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Takao K.,National Institute for Physiological science | Takao K.,Japan Science and Technology Agency | Miyakawa T.,National Institute for Physiological science | Miyakawa T.,Japan Science and Technology Agency | Miyakawa T.,Health Science University
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

The use of mice as animal models has long been considered essential in modern biomedical research, but the role of mouse models in research was challenged by a recent report that genomic responses in mouse models poorly mimic human inflammatory diseases. Here we reevaluated the same gene expression datasets used in the previous study by focusing on genes whose expression levels were significantly changed in both humans and mice. Contrary to the previous findings, the gene expression levels in the mouse models showed extraordinarily significant correlations with those of the human conditions (Spearman's rank correlation coefficient: 0.43-0.68; genes changed in the same direction: 77-93%; P = 6.5 × 10-11 to 1.2 × 10-35). Moreover, meta-analysis of those datasets revealed a number of pathways/biogroups commonly regulated by multiple conditions in humans and mice. These findings demonstrate that gene expression patterns in mouse models closely recapitulate those in human inflammatory conditions and strongly argue for the utility of mice as animal models of human disorders.


Inui K.,National Institute for Physiological science | Kakigi R.,National Institute for Physiological science
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2012

The choice of a system specific stimulus is difficult when investigating the human nociceptive system, in contrast with the tactile, auditory and visual systems, because it should be noxious but not actually damage the tissue. The discomfort accompanying system specific stimulation must be kept to a minimum for ethical reasons. In this review, recent progress made in the study of human pain perception using intraepidermal electrical stimulation (IES) is described. Also, whether IES is a viable alternative to laser stimulation is discussed. IES selectively activates Aδ nociceptors, elicits a sharp pricking sensation with minimal discomfort and evokes cortical responses almost identical to those produced by laser stimulation. As IES does not require expensive equipment, and is easy to control, it would seem useful for pain research as well as clinical tests.


Darbin O.,University of South Alabama | Darbin O.,National Institute for Physiological science
Parkinsonism and Related Disorders | Year: 2012

Movement disorders are prevalent in the elderly and may have both central and peripheral origins. Age-related parkinsonism often results in movement disorders identical to some of the cardinal symptoms of typical Parkinson's disease (TPD). Nevertheless, there may be limited similarity in the underlying dysfunction of the sensory-motor circuitry since these two conditions exhibit different changes in the nigro-striatal pathway. In this short review, we highlight some of the key distinctions between aging and TPD regarding striatal dopaminergic activity and discuss them in the context of therapeutic strategies to alleviate motor decline in the elderly. © 2011 Elsevier Ltd.


Nambu A.,National Institute for Physiological science
Frontiers in Neuroanatomy | Year: 2011

Somatotopic organization is a fundamental and key concept to understand how the corticobasal ganglia loop works. It is also indispensable knowledge to perform stereotaxic surgery for movement disorders. Here I would like to describe the somatotopic organization of the basal ganglia, which consist of the striatum, subthalamic nucleus, globus pallidus, and substantia nigra. Projections from motor cortical regions representing different body parts terminate in different regions of these nuclei. Basal ganglia neurons respond not only to the stimulation of the corresponding regions of the motor cortices, but also to active and passive movements of the corresponding body parts. On the basis of these anatomical and physiological findings, somatotopic organization can be identified in the motor territories of these nuclei in the basal ganglia. In addition, projections from functionally interrelated cortical areas partially converge through the cortico-basal ganglia loop, but nevertheless the somatotopy is still preserved. Disorganized somatotopy may explain, at least in part, the pathophysiology of movement disorders, such as Parkinson's disease and dystonia. © 2011 Nambu.


Takebayashi H.,Niigata University | Ikenaka K.,National Institute for Physiological science
GLIA | Year: 2015

Oligodendrocytes (OLs) are glial cells, which generate myelin in the central nervous system. Their interesting developmental features attract many neurobiologists eager to study cell differentiation, gene expression regulation, or dynamic morphogenesis. Their primary role in protecting the axons has major impacts in the medical research field: in multiple sclerosis, a demyelinating disease in which remyelination is blocked. Oligodendrogenesis is involved in higher brain function including motor skill learning and cognitive function. Here, we review advances in the research on OL development and highlight areas where questions remain to be answered in both developmental biology and neurobiology related aspects. © 2015 Wiley Periodicals, Inc.


Kubota Y.,National Institute for Physiological science | Kubota Y.,Graduate University for Advanced Studies | Kubota Y.,Japan Science and Technology Agency
Current Opinion in Neurobiology | Year: 2014

The cerebral cortical microcircuit is composed of pyramidal and non-pyramidal cells and subcortical and cortico-cortical afferents. These constitute a complex wiring structure that remains poorly understood. At least ten non-pyramidal cell subtypes are known. These innervate different target neuronal domains, and have a key role in regulating cortical neuronal activity. Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the cerebral cortex, and most cortical inhibitory synapses originate from non-pyramidal cells. Therefore, investigating the morphological and functional wiring properties of GABAergic non-pyramidal cells is critical to understanding the functional architecture of the cortical microcircuitry. This review focuses on current understanding of the different roles of inhibitory GABAergic non-pyramidal cell subtypes in cortical functions. © 2013 Elsevier Ltd.


Yoshimura T.,Baylor College of Medicine | Yoshimura T.,National Institute for Physiological science | Rasband M.N.,Baylor College of Medicine
Current Opinion in Neurobiology | Year: 2014

The axon initial segment (AIS) is a structurally and molecularly unique neuronal compartment of the proximal axon that functions as both a physiological and physical bridge between the somatodendritic and axonal domains. The AIS has two main functions: to initiate action potentials and to maintain neuronal polarity. The cytoskeletal scaffold ankyrinG is responsible for these functions and clusters ion channels at the AIS. Recent studies reveal how the AIS forms and remarkable diversity in its structure, function, and composition that may be modulated by neuronal activity and posttranslational modifications of AIS proteins. Furthermore, AIS proteins have been implicated in a variety of human diseases. Here, we discuss these findings and what they teach us about the dynamic AIS. © 2014 Elsevier Ltd.


Sanada T.M.,National Institute for Physiological science | DeAngelis G.C.,University of Rochester
Journal of Neuroscience | Year: 2014

Neural processing of 2D visual motion has been studied extensively, but relatively little is known about how visual cortical neurons represent visual motion trajectories that include a component toward or away from the observer (motion in depth). Psychophysical studies have demonstrated that humans perceive motion in depth based on both changes in binocular disparity over time (CD cue) and interocular velocity differences (IOVD cue). However, evidence for neurons that represent motion in depth has been limited, especially in primates, and it is unknown whether such neurons make use of CD or IOVD cues. We show that approximately one-half of neurons in macaque area MT are selective for the direction of motion in depth, and that this selectivity is driven primarily by IOVD cues, with a small contribution from the CD cue. Our results establish that area MT, a central hub of the primate visual motion processing system, contains a 3D representation of visual motion. © 2014 the authors.


Akita T.,National Institute for Physiological science | Okada Y.,National Institute for Physiological science
Journal of Physiology | Year: 2011

Volume-sensitive outwardly rectifying (VSOR) anion channels play a key role in a variety of essential cell functions including cell volume regulation, cell death induction and intercellular communications. We previously demonstrated that, in cultured mouse cortical astrocytes, VSOR channels are activated in response to an inflammatory mediator, bradykinin, even without an increase in cell volume. Here we report that this VSOR channel activation must be mediated firstly by 'nanodomains' of high [Ca 2+] i generated at the sites of both Ca 2+ release from intracellular Ca 2+ stores and Ca 2+ entry at the plasma membrane. Bradykinin elicited a [Ca 2+] i rise, initially caused by Ca 2+ release and then by Ca 2+ entry. Suppression of the [Ca 2+] i rise by removal of extracellular Ca 2+ and by depletion of Ca 2+ stores suppressed the VSOR channel activation in a graded manner. Quantitative RT-PCR and suppression of gene expression with small interfering RNAs indicated that Orai1, TRPC1 and TRPC3 channels are involved in the Ca 2+ entry and especially the entry through TRPC1 channels is strongly involved in the bradykinin-induced activation of VSOR channels. Moreover, Ca 2+-dependent protein kinases Cα and β were found to mediate the activation after the [Ca 2+] i rise through inducing generation of reactive oxygen species. Intracellular application of a slow Ca 2+ chelator, EGTA, at 10 mm or a fast chelator, BAPTA, at 1 mm, however, had little effect on the VSOR channel activation. Application of BAPTA at 10 mm suppressed significantly the activation to one-third. These suggest that the VSOR channel activation induced by bradykinin is regulated by Ca 2+ in the vicinity of individual Ca 2+ release and entry channels, providing a basis for local control of cell volume regulation and intercellular communications. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.


Nakajo K.,National Institute for Physiological science | Kubo Y.,National Institute for Physiological science
Nature Communications | Year: 2014

In voltage-gated K + channels, membrane depolarization induces an upward movement of the voltage-sensing domains (VSD) that triggers pore opening. KCNQ1 is a voltage-gated K + channel and its gating behaviour is substantially modulated by auxiliary subunit KCNE proteins. KCNE1, for example, markedly shifts the voltage dependence of KCNQ1 towards the positive direction and slows down the activation kinetics. Here we identify two phenylalanine residues on KCNQ1, Phe232 on S4 (VSD) and Phe279 on S5 (pore domain) to be responsible for the gating modulation by KCNE1. Phe232 collides with Phe279 during the course of the VSD movement and hinders KCNQ1 channel from opening in the presence of KCNE1. This steric hindrance caused by the bulky amino-acid residues destabilizes the open state and thus shifts the voltage dependence of KCNQ1/KCNE1 channel. © 2014 Macmillan Publishers Limited. All rights reserved.

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