Different cholinergic cell groups in the basal forebrain regulate social interaction and social recognition memory.

Social behaviour is a complex construct that is reported to include several components of social approach, interaction and recognition memory. Alzheimer's disease (AD) is mainly characterized by progressive dementia and is accompanied by cognitive impairments, including a decline in social ability. The cholinergic system is a potential constituent for the neural mechanisms underlying social behaviour, and impaired social ability in AD may have a cholinergic basis. However, the involvement of cholinergic function in social behaviour has not yet been fully understood. Here, we performed a selective elimination of cholinergic cell groups in the basal forebrain in mice to examine the role of cholinergic function in social interaction and social recognition memory by using the three-chamber test. Elimination of cholinergic neurons in the medial septum (MS) and vertical diagonal band of Broca (vDB) caused impairment in social interaction, whereas ablating cholinergic neurons in the nucleus basalis magnocellularis (NBM) impaired social recognition memory. These impairments were restored by treatment with cholinesterase inhibitors, leading to cholinergic system activation. Our findings indicate distinct roles of MS/vDB and NBM cholinergic neurons in social interaction and social recognition memory, suggesting that cholinergic dysfunction may explain social ability deficits associated with AD symptoms.

The role of the hippocampal theta rhythm in non-spatial discrimination and associative learning task.

The configural association theory and the conflict resolution model propose that hippocampal function is involved in learning negative patterning tasks (A+, B+, AB-). The first theory suggests a critical role of the hippocampus in the formation of configural representations of compound stimuli, in which stimuli A and B are presented simultaneously. The second theory hypothesizes that the hippocampus is important for inhibiting the response to a stimulus that is in conflict with response tendencies. Although these theories propose different interpretations of the link between hippocampal function and non-spatial discrimination tasks, they both predict that the hippocampus is involved in the information processing of compound stimuli in negative patterning tasks. Recently, our electrophysiological approach has shown that the hippocampal theta power correlate with response inhibition in a negative patterning task, positive patterning, simultaneous/serial feature negative task. These findings provide strong support for the assumption of the conflict resolution model that the role of the hippocampus in learning is to inhibit responses to conflicting stimuli during non-spatial stimulus discrimination tasks.

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.

The transient decline in hippocampal theta power during response inhibition in a positive patterning task.

It is believed that a transient decline in hippocampal theta power is induced by behavioral inhibition during a go/no-go stimulus discrimination task. In a previously reported positive patterning (PP) task, rats learn to lever press when a compound stimulus, both tone and light, is presented and inhibit their lever press when a single stimulus, tone or light, is presented. In this task, rats were required to inhibit their response to the single stimulus in a task where both compound and single stimuli were presented with an overlapping element. Thus, we hypothesized that there would be a transient decline in hippocampal theta power induced by behavioral inhibition to the presence of a single stimuli in the PP task. The result of this study showed that a decline in hippocampal theta power occurred during response inhibition to the presence of a single tone stimulus in the PP task, supporting our hypothesis. However, we did not observe any decline in hippocampal theta power during response inhibition to the presence of a single light stimulus. We found that the error response rate for the tone stimulus was slightly lower than that for light stimulus in the PP task. Thus, we proposed that the decline in hippocampal theta power related to more accurate response inhibition to the stimulus that had 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.

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.

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.

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.

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.

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.

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.

The decline in rat hippocampal theta activity during response inhibition for the compound stimulus of negative patterning and simultaneous feature-negative tasks.

In experiment 1 of this study, we compared hippocampal theta activity between negative patterning and simple discrimination tasks. Our results demonstrated a transient decline in theta activity during response inhibition for a compound stimulus in the negative patterning task. In experiment 2 of this study, we compared hippocampal theta activity among simultaneous feature-negative, compound stimulus discrimination, and simple discrimination tasks in order to determine the cause of the decline in hippocampal theta activity during negative patterning tasks. Our results revealed that the decline in hippocampal theta activity occurred during the response inhibition for a compound stimulus in the simultaneous feature-negative task but not during the compound stimulus discrimination or simple discrimination tasks. Thus, we conclude that the transient decline in hippocampal theta activity is related to the inhibition in response to a compound stimulus that has an element that overlaps with a single stimulus.

Transient decline in hippocampal theta activity during the acquisition process of the negative patterning task.

Hippocampal function is important in the acquisition of negative patterning but not of simple discrimination. This study examined rat hippocampal theta activity during the acquisition stages (early, middle, and late) of the negative patterning task (A+, B+, AB-). The results showed that hippocampal theta activity began to decline transiently (for 500 ms after non-reinforced stimulus presentation) during the late stage of learning in the negative patterning task. In addition, this transient decline in hippocampal theta activity in the late stage was lower in the negative patterning task than in the simple discrimination task. This transient decline during the late stage of task acquisition may be related to a learning process distinctive of the negative patterning task but not the simple discrimination task. We propose that the transient decline of hippocampal theta activity reflects inhibitory learning and/or response inhibition after the presentation of a compound stimulus specific to the negative patterning task.

Transient decline in rats' hippocampal theta power relates to inhibitory stimulus-reward association.

The hippocampus is important in learning during a discrimination-reversal task. In this task, animals first learn to emit the go response to one stimulus and the no-go response to another stimulus (S1+, S2-) during the discrimination phase, and then they learn to reverse these relationships between stimulus and response during the reversal phase (S1-, S2+). To emit a no-go response for non-reinforced trial during the reversal phase, animals needed to inhibit the previously learned response pattern. This study examined the relationship between the reversal phase of the discrimination-reversal task and hippocampal electric activity in operant conditioning. The results revealed that hippocampal theta power transiently declined during the non-reinforced trial in the reversal phase compared with that during the discrimination phase. This decrease was observed during the 400-600-ms epoch after the onset of stimulus presentation. This study suggested that transient decline in hippocampal theta power is related to negative memory retrieval.

Neural activity in the hippocampus during conflict resolution.

This study examined configural association theory and conflict resolution models in relation to hippocampal neural activity during positive patterning tasks. According to configural association theory, the hippocampus is important for responses to compound stimuli in positive patterning tasks. In contrast, according to the conflict resolution model, the hippocampus is important for responses to single stimuli in positive patterning tasks. We hypothesized that if configural association theory is applicable, and not the conflict resolution model, the hippocampal theta power should be increased when compound stimuli are presented. If, on the other hand, the conflict resolution model is applicable, but not configural association theory, then the hippocampal theta power should be increased when single stimuli are presented. If both models are valid and applicable in the positive patterning task, we predict that the hippocampal theta power should be increased by presentation of both compound and single stimuli during the positive patterning task. To examine our hypotheses, we measured hippocampal theta power in rats during a positive patterning task. The results showed that hippocampal theta power increased during the presentation of a single stimulus, but did not increase during the presentation of a compound stimulus. This finding suggests that the conflict resolution model is more applicable than the configural association theory for describing neural activity during positive patterning tasks.

Hippocampal theta wave activity during configural and non-configural tasks in rats.

This study examined hippocampal theta power during configural and non-configural tasks in rats. Experiment 1 compared hippocampal theta power during a negative patterning task (A+, B+, AB-) to a configural task and a simple discrimination task (A+, B-) as a non-configural task. The results showed that hippocampal theta power during the non-reinforcement trial (non-RFT) of the negative patterning task was higher than that during the simple discrimination task. However, this hippocampal power may reflect sensory processing for compound stimuli that have cross-modality features (the non-RFT of the negative patterning task was presented together with visual and auditory stimuli, but the non-RFT of the simple discrimination task was presented with visual or auditory stimulus alone). Thus, in experiment 2, we examined whether the experiment 1 results were attributable to sensory processing of a compound stimulus by comparing hippocampal theta power during negative patterning (A+, B+, AB-), simultaneous feature-negative (A+, AB-), and simple discrimination tasks (A+, B-). Experiment 2 showed that hippocampal theta activity during the non-RFT in the negative patterning task was higher than that in the simultaneous feature-negative and simple discrimination tasks. Thus, we showed that hippocampal theta activity increased during configural tasks but not during non-configural tasks.

Environmental enrichment alters gene expression of steroidogenic enzymes in the rat hippocampus.

Neuroactive steroids are synthesized in the central and peripheral nervous systems. The purpose of this study was to analyze the effects of environmental enrichment on neuroactive steroidogenesis in the rat hippocampus. Environmental enrichment rats were housed in a group of nine in a large cage and three groups of pair-housed rats were housed in a standard cage for 8 weeks. The levels of mRNAs for steroidogenic enzymes and proteins in hippocampus were quantified by real-time RT-PCR. Environmental enrichment increased the mRNA expression levels of 5α-reductase-1 and 3α-hydroxysteroid dehydrogenase, which catalyze synthesis of allopregnanolone from progesterone. Hence, environmental enrichment appears to affect allopregnanolone synthesis.

Identification of rat P3-like processes in the anterior cingulate cortex and hippocampus.

The purpose of this study was to investigate whether the rat P3-like potential reflects "attention processes" rather than "arousal level". After controlling for arousal levels, event-related potentials (ERPs) of the rat were recorded at the anterior cingulate cortex and hippocampal CA1 during active and passive oddball paradigms. The arousal level of the passive group was equivalent to that of the active group, while the amplitude of the P3-like potential during the active paradigm was greater than that during the passive paradigm for both sites. These results provide evidence that the rat P3-like component reflects "attention processes", which is also the case for the human P3 component. Rats can provide a useful model for investigation of the neural mechanisms of the P3 in humans.

Social isolation stimulates hippocampal estradiol synthesis.

17beta-estradiol is synthesized de novo in the rat hippocampus. However, the regulatory mechanism of hippocampal estradiol synthesis has remained unclear. We investigated the effects of social isolation on rat hippocampal estradiol synthesis. Rats were divided into two groups: social isolation and pair housed group. Socially isolated rats were housed individually while pair housed rats were housed two per cage for 8 weeks. Social isolation activated the transcription of neurosteroidogenic molecules, including steroidogenic acute regulatory protein (StAR) and CYP19 (cytochrome P450arom). These two molecules are involved in the regulatory step for steroidogenesis and final step of estradiol synthesis. In contrast, the mRNA levels were not affected in rat olfactory bulb. The hippocampal estradiol content was increased in accordance with the increased mRNA levels. The hippocampal estradiol content exhibited correlations with the StAR and P450arom mRNA levels. These data suggest that social isolation may enhance de novo estradiol synthesis in the hippocampus.

Timing and hippocampal theta in animals.

All animals have at least two different internal clocks, one governing cognition of time of day, and the other concerning awareness of seconds and minutes. In the latter case, organisms show scalar properties. The timing mechanisms in the brain may function similarly throughout the animal kingdom, but this is not yet clear. Previous studies have shown that the hippocampus is intricately involved with the process of interval timing. Data concerning electrophysiological field potentials in the hippocampus show obviously rhythmic activity, known as hippocampal theta activity. An information-processing model of interval timing postulates three distinct stages: a clock, a memory, and a decision stage /11/. The timing process includes memory processing, which means that the hippocampus works together with working memory to estimate current time passing.