difference in hippocampal theta power among the fast, intermediate, and slow FN-learning groups, and rats that learned a simple discrimination task (SD group). We observed that compared to the SD group, the slow FN-learning group, but not the fast FN-learning group, showed an increase in hippocampal theta power. In addition, a transient decline of hippocampal theta power occurred in the fast FN-learning group, but not in the slow FN-learning group. These results indicate that the hippocampal theta activity during response inhibition in the FN task differed between fast- and slow-learning rats. Thus, we propose that a difference in learning speed affected hippocampal theta activity during response inhibition under a conflict state.

Small Deviations from the Scalar Property and Carry-Over Effects

In order to measure the extent to which timing behavior diverges from a scalar property, the authors tested their recently published model of timing behavior [1]. With rats as subjects, peak-interval procedures were performed. For each interval length presented to subjects, the model was used to identify the length of the basic clock period and the weight of the clocks. A carry over effect was observed on the basic clock period, suggesting the uniqueness of the clock (stopwatch) system. Analysis indicated that, when coping with peak-interval procedures of different lengths, the rats changed not only the basic clock period but also the weights of the clocks. It was the changes in the clocks’ weights that led to the observed small deviations from the scalar property, and this also suggested the uniqueness of the clock (stopwatch) system in the range tested in the experiment.