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Androgen receptor (AR) is abundantly expressed in the preoptico-hypothalamic area, bed nucleus of stria terminalis, and medial amygdala of the brain where androgen plays an important role in regulating male sociosexual, emotional and aggressive behaviors. In addition to these brain regions, AR is also highly expressed in the hippocampus, suggesting that the hippocampus is another major target of androgenic modulation. It is known that androgen can modulate synaptic plasticity in the CA1 hippocampal subfield. However, to date, the effects of androgen on the intrinsic plasticity of hippocampal neurons have not been clearly elucidated. In this study, the effects of androgen on the expression of AR in the hippocampus and on the dynamics of intrinsic plasticity of CA1 pyramidal neurons were examined using immunohistochemistry, Western blotting and whole-cell current-clamp recording in unoperated, sham-operated, orchiectomized (OCX), OCX + testosterone (T) or OCX + dihydrotestosterone (DHT)-primed adolescent male rats. Orchiectomy significantly decreased AR-immunoreactivity, resting membrane potential, action potential numbers, afterhyperpolarization amplitude and membrane resistance, whereas it significantly increased action potential threshold and membrane capacitance. These effects were successfully reversed by treatment with either aromatizable androgen T or non-aromatizable androgen DHT. Furthermore, administration of the AR-antagonist flutamide in intact rats showed similar changes to those in OCX rats, suggesting that androgens affect the excitability of CA1 pyramidal neurons possibly by acting on the AR. Our current study potentially clarifies the role of androgen in enhancing the basal excitability of the CA1 pyramidal neurons, which may influence selective neuronal excitation/activation to modulate certain hippocampal functions.

We expose various kinds of context in our everyday lives and hence contextual memory is critically important for us. Since hippocampus is a major area for processing contextual memory, it needs to encode different components of various contexts such as ‘what’, ‘where’ and ‘when’, etc. However, the underlying mechanism by which the hippocampus differentially encodes various kinds of contextual information is interesting but not yet revealed completely. Since long-term potentiation (LTP) had been discovered and believed to be mechanism of learning, many studies were conducted to investigate the underlying detailed mechanism of memory formation by using various LTP induction protocols. By combining HSV-mediated in vivo gene delivery with in vitro patch-clamp recordings, it was found that LTP can induce plastic changes such as delivery of GluA1-containing AMPA receptor to the dorsal CA1 synapses of the hippocampus and also the causal relationship between this AMPA receptor delivery and learning was discovered. Then it was found that learning induced synaptic plasticity with diverse pattern highlighting the importance of this diversity in contextual memory formation. Here, we mostly review the studies which used hippocampal-dependent learning paradigm (inhibitory avoidance task) for better comparison and mapping of the concept about how learning induced diversity of synaptic plasticity at dorsal hippocampal CA1 synapses and how this diversity may become responsible as an underlying mechanism of contextual memory formation. We found that contextual learning induces synaptic plasticity at CA1 neurons with synapse-specific diversity, input-specific diversity, subregion- or subfield-specific diversity, episode-specific diversity but only a few studies revealed their functional significance. For complete understanding of learning-induced diversity of synaptic plasticity, it demands further studies for investigation of their functional correlation to learning performance by using new highly promising approaches like optogenetic techniques and cell-specific self-entropy analysis, etc.

Postnatal development of hippocampal function has been reported in numerous mammalian species, including humans. To obtain a synaptic evidence, we analyzed developmental changes in plasticity after an inhibitory avoidance task in rats. Learning performance was low in infants (postnatal 2 weeks) but clearly improved from the juvenile period (3–4 weeks) to adulthood (8 weeks). One hour after the training, we prepared brain slices and sequentially recorded miniature excitatory postsynaptic currents (mEPSCs) and inhibitory postsynaptic currents (mIPSCs) from the same hippocampal CA1 neuron. Although the training failed to affect the amplitude of either mEPSCs or mIPSCs at 2 weeks, it increased mEPSC, but not mIPSC, amplitude at 3 weeks. At 4 weeks, the training had increased the amplitude of both mEPSCs and mIPSCs, whereas mIPSC, but not mEPSC, amplitude was increased at 8 weeks. Because early-life physiological functions can affect performance, we also evaluated sensory–motor functions together with emotional state and found adequate sensory/motor functions from infancy to adulthood. Moreover, by analyzing performance of rats in multiple hippocampal-dependent tasks, we found that the developmental changes in the performance are task dependent. Taken together, these findings delineate a critical period for learning and plastic changes at hippocampal CA1 synapses.

The hippocampus is a primary area for contextual memory, known to process spatiotemporal information within a specific episode. Long-term strengthening of glutamatergic transmission is a mechanism of contextual learning in the dorsal cornu ammonis 1 (CA1) area of the hippocampus. CA1-specific immobilization or blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor delivery can impair learning performance, indicating a causal relationship between learning and receptor delivery into the synapse. Moreover, contextual learning also strengthens GABAA (gamma-aminobutyric acid) receptor-mediated inhibitory synapses onto CA1 neurons. Recently we revealed that strengthening of GABAA receptor-mediated inhibitory synapses preceded excitatory synaptic plasticity after contextual learning, resulting in a reduced synaptic excitatory/inhibitory (E/I) input balance that returned to pretraining levels within 10 min. The faster plasticity at inhibitory synapses may allow encoding a contextual memory and prevent cognitive dysfunction in various hippocampal pathologies. In this review, we focus on the dynamic changes of GABAA receptor mediated-synaptic currents after contextual learning and the intracellular mechanism underlying rapid inhibitory synaptic plasticity. In addition, we discuss that several pathologies, such as Alzheimer’s disease, autism spectrum disorders and epilepsy are characterized by alterations in GABAA receptor trafficking, synaptic E/I imbalance and neuronal excitability.

The hippocampus is functionally heterogeneous between the dorsal and ventral subfields with left–right asymmetry. To determine the possible location of contextual memory, we performed an inhibitory avoidance task to analyze synaptic plasticity using slice patch-clamp technique. The training bilaterally increased the AMPA/NMDA ratio at dorsal CA3–CA1 synapses, whereas the training did not affect the ratio at ventral CA3–CA1 synapses regardless of the hemisphere. Moreover, sequential recording of miniature excitatory postsynaptic currents and miniature inhibitory postsynaptic currents from the same CA1 neuron clearly showed learning-induced synaptic plasticity. In dorsal CA1 neurons, the training dramatically strengthened both excitatory and inhibitory postsynaptic responses in both hemispheres, whereas the training did not promote the plasticity in either hemisphere in ventral CA1 neurons. Nonstationary fluctuation analysis further revealed that the training bilaterally increased the number of AMPA or GABAA receptor channels at dorsal CA1 synapses, but not at ventral CA1 synapses, suggesting functional heterogeneity of learning-induced receptor mobility. Finally, the performance clearly impaired by the bilateral microinjection of plasticity blockers in dorsal, but not ventral CA1 subfields, suggesting a crucial role for contextual learning. The quantification of synaptic diversity in specified CA1 subfields may help us to diagnose and evaluate cognitive disorders at the information level.

The hippocampus is a primary area for contextual memory, known to process spatiotemporal information within a specific episode. Long-term strengthening of glutamatergic transmission is a mechanism of contextual learning in the dorsal cornu ammonis 1 (CA1) area of the hippocampus. CA1-specific immobilization or blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor delivery can impair learning performance, indicating a causal relationship between learning and receptor delivery into the synapse. Moreover, contextual learning also strengthens GABAA (gamma-aminobutyric acid) receptor-mediated inhibitory synapses onto CA1 neurons. Recently we revealed that strengthening of GABAA receptor-mediated inhibitory synapses preceded excitatory synaptic plasticity after contextual learning, resulting in a reduced synaptic excitatory/inhibitory (E/I) input balance that returned to pretraining levels within 10 min. The faster plasticity at inhibitory synapses may allow encoding a contextual memory and prevent cognitive dysfunction in various hippocampal pathologies. In this review, we focus on the dynamic changes of GABAA receptor mediated-synaptic currents after contextual learning and the intracellular mechanism underlying rapid inhibitory synaptic plasticity. In addition, we discuss that several pathologies, such as Alzheimer’s disease, autism spectrum disorders and epilepsy are characterized by alterations in GABAA receptor trafficking, synaptic E/I imbalance and neuronal excitability.

Contextual learning requires the delivery of AMPA receptors to CA1 synapses in the dorsal hippocampus. However, proximodistal heterogeneity of pathway-specific plasticity remains unclear. Here, we examined the proximodistal heterogeneity in learning-induced plasticity at the CA1 synapses with inputs from the entorhinal cortex layer III (ECIII) or from CA3. We subjected male rats to an inhibitory avoidance task and prepared acute hippocampal slices for whole-cell patch clamp experiments, where we stimulated ECIII-CA1 or CA3-CA1 input fibers to analyze evoked excitatory postsynaptic currents (EPSCs). Compared to untrained controls, trained rats exhibited higher AMPA/NMDA current ratios at CA3-CA1 synapses of proximal and intermediate, but not distal CA1 neurons, which suggested that region-specific plasticity occurred after learning. Moreover, trained rats exhibited higher AMPA/NMDA current ratios at ECIII-CA1 synapses of intermediate and distal, but not proximal CA1 neurons. These findings suggested the presence of proximodistal heterogeneity in pathway-specific postsynaptic plasticity. Regarding presynaptic plasticity, training slightly, but significantly increased the paired-pulse ratios of CA3-CA1 synapses of proximal and intermediate, but not distal CA1 neurons. Moreover, trained rats exhibited higher paired-pulse ratios at ECIII-CA1 synapses of intermediate and distal, but not proximal CA1 neurons, which suggested region-specific presynaptic plasticity. Finally, learning was clearly prevented by the bilateral microinjection of a plasticity blocker in the proximal or intermediate, but not distal CA1 subfields, which suggested functional heterogeneity along the proximodistal axis. Understanding region- and pathway-specific plasticity at dorsal CA1 synapses could aid in controlling encoded memory.

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.

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.

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.

The slice patch clamp technique is a powerful tool for investigating learning-induced neural plasticity in specific brain regions. To analyze motor-learning induced plasticity, we trained rats using an accelerated rotor rod task. Rats performed the task 10 times at 30-s intervals for 1 or 2 days. Performance was significantly improved on the training days compared to the first trial. We then prepared acute brain slices of the primary motor cortex (M1) in untrained and trained rats. Current-clamp analysis showed dynamic changes in resting membrane potential, spike threshold, afterhyperpolarization, and membrane resistance in layer II/III pyramidal neurons. Current injection induced many more spikes in 2-day trained rats than in untrained controls. To analyze contextual-learning induced plasticity, we trained rats using an inhibitory avoidance (IA) task. After experiencing foot-shock in the dark side of a box, the rats learned to avoid it, staying in the lighted side. We prepared acute hippocampal slices from untrained, IA-trained, unpaired, and walk-through rats. Voltage-clamp analysis was used to sequentially record miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) from the same CA1 neuron. We found different mean mEPSC and mIPSC amplitudes in each CA1 neuron, suggesting that each neuron had different postsynaptic strengths at its excitatory and inhibitory synapses. Moreover, compared with untrained controls, IA-trained rats had higher mEPSC and mIPSC amplitudes, with broad diversity. These results suggested that contextual learning creates postsynaptic diversity in both excitatory and inhibitory synapses at each CA1 neuron. AMPA or GABAA receptors seemed to mediate the postsynaptic currents, since bath treatment with CNQX or bicuculline blocked the mEPSC or mIPSC events, respectively. This technique can be used to study different types of learning in other regions, such as the sensory cortex and amygdala.

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.

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.

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.

本研究では海馬θ波と非線形課題の関係を2 つの実験から検討した。実験1では非線形課題の一つである負パターン課題と線形課題の一つである単純弁別課題中の海馬θ波を記録した。実験2では正パターン課題と単純弁別課題中の海馬θ波を記録した。実験1と2の結果から，負パターン課題の複合刺激において海馬θパワが増加した。しかし，正パターン課題と単純弁別課題中にはこのような海馬θパワの増加は見られなかった。これらのことから，海馬θ波が負パターン課題の複合刺激に関係していることが明らかとなった。

The configural association theory and the conflict resolution model both propose a hippocampal function in the non-spatial Go/No-go stimulus discrimination task. The first theory suggests a critical role of the hippocampus in the formation of configural representations for compound stimuli in which multiple stimuli are simultaneously presented. The second theory relates to explaining how the hippocampus is important in no-go response for conflict stimulus with incompatible goals or response tendencies. While the theories presented have been perceived in different contexts towards joining the hippocampal functions and the associated non-spatial discrimination tasks, together they also indicate that hippocampus is associated with learning a negative patterning task. Current update in the context of electrophysiological approaches is indicative of reductions in hippocampal theta power due to the compound stimulus of negative patterning tasks. However, this is indicative of hippocampal theta powers not being relational to compound stimulus of feature negative task. These results showed that the decline in hippocampal theta activity was elicited by behavioral inhibition for conflict stimuli having overlapping elements. This finding strongly supports the conflict resolution model and suggests a hippocampal role in learning of behavioral inhibition for conflict stimulus during non-spatial stimulus discrimination tasks.

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.

It has been shown that solving a simple discrimination task (A+, B-) and a simultaneous feature-negative task (FN) (A+, AB-) uses 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 suggest that solving the FN task relies on a different strategy than the simple discrimination task. In this study, we provide supportive evidence that solving the FN and simple discrimination tasks involve 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 conclude that solving the FN task uses a different strategy than the simple discrimination task.

To determine the developmental trajectory of hippocampal function in rats, we examined 24-h changes in extracellular acetylcholine (ACh) levels and contextual learning performance. Extracellular ACh significantly correlated with spontaneous behavior, exhibiting a 24-h rhythm in juvenile (4-week-old), pubertal (6-week-old) and adult (9- to 12-week-old) rats. Although juveniles of both sexes exhibited low ACh levels, adult males had higher ACh levels than adult females. Moreover, juveniles exhibited much more spontaneous activity than adults when they showed equivalent ACh levels. Similarly, juveniles of both sexes exhibited relatively low contextual learning performance. Because contextual learning performance was significantly increased only in males, adult males exhibited better performance than adult females. We also observed a developmental relationship between contextual learning and ACh levels. Scopolamine pretreatment blocked contextual learning and interrupted the correlation. Since long-term scopolamine treatment after weaning impaired contextual learning in juveniles, the cholinergic input may participate in the development of hippocampus.

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.

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.

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.