Yasushi Miyashita

Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons

Dendritic spines serve as preferential sites of excitatory synaptic connections and are pleomorphic. To address the structure–function relationship of the dendritic spines, we used two-photon uncaging of glutamate to allow mapping of functional glutamate receptors at the level of the single synapse. Our analyses of the spines of CA1 pyramidal neurons reveal that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors are abundant (up to 150/spine) in mushroom spines but sparsely distributed in thin spines and filopodia. The latter may be serving as the structural substrates of the silent synapses that have been proposed to play roles in development and plasticity of synaptic transmission. Our data indicate that distribution of functional AMPA receptors is tightly correlated with spine geometry and that receptor activity is independently regulated at the level of single spines.

Top-down signal from prefrontal cortex in executive control of memory retrieval

Knowledge or experience is voluntarily recalled from memory by reactivation of the neural representations in the cerebral association cortex. In inferior temporal cortex, which serves as the storehouse of visual long-term memory, activation of mnemonic engrams through electric stimulation results in imagery recall in humans, and neurons can be dynamically activated by the necessity for memory recall in monkeys. Neuropsychological studies and previous split-brain experiments predicted that prefrontal cortex exerts executive control upon inferior temporal cortex in memory retrieval; however, no neuronal correlate of this process has ever been detected. Here we show evidence of the top-down signal from prefrontal cortex. In the absence of bottom-up visual inputs, single inferior temporal neurons were activated by the top-down signal, which conveyed information on semantic categorization imposed by visual stimulus–stimulus association. Behavioural performance was severely impaired with loss of the top-down signal. Control experiments confirmed that the signal was transmitted not through a subcortical but through a fronto-temporal cortical pathway. Thus, feedback projections from prefrontal cortex to the posterior association cortex appear to serve the executive control of voluntary recall.

Transient activation of inferior prefrontal cortex during cognitive set shifting

The Wisconsin Card Sorting Test, which probes the ability to shift attention from one category of stimulus attributes to another (shifting cognitive sets), is the most common paradigm used to detect human frontal lobe pathology. However, the exact relationship of this card test to prefrontal function and the precise anatomical localization of the cognitive shifts involved are controversial. By isolating shift-related signals using the temporal resolution of functional magnetic resonance imaging, we reproducibly found transient activation of the posterior part of the bilateral inferior frontal sulci. This activation was larger as the number of dimensions (relevant stimulus attributes that had to be recognized) were increased. These results suggest that the inferior frontal areas play an essential role in the flexible shifting of cognitive sets.

No-go dominant brain activity in human inferior prefrontal cortex revealed by functional magnetic resonance imaging

We investigated the response inhibition function of the prefrontal cortex associated with the go/no‐go task using functional magnetic resonance imaging in five human subjects. The go/no‐go task consisted of go and no‐go trials given randomly with roughly equal probability. In go trials a green square was presented and the subjects had to respond by promptly pushing a button using their right or left thumbs, but in no‐go trials a red square was presented and subjects were instructed not to respond. When brain activity in no‐go trials is dominant over that in go trials in areas in the prefrontal cortex, this no‐go dominant brain activity would reflect the neural processes for inhibiting inherent response tendency. We used a new strategy of image data analysis by which transient brain activity in go or no‐go trials can be analysed separately, and looked for the prefrontal areas in which the brain activity in no‐go trials is dominant over that in go trials. We found the no‐go dominant foci in the posterior part of the right inferior frontal sulcus reproducibly among the subjects. This was true whether the right or left hand was used. These results suggest that this region in the prefrontal cortex is related to the neural mechanisms underlying the response inhibition function.

Subcellular distribution of Ca2+ release channels underlying Ca2+ waves and oscillations in exocrine pancreas

Agonists trigger Ca2+ waves and oscillations in exocrine gland cells. Our confocal Ca2+ imaging revealed three distinct phases during the Ca2+ waves in the rat pancreatic acinar cell. Rises in Ca2+ concentration were initiated at a small trigger zone, or T zone, in the granular area; then, Ca2+ waves rapidly spread within the area and, at high agonist concentrations, propagated slowly toward the basal pole. Injection of inositol 1,4,5-trisphosphate (IP3) or Ca2+ from patch pipettes demonstrated the presence of high sensitivity IP3 receptors at the T zone, Ca(2+)-induced Ca2+ release channels in the granular area, and low sensitivity IP3 receptors in the basal area. The IP3 receptors at the T zone appeared to generate autonomous Ca2+ spikes and to initiate patterned Ca2+ oscillations. Thus, heterogeneous cytosolic localization of Ca2+ release channels plays a key role in Ca2+ waves and oscillations.

Functional magnetic resonance imaging of macaque monkeys performing visually guided saccade tasks: comparison of cortical eye fields with humans.

The frontal and parietal eye fields serve as functional landmarks of the primate brain, although their correspondences between humans and macaque monkeys remain unclear. We conducted fMRI at 4.7 T in monkeys performing visually-guided saccade tasks and compared brain activations with those in humans using identical paradigms. Among multiple parietal activations, the dorsal lateral intraparietal area in monkeys and an area in the posterior superior parietal lobule in humans exhibited the highest selectivity to saccade directions. In the frontal cortex, the selectivity was highest at the junction of the precentral and superior frontal sulci in humans and in the frontal eye field (FEF) in monkeys. BOLD activation peaks were also found in premotor areas (BA6) in monkeys, which suggests that the apparent discrepancy in location between putative human FEF (BA6, suggested by imaging studies) and monkey FEF (BA8, identified by microstimulation studies) partly arose from methodological differences.

Activation of Right Inferior Frontal Gyrus during Response Inhibition across Response Modalities

The go/no-go task, which effectively taps the ability to inhibit prepotent response tendency, has consistently activated the lateral prefrontal cortex, particularly the right inferior frontal gyrus (rIFG). On the other hand, rIFG activation has rarely been reported in the antisaccade task, seemingly an oculomotor version of the manual go/no-go task. One possible explanation for the variable IFG activation is the modality difference of the two tasks: The go/no-go task is performed manually, whereas the antisaccade task is performed in the oculomotor modality. Another explanation is that these two tasks have different task structures that require different cognitive processes: The traditional antisaccade task requires (i) configuration of a preparatory set prior to antisaccade execution and (ii) response inhibition at the time of antisaccade execution, whereas the go/no-go task requires heightened response inhibition under a minimal preparatory set. To test these possibilities, the traditional antisaccade task was modified in the present functional magnetic resonance imaging study such that it required heightened response inhibition at the time of antisaccade execution under a minimal preparatory set. Prominent activation related to response inhibition was observed in multiple frontoparietal regions, including the rIFG. Moreover, meta-analyses revealed that the rIFG activation in the present study was observed in the go/no-go tasks but not in the traditional antisaccade task, indicating that the rIFG activation was sensitive to the task structure difference, but not to the response modality difference. These results suggest that the rIFG is part of a network active during response inhibition across different response modalities.

Preparation to Inhibit a Response Complements Response Inhibition during Performance of a Stop-Signal Task

Inhibition of inappropriate responses is an essential executive function needed for adaptation to changing environments. In stop-signal tasks, which are often used to investigate response inhibition, subjects make “go” responses while they prepare to stop at a suddenly given “stop” signal. However, the preparatory processes ongoing before response inhibition have rarely been investigated, and it remains unclear how the preparation contributes to response inhibition. In the present study, a stop-signal task was designed so that the extent of the preparation could be estimated using behavioral and neuroimaging measures. Specifically, in addition to the conventional go trials where preparation to stop was required (“uncertain-go” trials), another type of go trial was introduced where a stop-signal was never given and such preparation was unnecessary (“certain-go” trials). An index reflecting the “preparation cost” was then calculated by subtracting the reaction times in the certain-go trials from those in the uncertain-go trials. It was revealed that the stop signal reaction time, a common index used to evaluate the efficiency of response inhibition, decreased as the preparation cost increased, indicating greater preparation supports more efficient inhibition. In addition, imaging data showed that response inhibition recruited frontoparietal regions (the contrast “stop vs uncertain-go”) and that preparation recruited most of the inhibition-related frontoparietal regions (the contrast “uncertain-go vs certain-go”). It was also revealed that the inhibition-related activity declined as the preparation cost increased. These behavioral and imaging results suggest preparation makes a complementary contribution to response inhibition during performance of a stop-signal task.

Functional Dissociation in Right Inferior Frontal Cortex during Performance of Go/No-Go Task

The contribution of the right inferior frontal cortex to response inhibition has been demonstrated by previous studies of neuropsychology, electrophysiology, and neuroimaging. The inferior frontal cortex is also known to be activated during processing of infrequent stimuli such as stimulus-driven attention. Response inhibition has most often been investigated using the go/no-go task, and the no-go trials are usually given infrequently to enhance prepotent response tendency. Thus, it has not been clarified whether the inferior frontal activation during the go/no-go task is associated with response inhibition or processing of infrequent stimuli. In the present functional magnetic resonance imaging study, we employed not only frequent-go trials but also infrequent-go trials that were presented as infrequently as the no-go trials. The imaging results demonstrated that the posterior inferior frontal gyrus (pIFG) was activated during response inhibition as revealed by the no-go vs. infrequent-go trials, whereas the inferior frontal junction (IFJ) region was activated primarily during processing of infrequent stimuli as revealed by the infrequent-go versus frequent-go trials. These results indicate that the pIFG and IFJ within the inferior frontal cortex are spatially close but are associated with different cognitive control processes in the go/no-go paradigm.

Specific effects of unilateral lesions in the flocculus upon eye movements in albino rabbits

SummaryThe horizontal vestibulo-ocular reflex (HVOR) and optokinetic response (OKR) were examined in alert albino rabbits following unilateral flocculectomy. Chemical flocculectomy with local application of kainic acid was used to avoid the retrograde degeneration of inferior olive neurons that accompanies surgical flocculectomy. Effects of chemical flocculectomy, however, were identical to those of surgical flocculectomy. The following functional deficiencies were observed in the movements of the ipsilateral eye: (1) reduction of the HVOR gain; (2) increased lag of the HVOR phase; (3) increased non-linearity of the relationship between the HVOR gain and the amplitude of turntable rotation; (4) decreased OKR gain; (5) delay with increased variation in the OKR phase; (6) impairment of rapid visual-vestibular interaction; (7) loss of the adaptation of the HVOR. Only a transient depression of the HVOR gain was seen in the contralateral eye. Control experiments with lesions in the paraflocculus, nodulus, and uvula, or lobules VI and VII, revealed no such deficiencies, except that lesions in the nodulus and uvula produced marked advancement of the HVOR phase. The effects of flocculectomy are consistent with present knowledge of both neuronal circuitry and activity of the rabbit flocculus.