Toshio Iijima

Entorhinal-Hippocampal Interactions Revealed by Real-Time Imaging

The entorhinal cortex provides the major cortical input to the hippocampus, and both structures have been implicated in memory processes. The dynamics of neuronal circuits in the entorhinal-hippocampal system were studied in slices by optical imaging with high spatial and temporal resolution. Reverberation of neural activity was detected in the entorhinal cortex and was more prominent when the inhibition due to γ-aminobutyric acid was slightly suppressed. Neural activity was transferred in a frequency-dependent way from the entorhinal cortex to the hippocampus. The entorhinal neuronal circuit could contribute to memory processes by holding information and selectively gating the entry of information into the hippocampus.

An improved method for recovering rabies virus from cloned cDNA.

A new system for recovery of rabies virus from cDNA plasmid, the transcription of which was driven by cellular RNA polymerase II, was developed. The plasmid contains full-length viral cDNA flanked by hammerhead ribozyme and hepatitis delta ribozyme sequences, arranged downstream of the cytomegalovirus (CMV) promotor. Transfection with the full-length cDNA plasmid together with helper plasmids encoding viral N, P, and L proteins without supply of T7 RNA polymerase produced a recombinant rabies virus in several cell lines. The efficiency of recovery between the conventional T7 promotor system and the new CMV promotor system was compared using these plasmid constructs. The newly established system is applicable to various cell lines and allows rapid and efficient generation of recombinant rabies virus.

Dual Transneuronal Tracing in the Rat Entorhinal-Hippocampal Circuit by Intracerebral Injection of Recombinant Rabies Virus Vectors

Dual transneuronal tracing is a novel viral tracing methodology which employs two recombinant viruses, each expressing a different reporter protein. Peripheral injection of recombinant pseudorabies viruses has been used as a powerful method to define neurons that coordinate outputs to various peripheral targets of motor and autonomic systems. Here, we assessed the feasibility of recombinants of rabies virus (RV) vector for dual transneuronal tracing in the central nervous system. First, we examined whether two different RV-vectors can double label cells in vitro, and showed that efficient double labeling can be realized by infecting targeted cells with the two RV-vectors within a short time interval. The potential of dual transneuronal tracing was then examined in vivo in the entorhinal-hippocampal circuit, using the chain of projections from CA3 pyramidal cells to CA1 pyramidal cells and subsequently to entorhinal cortex. Six days after the injection of two RV-vectors into the left and right entorhinal cortex respectively, double-labeled neurons were observed in CA3 bilaterally. Some double-labeled neurons showed a Golgi-like labeling. Dual transneuronal tracing potentially provides a powerful and sensitive method to study issues such as the amount of convergence and divergence within and between circuits in the central nervous system. Using this sensitive technique, we established that single neurons in CA3 are connected to the entorhinal cortex bilaterally with only one synaptic relay.

Neuroanatomical discrimination between manipulating and maintaining processes involved in verbal working memory; a functional MRI study

We used functional magnetic resonance imaging (fMRI) to investigate neural correlates of processes concerning store and manipulation in verbal working memory. We prepared a revised lag 1 digit span, digit span and a simple number detection task. Specific activities in association with manipulating process were identified in the right middle (BA 9/46) and left precentral gyrus (BA 6). Activated areas specific to maintaining process were detected in the right middle (right BA 11/10) and medial (BA 6) frontal gyri, the right inferior parietal lobule (BA 40), and the left middle (BA 9) and inferior frontal gyri (BA 44). The process-nonspecific activated areas common to two processes were identified in the right inferior frontal gyrus (BA 47) and the left superior parietal lobule (BA 7). Using the signal percent change of each subject, we calculated the correlation coefficients among each activated area. The results of this analysis showed that two processes of verbal working memory were clearly discriminated. The two essential processes of manipulation and maintenance in working memory seem to activate process-specific and overlapping (process-nonspecific) areas, but the patterns of combination were definitely different.

Segregated and Integrated Coding of Reward and Punishment in the Cingulate Cortex

Reward and punishment have opposite affective value but are both processed by the cingulate cortex. However, it is unclear whether the positive and negative affective values of monetary reward and punishment are processed by separate or common subregions of the cingulate cortex. We performed a functional magnetic resonance imaging study using a free-choice task and compared cingulate activations for different levels of monetary gain and loss. Gain-specific activation (increasing activation for increasing gain, but no activation change in relation to loss) occurred mainly in the anterior part of the anterior cingulate and in the posterior cingulate cortex. Conversely, loss-specific activation (increasing activation for increasing loss, but no activation change in relation to gain) occurred between these areas, in the middle and posterior part of the anterior cingulate. Integrated coding of gain and loss (increasing activation throughout the full range, from biggest loss to biggest gain) occurred in the dorsal part of the anterior cingulate, at the border with the medial prefrontal cortex. Finally, unspecific activation increases to both gains and losses (increasing activation to increasing gains and increasing losses, possibly reflecting attention) occurred in dorsal and middle regions of the cingulate cortex. Together, these results suggest separate and common coding of monetary reward and punishment in distinct subregions of the cingulate cortex. Further meta-analysis suggested that the presently found reward- and punishment-specific areas overlapped with those processing positive and negative emotions, respectively.

Reward Prediction Error Coding in Dorsal Striatal Neurons

In the current theory of learning, the reward prediction error (RPE), the difference between expected and received reward, is thought to be a key factor in reward-based learning, working as a teaching signal. The activity of dopamine neurons is known to code RPE, and the release of dopamine is known to modify the strength of synaptic connectivity in the target neurons. A fundamental interest in current neuroscience concerns the origin of RPE signals in the brain. Here, we show that a group of rat striatal neurons show a clear parametric RPE coding similar to that of dopamine neurons when tested under probabilistic pavlovian conditioning. Together with the fact that striatum and dopamine neurons have strong direct and indirect fiber connections, the result suggests that the striatum plays an important role in coding RPE signal by cooperating with dopamine neurons.

Changes in brain activation associated with use of a memory strategy: a functional MRI study

It has been confirmed that some kinds of what are called memory strategies dramatically improve the performance of memory recall. However, there has been no direct research to examine changes in brain activity associated with the use of the method of loci within individuals. In the present study, using fMRI, we compared brain activations before and after instruction in the method of loci during both the encoding and recall phases. The resulting behavioral data showed that the use of the method of loci significantly increased scores for memory recall. The imaging data showed that encoding after instruction in the method of loci, relative to encoding before it, was associated with signal increases in the right inferior frontal gyrus, bilateral middle frontal gyrus, left fusiform gyrus, and bilateral lingual gyrus/posterior cingulate gyrus. Comparison of recall after instruction in the method of loci with that before it showed significant activation in the left parahippocampal gyrus/retrosplenial cortex/cingulate gyrus/lingual gyrus, left precuneus, left fusiform gyrus, and right lingual gyrus/cingulate gyrus. The present study demonstrated the changes in brain activation pattern associated with the use of the method of loci; left fusiform and lingual activity was associated with both the encoding and recall phases, bilateral prefrontal activity with the encoding phase, and activity of the posterior part of the parahippocampal gyrus, retrosplenial cortex, and precuneus with the recall phase. These findings suggest that brain networks mediating episodic encoding and retrieval vary with how individuals encode the same stimuli.

Voltage-sensitive dye versus intrinsic signal optical imaging : comparison of optically determined functional maps from rat barrel cortex

Using intrinsic and voltage-sensitive dye optical imaging methods, somatosensory-evoked neural activity and the consequent metabolic activity were visualized in the barrel cortex at high temporal and spatial resolution. We compared maps of neural and metabolic activity from the perspective of spatial distribution in the cortex. There was good agreement between the two functional maps, if the extent of metabolic activity before a prominent increase in cerebral blood volume (CBV) was assessed. This result indicates that oxygen consumption occurs before CBV changes, in approximately the same cortical area as that in which the preceding neural activity was evoked. This also suggests that the intrinsic signal reflects subthreshold synaptic activity, as well as spiking activity, which is similar to the dye-related signals.

Prediction of arm trajectory from a small number of neuron activities in the primary motor cortex

Monkey arm movement was reconstructed from neuron activities recorded in the primary motor cortex (Ml). We recorded single neuron activities from a monkeys Ml, while the animal performed an arm reaching task. We also recorded electromyographic (EMG) activity and movement trajectories during the task. First, we reconstructed the EMG signals from the neuron activities. The EMG signals were reliably reconstructed with a linear summation of the neuron activities. Next, we reconstructed joint angles from the reconstructed EMG signals with an artificial neural network model. The reconstructed trajectories of the hand position and elbow position showed good correlation with the actual arm movement. This model appropriately reflected the anatomical characteristics.

Time-dependent neural activations related to recognition of people's names in emotional and neutral face-name associative learning:: an fMRI study

Previous data have indicated that the left anterior temporal lobe contributes to the retrieval of familiar peoples names, and that the extended network including the bilateral anterior temporal lobe plays an important role in the retrieval of newly learned peoples names. However, there has been no direct evidence for time-dependent change in brain activation in face-name associations. In addition, previous studies have demonstrated that emotional information such as emotional faces may contribute to the organization of long-lasting episodic memory. In the present study, we investigated the activations related to the recognition of peoples names in the context of emotional and neutral face-name associative learning. Before fMRI scanning, subjects learned face-name associations that included emotionally positive and neutral facial expressions. In immediate (5 min later) and delayed (2 weeks later) recognition with fMRI scanning, subjects were presented with studied faces with two names, and were asked to choose the correct associative name learned previously. Recognition-related activations were identified in the anterior part of bilateral temporal lobe for immediate recognition and only in the left temporal lobe for delayed recognition. Further analysis confirmed the time-dependent change in activation of the right anterior temporal lobe. Activation related to the processing of faces with positive expressions were observed in the left periamygdaloid area and temporal pole, although emotional information did not have an influence on task performance in this study. These findings suggest that the neural network involving the bilateral temporal lobe contributes to the retrieval of newly learned peoples names, and that the left temporal lobe has a crucial and stable role in retrieval of peoples names from faces, whereas the role of the right temporal lobe in retrieval of peoples names may decrease with the time course.