A systematic analysis of neurons with large somatosensory receptive fields covering multiple body regions in the secondary somatosensory area of macaque monkeys.

Previous neurophysiological studies performed in macaque monkeys have revealed complex somatosensory responses in the secondary somatosensory area (SII), such as large receptive fields (RFs), as well as bilateral ones. However, systematic analyses of neurons with large RFs have not been performed. In the present study, we recorded single-unit activities in SII of awake macaque monkeys to investigate systematically large RFs by dividing the whole body into four body regions (head, trunk, forelimb, and hindlimb). Recorded neurons were classified into two types, according to whether the RFs were confined to one body region: single (n = 817) and combined (n = 282) body-region types. These two types were distinct in terms of the percentage of bilateral RFs: 55% in the single-region type and 90% in the combined type, demonstrating that two types of RF enlargement occur simultaneously in the combined type, namely, RF convergence from different body regions and RF convergence from both hemibodies. Among the combined-type RFs, two tendencies of RF convergence were found: 1) the distal parts of the limbs (i.e., hand and foot) and the mouth are interconnected, and 2) the trunk RFs extend continuously toward the distal parts of the limb and head to cover the entire body surface. Our distribution analysis on unfolded maps clarified that neurons having RFs with these two tendencies were distributed within specific subregions in SII.

Gray and white matter changes associated with tool-use learning in macaque monkeys.

We used noninvasive MRI and voxel-based morphometry (VBM) to detect changes in brain structure in three adult Japanese macaques trained to use a rake to retrieve food rewards. Monkeys, who were naive to any previous tool use, were scanned repeatedly in a 4-T scanner over 6 weeks, comprising 2 weeks of habituation followed by 2 weeks of intensive daily training and a 2-week posttraining period. VBM analysis revealed significant increases in gray matter with rake performance across the three monkeys. The effects were most significant (P < 0.05 corrected for multiple comparisons across the whole brain) in the right superior temporal sulcus, right second somatosensory area, and right intraparietal sulcus, with less significant effects (P < 0.001 uncorrected) in these same regions of the left hemisphere. Bilateral increases were also observed in the white matter of the cerebellar hemisphere in lobule 5. In two of the monkeys who exhibited rapid learning of the rake task, gray matter volume in peak voxels increased by up to 17% during the intensive training period; the earliest changes were seen after 1 week of intensive training, and they generally peaked when performance on the task plateaued. In the third monkey, who was slower to learn the task, peak voxels showed no systematic changes. Thus, VBM can detect significant brain changes in individual trained monkeys exposed to tool-use training for the first time. This approach could open up a means of investigating the underlying neurobiology of motor learning and other higher brain functions in individual animals.

Population-averaged standard template brain atlas for the common marmoset (Callithrix jacchus).

Advanced magnetic resonance (MR) neuroimaging analysis techniques based on voxel-wise statistics, such as voxel-based morphometry (VBM) and functional MRI, are widely applied to cognitive brain research in both human subjects and in non-human primates. Recent developments in imaging have enabled the evaluation of smaller animal models with sufficient spatial resolution. The common marmoset (Callithrix jacchus), a small New World primate species, has been widely used in neuroscience research, to which voxel-wise statistics could be extended with a species-specific brain template. Here, we report, for the first time, a tissue-segmented, population-averaged standard template of the common marmoset brain. This template was created by using anatomical T(1)-weighted images from 22 adult marmosets with a high-resolution isotropic voxel size of (0.2 mm)(3) at 7-Tesla and DARTEL algorithm in SPM8. Whole brain templates are available at International Neuroinformatics Japan Node website, http://brainatlas.brain.riken.jp/marmoset/.

Creating a population-averaged standard brain template for Japanese macaques (M. fuscata).

A number of modern digital anatomy techniques, based on structural MR brain images, have recently become applicable to the non-human primate brain. Such voxel-based quantitative techniques require a species-specific standardized brain template. Here we present a brain template for the Japanese macaque (Macaca fuscata). The template was designed to be used as a tool for spatially normalising Japanese macaque brains into a standard space. Although this species of macaque monkey is widely used in neuroscience research, including studies of higher cognitive brain functions, no standard MRI template of its brain is presently available. The template presented here is based on T1/T2* weighted, high-resolution 4T MR images obtained from 16 male adult Japanese macaque monkeys. T1/T2* images were used to correct the signal inequalities resulting from the use of a surface coil. Based on these images, population-averaged probability maps were created for grey matter, white matter and cerebrospinal fluid. The new template presented here should facilitate future brain research using the Japanese macaque monkey. Whole brain templates are available at http://brainatlas.brain.riken.jp/jm/modules/xoonips/listitem.php?index_id=9.

Long-term potentiation in the motor cortex.

Long-term potentiation (LTP) is a model for learning and memory processes. Tetanic stimulation of the sensory cortex produces LTP in motor cortical neurons, whereas tetanization of the ventrolateral nucleus of the thalamus, which also projects to the motor cortex, does not. However, after simultaneous high-frequency stimulation of both the sensory cortex and the ventrolateral nucleus of the thalamus, LTP of thalamic input to motor cortical neurons is induced. This associative LTP occurs only in neurons in the superficial layers of the motor cortex that receive monosynaptic input from both the sensory cortex and the ventrolateral nucleus of the thalamus. Associative LTP in the motor cortex may constitute a basis for the retention of motor skills.

Neural changes in the primate brain correlated with the evolution of complex motor skills.

Complex motor skills of eventual benefit can be learned after considerable trial and error. What do structural brain changes that accompany such effortful long-term learning tell us about the mechanisms for developing innovative behavior? Using MRI, we monitored brain structure before, during and after four marmosets learnt to use a rake, over a long period of 10-13 months. Throughout learning, improvements in dexterity and visuo-motor co-ordination correlated with increased volume in the lateral extrastriate cortex. During late learning, when the most complex behavior was maintained by sustained motivation to acquire the skill, the volume of the nucleus accumbens increased. These findings reflect the motivational state required to learn, and show accelerated function in higher visual cortex that is consistent with neurocognitive divergence across a spectrum of primate species.

Comparative analysis of developmentally regulated expressions of Gadd45a, Gadd45b, and Gadd45g in the mouse and marmoset cerebral cortex.

The cerebral cortex is an indispensable region that is involved in higher cognitive function in the mammalian brain, and is particularly evolved in the primate brain. It has been demonstrated that cortical areas are formed by both innate and activity-dependent mechanisms. However, it remains unknown what molecular changes induce cortical expansion and complexity during primate evolution. Active DNA methylation/demethylation is one of the epigenetic mechanisms that can modify gene expression via the methylation/demethylation of promoter regions. Three growth arrest and DNA damage-inducible small nuclear proteins, Gadd45 alpha, beta, and gamma, have been identified as regulators of methylation status. To understand the involvement of epigenetic factors in primate cortical evolution, we started by analyzing expression of these demethylation genes in the developing common marmoset (Callithrix jacchus) and mouse (Mus musculus) brain. In the marmoset brain, we found that cortical expression levels of Gadd45 alpha and gamma were reduced during development, whereas there was high expression of Gadd45 beta in some areas of the adult brain, including the prefrontal, temporal, posterior parietal and insula cortices, which are particularly expanded in greater primates and humans. Compared to the marmoset brain, there were no clear regional differences and constant or reduced Gadd45 expression was seen between juvenile and adult mouse brain. Double staining with a neuronal marker revealed that most Gadd45-expressing cells were NeuN-positive neurons. Thus, these results suggest the possibility that differential Gadd45 expression affects neurons, contributing cortical evolution and diversity.

Neural correlates of electrointestinography: insular activity modulated by signals recorded from the abdominal surface.

Although the neural correlates that underlie abdominal pain have been investigated, so-called brain processes involved in modulating "gut feelings" remain unclear. In the current study, we used electrointestinography (EIG) to measure intestinal activity of healthy humans at rest. EIG measured myoelectrical activity of intestinal smooth muscles from the abdominal surface and was simultaneously conducted along with brain activity measurement using functional magnetic resonance imaging (fMRI). Correlations between the frequency powers of EIG and fMRI signals during 30min of rest were then examined to elucidate gut-brain interactions. Neural activity correlating with 0.14- to 0.21-Hz EIG (suggested to reflect intestinal activity) was observed in the right anterior and middle insula. Moreover, this EIG frequency band correlated with anxiety scores along with resting-state functional connectivity between the insula and dorsal anterior cingulate cortex. These findings suggest that the insular cortex could be the core region involved in central visceral processes associated with subjective feelings.

Bilateral activity and callosal connections in the somatosensory cortex.

Earlier studies recording single neuronal activity in the postcentral somatosensory cortex of monkeys converged in suggesting that the bilateral receptive fields were related exclusively to the body midline including the trunk, perioral face, and oral cavity. These neurons were recorded mostly in the rostral part of the gyrus, areas 3b and 1. However, the authors recently found a substantial number of neurons with bilateral receptive fields on extremities, hand/digits, shoulders/arms, or legs/feet in the caudalmost part (areas 2 and 5) of the postcentral gyrus. The authors review these results and discuss functional implications of the bilateral representation in the postcentral somatosensory cortex.

Identification of neurons producing long-term potentiation in the cat motor cortex: intracellular recordings and labeling.

Intracellular, in vivo recordings were used to identify and subsequently to label neurons in the cat motor cortex in which long-term potentiation (LTP) was induced. Thirty-nine motor cortical neurons that produced excitatory postsynaptic potentials (EPSPs) in response to microstimulation in areas 1-2 (SI) or in area 5a (SIII) were studied. Amplitudes of EPSPs produced in response to test stimulation (1 Hz) were recorded before and after tetanic stimulation (200 Hz, 20 seconds). In 25/39 cells (64%), EPSP amplitudes were significantly increased following the tetanic stimulation (65 +/- 51% average increase), and remained at the potentiated level as long as stable recordings could be maintained (20 +/- 18 minutes, maximum = 90 minutes). LTP was induced exclusively in cells that produced monosynaptic EPSPs in response to area 1-2 or area 5a stimulation. Of the 39 analyzed cells, 13 were labeled by intracellular injections of 5% biocytin. Neurons in which LTP was induced included both pyramidal and nonpyramidal cells and were located exclusively in layers II or III of the motor cortex; cells in deeper cortical layers were not potentiated. These findings indicate that various corticocortical inputs can increase the efficacy of synaptic transmission in a subset of motor cortical neurons. We propose that this plasticity in synaptic transmission constitutes one of the bases of motor learning and memory.

Trigeminal mesencephalic neurons innervating functionally identified muscle spindles and involved in the monosynaptic stretch reflex of the lateral pterygoid muscle of the guinea pig.

Location of the neurons in the trigeminal mesencephalic nucleus innervating stretch receptors of the lateral pterygoid muscle and the mode of their synaptic connection on the lateral pterygoid motoneurons of the guinea pig were studied physiologically as well as morphologically, in comparison with the trigeminal mesencephalic neurons innervating muscle spindles in the superficial masseter muscle, with the following results: stimulation of the caudal half of the trigeminal mesencephalic nucleus evoked monosynaptic excitatory postsynaptic potentials in the ipsilateral lateral pterygoid motoneurons. Stimulation of the lateral pterygoid nerve directly evoked spike potentials in the neurons located in the caudal half of the ipsilateral trigeminal mesencephalic nucleus, which responded with increased firing to stretch, and with silent period to twitch, of the ipsilateral lateral pterygoid muscle. Averaging of intracellular potentials of the lateral pterygoid motoneurons with extracellular spike potentials of these trigeminal mesencephalic neurons revealed excitatory postsynaptic potentials after a monosynaptic latency, but no inhibitory postsynaptic potentials. Injection of horseradish peroxidase into the lateral pterygoid muscle labeled 15-20 cells in the caudal half of the ipsilateral trigeminal mesencephalic nucleus, while 174-228 cells retrogradely labeled by horseradish peroxidase were found throughout the whole rostrocaudal extent of the ipsilateral trigeminal mesencephalic nucleus following injection of horseradish peroxidase into the masseter muscle. It was concluded that neurons in the caudal half of the trigeminal mesencephalic nucleus send their peripheral processes to stretch receptors, presumably muscle spindles, in the ipsilateral lateral pterygoid muscle and that their central processes have excitatory synapses on ipsilateral lateral pterygoid motoneurons, thus comprising the afferent limb of a monosynaptic stretch reflex arc of the lateral pterygoid muscle of the guinea pig.

Subjective image of invisible hand coded by monkey intraparietal neurons.

Humans can perform purposeful hand actions even blindly in the dark, perhaps using mental images of the hand. To demonstrate such subjective body images, this study describes the activities of bimodal (somatosensory and visual) neurons in the monkey intraparietal cortex. Visual stimuli moving into the space encompassing their somatosensory receptive fields (s-RFs) on the hand activated these neurons, forming visual receptive fields (v-RFs) as if coding a hand-image. After the hand was hidden by covering it with an opaque plate, the v-RF persisted over the plate above the invisible s-RF. Furthermore, when the hand was moved invisibly under the plate, the v-RF moved over the plate to follow the invisible s-RF. Thus, monkeys can maintain and update subjective body images in the mind, and they are coded by intraparietal bimodal neurons.

Coding of modified body schema during tool use by macaque postcentral neurones.

A tool is an extension of the hand in both a physical and a perceptual sense. The presence of body schemata has been postulated as the basis of the perceptual assimilation of tool and hand. We trained macaque monkeys to retrieve distant objects using a rake, and neuronal activity was recorded in the caudal postcentral gyrus where the somatosensory and visual signals converge. There we found a large number of bimodal neurones which appeared to code the schema of the hand. During tool use, their visual receptive fields were altered to include the entire length of the rake or to cover the expanded accessible space. These findings may represent neural correlates of the modified schema of the hand in which the tool was incorporated.

Long-lasting facilitation of pyramidal tract input to spinal interneurons.

The purpose of this study was to determine whether long-term changes in synaptic efficacy can be induced in the pyramidal tract (PT). Tetanic stimulation of the PT induced long-term facilitation of PT input to spinal cord neurons. In contrast, tetanic stimulation of the pyramidal tract did not alter the efficacy of synaptic inputs of PT cells' intracortical axon collaterals to other cortical neurons. These findings suggest that the PT participates in motor learning by modulating the excitability of spinal cord neurons. The results also indicate that induction of LTP in the PT is dependent on postsynaptic mechanisms.

Attention-induced neuronal activity in the monkey somatosensory cortex revealed by pupillometrics.

Detection of a sensory stimulus is facilitated when attention is directed towards the stimulus source. Neuronal substrates for this psychological effect were studied in monkeys performing an attention-demanding task, by simultaneous recording of neuronal activity and pupillary dilation as an indicator of attentive state. We found that neurons in the postcentral somatosensory cortex (SI) started to discharge concurrent with the pupil dilation onset which occurred well before the somatosensory stimulus. Neuronal firing rates were positively correlated with the degree of dilation, suggesting that the SI neural activity is under the direct influence of the attentional process.

Self-images in the video monitor coded by monkey intraparietal neurons.

When playing a video game, or using a teleoperator system, we feel our self-image projected into the video monitor as a part of or an extension of ourselves. Here we show that such a self image is coded by bimodal (somatosensory and visual) neurons in the monkey intraparietal cortex, which have visual receptive fields (RFs) encompassing their somatosensory RFs. We earlier showed these neurons to code the schema of the hand which can be altered in accordance with psychological modification of the body image; that is, when the monkey used a rake as a tool to extend its reach, the visual RFs of these neurons elongated along the axis of the tool, as if the monkey's self image extended to the end of the tool. In the present experiment, we trained monkeys to recognize their image in a video monitor (despite the earlier general belief that monkeys are not capable of doing so), and demonstrated that the visual RF of these bimodal neurons was now projected onto the video screen so as to code the image of the hand as an extension of the self. Further, the coding of the imaged hand could intentionally be altered to match the image artificially modified in the monitor.

Processing of tactile and kinesthetic signals from bilateral sides of the body in the postcentral gyrus of awake monkeys.

Earlier studies pointed out that in the primary somatosensory cortex (SI) the receptive fields (RF) of bilateral neurons were related exclusively to the body midline. We recently found a substantial number of neurons with bilateral RFs on hand digits, shoulders/arms or legs/feet in the caudalmost part (areas 2 and 5) of the postcentral gyrus in awake macaque monkeys. The RFs of these neurons were generally of the most complex types found in this region of the cortex, and thus they were considered to be at the highest level along the hierarchical chain of information processing. We conclude that there are two types of bilateral RFs in the postcentral gyrus, one representing the midline structures such as the intraoral cavity, chin or trunk and the other related to limb structures such as fingers, hands, arms, shoulders, legs and girdles. Functional significance of the bilateral activity could be understood in behavioral context as it is seen more extensively in the body parts where bilateral coordination is essential.

Morphine and electroacupuncture: comparison of the effects on the cortical evoked responses after tooth pulp stimulation in rats.

The effects of morphine and electroacupuncture on the cortical evoked responses after tooth pulp stimulation were investigated in rats. Morphine suppressed these responses more strongly in secondary somatosensory areas than those in primary somatosensory areas, while electroacupuncture suppressed the responses to the same degree in both areas. These results might suggest that there are some differences in noxious-suppressive action between morphine and the endogenous opiates released by electroacupuncture stimulation.

Feeding behavior in mammals: corticobulbar projection is reorganized during conversion from sucking to chewing.

It is known that repetitive stimulation of the frontal cortex (cortical masticatory area, CMA) induces rhythmical jaw movements similar to chewing in adult mammals. In the present study we were able to induce rhythmical jaw movements similar to sucking by repetitive stimulation of the frontal cortex in neonatal guinea pigs. This area, which we named the cortical sucking area (CSA), was located rostral to the CMA which was later formed upon maturation. Neurons of the CSA were shown electrophysiologically and morphologically to project primarily to the dorsal part of the paragigantocellular reticular nucleus of the contralateral side. This was the site which the CMA neurons, later, projected to induce chewing. It is generally thought that tooth eruption triggers the conversion from sucking to chewing. However, guinea pigs are born with a complete permanent dentition and therefore devoid of this peripheral trigger for the conversion to chewing. Accordingly we propose that shift of the cortical projection area from the CSA to the CMA during the maturation causes the conversion of the mammalian feeding behavior. It is discussed that this transition involves extensive reorganization of the cortical efferent system including the pyramidal tract during early postnatal development.

Quantitative relations between noxious stimulus intensity and magnitude of central afferent evoked responses in rat.

Relations between intensities of electrical noxious stimulus applied to the tooth pulp and magnitudes of evoked responses at various relay stations of tooth pulp afferents were investigated with lightly anesthetized rats. The stimulus-response function in each relay station and the cerebral cortex follows the power function only in the range of lower, but noxious, stimulus intensities; however, it deviates from it in the range of higher ones, the exponent of the function becoming smaller. The higher the relay station locates, the smaller the exponent value is.