Updated on 2025/06/23

写真a

 
SASAOKA Toshikuni
 
Organization
Brain Research Institute Center for Bioresources Professor
Title
Professor
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Degree

  • Doctor ( 1990.3   Nagoya University )

Research Interests

  • dopamine

  • Parkinson disease

  • dopamine receptor

  • motor control

  • genetically modified mice

  • Developmental and reproductive engineering

  • learning and memory

Research Areas

  • Life Science / Neuroscience-general

  • Life Science / Pathological biochemistry

  • Life Science / Laboratory animal science

  • Life Science / Function of nervous system  / Parkinson's disease, dopamine, dopamine receptors, motor control, memory and learning, genetically engineered mice, developmental engineering, mouse embryo manipulation

Research History (researchmap)

  • Niigata University   Brain Research Institute Center for Bioresources   Professor

    2013.6

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  • Kitasato University   School of Medicine   Professor

    2010.7 - 2013.6

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    Country:Japan

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  • National Institute for Basic Biology   Center for Transgenic Animals and Plants   Associate Professor

    2003.8 - 2011.3

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    Country:Japan

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  • National Center of Neurology and Psychiatry   National Institute of Neuroscience, Ncnp   Section Chief

    1996.4 - 2003.7

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    Country:Japan

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  • Massachusetts Institute of Technology   Center for Cancer Research   Postdoctoral fellow

    1993.7 - 1996.3

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    Country:United States

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  • Tufts University School of Medicine   Neuroscience Department   Research Associate

    1992.12 - 1993.6

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    Country:United States

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  • Kyushu University   Medical Institute of Bioregulation   Assistant Professor

    1992.4 - 1995.11

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    Country:Japan

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  • Japan Society for the Promotion of Science   Special Research Fellow (PD)

    1990.4 - 1992.3

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Research History

  • Niigata University   Brain Research Institute Center for Bioresources   Professor

    2013.6

Education

  • Nagoya University   Graduate School of Medicine   Biochemistry

    1986.4 - 1990.3

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    Country: Japan

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  • Nagoya University   School of Medicine

    1980.4 - 1986.3

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    Country: Japan

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Professional Memberships

Studying abroad experiences

  • Center for Cancer Research, Massachusetts Institute of Technology   Postdoctoral fellow

    1993.7 - 1996.3

Qualification acquired

  • Doctor

 

Papers

  • Neurotransmission through dopamine D1 receptors is required for aversive memory formation and Arc activation in the cerebral cortex. Reviewed International journal

    Nae Saito, Kazuki Tainaka, Tom Macpherson, Takatoshi Hikida, Shun Yamaguchi, Toshikuni Sasaoka

    Neuroscience research   156   58 - 65   2020.7

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    Dopaminergic neurotransmission is considered to play an important role not only in reward-based learning, but also in aversive learning. Here, we investigated the role of dopaminergic neurotransmission via dopamine D1 receptors (D1Rs) in aversive memory formation in a passive avoidance test using D1R knockdown (KD) mice, in which the expression of D1Rs can conditionally and reversibly be controlled by doxycycline (Dox) treatment. We also performed whole-brain imaging after aversive footshock stimulation in activity-regulated cytoskeleton protein (Arc)-dVenus D1RKD mice, which were crossbred from Arc-dVenus transgenic mice and D1RKD mice, to examine the distribution of Arc-controlled dVenus expression in the hippocampus and cerebral cortex during aversive memory formation. Knockdown of D1R expression following Dox treatment resulted in impaired performance in the passive avoidance test and was associated with a decrease in dVenus expression in the cerebral cortex (visual, somatosensory, and motor cortices), but not the hippocampus, compared with control mice without Dox treatment. These findings indicate that D1R-mediated dopaminergic transmission is critical for aversive memory formation, specifically by influencing Arc expression in the cerebral cortex.

    DOI: 10.1016/j.neures.2020.04.006

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  • Differential behavioral phenotypes of dopamine D1 receptor knockdown mice at the embryonic, postnatal, and adult stages. Reviewed International journal

    Tadashi Okubo, Asako Sato, Hirotsugu Okamoto, Toshiya Sato, Toshikuni Sasaoka

    International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience   66   1 - 8   2018.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier Ltd  

    DOI: 10.1016/j.ijdevneu.2017.11.004

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  • Dopamine D1 Receptor-Mediated Transmission Maintains Information Flow Through the Cortico-Striato-Entopeduncular Direct Pathway to Release Movements. Reviewed International journal

    Satomi Chiken, Asako Sato, Chikara Ohta, Makoto Kurokawa, Satoshi Arai, Jun Maeshima, Tomoko Sunayama-Morita, Toshikuni Sasaoka, Atsushi Nambu

    Cerebral cortex (New York, N.Y. : 1991)   25 ( 12 )   4885 - 97   2015.12

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    DOI: 10.1093/cercor/bhv209

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  • Distinct motor impairments of dopamine D1 and D2 receptor knockout mice revealed by three types of motor behavior. Reviewed International journal

    Toru Nakamura, Asako Sato, Takashi Kitsukawa, Toshihiko Momiyama, Tetsuo Yamamori, Toshikuni Sasaoka

    Frontiers in integrative neuroscience   8   56 - 56   2014

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Frontiers Research Foundation  

    DOI: 10.3389/fnint.2014.00056

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  • Pathological analysis of muscle hypertrophy and degeneration in muscular dystrophy in gamma-sarcoglycan-deficient mice. Reviewed International journal

    Toshikuni Sasaoka, Michihiro Imamura, Kenji Araishi, Satoru Noguchi, Yuji Mizuno, Naomi Takagoshi, Hiroshi Hama, Eriko Wakabayashi-Takai, Yukiko Yoshimoto-Matsuda, Ikuya Nonaka, Kiyotoshi Kaneko, Mikiharu Yoshida, Eijiro Ozawa

    Neuromuscular disorders : NMD   13 ( 3 )   193 - 206   2003.3

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/S0960-8966(02)00220-1

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  • Caveolin-3 deficiency causes muscle degeneration in mice

    Y Hagiwara, T Sasaoka, K Araishi, M Imamura, H Yorifuji, Nonaka, I, E Ozawa, T Kikuchi

    HUMAN MOLECULAR GENETICS   9 ( 20 )   3047 - 3054   2000.12

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  • Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions.

    Wang Y, Xu R, Sasaoka T, Tonegawa S, Kung M P, Sankoorikal E B

    J Neurosci   20 ( 22 )   8305 - 8314   2000.11

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    The dopamine D2 receptor (D2) system has been implicated in several neurological and psychiatric disorders, such as schizophrenia and Parkinson's disease. There are two isoforms of the D2 receptor: the long form (D2L) and the short form (D2S). The two isoforms are generated by alternative splicing of the same gene and differ only by 29 amino acids in their protein structures. Little is known about the distinct functions of either D2 isoform, primarily because selective pharmacological agents are not available. We generated D2L receptor-deficient (D2L-/-) mice by making a subtle mutation in the D2 gene. D2L-/- mice (which still express functional D2S) displayed reduced levels of locomotion and rearing behavior. Interestingly, haloperidol produced significantly less catalepsy and inhibition of locomotor activity in D2L-/- mice. These findings suggest that D2L and D2S may contribute differentially to the regulation of certain motor functions and to the induction of the extrapyramidal side effects associated with the use of typical antipsychotic drugs (e.g., haloperidol). Quinpirole induced a similar initial suppression of locomotor activity in both D2L-/- and wild-type mice. In ad

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  • Loss of the sarcoglycan complex and sarcospan leads to muscular dystrophy in beta-sarcoglycan-deficient mice

    K Araishi, T Sasaoka, M Imamura, S Noguchi, H Hama, E Wakabayashi, M Yoshida, T Hori, E Ozawa

    HUMAN MOLECULAR GENETICS   8 ( 9 )   1589 - 1598   1999.9

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    DOI: 10.1093/hmg/8.9.1589

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  • ANALYSIS OF THE HUMAN TYROSINE-HYDROXYLASE PROMOTER-CHLORAMPHENICOL ACETYLTRANSFERASE CHIMERIC GENE-EXPRESSION IN TRANSGENIC MICE Reviewed

    T SASAOKA, K KOBAYASHI, NAGATSU, I, R TAKAHASHI, M KIMURA, M YOKOYAMA, T NOMURA, M KATSUKI, T NAGATSU

    MOLECULAR BRAIN RESEARCH   16 ( 3-4 )   274 - 286   1992.12

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/0169-328X(92)90236-5

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  • STRUCTURE OF HUMAN PHENYLETHANOLAMINE N-METHYLTRANSFERASE GENE - EXISTENCE OF 2 TYPES OF MESSENGER-RNA WITH DIFFERENT TRANSCRIPTION INITIATION SITES Reviewed

    T SASAOKA, N KANEDA, Y KUROSAWA, K FUJITA, T NAGATSU

    NEUROCHEMISTRY INTERNATIONAL   15 ( 4 )   555 - 565   1989

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    Authorship:Lead author   Language:English   Publishing type:Doctoral thesis  

    DOI: 10.1016/0197-0186(89)90176-9

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  • Production of marmoset eggs and embryos from xenotransplanted ovary tissues

    Runa Hirayama, Hiroaki Taketsuru, Ena Nakatsukasa, Rie Natsume, Nae Saito, Shuko Adachi, Sayaka Kuwabara, Jun Miyamoto, Shiori Miura, Nobuyoshi Fujisawa, Yoshitaka Maeda, Keizo Takao, Manabu Abe, Toshikuni Sasaoka, Kenji Sakimura

    Scientific Reports   13 ( 1 )   2023.10

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    Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract

    The common marmoset (Callithrix jacchus) has attracted attention as a valuable primate model for the analysis of human diseases. Despite the potential for primate genetic modification, however, its widespread lab usage has been limited due to the requirement for a large number of eggs. To make up for traditional oocyte retrieval methods such as hormone administration and surgical techniques, we carried out an alternative approach by utilizing ovarian tissue from deceased marmosets that had been disposed of. This ovarian tissue contains oocytes and can be used as a valuable source of follicles and oocytes. In this approach, the ovarian tissue sections were transplanted under the renal capsules of immunodeficient mice first. Subsequent steps consist of development of follicles by hormone administrations, induction of oocyte maturation and fertilization, and culture of the embryo. This method was first established with rat ovaries, then applied to marmoset ovaries, ultimately resulting in the successful acquisition of the late-stage marmoset embryos. This approach has the potential to contribute to advancements in genetic modification research and disease modeling through the use of primate models, promoting biotechnology with non-human primates and the 3Rs principle in animal experimentation.

    DOI: 10.1038/s41598-023-45224-x

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    Other Link: https://www.nature.com/articles/s41598-023-45224-x

  • Axonal mRNA binding of hnRNP A/B is crucial for axon targeting and maturation of olfactory sensory neurons Reviewed

    Nanaho Fukuda, Tomoyuki Fukuda, Piergiorgio Percipalle, Kanako Oda, Nobuyuki Takei, Kevin Czaplinski, Kazushige Touhara, Yoshihiro Yoshihara, Toshikuni Sasaoka

    Cell Reports   42 ( 5 )   112398 - 112398   2023.5

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    Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.celrep.2023.112398

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  • Amelioration of Nicotine-Induced Conditioned Place Preference Behaviors in Mice by an FABP3 Inhibitor Reviewed International journal

    Wenbin Jia, Ichiro Kawahata, An Cheng, Takuya Sasaki, Toshikuni Sasaoka, Kohji Fukunaga

    International Journal of Molecular Sciences   24 ( 7 )   2023.4

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    We previously demonstrated that fatty acid-binding protein 3 null (FABP3-/-) mice exhibit resistance to nicotine-induced conditioned place preference (CPP). Here, we confirm that the FABP3 inhibitor, MF1 ((4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid), successfully reduces nicotine-induced CPP scores in mice. MF1 (0.3 or 1.0 mg/kg) was orally administered 30 min before nicotine, and CPP scores were assessed in the conditioning, withdrawal, and relapse phases. MF1 treatment decreased CPP scores in a dose-dependent manner. Failure of CPP induction by MF1 (1.0 mg/kg, p.o.) was associated with the inhibition of both CaMKII and ERK activation in the nucleus accumbens (NAc) and hippocampal CA1 regions. MF1 treatment reduced nicotine-induced increases in phosphorylated CaMKII and cAMP-response element-binding protein (CREB)-positive cells. Importantly, the increase in dopamine D2 receptor (D2R) levels following chronic nicotine exposure was inhibited by MF1 treatment. Moreover, the quinpirole (QNP)-induced increase in the level of CaMKII and ERK phosphorylation was significantly inhibited by MF1 treatment of cultured NAc slices from wild type (WT) mice; however, QNP treatment had no effect on CaMKII and ERK phosphorylation levels in the NAc of D2R null mice. Taken together, these results show that MF1 treatment suppressed D2R/FABP3 signaling, thereby preventing nicotine-induced CPP induction. Hence, MF1 can be used as a novel drug to block addiction to nicotine and other drugs by inhibiting the dopaminergic system.

    DOI: 10.3390/ijms24076644

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  • Quantitative analysis of NMDA receptor subunits proteins in mouse brain. Reviewed International journal

    Yasuhiro Suzuki, Chihiro Nakamoto, Izumi Watanabe-Iida, Masahiko Watanabe, Tomonori Takeuchi, Toshikuni Sasaoka, Manabu Abe, Kenji Sakimura

    Neurochemistry international   165   105517 - 105517   2023.3

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    NMDA-type glutamate receptors (NMDARs) are tetrameric channel complex composed of two subunits of GluN1, which is encoded by a single gene and diversified by alternative splicing, and two subunits from four subtypes of GluN2, leading to various combinations of subunits and channel specificities. However, there is no comprehensive quantitative analysis of GluN subunit proteins for relative comparison, and their compositional ratios at various regions and developmental stages have not been clarified. Here we prepared six chimeric subunits, by fusing an N-terminal side of the GluA1 subunit with a C-terminal side of each of two splicing isoforms of GluN1 subunit and four GluN2 subunits, with which titers of respective NMDAR subunit antibodies could be standardized using common GluA1 antibody, thus enabling quantification of relative protein levels of each NMDAR subunit by western blotting. We determined relative protein amounts of NMDAR subunits in crude, membrane (P2) and microsomal fractions prepared from the cerebral cortex, hippocampus and cerebellum in adult mice. We also examined amount changes in the three brain regions during developmental stages. Their relative amounts in the cortical crude fraction were almost parallel to those of mRNA expression, except for some subunits. Interestingly, a considerable amount of GluN2D protein existed in adult brains, although its transcription level declines after early postnatal stages. GluN1 was larger in quantity than GluN2 in the crude fraction, whereas GluN2 increased in the membrane component-enriched P2 fraction, except in the cerebellum. These data will provide the basic spatio-temporal information on the amount and composition of NMDARs.

    DOI: 10.1016/j.neuint.2023.105517

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  • Attempts for deriving extended pluripotent stem cells from common marmoset embryonic stem cells. Reviewed International journal

    Sho Yoshimatsu, Mayutaka Nakajima, Iki Sonn, Rie Natsume, Kenji Sakimura, Ena Nakatsukasa, Toshikuni Sasaoka, Mari Nakamura, Takashi Serizawa, Tsukika Sato, Erika Sasaki, Hongkui Deng, Hideyuki Okano

    Genes to cells : devoted to molecular & cellular mechanisms   28 ( 2 )   156 - 169   2023.2

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    Extended pluripotent stem cells (EPSCs) derived from mice and humans showed an enhanced potential for chimeric formation. By exploiting transcriptomic approaches, we assessed the differences in gene expression profile between extended EPSCs derived from mice and humans, and those newly derived from the common marmoset (marmoset; Callithrix jacchus). Although the marmoset EPSC-like cells displayed a unique colony morphology distinct from murine and human EPSCs, they displayed a pluripotent state akin to embryonic stem cells (ESCs), as confirmed by gene expression and immunocytochemical analyses of pluripotency markers and three-germ-layer differentiation assay. Importantly, the marmoset EPSC-like cells showed interspecies chimeric contribution to mouse embryos, such as E6.5 blastocysts in vitro and E6.5 epiblasts in vivo in mouse development. Also, we discovered that the perturbation of gene expression of the marmoset EPSC-like cells from the original ESCs resembled that of human EPSCs. Taken together, our multiple analyses evaluated the efficacy of the method for the derivation of marmoset EPSCs.

    DOI: 10.1111/gtc.13000

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  • Cerebrocortical activation following unilateral labyrinthectomy in mice characterized by whole-brain clearing: implications for sensory reweighting. Reviewed International journal

    Ryota Kai, Kuniyuki Takahashi, Kazuki Tainaka, Yuriko Iwakura, Hisaaki Namba, Nae Saito, Toshikuni Sasaoka, Shun Yamaguchi, Hiroyuki Nawa, Arata Horii

    Scientific reports   12 ( 1 )   15424 - 15424   2022.9

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    Posture and gait are maintained by sensory inputs from the vestibular, visual, and somatosensory systems and motor outputs. Upon vestibular damage, the visual and/or somatosensory systems functionally substitute by cortical mechanisms called "sensory reweighting". We investigated the cerebrocortical mechanisms underlying sensory reweighting after unilateral labyrinthectomy (UL) in mice. Arc-dVenus transgenic mice, in which the gene encoding the fluorescent protein dVenus is transcribed under the control of the promoter of the immediate early gene Arc, were used in combination with whole-brain three-dimensional (3D) imaging. Performance on the rotarod was measured as a behavioral correlate of sensory reweighting. Following left UL, all mice showed the head roll-tilt until UL10, indicating the vestibular periphery damage. The rotarod performance worsened in the UL mice from UL1 to UL3, which rapidly recovered. Whole-brain 3D imaging revealed that the number of activated neurons in S1, but not in V1, in UL7 was higher than that in sham-treated mice. At UL7, medial prefrontal cortex (mPFC) and agranular insular cortex (AIC) activation was also observed. Therefore, sensory reweighting to the somatosensory system could compensate for vestibular dysfunction following UL; further, mPFC and AIC contribute to the integration of sensory and motor functions to restore balance.

    DOI: 10.1038/s41598-022-19678-4

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  • Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism Reviewed

    Yohko Yoshida, Ippei Shimizu, Atsuhiro Shimada, Keita Nakahara, Sachiko Yanagisawa, Minoru Kubo, Shinji Fukuda, Chiharu Ishii, Hiromitsu Yamamoto, Takamasa Ishikawa, Kuniyuki Kano, Junken Aoki, Goro Katsuumi, Masayoshi Suda, Kazuyuki Ozaki, Yutaka Yoshida, Shujiro Okuda, Shigeo Ohta, Shiki Okamoto, Yasuhiko Minokoshi, Kanako Oda, Toshikuni Sasaoka, Manabu Abe, Kenji Sakimura, Yoshiaki Kubota, Norihiko Yoshimura, Shingo Kajimura, Maria Zuriaga, Kenneth Walsh, Tomoyoshi Soga, Tohru Minamino

    Scientific Reports   12 ( 1 )   14883   2022.9

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    Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. Brown adipose tissue (BAT) was initially characterised as a thermogenic organ, and recent studies have suggested it plays a crucial role in maintaining systemic metabolic health. While these reports suggest a potential link between BAT and heart failure, the potential role of BAT dysfunction in heart failure has not been investigated. Here, we demonstrate that alteration of BAT function contributes to development of heart failure through disorientation in choline metabolism. Thoracic aortic constriction (TAC) or myocardial infarction (MI) reduced the thermogenic capacity of BAT in mice, leading to significant reduction of body temperature with cold exposure. BAT became hypoxic with TAC or MI, and hypoxic stress induced apoptosis of brown adipocytes. Enhancement of BAT function improved thermogenesis and cardiac function in TAC mice. Conversely, systolic function was impaired in a mouse model of genetic BAT dysfunction, in association with a low survival rate after TAC. Metabolomic analysis showed that reduced BAT thermogenesis was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. Genetic or pharmacological inhibition of flavin-containing monooxygenase reduced the plasma TMAO level in mice, and improved cardiac dysfunction in animals with left ventricular pressure overload. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next-generation therapies for heart failure.

    DOI: 10.1038/s41598-022-19245-x

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    Other Link: https://www.nature.com/articles/s41598-022-19245-x

  • Elucidating the role of neurotransmission via D1 and D2 dopamine receptors in the mechanisms of motor control, learning, and memory Reviewed

    Nae Saito, Makoto Itakura, Kazuki Tainaka, Tom Macpherson, Takatoshi Hikida, Shun Yamaguchi, Asako Sato, Tadashi Okubo, Satomi Chiken, Atsushi Nambu, Toshikuni Sasaoka

    Japanese Journal of Biological Psychiatry   33 ( 3 )   100 - 105   2022.9

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    DOI: 10.11249/jsbpjjpp.33.3_100

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  • 新潟大学における研究リスク管理 病原体等の適正管理のための取り組み

    三浦 詩織, 深見 克哉, 相馬 恵, 野水 和美, 中山 亮, 笹岡 俊邦, 神吉 智丈, 松本 壮吉, 末吉 邦

    新潟医学会雑誌   136 ( 4 )   117 - 126   2022.4

  • Mental construction of object symbols from meaningless elements by Japanese macaques (Macaca fuscata). Reviewed International journal

    Nanxi Liu, Atsuhiko Iijima, Yutaka Iwata, Kento Ohashi, Nobuyoshi Fujisawa, Toshikuni Sasaoka, Isao Hasegawa

    Scientific reports   12 ( 1 )   3566 - 3566   2022.3

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    When writing an object's name, humans mentally construct its spelling. This capacity critically depends on use of the dual-structured linguistic system, in which meaningful words are represented by combinations of meaningless letters. Here we search for the evolutionary origin of this capacity in primates by designing dual-structured bigram symbol systems where different combinations of meaningless elements represent different objects. Initially, we trained Japanese macaques (Macaca fuscata) in an object-bigram symbolization task and in a visually-guided bigram construction task. Subsequently, we conducted a probe test using a symbolic bigram construction task. From the initial trial of the probe test, the Japanese macaques could sequentially choose the two elements of a bigram that was not actually seen but signified by a visually presented object. Moreover, the animals' spontaneous choice order bias, developed through the visually-guided bigram construction learning, was immediately generalized to the symbolic bigram construction test. Learning of dual-structured symbols by the macaques possibly indicates pre-linguistic adaptations for the ability of mentally constructing symbols in the common ancestors of humans and Old World monkeys.

    DOI: 10.1038/s41598-022-07563-z

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  • D1 receptor mediated dopaminergic neurotransmission facilitates remote memory of contextual fear conditioning Reviewed International journal

    Nae Saito, Makoto Itakura, Toshikuni Sasaoka

    Frontiers in Behavioral Neuroscience   16   751053 - 751053   2022.2

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Dopaminergic neurotransmission via dopamine D1 receptors (D1Rs) is considered to play an important role not only in reward-based learning but also in aversive learning. The contextual and auditory cued fear conditioning tests involve the processing of classical fear conditioning and evaluates aversive learning memory. It is possible to evaluate aversive learning memory in two different types of neural transmission circuits. In addition, when evaluating the role of dopaminergic neurotransmission via D1R, to avoid the effects in D1R-mediated neural circuitry alterations during development, it is important to examine using mice who D1R expression in the mature stage is suppressed. Herein, we investigated the role of dopaminergic neurotransmission via D1Rs in aversive memory formation in contextual and auditory cued fear conditioning tests using D1R knockdown (KD) mice, in which the expression of D1Rs could be conditionally and reversibly controlled with doxycycline (Dox) treatment. For aversive memory, we examined memory formation using recent memory 1 day after conditioning, and remote memory 4 weeks after conditioning. Furthermore, immunostaining of the brain tissues of D1RKD mice was performed after aversive footshock stimulation to investigate the distribution of activated c-Fos, an immediate-early gene, in the hippocampus (CA1, CA3, dentate gyrus), striatum, amygdala, and prefrontal cortex during aversive memory formation. After aversive footshock stimulation, immunoblotting was performed using hippocampal, striatal, and amygdalar samples from D1RKD mice to investigate the increase in the amount of c-Fos and phosphorylated SNAP-25 at Ser187 residue. When D1R expression was suppressed using Dox, behavioral experiments revealed impaired contextual fear learning in remote aversion memory following footshock stimulation. Furthermore, expression analysis showed a slight increase in the post-stimulation amount of c-Fos in the hippocampus and striatum, and a significant increase in the amount of phosphorylated SNAP-25 in the hippocampus, striatum, and prefrontal cortex before and after stimulation. These findings indicate that deficiency in D1R-mediated dopaminergic neurotransmission is an important factor in impairing contextual fear memory formation for remote memory.

    DOI: 10.3389/fnbeh.2022.751053

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  • Importance of the Q/N-rich segment for protein stability and activity of endogenous mouse TDP-43 Reviewed

    Toshiya Sato, Kanako Oda, Seiko Sakai, Rika Kato, Saori Yamamori, Makoto Itakura, Yoshio Kodera, Masatoyo Nishizawa, Toshikuni Sasaoka, Osamu Onodera, Minesuke Yokoyama

    Scientific Reports   2022.2

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  • Neurexins in serotonergic neurons regulate serotonin transmission and complex mouse behaviors Reviewed

    Amy Cheung, Aya Matsui, Manabu Abe, Kenji Sakimura, Toshikuni Sasaoka, Takeshi Uemura, Yuka Imamura Kawasawa, Kensuke Futai

    bioRexiv   2022.2

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  • The dual role of dopamine in the modulation of information processing in the prefrontal cortex underlying social behavior Reviewed International journal

    Hidekazu Sotoyama, Hiroyoshi Inaba, Yuriko Iwakura, Hisaaki Namba, Nobuyuki Takei, Toshikuni Sasaoka, Hiroyuki Nawa

    The FASEB Journal   36 ( 2 )   e22160   2022.1

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    Dopamine in the prefrontal cortex is essential for the regulation of social behavior. However, stress-causing social withdrawal also promotes dopamine release in the prefrontal cortex. Thus, this evidence suggests opposite functions of dopamine in the prefrontal cortex. However, the influence of dopamine on prefrontal functions is yet to be fully understood. Here, we show that dopamine differentially modulated the neuronal activity triggered by social stimuli in the prefrontal cortex, depending on the duration of the dopamine activation (transient or sustained activation). Using chemogenetic techniques, we have found that social behavior was negatively regulated by a sustained increase in dopamine neuronal activity in the ventral tegmental area, while it was positively regulated by an acute increase. The duration of social interactions was positively correlated with the transient dopamine release triggered by social stimuli in the prefrontal cortex and negatively correlated with the sustained increase in prefrontal dopamine levels. Furthermore, the elevation of neural calcium signal, triggered by social stimuli, in the prefrontal cortex was attenuated by the persistent elevation of prefrontal dopamine levels, whereas an acute increase in dopamine levels enhanced it. Additionally, the chronic excess of dopamine suppressed c-Fos induction triggered by social stimuli in prefrontal neurons expressing dopamine D1 receptors, but not D2 receptors. These results suggest that sustained activation of prefrontal dopamine, at the opposite of its transient activation, can reduce prefrontal activity associated with social behavior, even for identical dopamine concentrations. Thus, dopamine plays opposite roles in modulating prefrontal activity depending on the duration of its action.

    DOI: 10.1096/fj.202101637R

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  • Establishment of a long-term survival swine model for observation of transplanted islets: A preliminary step in an allogeneic transplant experiment Reviewed International journal

    Miura K, Kobayashi T, Zhang Z, Prasoon P, Hirose Y, Ishikawa H, Takizawa K, Sakata J, Miura S, Sasaoka T, Wakai T

    Transplantation Proceedings   54 ( 2 )   507 - 512   2021.12

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    BACKGROUND: Evaluation of an experimental and preclinical islet transplantation (IsletTx) model to elucidate associated clinical problems is vital. This study aimed to introduce a simple methodology for producing a swine autologous IsletTx model as a preliminary step in an allogeneic transplant experiment. METHODS AND MATERIALS: Twenty-seven pigs were included in the study. Total pancreatectomy (TP) was performed in 8 pigs (TP group), TP with autologous IsletTx in 9 (TP + IsletTx group), and distal pancreatectomy (DP) with autologous IsletTx in 10 (DP + IsletTx group). An open biopsy was performed on all pigs during postoperative day 14 using an infrared imaging (IRI) system. Laboratory data and postoperative survival were analyzed and compared according to the procedures done. RESULTS: Postoperative survival rate was significantly higher in the pigs with autologous IsletTx than in those without (P = .026). There were no significant differences in survival between the TP + IsletTx and DP + IsletTx groups (P = .746). Significant hyperglycemia was not observed in both groups, but the DP + IsletTx group remained relatively stable throughout the postoperative course. There were no differences in serum creatinine, aspartate aminotransferase, and alanine aminotransferase levels between the 2 groups. By selective liver lobe transplantation and administration of the IRI system, localization of the transplanted islets via open biopsy was achieved. CONCLUSIONS: We successfully developed an autologous IsletTx model and an open biopsy system using a swine model. This study will aid in the development of an allogeneic IsletTx experiment that may improve transplantation outcomes.

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  • Dopamine D2 Long Receptors Are Critical for Caveolae-Mediated α-Synuclein Uptake in Cultured Dopaminergic Neurons. Reviewed International journal

    Ichiro Kawahata, Tomoki Sekimori, Haoyang Wang, Yanyan Wang, Toshikuni Sasaoka, Luc Bousset, Ronald Melki, Tomohiro Mizobata, Yasushi Kawata, Kohji Fukunaga

    Biomedicines   9 ( 1 )   2021.1

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    α-synuclein accumulation into dopaminergic neurons is a pathological hallmark of Parkinson's disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3) is critical for α-synuclein uptake and propagation to accumulate in dopaminergic neurons. FABP3 is abundant in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D2L). Here, we investigated the importance of dopamine D2L receptors in the uptake of α-synuclein monomers and their fibrils. We employed mesencephalic neurons derived from dopamine D2L
    -/-, dopamine D2 receptor null (D2 null), FABP3-/-, and wild type C57BL6 mice, and analyzed the uptake ability of fluorescence-conjugated α-synuclein monomers and fibrils. We found that D2L receptors are co-localized with FABP3. Immunocytochemistry revealed that TH+ D2L-/- or D2 null neurons do not take up α-synuclein monomers. The deletion of α-synuclein C-terminus completely abolished the uptake to dopamine neurons. Likewise, dynasore, a dynamin inhibitor, and caveolin-1 knockdown also abolished the uptake. D2L and FABP3 were also critical for α-synuclein fibrils uptake. D2L and accumulated α-synuclein fibrils were well co-localized. These data indicate that dopamine D2L with a caveola structure coupled with FABP3 is critical for α-synuclein uptake by dopaminergic neurons, suggesting a novel pathogenic mechanism of synucleinopathies, including Parkinson's disease.

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  • Tyrosine hydroxylase conditional KO mice reveal peripheral tissue-dependent differences in dopamine biosynthetic pathways Reviewed International journal

    Katsuya Miyajima, Chiaki Kawamoto, Satoshi Hara, Masayo Mori-Kojima, Tamae Ohye, Chiho Sumi-Ichinose, Nae Saito, Toshikuni Sasaoka, Daniel Metzger, Hiroshi Ichinose

    Journal of Biological Chemistry   296   100544 - 100544   2021.1

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    Dopamine (DA) exerts well-known functions in the brain as a neurotransmitter. In addition, it plays important physiological roles in peripheral organs, but it is largely unknown how and where peripheral DA is synthesized and regulated. Catecholamines in peripheral tissues are either produced within the tissue itself and/or derived from sympathetic neurons, which release neurotransmitters for uptake by peripheral tissues. To evaluate DA-producing ability of each peripheral tissue, we generated conditional KO mice (cKO mice) in which the tyrosine hydroxylase (TH) gene is ablated in the sympathoadrenal system, thus eliminating sympathetic neurons as a DA source. We then examined the alterations in the noradrenaline (NA), DA, and 3,4-dihydroxyphenylalanine (DOPA) contents in peripheral organs and performed immunohistochemical analyses of TH-expressing cells. In the heart and pancreas of cKO mice, both the TH protein and NA levels were significantly decreased, and the DA contents were decreased in parallel with NA contents, indicating that the DA supply originated from sympathetic neurons. We found TH-immunoreactive cells in the stomach and lung, where the TH protein showed a decreasing trend, but the DA levels were not decreased in cKO mice. Moreover, we found a significant correlation between the DA content in the kidney and the plasma DOPA concentration, suggesting that the kidney takes up DOPA from blood to make DA. The aforementioned data unravel differences in the DA biosynthetic pathway among tissues and support the role of sympathetic neurons as a DA supplier.

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  • Specific Neuroligin3-αNeurexin1 signaling regulates GABAergic synaptic function in mouse hippocampus. Reviewed International journal

    Motokazu Uchigashima, Kohtarou Konno, Emily Demchak, Amy Cheung, Takuya Watanabe, David G Keener, Manabu Abe, Timmy Le, Kenji Sakimura, Toshikuni Sasaoka, Takeshi Uemura, Yuka Imamura Kawasawa, Masahiko Watanabe, Kensuke Futai

    eLife   9   2020.12

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    Synapse formation and regulation require signaling interactions between pre- and postsynaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the functions of neuroligins (Nlgns), postsynaptic CAMs, rely on the formation of trans-synaptic complexes with neurexins (Nrxns), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated via Nrxn interactions is unknown. Here we demonstrate that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3-expressing (VGT3+) inhibitory terminals and regulates VGT3+ inhibitory interneuron-mediated synaptic transmission in mouse organotypic slice cultures. Gene expression analysis of interneurons revealed that the αNrxn1+AS4 splice isoform is highly expressed in VGT3+ interneurons as compared with other interneurons. Most importantly, postsynaptic Nlgn3 requires presynaptic αNrxn1+AS4 expressed in VGT3+ interneurons to regulate inhibitory synaptic transmission. Our results indicate that specific Nlgn-Nrxn signaling generates distinct functional properties at synapses.

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  • [Dopamine and NMDA Receptors in Basal Ganglia Circuits and Their Roles regarding Motor Control and Learning].

    Nae Saito, Toshikuni Sasaoka

    Brain and nerve = Shinkei kenkyu no shinpo   72 ( 11 )   1135 - 1142   2020.11

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    Dopamine (DA) plays an important role in the basal ganglia (BG) for motor control, and DA deficiency as seen in Parkinson's disease, causes movement disorders. DA activates the direct pathway nerve via the D1 receptor (D1R) and inhibits the indirect pathway nerve via the D2 receptor (D2R). To understand the role of DA signaling, we review recent studies of the roles of D1R and D2R with respect to motor control, neural activity and memory learning using genetically engineered mice, and investigate their involvement in the BG oscillation phenomenon.

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  • Cardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure. Reviewed International journal

    Toshihiro Yamaguchi, Tomokazu S Sumida, Seitaro Nomura, Masahiro Satoh, Tomoaki Higo, Masamichi Ito, Toshiyuki Ko, Kanna Fujita, Mary E Sweet, Atsushi Sanbe, Kenji Yoshimi, Ichiro Manabe, Toshikuni Sasaoka, Matthew R G Taylor, Haruhiro Toko, Eiki Takimoto, Atsuhiko T Naito, Issei Komuro

    Nature communications   11 ( 1 )   4364 - 4364   2020.8

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    Pathophysiological roles of cardiac dopamine system remain unknown. Here, we show the role of dopamine D1 receptor (D1R)-expressing cardiomyocytes (CMs) in triggering heart failure-associated ventricular arrhythmia. Comprehensive single-cell resolution analysis identifies the presence of D1R-expressing CMs in both heart failure model mice and in heart failure patients with sustained ventricular tachycardia. Overexpression of D1R in CMs disturbs normal calcium handling while CM-specific deletion of D1R ameliorates heart failure-associated ventricular arrhythmia. Thus, cardiac D1R has the potential to become a therapeutic target for preventing heart failure-associated ventricular arrhythmia.

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  • Dopamine D1 and muscarinic acetylcholine receptors in dorsal striatum are required for high speed running. Reviewed International journal

    Toru Nakamura, Luis Carl Rios, Takeshi Yagi, Toshikuni Sasaoka, Takashi Kitsukawa

    Neuroscience research   156   50 - 57   2020.7

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    Dopamine (DA) signaling in the basal ganglia plays important roles in motor control. Motor deficiencies were previously reported in dopamine receptor D1 (D1R) and D2 (D2R) knockout mice. While these results indicate the involvement of DA receptors in motor execution, the null knockout (KO) mouse lacks the specificity necessary to determine when and where in the brain D1R and D2R function in motor execution. To address these questions, we restricted the loss of function temporally and spatially by using D1R conditional knockdown (cKD) mice and mice injected with antagonists against DA receptors directly into the dorsal striatum. In addition, we address the DA and acetylcholine (ACh) balance hypothesis by using antagonists against ACh receptors. We tested the motor ability of the mice with a newly devised task named the accelerating step-wheel. In this task, the maximum running speed was measured in a situation where the wheel rotation speed was gradually accelerated in one trial. We found significant decreases in the maximum running speed of D1R cKD mice and the mice injected with the antagonist against D1R or muscarinic ACh receptor. These results indicated that D1R and muscarinic ACh receptor in the dorsal striatum play pivotal roles in the execution of walking/running.

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  • Generation of Lungs by Blastocyst Complementation in Apneumic Fgf10-Deficient Mice. Reviewed International journal

    Akihiko Kitahara, Qingsong Ran, Kanako Oda, Akihiro Yasue, Manabu Abe, Xulu Ye, Toshikuni Sasaoka, Masanori Tsuchida, Kenji Sakimura, Yoichi Ajioka, Yasuo Saijo, Qiliang Zhou

    Cell reports   31 ( 6 )   107626 - 107626   2020.5

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    The shortage of donor lungs hinders lung transplantation, the only definitive option for patients with end-stage lung disease. Blastocyst complementation enables the generation of transplantable organs from pluripotent stem cells (PSCs) in animal models. Pancreases and kidneys have been generated from PSCs by blastocyst complementation in rodent models. Here, we report the generation of lungs using mouse embryonic stem cells (ESCs) in apneumic Fgf10 Ex1mut/Ex3mutmice by blastocyst complementation. Complementation with ESCs enables Fgf10-deficient mice to survive to adulthood without abnormalities. Both the generated lung alveolar parenchyma and the interstitial portions, including vascular endothelial cells, vascular and parabronchial smooth muscle cells, and connective tissue, largely originate from the injected ESCs. These data suggest that Fgf10 Ex1mut/Ex3mutblastocysts provide an organ niche for lung generation and that blastocyst complementation could be a viable approach for generating whole lungs.

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  • Generation of Thyroid Tissues From Embryonic Stem Cells via Blastocyst Complementation In Vivo. Reviewed International journal

    Qingsong Ran, Qiliang Zhou, Kanako Oda, Akihiro Yasue, Manabu Abe, Xulu Ye, Yingchun Li, Toshikuni Sasaoka, Kenji Sakimura, Yoichi Ajioka, Yasuo Saijo

    Frontiers in endocrinology   11   609697 - 609697   2020

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    The generation of mature, functional, thyroid follicular cells from pluripotent stem cells would potentially provide a therapeutic benefit for patients with hypothyroidism, but in vitro differentiation remains difficult. We earlier reported the in vivo generation of lung organs via blastocyst complementation in fibroblast growth factor 10 (Fgf10), compound, heterozygous mutant (Fgf10 Ex1mut/Ex3mut) mice. Fgf10 also plays an essential role in thyroid development and branching morphogenesis, but any role thereof in thyroid organogenesis remains unclear. Here, we report that the thyroids of Fgf10 Ex1mut/Ex3mut mice exhibit severe hypoplasia, and we generate thyroid tissues from mouse embryonic stem cells (ESCs) in Fgf10 Ex1mut/Ex3mut mice via blastocyst complementation. The tissues were morphologically normal and physiologically functional. The thyroid follicular cells of Fgf10 Ex1mut/Ex3mut chimeric mice were derived largely from GFP-positive mouse ESCs although the recipient cells were mixed. Thyroid generation in vivo via blastocyst complementation will aid functional thyroid regeneration.

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  • Crucial Role of Dopamine D2 Receptor Signaling in Nicotine-Induced Conditioned Place Preference. Reviewed International journal

    Gofarana Wilar, Yasuharu Shinoda, Toshikuni Sasaoka, Kohji Fukunaga

    Molecular neurobiology   56 ( 12 )   7911 - 7928   2019.12

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    Nicotine in tobacco causes psychological dependence through its rewarding effect in the central nervous system (CNS). Although nicotine dependence is explained by dopamine receptor (DR) signaling together with nicotinic acetylcholine receptors (nAChRs), the synaptic molecular mechanism underlying the interaction between dopamine receptor and nAChRs remains unclear. Since reward signaling is mediated by dopamine receptors, we hypothesized that the dopamine D2 receptor (D2R), in part, mediates the synaptic modulation of nicotine-induced conditioned place preference (CPP) in addition to dopamine D1 receptor. To investigate the involvement of D2R, wild-type (WT) and dopamine D2 receptor knockout (D2RKO) mice were assessed using the CPP task after induction of nicotine-induced CPP. As expected, D2RKO mice failed to induce CPP behaviors after repeated nicotine administration (0.5 mg/kg). When kinase signaling was assessed in the nucleus accumbens and hippocampal CA1 region after repeated nicotine administration, both Ca2+/calmodulin-dependent protein kinase (CaMKII) and extracellular signal-regulated kinase (ERK) were upregulated in WT mice but not in D2RKO mice. Likewise, nicotine-induced CPP was associated with elevation of pro- brain-derived neurotropic factor (BDNF) and BDNF protein levels in WT mice, but not in D2RKO mice. Taken together, in addition to dopamine D1 receptor signaling, dopamine D2 receptor signaling is critical for induction of nicotine-induced CPP in mice.

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    Other Link: http://link.springer.com/article/10.1007/s12035-019-1635-x/fulltext.html

  • Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42. Reviewed International journal

    Shunta Hashiguchi, Hiroshi Doi, Misako Kunii, Yukihiro Nakamura, Misa Shimuta, Etsuko Suzuki, Shigeru Koyano, Masaki Okubo, Hitaru Kishida, Masaaki Shiina, Kazuhiro Ogata, Fumiko Hirashima, Yukichi Inoue, Shun Kubota, Noriko Hayashi, Haruko Nakamura, Keita Takahashi, Atsuko Katsumoto, Mikiko Tada, Kenichi Tanaka, Toshikuni Sasaoka, Satoko Miyatake, Noriko Miyake, Hirotomo Saitsu, Nozomu Sato, Kokoro Ozaki, Kiyobumi Ohta, Takanori Yokota, Hidehiro Mizusawa, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Shinichi Morishita, Shoji Tsuji, Hideyuki Takeuchi, Kinya Ishikawa, Naomichi Matsumoto, Taro Ishikawa, Fumiaki Tanaka

    Neurobiology of disease   130   104516 - 104516   2019.10

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    Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

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  • Dopamine D2L Receptor Deficiency Causes Stress Vulnerability through 5-HT1A Receptor Dysfunction in Serotonergic Neurons. Reviewed International journal

    Norifumi Shioda, Yoshiki Imai, Yasushi Yabuki, Wataru Sugimoto, Kouya Yamaguchi, Yanyan Wang, Takatoshi Hikida, Toshikuni Sasaoka, Michihiro Mieda, Kohji Fukunaga

    The Journal of neuroscience : the official journal of the Society for Neuroscience   39 ( 38 )   7551 - 7563   2019.9

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    Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin [5-hydroxytryptamine (5-HT)] 1A receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knock-out (KO) male mice compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT efflux in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was upregulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR-activated G-protein-activated inwardly rectifying potassium conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.SIGNIFICANCE STATEMENT Etiologies of mental disorders are multifactorial, e.g., interactions between genetic and environmental factors. In this study, using a mouse model, we showed that genetic depletion of an isoform of dopamine D2 receptor, D2LR, causes stress vulnerability associated with dysfunction of serotonin 1A receptor, 5-HT1AR in serotonergic neurons. The D2LR/5-HT1AR inhibitory G-protein-coupled heteromer may function as a negative feedback regulator to suppress psychosocial stress.

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  • Chemical Landscape for Tissue Clearing based on Hydrophilic Reagents Reviewed International journal

    Kazuki Tainaka, Tatsuya C. Murakam, Etsuo A. Susaki, Chika Shimizu, Rie Saito, Kei Takahashi, Akiko Hayashi-Takagi, Hiroshi Sekiya, Yasunobu Arima, Satoshi Nojima, Masako Ikemura, Tetsuo Ushiku, Yoshihiro Shimizu, Masaaki Murakami, Kenji F. Tanaka, Masamitsu Iino, Haruo Kasai, Toshikuni Sasaoka, Kazuto Kobayashi, Kohei Miyazono, Eiichi Morii, Tadashi Isa, Masashi Fukayama, Akiyoshi Kakita, Hiroki R. Ueda

    Cell Reports   24 ( 8 )   2196 - 2210   2018.8

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  • 胚盤胞補完法を利用したマウスES細胞による肺再生

    北原 哲彦, 周 啓亮, 冉 慶松, 叶 許緑, 小田 佳奈子, 笹岡 俊邦, 阿部 学, 崎村 建司, 味岡 洋一, 泰江 章博, 土田 正則, 西條 康夫

    日本外科学会定期学術集会抄録集   118回   1340 - 1340   2018.4

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  • D1/D2ドーパミン受容体コンディショナル発現マウスによる運動制御機構の解明

    笹岡 俊邦, 佐藤 朝子, 知見 聡美, 大久保 直, 阿部 学, 川村 名子, 中尾 聡宏, 齊藤 奈英, 酒井 清子, 小田 佳奈子, 前田 宜俊, 神保 幸弘, 田中 稔, 山本 美丘, 佐藤 俊哉, 藤澤 信義, 崎村 建司, 南部 篤

    生命科学系学会合同年次大会   2017年度   [4LT08 - 1195)]   2017.12

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  • Cleavage of β-dystroglycan occurs in sarcoglycan-deficient skeletal muscle without MMP-2 and MMP-9. Reviewed International journal

    Yuta Fukai, Yutaka Ohsawa, Hideaki Ohtsubo, Shin-Ichiro Nishimatsu, Hiroki Hagiwara, Makoto Noda, Toshikuni Sasaoka, Tatsufumi Murakami, Yoshihide Sunada

    Biochemical and biophysical research communications   492 ( 2 )   199 - 205   2017.10

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  • Redundancy of matrix metalloproteinases cleaving beta-dystroglycan: Implications for the pathogenesis of sarcoglycanopathy Reviewed

    Yuta Fukai, Yutaka Ohsawa, Hideaki Ohtsubo, Shin-ichiro Nishimatsu, Hiroki Hagiwara, Makoto Noda, Toshikuni Sasaoka, Tatsufumi Murakami, Yoshihide Sunada

    Biochem. Biophys. Res. Comm.   492 ( 2 )   199 - 205   2017.8

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  • Endocytosis following dopamine D-2 receptor activation is critical for neuronal activity and dendritic spine formation via Rabex-5/PDGFR beta signaling in striatopallidal medium spiny neurons Reviewed

    N. Shioda, Y. Yabuki, Y. Wang, M. Uchigashima, T. Hikida, T. Sasaoka, H. Mori, M. Watanabe, M. Sasahara, K. Fukunaga

    MOLECULAR PSYCHIATRY   22 ( 8 )   1205 - 1222   2017.8

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  • Striatal hypodopamine phenotypes found in transgenic mice that overexpress glial cell line-derived neurotrophic factor. Reviewed International journal

    Hidekazu Sotoyama, Yuriko Iwakura, Kanako Oda, Toshikuni Sasaoka, Nobuyuki Takei, Akiyoshi Kakita, Hideki Enomoto, Hiroyuki Nawa

    Neuroscience letters   654   99 - 106   2017.7

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  • BRAG2a, a Guanine Nucleotide Exchange Factor for Arf6, Is a Component of the Dystrophin-Associated Glycoprotein Complex at the Photoreceptor Terminal. Reviewed International journal

    Hiroyuki Sakagami, Osamu Katsumata, Yoshinobu Hara, Toshikuni Sasaoka, Masahiro Fukaya

    Investigative ophthalmology & visual science   58 ( 9 )   3795 - 3803   2017.7

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  • Leucine-rich repeat kinase 2 (LRRK2) regulates α-synuclein clearance in microglia. Reviewed International journal

    Tatsunori Maekawa, Toshikuni Sasaoka, Sadahiro Azuma, Takafumi Ichikawa, Heather L Melrose, Matthew J Farrer, Fumiya Obata

    BMC neuroscience   17 ( 1 )   77 - 77   2016.11

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  • Dopamine D2L Receptor Is Required for Visual Discrimination and Reversal Learning. Reviewed International journal

    Makiko Morita, Yanyan Wang, Toshikuni Sasaoka, Kinya Okada, Minae Niwa, Akira Sawa, Takatoshi Hikida

    Molecular neuropsychiatry   2 ( 3 )   124 - 132   2016.10

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    The corticostriatothalamic circuit regulates learning behaviors via dopamine neurotransmission. D2 long (D2L) receptors are an isoform of dopamine D2 receptors (D2Rs) and may act mainly at postsynaptic sites. It is well known that D2Rs influence high brain functions, but the roles of individual D2R isoforms are still unclear. To assess the influence of D2L receptors in visual discrimination learning, we performed visual discrimination and reversal tasks with D2L knockout mice using a touchscreen operant system. There were no significant differences in an operant conditioning task between genotypes. However, D2L knockout mice were impaired in both visual discrimination and reversal learning tasks. D2L knockout mice were also significantly slower than wild-type mice in collecting the reward in the visual discrimination task. These results indicate that D2L receptors play an important role in visual discrimination and reversal learning.

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  • Nucleus accumbens dopamine D2-receptor expressing neurons control behavioral flexibility in a place discrimination task in the IntelliCage. Reviewed International journal

    Tom Macpherson, Makiko Morita, Yanyan Wang, Toshikuni Sasaoka, Akira Sawa, Takatoshi Hikida

    Learning & memory (Cold Spring Harbor, N.Y.)   23 ( 7 )   359 - 64   2016.7

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    Considerable evidence has demonstrated a critical role for the nucleus accumbens (NAc) in the acquisition and flexibility of behavioral strategies. These processes are guided by the activity of two discrete neuron types, dopamine D1- or D2-receptor expressing medium spiny neurons (D1-/D2-MSNs). Here we used the IntelliCage, an automated group-housing experimental cage apparatus, in combination with a reversible neurotransmission blocking technique to examine the role of NAc D1- and D2-MSNs in the acquisition and reversal learning of a place discrimination task. We demonstrated that NAc D1- and D2-MSNs do not mediate the acquisition of the task, but that suppression of activity in D2-MSNs impairs reversal learning and increased perseverative errors. Additionally, global knockout of the dopamine D2L receptor isoform produced a similar behavioral phenotype to D2-MSN-blocked mice. These results suggest that D2L receptors and NAc D2-MSNs act to suppress the influence of previously correct behavioral strategies allowing transfer of behavioral control to new strategies.

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  • Leucine-rich repeat kinase 2 is a regulator of B cell function, affecting homeostasis, BCR signaling, IgA production, and TI antigen responses. Reviewed International journal

    Makoto Kubo, Ryuichi Nagashima, Etsuro Ohta, Tatsunori Maekawa, Yumiko Isobe, Mitsue Kurihara, Koji Eshima, Kazuya Iwabuchi, Toshikuni Sasaoka, Sadahiro Azuma, Heather L Melrose, Matthew J Farrer, Fumiya Obata

    Journal of neuroimmunology   292   1 - 8   2016.3

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  • D1ドーパミン受容体を介するシグナルによる運動量の維持

    笹岡 俊邦, 佐藤 朝子, 知見 聡美, 大久保 直, 前島 純, 新井 慧, 砂山 智子[森田], 小田 佳奈子, 酒井 清子, 前田 宜俊, 神保 幸弘, 馬川 恵梨子, 佐藤 俊哉, 藤澤 信義, 横山 峯介, 南部 篤

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [3P1337] - [3P1337]   2015.12

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  • Erratum: G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy. Reviewed International journal

    Nozomi Hayashiji, Shinsuke Yuasa, Yuko Miyagoe-Suzuki, Mie Hara, Naoki Ito, Hisayuki Hashimoto, Dai Kusumoto, Tomohisa Seki, Shugo Tohyama, Masaki Kodaira, Akira Kunitomi, Shin Kashimura, Makoto Takei, Yuki Saito, Shinichiro Okata, Toru Egashira, Jin Endo, Toshikuni Sasaoka, Shin'ichi Takeda, Keiichi Fukuda

    Nature communications   6   7295 - 7295   2015.6

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  • 【精神疾患動物モデルの可能性と課題】統合失調症モデルマウスの行動解析方法の試み

    笹岡 俊邦, 佐藤 朝子, 中村 徹, 大久保 直, 佐藤 俊哉, 藤澤 信義, 前田 宜俊, 小田 佳奈子, 酒井 清子, 神保 幸弘, 馬川 恵梨子, 木津川 尚史, 籾山 俊彦, 山森 哲雄

    日本生物学的精神医学会誌   26 ( 2 )   87 - 94   2015.6

  • G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy. Reviewed International journal

    Nozomi Hayashiji, Shinsuke Yuasa, Yuko Miyagoe-Suzuki, Mie Hara, Naoki Ito, Hisayuki Hashimoto, Dai Kusumoto, Tomohisa Seki, Shugo Tohyama, Masaki Kodaira, Akira Kunitomi, Shin Kashimura, Makoto Takei, Yuki Saito, Shinichiro Okata, Toru Egashira, Jin Endo, Toshikuni Sasaoka, Shin'ichi Takeda, Keiichi Fukuda

    Nature communications   6   6745 - 6745   2015.4

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  • Expression pattern of immediate early genes in the cerebellum of D1R KO, D2R KO, and wild type mice under vestibular-controlled activity. Reviewed International journal

    Toru Nakamura, Asako Sato, Takashi Kitsukawa, Toshikuni Sasaoka, Tetsuo Yamamori

    Frontiers in cell and developmental biology   3   38 - 38   2015

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    We previously reported the different motor abilities of D1R knockout (KO), D2R KO and wild-type (WT) mice. To understand the interaction between the cerebellum and the striatal direct and indirect pathways, we examined the expression patterns of immediate early genes (IEG) in the cerebellum of these three genotypes of mice. In the WT naive mice, there was little IEG expression. However, we observed a robust expression of c-fos mRNA in the vermis and hemisphere after running rota-rod tasks. In the vermis, c-fos was expressed throughout the lobules except lobule 7, and also in crus 1 of the ansiform lobule (Crus1), copula of the pyramis (Cop) and most significantly in the flocculus in the hemisphere. jun-B was much less expressed but more preferentially expressed in Purkinje cells. In addition, we observed significant levels of c-fos and jun-B expressions after handling mice, and after the stationary rota-rod task in naive mice. Surprisingly, we observed significant expression of c-fos and jun-B even 30 min after single weighing. Nonetheless, certain additional c-fos and jun-B expressions were observed in three genotypes of the mice that experienced several sessions of motor tasks 24 h after stationary rota-rod task and on days 1 and 5 after rota-rod tasks, but no significant differences in expressions after the running rota-rod tasks were observed among the three genotypes. In addition, there may be some differences 24 h after the stationary rota-rod task between the naive mice and the mice that experienced several sessions of motor tasks.

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  • Enhanced stability of hippocampal place representation caused by reduced magnesium block of NMDA receptors in the dentate gyrus. Reviewed International journal

    Yuichiro Hayashi, Yoko Nabeshima, Katsunori Kobayashi, Tsuyoshi Miyakawa, Koichi Tanda, Keizo Takao, Hidenori Suzuki, Eisaku Esumi, Shigeru Noguchi, Yukiko Matsuda, Toshikuni Sasaoka, Tetsuo Noda, Jun-ichi Miyazaki, Masayoshi Mishina, Kazuo Funabiki, Yo-ichi Nabeshima

    Molecular brain   7 ( 1 )   44 - 44   2014.6

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  • GABAergic synaptic transmission onto striatal cholinergic interneurons in dopamine D2 receptor knock-out mice

    A. Sato, T. Sasaoka, T. Nishijo, T. Momiyama

    Neuroscience   263   138 - 147   2014.3

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    DOI: 10.1016/j.neuroscience.2014.01.010

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  • Lack of dopaminergic inputs elongates the primary cilia of striatal neurons. International journal

    Ko Miyoshi, Kyosuke Kasahara, Shinki Murakami, Mika Takeshima, Natsuko Kumamoto, Asako Sato, Ikuko Miyazaki, Shinsuke Matsuzaki, Toshikuni Sasaoka, Taiichi Katayama, Masato Asanuma

    PloS one   9 ( 5 )   e97918 - e97918   2014

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  • PTB Deficiency Causes the Loss of Adherens Junctions in the Dorsal Telencephalon and Leads to Lethal Hydrocephalus Reviewed

    Takayuki Shibasaki, Akinori Tokunaga, Reiko Sakamoto, Hiroshi Sagara, Shigeru Noguchi, Toshikuni Sasaoka, Nobuaki Yoshida

    CEREBRAL CORTEX   23 ( 8 )   1824 - 1835   2013.8

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  • PTB deficiency causes the loss of adherens junctions in the dorsal telencephalon and leads to lethal hydrocephalus. International journal

    Takayuki Shibasaki, Akinori Tokunaga, Reiko Sakamoto, Hiroshi Sagara, Shigeru Noguchi, Toshikuni Sasaoka, Nobuaki Yoshida

    Cerebral cortex (New York, N.Y. : 1991)   23 ( 8 )   1824 - 35   2013.8

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  • Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors. International journal

    Takatoshi Hikida, Satoshi Yawata, Takashi Yamaguchi, Teruko Danjo, Toshikuni Sasaoka, Yanyan Wang, Shigetada Nakanishi

    Proceedings of the National Academy of Sciences of the United States of America   110 ( 1 )   342 - 7   2013.1

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    DOI: 10.1073/pnas.1220358110

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  • Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors. Reviewed

    Hikida T, Yawata S, Yamaguchi T, Danjo T, Sasaoka T, Wang Y, Nakanishi S

    Proceedings of the National Academy of Sciences of the United States of America   110   342 - 347   2013.1

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  • A molecular genetic approach to uncovering the differential functions of dopamine D2 receptor isoforms. International journal

    Yanyan Wang, Toshikuni Sasaoka, Mai T Dang

    Methods in molecular biology (Clifton, N.J.)   964   181 - 200   2013

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    Alterations in the activity of the dopamine D2 receptor (D2R) have been implicated in several neurological and psychiatric disorders, including schizophrenia, Parkinson's disease, Huntington's disease, Tourette syndrome, attention-deficit hyperactivity disorder (ADHD), and drug addiction. Two isoforms of D2R, long form (D2LR) and short form (D2SR), have been identified. The specific function of each D2R isoform is poorly understood, primarily because isoform-selective pharmacological agents are not available. Using homologous recombination, we have generated D2LR knockout (KO) mice. D2LR KO mice are completely deficient in D2LR, but still express functional D2SR at a level similar to the total D2R level in wild-type (WT) mice. D2LR is generally the predominant isoform expressed in WT mice. We showed that D2LR KO mice displayed a number of robust behavioral phenotypes distinct from WT mice, indicating that D2LR and D2SR have differential functions. In this chapter we describe the generation and characterization of the D2LR KO mouse. This genetic approach provides a valuable research tool to investigate the functional role of individual D2R isoforms in the mammalian central nervous system (CNS).

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  • A molecular genetic approach to uncovering the differential functions of dopamine D2 receptor isoforms Reviewed

    Yanyan Wang, Toshikuni Sasaoka, Mai T. Dang

    Methods in Molecular Biology   964   181 - 200   2013

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    DOI: 10.1007/978-1-62703-251-3_11

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  • PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders. International journal

    Lily Paemka, Vinit B Mahajan, Jessica M Skeie, Levi P Sowers, Salleh N Ehaideb, Pedro Gonzalez-Alegre, Toshikuni Sasaoka, Hirotaka Tao, Asuka Miyagi, Naoto Ueno, Keizo Takao, Tsuyoshi Miyakawa, Shu Wu, Benjamin W Darbro, Polly J Ferguson, Andrew A Pieper, Jeremiah K Britt, John A Wemmie, Danielle S Rudd, Thomas Wassink, Hatem El-Shanti, Heather C Mefford, Gemma L Carvill, J Robert Manak, Alexander G Bassuk

    PloS one   8 ( 12 )   e80737 - e80737   2013

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  • Classification of various muscular tissues using miRNA profiling.

    Kosuke Endo, Huachun Weng, Yukiko Naito, Toshikuni Sasaoka, Akio Takahashi, Yasue Fukushima, Naoharu Iwai

    Biomedical research (Tokyo, Japan)   34 ( 6 )   289 - 99   2013

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  • Oxidative stress in neurodegenerative diseases: friend and foe. International journal

    Toshikuni Sasaoka

    Clinical and experimental pharmacology & physiology   39 ( 7 )   597 - 8   2012.7

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    DOI: 10.1111/j.1440-1681.2012.05723.x

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  • Methyl CpG-binding protein isoform MeCP2_e2 is dispensable for Rett syndrome phenotypes but essential for embryo viability and placenta development. International journal

    Masayuki Itoh, Candice G T Tahimic, Shuhei Ide, Akihiro Otsuki, Toshikuni Sasaoka, Shigeru Noguchi, Mitsuo Oshimura, Yu-ichi Goto, Akihiro Kurimasa

    The Journal of biological chemistry   287 ( 17 )   13859 - 67   2012.4

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  • Abnormal epithelial cell polarity and ectopic Epidermal Growth Factor Receptor (EGFR) expression induced in Emx2 KO Embryonic Gonads Reviewed

    Masatomo Kusaka, Yuko Katoh-Fukui, Hidesato Ogawa, Kanako Miyabayashi, Takashi Baba, Yuichi Shima, Noriyuki Sugiyama, Yukihiko Sugimoto, Yasushi Okuno, Ryuji Kodama, Akiko Iizuka-Kogo, Takao Senda, Toshikuni Sasaoka, Kunio Kitamura, Shinichi Aizawa, Ken-Ichirou Morohashi

    Endocrinology   151 ( 12 )   5893 - 5904   2010.12

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    DOI: 10.1210/en.2010-0915

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  • Abnormal epithelial cell polarity and ectopic epidermal growth factor receptor (EGFR) expression induced in Emx2 KO embryonic gonads. International journal

    Masatomo Kusaka, Yuko Katoh-Fukui, Hidesato Ogawa, Kanako Miyabayashi, Takashi Baba, Yuichi Shima, Noriyuki Sugiyama, Yukihiko Sugimoto, Yasushi Okuno, Ryuji Kodama, Akiko Iizuka-Kogo, Takao Senda, Toshikuni Sasaoka, Kunio Kitamura, Shinichi Aizawa, Ken-ichirou Morohashi

    Endocrinology   151 ( 12 )   5893 - 904   2010.12

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    The gonadal primordium first emerges as a thickening of the embryonic coelomic epithelium, which has been thought to migrate mediodorsally to form the primitive gonad. However, the early gonadal development remains poorly understood. Mice lacking the paired-like homeobox gene Emx2 display gonadal dysgenesis. Interestingly, the knockout (KO) embryonic gonads develop an unusual surface accompanied by aberrant tight junction assembly. Morphological and in vitro cell fate mapping studies showed an apparent decrease in the number of the gonadal epithelial cells migrated to mesenchymal compartment in the KO, suggesting that polarized cell division and subsequent cell migration are affected. Microarray analyses of the epithelial cells revealed significant up-regulation of Egfr in the KO, indicating that Emx2 suppresses Egfr gene expression. This genetic correlation between the two genes was reproduced with cultured M15 cells derived from mesonephric epithelial cells. Epidermal growth factor receptor signaling was recently shown to regulate tight junction assembly through sarcoma viral oncogene homolog tyrosine phosphorylation. We show through Emx2 KO analyses that sarcoma viral oncogene homolog tyrosine phosphorylation, epidermal growth factor receptor tyrosine phosphorylation, and Egfr expression are up-regulated in the embryonic gonad. Our results strongly suggest that Emx2 is required for regulation of tight junction assembly and allowing migration of the gonadal epithelia to the mesenchyme, which are possibly mediated by suppression of Egfr expression.

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  • Mouse prickle1, the homolog of a PCP gene, is essential for epiblast apical-basal polarity. International journal

    Hirotaka Tao, Makoto Suzuki, Hiroshi Kiyonari, Takaya Abe, Toshikuni Sasaoka, Naoto Ueno

    Proceedings of the National Academy of Sciences of the United States of America   106 ( 34 )   14426 - 31   2009.8

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    DOI: 10.1073/pnas.0901332106

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  • Mouse prickle1, the homolog of a PCP gene, is essential for epiblast apical-basal polarity Reviewed

    Hirotaka Tao, Makoto Suzuki, Hiroshi Kiyonari, Takaya Abe, Toshikuni Sasaoka, Naoto Ueno

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   106 ( 34 )   14426 - 14431   2009.8

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  • Ras signaling directs endothelial specification of VEGFR2+ vascular progenitor cells. International journal

    Kyoko Kawasaki, Tetsuro Watabe, Hitoshi Sase, Masanori Hirashima, Hiroshi Koide, Yasuyuki Morishita, Keiko Yuki, Toshikuni Sasaoka, Toshio Suda, Motoya Katsuki, Kohei Miyazono, Keiji Miyazawa

    The Journal of cell biology   181 ( 1 )   131 - 41   2008.4

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    Vascular endothelial growth factor receptor 2 (VEGFR2) transmits signals of crucial importance to vasculogenesis, including proliferation, migration, and differentiation of vascular progenitor cells. Embryonic stem cell-derived VEGFR2(+) mesodermal cells differentiate into mural lineage in the presence of platelet derived growth factor (PDGF)-BB or serum but into endothelial lineage in response to VEGF-A. We found that inhibition of H-Ras function by a farnesyltransferase inhibitor or a knockdown technique results in selective suppression of VEGF-A-induced endothelial specification. Experiments with ex vivo whole-embryo culture as well as analysis of H-ras(-/-) mice also supported this conclusion. Furthermore, expression of a constitutively active H-Ras[G12V] in VEGFR2(+) progenitor cells resulted in endothelial differentiation through the extracellular signal-related kinase (Erk) pathway. Both VEGF-A and PDGF-BB activated Ras in VEGFR2(+) progenitor cells 5 min after treatment. However, VEGF-A, but not PDGF-BB, activated Ras 6-9 h after treatment, preceding the induction of endothelial markers. VEGF-A thus activates temporally distinct Ras-Erk signaling to direct endothelial specification of VEGFR2(+) vascular progenitor cells.

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  • Ras signaling directs endothelial specification of VEGFR2(+) vascular progenitor cells Reviewed

    Kyoko Kawasaki, Tetsuro Watabe, Hitoshi Sase, Masanori Hirashima, Hiroshi Koide, Yasuyuki Morishita, Keiko Yuki, Toshikuni Sasaoka, Toshio Suda, Motoya Katsuki, Kohei Miyazono, Keiji Miyazawa

    JOURNAL OF CELL BIOLOGY   181 ( 1 )   131 - 141   2008.4

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  • D1/D2ドーパミン受容体二重欠損マウスを用いた運動制御機構の解明

    笹岡 俊邦, 佐藤 朝子, 荒川 聡子[小林], 森田 智子, 勝木 邦子, 勝木 元也

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   80回・30回   3T14 - 5   2007.11

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  • Platelet-derived growth factor (PDGF)-BB inhibits AMPA receptor-mediated synaptic transmission via PDGF receptor-beta in murine nucleus tractus solitarius. International journal

    Yoshiaki Ohi, Yoko Ishii, Akira Haji, Shigeru Noguchi, Toshikuni Sasaoka, Toshihiko Fujimori, Yo-ichi Nabeshima, Masakiyo Sasahara, Yuichi Hattori

    Brain research   1159   77 - 85   2007.7

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    Although platelet-derived growth factor (PDGF)-BB activates PDGF receptor-beta (PDGFR-beta) and, in turn, inhibits the glutamate N-methyl-D-aspartate (NMDA) receptor function, whether PDGF-BB modulates the CNS function mediated by another glutamate receptors, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, remains poorly understood. Here we now report the inhibitory effect of PDGF-BB on the AMPA receptor function in the nucleus tractus solitarius (NTS) by using slice patch-clamp techniques. Excitatory postsynaptic currents (EPSCs) were evoked by electrical stimulation of the tractus solitarius in mouse NTS second-order neurons. EPSCs were nearly completely eliminated by CNQX but not by MK-801, implying mediation through non-NMDA receptors. PDGF-BB significantly decreased the amplitude of EPSCs without affecting the mean decay time constant. This inhibitory effect was transient and reversible after removing PDGF-BB. Furthermore, PDGF-BB significantly reduced the amplitude of AMPA-induced currents in NTS neurons, which showed that PDGF-BB could suppress the AMPA receptor-mediated excitatory input via the postsynaptic mechanism. The inhibitory effect of PDGF-BB on EPSCs was not observed in mutant mice with conditional deletion of the PDGFR-beta gene in neurons. Together, these studies suggest that the PDGF-B/PDGFR-beta axis inhibits the AMPA receptor-mediated synaptic transmission that comprises the major part of the primary afferent to the NTS second-order neuron. The detected inhibitory action may be involved in the CNS regulation of the respiratory response.

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  • Cys669-Cys713 disulfide bridge formation is a key to dystroglycan cleavage and subunit association. International journal

    Noriyuki Watanabe, Toshikuni Sasaoka, Satoru Noguchi, Ichizo Nishino, Torahiko Tanaka

    Genes to cells : devoted to molecular & cellular mechanisms   12 ( 1 )   75 - 88   2007.1

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  • Caveolin-3 deficiency decreases the gene expression level of osteopontin in mdx mouse skeletal muscle

    Yasuko Hagiwara, M. Fujita, M. Imamura, S. Noguchi, T. Sasaoka

    Acta Myologica   25 ( 2 )   53 - 61   2006.10

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  • Mouse brains deficient in neuronal PDGF receptor-beta develop normally but are vulnerable to injury. International journal

    Yoko Ishii, Takeshi Oya, Lianshun Zheng, Zhiyang Gao, Makoto Kawaguchi, Hemragul Sabit, Takako Matsushima, Ayano Tokunaga, Shin Ishizawa, Etsuro Hori, Yo-ichi Nabeshima, Toshikuni Sasaoka, Toshihiko Fujimori, Hisashi Mori, Masakiyo Sasahara

    Journal of neurochemistry   98 ( 2 )   588 - 600   2006.7

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    Platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) are widely expressed in the mammalian CNS, though their functional significance remains unclear. The corresponding null-knockout mutations are lethal. Here, we developed novel mutant mice in which the gene encoding the beta subunit of PDGFR (PDGFR-beta) was genetically deleted in CNS neurons to elucidate the role of PDGFR-beta, particularly in the post-natal stage. Our mutant mice reached adulthood without apparent anatomical defects. In the mutant brain, immunohistochemical analyses showed that PDGFR-beta detected in neurons and in the cells in the subventricular zone of the lateral ventricle in wild-type mice was depleted, but PDGFR-beta detected in blood vessels remained unaffected. The cerebral damage after cryogenic injury was severely exacerbated in the mutants compared with controls. Furthermore, TdT-mediated dUTP-biotin nick end labeling (TUNEL)-positive neuronal cell death and lesion formation in the cerebral hemisphere were extensively exacerbated in our mutant mice after direct injection of NMDA without altered NMDA receptor expression. Our results clearly demonstrate that PDGFR-beta expressed in neurons protects them from cryogenic injury and NMDA-induced excitotoxicity.

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  • Inactivation of aPKClambda results in the loss of adherens junctions in neuroepithelial cells without affecting neurogenesis in mouse neocortex. International journal

    Fumiyasu Imai, Syu-ichi Hirai, Kazunori Akimoto, Hiromichi Koyama, Takaki Miyata, Masaharu Ogawa, Shigeru Noguchi, Toshikuni Sasaoka, Tetsuo Noda, Shigeo Ohno

    Development (Cambridge, England)   133 ( 9 )   1735 - 44   2006.5

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  • Molecular and cell biology of the sarcoglycan complex. International journal

    Eijiro Ozawa, Yuji Mizuno, Yasuko Hagiwara, Toshikuni Sasaoka, Mikiharu Yoshida

    Muscle & nerve   32 ( 5 )   563 - 76   2005.11

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  • Beta-synemin localizes to regions of high stress in human skeletal myofibers. International journal

    Yuji Mizuno, Jeffrey R Guyon, Simon C Watkins, Kazuyuki Mizushima, Toshikuni Sasaoka, Michihiro Imamura, Louis M Kunkel, Koichi Okamoto

    Muscle & nerve   30 ( 3 )   337 - 46   2004.9

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  • [Recombinant antibodies: basics and application to medicine].

    Torahiko Tanaka, Toshikuni Sasaoka

    Seikagaku. The Journal of Japanese Biochemical Society   75 ( 12 )   1551 - 5   2003.12

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  • Delivery of alpha- and beta-sarcoglycan by recombinant adeno-associated virus: Efficient rescue of muscle, but differential toxicity

    D Dressman, K Araishi, M Imamura, T Sasaoka, LA Liu, E Engvall, EP Hoffman

    HUMAN GENE THERAPY   13 ( 13 )   1631 - 1646   2002.9

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  • Analysis of the spatial, temporal and tissue-specific transcription of gamma-sarcoglycan gene using a transgenic mouse

    S Noguchi, E Wakabayashi-Takai, T Sasaoka, E Ozawa

    FEBS LETTERS   495 ( 1-2 )   77 - 81   2001.4

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    DOI: 10.1016/S0014-5793(01)02368-7

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  • Catecholamine synthesis is mediated by tyrosinase in the absence of tyrosine hydroxylase

    M Rios, B Habecker, T Sasaoka, G Eisenhofer, H Tian, S Landis, D Chikaraishi, S Roffler-Tarlov

    JOURNAL OF NEUROSCIENCE   19 ( 9 )   3519 - 3526   1999.5

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  • NMDA receptor-dependent refinement of somatotopic maps

    T Iwasato, RS Erzurumlu, PT Huerta, DF Chen, T Sasaoka, E Ulupinar, S Tonegawa

    NEURON   19 ( 6 )   1201 - 1210   1997.12

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  • Neural tube defects and abnormal brain development in F52-deficient mice

    M Wu, DF Chen, T Sasaoka, S Tonegawa

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   93 ( 5 )   2110 - 2115   1996.3

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  • GENE REPLACEMENT OF THE P53 GENE WITH THE LACZ GENE IN MOUSE EMBRYONIC STEM-CELLS AND MICE BY USING 2 STEPS OF HOMOLOGOUS RECOMBINATION

    Y GONDO, K NAKAMURA, K NAKAO, T SASAOKA, K ITO, M KIMURA, M KATSUKI

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   202 ( 2 )   830 - 837   1994.7

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  • NORMALIZATION OF TYROSINE-HYDROXYLASE ACTIVITY IN-VIVO IN THE STRIATUM OF TRANSGENIC MICE CARRYING HUMAN TYROSINE-HYDROXYLASE GENE - A MICRODIALYSIS STUDY

    D NAKAHARA, H HASHIGUTI, N KANEDA, T SASAOKA, T NAGATSU

    NEUROSCIENCE LETTERS   158 ( 1 )   44 - 46   1993.8

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    DOI: 10.1016/0304-3940(93)90608-N

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  • REGULATORY MECHANISM OF DOPAMINE BIOSYNTHESIS IN THE STRIATUM OF TRANSGENIC MICE CARRYING HUMAN TYROSINE-HYDROXYLASE GENE

    K KIUCHI, K KIUCHI, N KANEDA, T SASAOKA, H HIDAKA, T NAGATSU

    NEUROSCIENCE LETTERS   151 ( 1 )   55 - 58   1993.3

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  • GENETIC ALTERATION OF CATECHOLAMINE SPECIFICITY IN TRANSGENIC MICE

    K KOBAYASHI, T SASAOKA, S MORITA, NAGATSU, I, A IGUCHI, Y KUROSAWA, K FUJITA, T NOMURA, M KIMURA, M KATSUKI, T NAGATSU

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   89 ( 5 )   1631 - 1635   1992.3

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    DOI: 10.1073/pnas.89.5.1631

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  • STRUCTURE OF THE MOUSE TYROSINE-HYDROXYLASE GENE

    N IWATA, K KOBAYASHI, T SASAOKA, H HIDAKA, T NAGATSU

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   182 ( 1 )   348 - 354   1992.1

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    DOI: 10.1016/S0006-291X(05)80151-2

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  • ENHANCED EXPRESSION OF HUMAN TYROSINE-HYDROXYLASE IN THE LOWER BRAIN-STEM OF TRANSGENIC MICE

    K YAMADA, M SAKAI, T TAKEUCHI, N KARASAWA, N KANEDA, T SASAOKA, K KOBAYASHI, M YOKOYAMA, T NOMURA, M KATSUKI, K FUJITA, T NAGATSU, NAGATSU, I

    NEUROSCIENCE LETTERS   134 ( 1 )   57 - 61   1991.12

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  • EXPRESSION IN BRAIN SENSORY NEURONS OF THE TRANSGENE IN TRANSGENIC MICE CARRYING HUMAN TYROSINE-HYDROXYLASE GENE

    NAGATSU, I, K YAMADA, N KARASAWA, M SAKAI, T TAKEUCHI, N KANEDA, T SASAOKA, K KOBAYASHI, M YOKOYAMA, T NOMURA, M KATSUKI, K FUJITA, T NAGATSU

    NEUROSCIENCE LETTERS   127 ( 1 )   91 - 95   1991.6

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  • PRIMARY STRUCTURE OF MOUSE TYROSINE-HYDROXYLASE DEDUCED FROM ITS CDNA

    S ICHIKAWA, T SASAOKA, T NAGATSU

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   176 ( 3 )   1610 - 1616   1991.5

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    DOI: 10.1016/0006-291X(91)90472-J

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  • TISSUE-SPECIFIC AND HIGH-LEVEL EXPRESSION OF THE HUMAN TYROSINE-HYDROXYLASE GENE IN TRANSGENIC MICE

    N KANEDA, T SASAOKA, K KOBAYASHI, K KIUCHI, NAGATSU, I, Y KUROSAWA, K FUJITA, M YOKOYAMA, T NOMURA, M KATSUKI, T NAGATSU

    NEURON   6 ( 4 )   583 - 594   1991.4

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  • MOLECULAR BIOLOGICAL APPROACHES TO CATECHOLAMINE NEUROTRANSMITTERS AND BRAIN AGING Reviewed

    N KANEDA, K KOBAYASHI, H ICHINOSE, T SASAOKA, A ISHII, K KIUCHI, Y KUROSAWA, K FUJITA, T NAGATSU

    AGING OF THE BRAIN   13   53 - 66   1990

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  • GENES OF HUMAN CATECHOLAMINE-SYNTHESIZING ENZYMES Reviewed

    T NAGATSU, N KANEDA, K KOBAYASHI, H ICHINOSE, T SASAOKA, A ISHII, K KIUCHI, K FUJITA, K TITANI, Y KUROSAWA

    BASIC, CLINICAL, AND THERAPEUTIC ASPECTS OF ALZHEIMERS AND PARKINSONS DISEASES, VOL 1   38   481 - 486   1990

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  • DETECTION OF TETRAHYDROISOQUINOLINE IN PARKINSONIAN BRAIN AS AN ENDOGENOUS AMINE BY USE OF GAS-CHROMATOGRAPHY MASS-SPECTROMETRY

    T NIWA, N TAKEDA, T SASAOKA, N KANEDA, Y HASHIZUME, H YOSHIZUMI, A TATEMATSU, T NAGATSU

    JOURNAL OF CHROMATOGRAPHY-BIOMEDICAL APPLICATIONS   491 ( 2 )   397 - 403   1989.7

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  • ANALYSIS OF SALSOLINOL IN HUMAN-BRAIN USING HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION Reviewed

    T SASAOKA, N KANEDA, T NIWA, Y HASHIZUME, T NAGATSU

    JOURNAL OF CHROMATOGRAPHY-BIOMEDICAL APPLICATIONS   428 ( 1 )   152 - 155   1988.6

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  • Striatal dopamine release and metabolism in sinoaortic-denervated rats by in vivo microdialysis

    N. Alexander, D. Nakahara, N. Ozaki, N. Kaneda, T. Sasaoka, N. Iwata, T. Nagatsu

    American Journal of Physiology-Regulatory, Integrative and Comparative Physiology   254 ( 2 )   R396 - R399   1988.2

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    The purpose of this study was to provide new evidence favoring the hypothesis that cardiovascular information from arterial baroreceptors is integrated with the nigrostriatal system that contributes to regulation of motor activity. Samples of extracellular striatal dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were collected by the technique of in vivo microdialysis and analyzed by high-performance liquid chromatography-electron capture detection. Rats were prepared with a guide tube placed in the caudate-putamen for subsequent insertion of microdialysis probes. During the 1st wk after sinoaortic denervation (SAD) or sham operation (SO), a microdialysis probe was inserted and perfused with Ringer solution at the rate of 2 microliter/min in the freely moving rats. Samples were collected every 20 min before and after injection of pargyline, 100 mg/kg ip. The results showed that SAD rats have approximately 50% less extracellular striatal DA, DOPAC, and HVA than SO rats (P less than 0.01). After blockade of monoamine oxidase activity with pargyline, striatal DA accumulated three times faster in SO than SAD rats suggesting DA synthesis is reduced in SAD rats. These data provide further evidence that the arterial baroreceptor system affects dopaminergic metabolism in the nigrostriatal system possibly as a means for integration of cardiovascular and motor activity.

    DOI: 10.1152/ajpregu.1988.254.2.r396

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  • STRIATAL DOPAMINE RELEASE AND METABOLISM IN SINOAORTIC-DENERVATED RATS BY INVIVO MICRODIALYSIS

    N ALEXANDER, D NAKAHARA, N OZAKI, N KANEDA, T SASAOKA, N IWATA, T NAGATSU

    AMERICAN JOURNAL OF PHYSIOLOGY   254 ( 2 )   R396 - R399   1988.2

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  • HIGHLY SENSITIVE ASSAY FOR XANTHINE-OXIDASE ACTIVITY BY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY WITH FLUORESCENCE DETECTION Reviewed

    T SASAOKA, N KANEDA, T NAGATSU

    JOURNAL OF CHROMATOGRAPHY-BIOMEDICAL APPLICATIONS   424 ( 2 )   392 - 397   1988.2

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MISC

  • 胚盤胞補完法とES細胞を用いた甲状腺再生

    冉慶松, 周啓亮, 小田加奈子, 泰江彰浩, 阿部学, 笹岡俊邦, 崎村健司, 味岡洋一, 西條康夫

    日本再生医療学会総会(Web)   20th   2021

  • 胚盤胞補完法とES細胞を用いた甲状腺再生

    冉慶松, 周けい亮, 叶許緑, 小田加奈子, 泰江章博, 阿部学, 崎村建司, 笹岡俊邦, 味岡洋一, 西條康夫

    日本再生医療学会総会(Web)   19th   2020

  • 胚盤胞補完法とES細胞を用いたマウス生体内における肺臓器再生

    冉慶松, 周啓亮, 北原哲彦, 叶許緑, 佐々木健太, 齋木琢郎, 松本吉史, 森山雅人, 泰江章博, 阿部学, 味岡洋一, 笹岡俊邦, 西條康夫

    日本再生医療学会総会(Web)   18th   2019

  • ドーパミンD2L受容体は視覚弁別学習に関与する

    森田 真規子, 笹岡 俊邦, Wang Yanyan, 澤 明, 疋田 貴俊

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [1P1291] - [1P1291]   2015.12

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  • Effect of in vitro Culture of an Early Embryo on Development of a Mouse

    Oda Kanako, Sasaoka Toshikuni

    128 ( 12 )   635 - 646   2014.12

  • Pathway-specific modulation of nucleus accumbens in reward and aversive learning behaviors and drug addiction via selective transmitter receptors

    T. Hikida, S. Yawata, T. Yamaguchi, T. Danjo, T. Sasaoka, Y. Wang, S. Nakanishi

    INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY   17   45 - 45   2014.6

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  • 認知学習におけるD2L受容体の関与

    森田真規子, 笹岡俊邦, WANG Yanyan, 澤明, 疋田貴俊

    日本生物学的精神医学会誌   158   2014

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  • Analyses of motor activity and striatal GABAergic synaptic transmission in dopamine D1 and D2 receptor knock-out mice

    Toshihiko Momiyama, Asako Sato, Motoya Katsuki, Toshikuni Sasaoka

    NEUROSCIENCE RESEARCH   71   E87 - E87   2011

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    DOI: 10.1016/j.neures.2011.07.371

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  • Analysis of locomotor activity in transgenic mice harboring controllable D1R expression

    Asako Sato, Motoya Katsuki, Toshikuni Sasaoka

    NEUROSCIENCE RESEARCH   68   E145 - E146   2010

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    DOI: 10.1016/j.neures.2010.07.2219

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  • Functional role of dopamine D1 receptors in information processing through the basal ganglia analyzed by neuronal recording from transgenic mice in awake state

    Satomi Chiken, Chikara Ohta, Asako Sato, Toshikuni Sasaoka, Motoya Katsuki, Makoto Kurokawa, Atsushi Nambu

    NEUROSCIENCE RESEARCH   68   E373 - E373   2010

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    DOI: 10.1016/j.neures.2010.07.1652

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  • Analysis of locomotor control using transgenic mice having controllable D1R expression

    Asako Sato, Toshikuni Sasaoka, Satoko Arakawa, Tomoko Morita, Kuniko Katsuki, Motoya Katsuki

    NEUROSCIENCE RESEARCH   65   S77 - S78   2009

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    DOI: 10.1016/j.neures.2009.09.284

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  • GABAergic SYNAPTIC TRANSMISSION IN THE STRIATUM OF DOPAMINE RECEPTOR KNOCK-OUT MICE

    Toshihiko Momiyama, Toshikuni Sasaoka, Asako Sato, Motoya Matsuki

    JOURNAL OF PHYSIOLOGICAL SCIENCES   59   235 - 235   2009

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  • Characterization of GABAergic synaptic transmission onto striatal cholinergic interneurons in dopamine receptor knock-out mice

    Toshihiko Momiyama, Toshikuni Sasaoka, Asako Sato, Motoya Katsuki

    JOURNAL OF PHARMACOLOGICAL SCIENCES   109   116P - 116P   2009

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  • The therapeutic effect of myostatin-blockade on muscular dystrophic mice and gene expression analysis of the treated muscles

    S. Noguchi, M. Fujita, T. Sasaoka, I. Nishino

    NEUROMUSCULAR DISORDERS   16 ( 9-10 )   705 - 705   2006.10

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    DOI: 10.1016/j.nmd.2006.05.197

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  • Evaluation of the therapeutic effect of insulin-like growth factor 1 on muscular dystrophy by gene expression analysis

    S Noguchi, M Fujita, T Sasaoka, Nishino, I

    NEUROMUSCULAR DISORDERS   15 ( 9-10 )   729 - 729   2005.10

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  • Gene expression analysis of skeletal muscle from caveolin-3 knockout mice

    Y Hagiwara, T Sasaoka, M Imamura, M Fujita, S Noguchi

    JOURNAL OF PHARMACOLOGICAL SCIENCES   97   249P - 249P   2005

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  • Biochemical evidence for association of dystrobrevin with the sarcoglycan-sarcospan complex as a basis for understanding sarcoglycanopathy

    Mikiharu Yoshida, Hiroshi Hama, Michiko Ishikawa-Sakurai, Michihiro Imamura, Yuji Mizuno, Kenji Araishi, Eriko Wakabayashi-Takai, Satoru Noguchi, Toshikuni Sasaoka, Eijiro Ozawa

    Human Molecular Genetics   9 ( 7 )   1033 - 1040   2000.4

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  • Sarcoglycan-sarcospan complex interacts with syntrophins/alpha-dystrobrevin well as the dystroglycan complex.

    M Yoshida, H Hama, M Sakurai, M Imamura, Y Mizuno, K Araishi, T Sasaoka, E Wakabayashi, S Noguchi, E Ozawa

    AMERICAN JOURNAL OF HUMAN GENETICS   65 ( 4 )   A500 - A500   1999.10

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  • Loss of the sarcoglycan complex and sarcospan leads to muscular dystrophy in beta-sarcoglycan-deficient mice.

    K Araishi, T Sasaoka, M Imamura, S Noguchi, H Hama, E Wakabayashi, M Yoshida, T Hori, E Ozawa

    AMERICAN JOURNAL OF HUMAN GENETICS   65 ( 4 )   A5 - A5   1999.10

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  • Muscular dystrophic phenotype in the gamma-sarcoglycan-deficient mice

    SASAOKA Toshikuni, MIZUNO Yuji, NOGUCHI Satoru, IMAMURA Michihiro, WAKABAYASHI Eriko, YOSHIDA Mikiharu, OZAWA Eijiro

    21   690 - 690   1998.12

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  • CONSTRUCTION AND ANALYSIS OF P53-DEFICIENT MICE BY A NOVEL GENE REPLACEMENT SYSTEM - EVIDENCE FOR THE LOSS OF HETEROZYGOSITY OF THE P53 GENE IN TUMORS

    Y GONDO, K NAKAMURA, K NAKAO, T SASAOKA, M KATSUKI

    JOURNAL OF CELLULAR BIOCHEMISTRY   195 - 195   1994.1

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Research Projects

  • パーキンソン病治療法開発を目指したドーパミン受容体シグナルの機能の解明

    Grant number:25K09845

    2025.4 - 2028.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    笹岡 俊邦

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    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

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  • 気管移植を目指した胚盤胞補完法による生体内気管再生

    Grant number:24K11760

    2024.4 - 2027.3

    System name:科学研究費助成事業

    Research category:基盤研究(C)

    Awarding organization:日本学術振興会

    周 ケイリョウ, 笹岡 俊邦, 小田 佳奈子

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  • Generation of purely pluripotent stem cell derived lung organ

    Grant number:21H02923

    2021.4 - 2024.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    SAIJO YASUO

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    Grant amount:\16250000 ( Direct Cost: \12500000 、 Indirect Cost:\3750000 )

    This study aims to ultimately create lungs derived 100% from embryonic stem cells. Mouse ES cells were cultured in three dimensions to attempt the creation of pseudo-embryos. ES cells cultured in ESLIF medium were started in a 96 well plate, and the culture was continued with a change to N2B27 medium containing Chiron, promoting the development and differentiation of gastruloids. As a result of trying various conditions, the ES cells aggregated and formed an individual entity. Histologically, the development of the primitive gut or lung buds was not confirmed. Also, genetic analysis did not confirm the expression of genes involved in lung development. In addition, research on lung regeneration by blastocyst complementation method was continued. By transplanting rat ES cells into mice with lung deficiencies, lung regeneration was successful in five cases. Further analysis confirmed the creation of lungs derived from rat ES cells

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  • Generation of lungs by blastocyst complementation in interspecific setting using ES cells

    Grant number:20H03741

    2020.4 - 2024.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    ZHOU Qiliang

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    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

    We succeeded in the generation of lungs using mouse embryonic stem cells(ESCs) in apneumic Fgf10 Ex1mut/Ex3mut mice by blastocyst complementation. Then, we show that rat ESCs can rescue the lung organization in mouse by interspecific blastocyst complementation. Lungs in the chimera mouse were efficiently derived from the venus positive rat ESCs.
    An interspecific blastocyst complementation method using chimeric animals may be useful as a way to create lung in animals.

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  • Genetic alteration from in-vitro culture environment in mammalian offspring born through in vitro fertilization

    Grant number:19K09787

    2019.4 - 2022.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    NAOKI KJI

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    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    The effect of octanoic acid (OA) in the embryo culture medium was investigated. Mouse embryos were cultured in KSOM culture medium containing0.5% w/v of recombinant human albumin, 400 mmM of N-acetyl tryptophan, and 0, 400, and 600 mmM of OA, respectively. The blastocyst development rates were 32/34 (94%), 28/36 (78%), and 28/40 (70%), respectively, significantly decreased with increasing OA concentration. After embryo transfer to pseudo-pregnant female mice, average birth weight of female pup were 1.08 ± 0.06 g, 1.15 ± 0.09 g, and 1.45 ± 0.05 g, tended to increase with increasing OA concentration (p = 0.05 in the 0μM group and 60μM group). However, in males, there was no difference in birth weight due to OA concentration, and there was no significant difference in weight up to 4 weeks after birth both in males and females. It was suggested that exposure to high concentrations of octanoic acid during embryo culture could increase birth weight in females.

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  • Development of innovative embryo manipulation system for genetically modified marmoset

    Grant number:18K19375

    2018.6 - 2021.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Challenging Research (Exploratory)

    Awarding organization:Japan Society for the Promotion of Science

    Sasaoka Toshikuni

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    Grant amount:\6370000 ( Direct Cost: \4900000 、 Indirect Cost:\1470000 )

    The purpose of this study was to develop a reliable and low-cost technology for producing wild-type and genetically modified marmosets, and to achieve generalization as laboratory animals. For this purpose, we conducted research and development on three items. The first is "Development of a stable production method for marmoset mature and fertilized eggs," the second is "Generation of brain disease models using xenotransplanted oocytes," and the third is "Establishment of naiive ES cells and generation of genetically modified animals by blastocyst complementation. Various conditions have been examined and progress is generally being made smoothly.

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  • Understanding of motor control and learning and memory mechanism using mice harboring altered expression of D1/D2 dopamine receptors

    Grant number:18H02540

    2018.4 - 2021.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    Sasaoka Toshikuni

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    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

    To elucidate the cause of motor symptoms in Parkinson's disease, we analyzed the mechanism of motor control using genetically engineered mice, focusing on the roles of D1 and D2 dopamine receptors (D1R and D2R) and NMDA receptor-mediated signal transduction, and especially found the importance of D1R-mediated signal transduction. In addition, we found that D1R-mediated signaling is important for learning and memory of risk avoidance induced by aversive stimuli, and identified brain regions activated by aversive stimuli and molecules responsible for signaling.

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  • Generation interspecies germ cell and reproductive organ in the mice by nobel experimental system

    Grant number:18K05938

    2018.4 - 2021.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    Yamashiro Hideaki

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    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    The objective of this study was that the finally generating cattle and rat germ cell in the mouse by the Cas9 knockout and/or gene targeting method combined with interspecies blastocyst complementation. In this experiment, we found that (1) The Nanos gene family is required for germ cell development in diverse organisms. We successfully generated Nanos3 knockout mouse, results in the complete loss of germ cells in both testis and ovary. (2) GATA4 gene encodes a member of the GATA family of zinc-finger transcription factors. Hetero knockout mouse produced by crossing GATA4flox/flox mouse with GATA4flox/+;Vasa-Cre mouse. This hetero knockout mouse was maintained reproductive function, but showed a marked decreased in the number of litters compared to the wild type. In future, these results could be useful for the generation of not only animal but also human germ cells and organs into chimeric animals produced by xenogeneic Blastocyst complementation.

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  • Generation of lung organ derived from rat ES cells in FGF10 deficient mice

    Grant number:18H02817

    2018.4 - 2021.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    Saijo Yasuo

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    Grant amount:\16510000 ( Direct Cost: \12700000 、 Indirect Cost:\3810000 )

    Blastocyst complementation enables the generation of transplantable organs from pluripotent stem cells (PSCs) in animal models. Pancreases and kidneys have been generated from PSCs via blastocyst complementation in rodent models. Here, we report the generation of lungs using mouse embryonic stem cells (ESCs) in aFgf10 Ex1mut/Ex3mut mice via blastocyst complementation. Complementation with ESCs enabled Fgf10-deficient mice to survive to adulthood without abnormalities. Not only the generated lung alveolar parenchyma, but also the interstitial portions including vascular endothelial cells, vascular and parabronchial smooth muscle cells, and connective tissues were largely originated from the injected ESCs. These data indicated that Fgf10 Ex1mut/Ex3mut blastocysts may provide an organ niche for lung generation, and blastocyst complementation could be applied as a viable approach to generating whole lungs.

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  • Analysis of function of basal ganglia circuit using dopamine receptor and NMDA receptor mutant mice

    Grant number:18H04937

    2018.4 - 2020.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Awarding organization:Japan Society for the Promotion of Science

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    Grant amount:\5850000 ( Direct Cost: \4500000 、 Indirect Cost:\1350000 )

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  • The pathological role of secreted protein in promoting fibrosis in non alcoholic steatohepatitis.

    Grant number:17K19648

    2017.6 - 2019.3

    System name:Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)

    Research category:Grant-in-Aid for Challenging Research (Exploratory)

    Awarding organization:Japan Society for the Promotion of Science

    Shimizu Ippei, Minamino Tohru, Yoshida Yohko, Okuda Shujiro, Sakimura Kenji, Terai Shuji, Sasaoka Toshikuni, Nakagami Hironori

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    Grant amount:\6370000 ( Direct Cost: \4900000 、 Indirect Cost:\1470000 )

    Non-alcoholic fatty liver disease (NAFLD) develops with obesity. Non-alcoholic steatohepatitis (NASH) is the extreme form of NAFLD characterized with sterile inflammation and fibrosis in the liver. NASH patients are increasing in many societies, however, the molecular mechanisms of fibrosis in the liver are largely unknown. We found a significant increase in obesity associated pro-fibrotic protein (OAFP) level in the serum from NASH patients compared to control groups. Obese-NASH model developed significant liver fibrosis associated with high circulating OAFP level. Injection of a plasmid encoding OAFP into skeletal muscle promoted fibrosis in the liver. In contrast, genetic suppression of OAFP inhibited liver fibrosis. Our studies from humans and rodents suggest the pathological role of OAFP in promoting fibrotic responses in liver upon metabolic stress. Suppression of OAFP would become next generation therapy for NASH.

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  • ドーパミン受容体及びNMDA受容体変異マウスを用いた大脳基底核回路の機能解析

    Grant number:16H01606

    2016.4 - 2018.3

    System name:科学研究費助成事業

    Research category:新学術領域研究(研究領域提案型)

    Awarding organization:日本学術振興会

    笹岡 俊邦

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    Grant amount:\6240000 ( Direct Cost: \4800000 、 Indirect Cost:\1440000 )

    生理研の南部篤教授(本研究領域代表)、知見聡美(計画班員)らと共同し、応募者等が開発したD1Rノックダウン(D1R KD)マウスを用いて、D1Rを欠損させると運動量が減少し、大脳基底核神経細胞のin vivo電気生理学的解析により、直接路の投射先(脚内核)と、間接路神経の投射先(淡蒼球外節)の活動を記録すると、大脳皮質刺激による運動指令は大脳基底核の3つの経路により脚内核に達し、正常では3相性(興奮-抑制-興奮)の神経活動として出力されるが、D1R欠損の場合は抑制が消失した。この結果から、D1Rを介する情報伝達は直接路を通る信号の伝達と、運動の発現に不可欠であること、一方、大脳基底核の自発的神経活動は、D1R欠損状態であっても基底核出力部において変化しないことを見出した。この結果は直接路を通る信号の動的な伝達の減少がより本質的な変化であることを示した。 また、Rotarodによる運動学習試験、受動的回避試験による忌避学習と記憶の試験を行ったところ、成熟期のD1R KDマウスをD1R欠損とすると、D1Rストレート欠損マウスよりも成績が低下し、Dox投与停止でD1R発現が回復すると、学習記憶の成績が回復したことから、成熟期にD1Rを介する直接路の情報伝達が、学習・記憶に重要であることがわかった。併せて、新潟大学の崎村建司教授と共同で作製しているD2Rノックダウンマウスが完成し、今後、間接路に関する機能の解明のため、D1R KDマウスと同様の解析を行う。またNMDA 受容体異常活性化と異常発振を検討する為、アミノ酸置換によりNMDA 受容体異常活性化するマウスを作成した。
    <研究実績>
    (1)学術論文:10報 (2) 学会研究会発表:21件 (3) シンポジウムの主催:2件 (4) 著書執筆:1件 (5) 国際共同研究:1件 (6) 共同研究のための班員間の打合せ:10回開催

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  • GENERATION OF LUNG ORGAN FROM EMBRYONIC STEM CELLS VIA BLASTOCYST COMPLEMENTATION IN MIC

    Grant number:15K15320

    2015.4 - 2017.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Challenging Exploratory Research

    Awarding organization:Japan Society for the Promotion of Science

    SAIJO YASUO, SAKIMURA KENJI, OHUCHI HIDEYO

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    Grant amount:\3510000 ( Direct Cost: \2700000 、 Indirect Cost:\810000 )

    We have developed Fgf10-/- mice by CRISPR/Cas system . Since the Fgf10-/- die immediately after birth, the Fgf10+/- genotype mice are maintained. We implanted 40 control embryos that was not injected ES cells into pseudopregnant mice and we obtained 13 littermates (32.5%) from the mice. 4 littermates (30.7%) showed limb defect (Fgf10-/-) and they were confirmed histologically that they had hypoplastic or aplastic lung. EGFPposotive ES cells were injected into blacystocyte of Fgf10-/- mice. 45 littermates were obtained from those mice. 38 littermates were EGFP positive. All EGFP positive mice showed the lung organ histologically. We sacrificed and analyzed histology in EGFP positive mice over one month. EGFP was positive in their lungs. The tissue, cells, and structure of their lung were well developed and not different from normal mice lung by H-E staining. Frozen section of the lung showed EGFP positive in alveolar epithelium, endothelium, tracheal cartilage.

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  • Technical development of transplantation human iPS induced hapatoblast and hepatocyte to mice embryos.

    Grant number:26640060

    2014.4 - 2018.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Challenging Exploratory Research

    Awarding organization:Japan Society for the Promotion of Science

    MORITA KUNIE

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    Grant amount:\3900000 ( Direct Cost: \3000000 、 Indirect Cost:\900000 )

    This research has conducrted 4 years, from fiscal year 2013 to 2017. The first year of this research, the research reader had changed the laboratory, from Kumamoto University to Niigata University of Health and Welfare. We were granted human iPS cells fron RIKEN, and we strarted differentiation- induced experiment from iPS cells to hepatocytes. And then, we confirmed differentiation to hepatocytes by means of immunological staining, hepatocyes marker ALB, SERPINA1 and HNF4A.
    This achivemnnt would help education and research for unversity students trying to be medical techcologysts, the reseach reader instructed there.

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  • Elucidation of motor control mechanism by D1 / D2 dopamine receptor conditionally expressing mice

    Grant number:26290029

    2014.4 - 2017.3

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (B)

    Awarding organization:Japan Society for the Promotion of Science

    SASAOKA Toshikuni, NAKAO Satohiro, NAMBU Atsushi, CHIKEN Satomi

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    Grant amount:\16900000 ( Direct Cost: \13000000 、 Indirect Cost:\3900000 )

    Using genetically modified mice that reversibly suppress expression of dopamine D1 receptor (D1R) by drug (doxycycline) administration, D1R deficiency leads to decrease of motor activity. Normally, the electrical stimulation at motor cortex travels through three pathways (hyper-direct, direct and indirect pathways) and is recorded as neural activity of triphasic "excitation - suppression - excitement" in the entopeduncular nucleus, the output part of the basal ganglia. In the state of D1R deficiency, 'suppression' disappeared. It is believed that this "suppression" passes through the direct pathway of the basal ganglia circuit and works for induction of movement. In this study, information via D1R is thought to be indispensable for signaling of the direct pathway and induction of movement, and a decrease in the dynamic transmission of signals through the direct pathway is thought to lead to motor symptoms of Parkinson's disease.

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  • Understanding of regulatory mechanism of motor activity using D1 and D2 dopamine receptor gene-modified mice

    Grant number:22500343

    2010 - 2012

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    SASAOKA Toshikuni, OKUBO Tadashi, SATO Asako

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    Grant amount:\3640000 ( Direct Cost: \2800000 、 Indirect Cost:\840000 )

    In Parkinson disease the degeneration of nigro-striatal dopamine neuron leads to depletion of dopamine and motor deficit. It is known that D1 and D2 dopamine receptors (D1R, D2R) expressed in the medium spiny neurons of striatum are involved to motor control. However, the regulatory mechanism of motor control via D1R and D2R remains to be clarified. In this study we found the conditional D1R-expressing mice controlled by Tet-off system showed decrease of motor activity in the homecage when D1R expression was suppressed in adult stage. This finding was opposite to the marked increase of motor activity of D1R KO mice. These suggest the presence or absence of D1R expression during mouse development is closely related to up-regulation or down-regulation of motor activity in adult stage.

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  • Study of molecular mechanism of motor control using double D1/D2 dopamine receptor mutant mice.

    Grant number:19500334

    2007 - 2008

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    SASAOKA Toshikuni, SATO Asako, KATSUKI Motoya

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    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

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  • Reproduction and maintenance of experimental animals for the study of molecular mechanisms of sex differentiation

    Grant number:16086212

    2004 - 2008

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research on Priority Areas

    Awarding organization:Japan Society for the Promotion of Science

    SASAOKA Toshikuni, NAGAHAMA Yoshitaka, MOROHASHI Ken-ichirou, SASAOKA Toshikuni, SAYA Hideyuki, YAMADA Gen, NAGAHAMA Yoshitaka

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    Grant amount:\46500000 ( Direct Cost: \46500000 )

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  • ドーパミン受容体D1/D2ダブルノックアウトマウスによる摂食行動の分子機構の解析

    Grant number:16015310

    2004

    System name:科学研究費助成事業

    Research category:特定領域研究

    Awarding organization:日本学術振興会

    笹岡 俊邦, 勝木 元也

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    Grant amount:\6000000 ( Direct Cost: \6000000 )

    本研究では、ドーパミン神経系が司る機能の一つである摂食行動に着目し、調節中枢の探索と分子機構の解明を目的として、ドーパミン受容体コンディショナル発現マウスの作成と解析を行った。ドーパミン神経系は摂食行動・運動機能の調節、神経・精神疾患の病態に深く関わり、ドーパミン受容体はD1型受容体とD2型受容体に大別される。D1型受容体とD2型受容体は正反対の情報伝達の性質を持つが、多くの場面で協働する。我々は、D1受容体(D1R)とD2受容体(D2R)の二重欠損マウスを作成すると生後8日目頃から哺乳量が低下し、摂食もみられず成熟前に死亡することを見いだした。摂食開始にはD1R及びD2Rを介する情報伝達の両方が必要であることを示している。そこでテトラサイクリン発現調節系を利用してコンディショナルD1R発現マウスをD1R/D2R二重欠損の遺伝背景のもとで作成した。2種類のトランスジェニックマウス、すなわち(a)D1Rプロモーターの制御でテトラサイクリントランスアクチベーターを発現するマウス、及び(b)テトラサイクリンオペレーターの制御でD1Rを発現するマウスを多数系統作成し、(a)マウス系統と(b)マウス系統の各組合せをD1R/D2R二重欠損の遺伝背景となるように掛合せた中から、D1R/D2R二重欠損の摂食異常と致死性をレスキューできる系統を複数作成できた。さらに、テトラサイクリン系薬剤,ドキシサイクリン(Dox)の投与によりD1R遺伝子発現が抑制されることが確認され、コンディショナルD1R遺伝子発現マウスの作成に成功した。今後、特定の時期にDoxを投与してドーパミン情報伝達を遮断し、摂食行動の変化を観察する。そして観察される摂食異常とD1R発現部位から摂食調節の中枢を探索し、その形態的特徴および情報伝達機能変化を明らかにする。

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  • Analysis of function of NMDA receptor using genetically engineered mice by conditional mutagenesis

    Grant number:15500277

    2003 - 2004

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    SASAOKA Toshikuni, TANAKA Torahiko

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    Grant amount:\3300000 ( Direct Cost: \3300000 )

    To understand molecular mechanism causing the neurological phenotype through an activation of the N-methyl-D-aspartate receptor (NMDAR), we generated and analyzed mutant mice harboring activated NMDAR. We developed a conditional mutagenesis in mice to enable substitution of a critical sequence in NMDAR activation in a neuron-specific manner for purposes of functional analysis. We created mice carrying a tandem array of a normal exon and a mutated exon, separated by an artificial intron, in which the normal exon could be exclusively expressed. The normal exon was deleted by Cre-loxP recombination, allowing the alternative expression of the mutant exon. We successfully generated the mutant mice harboring an aberrant NMDAR activation by a substitution of a critical amino acid in the second trans-membrane domain of the NMDAR, and the mutant mice exhibited a clasping of the limbs.
    To block the clasping phenotype of the mutant mice we screened NMDAR agonists, NMDAR antagonists and several drugs for Parkinson's disease and found a non-competitive NMDAR antagonist completely blocked the clasping phenotype.
    We tried to develop a specific antibody recognizing the substituted amino acid of the NMDAR and obtained a rabbit polyclonal antibody recognizing the second trans-membrane domain of the NMDAR. The specificity of the polyclonal antibody recognizing the substituted amino acid is still being examined.
    We applied a recombinant antibody technology to develop a specific antibody against the substituted amino acid of the NMDAR. We established a simple, rapid and highly efficient ligation-transformation method for unidirectional subcloning to generate far larger numbers of transformants than previous procedures, and constructed single chain Fv phage-display libraries with a large-scale and a high-complexity consisting of approximately 1 x 109 independent clones. So far a recombinant antibody with a high affinity was obtained from the library. An antibody against the substituted amino acid of the NMDAR is being screened.

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  • Development of Somatosensory Area

    Grant number:12210020

    2000 - 2002

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research on Priority Areas

    Awarding organization:Japan Society for the Promotion of Science

    NAKAMURA Shun

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    Grant amount:\29100000 ( Direct Cost: \29100000 )

    SUMMARY OF Our research goal was
    Our research goal was to understand the molecular basis of functional development of somatosensory cortex. We made three approaches to address this research goal. First, the development of cortical area proceeds through several steps. In the early forebrain, morphogens, like FGF8, Wnt, and Shh are expressed in a gradient according to body axes and induce a series of transcription factors which in turn define the area specific properties of forebrain. One of the area specific genes is cadherin6, which is expressed in the region giving rise to future somatosensory cortex. The function of cadherin6 was uncertain in early areazation. Thus, we studied the function by using whole embryo culture system and electroporation of cadherin6 or a dominant negative form of the molecule. We found that cadherin6 is essential for stabilization of the future somatosensory area in the early forebrain. This study is further developed as a high-through put analysis of genes expressed in early somatosensory area by DNA microarry as well as identification of enhancers for area specific expression of cadherin6 genes using a BAC system. Second, genetically established cortical areas are further differentiated by innervations from subcortical area, that is, thalamic nuclei. We studied the central pattern formation mechanism. Several knockout mouse lines suggest the existence of genes for pattern formation of somatosensory cortex. In this area, the representation of peripheral whisker patterns are topographically arranged and called as barrel map. We asked the role of
    peripheral pattern on the central pattern formation by using an Adenovirus vector harboring chick Shh cDNA which is essential for whisker development. The virus was infected in utero to embryo epidermis, leading to abnormal whisker pattern. The central pattern was the topographic map of the peripheral map. This result showed that the peripheral pattern is the final determinant of the central pattern. Third, the innervated thalamic terminals make excitatory synapses with cortical layer 4 neurons. The early synapses just after birth contains only NMDA receptors, thus are functionally silent. During critical period (6-7days after birth), silent synapses are converted to active synapses containing AMPA receptors too. We found that brain-derived neurotrophic factor, BDNF is essential for this activation process synergistically with neuronal activity mediated by NMDA receptor. This study is further developing as a trafficking mechanism study of AMAP receptors.

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  • Research on muscular dystrophy using mouse developmental biotechnology

    Grant number:10670150

    1998 - 2000

    System name:Grants-in-Aid for Scientific Research

    Research category:Grant-in-Aid for Scientific Research (C)

    Awarding organization:Japan Society for the Promotion of Science

    SASAOKA Toshikuni

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    Grant amount:\3200000 ( Direct Cost: \3200000 )

    Sarcoglycanopathy (SGP) is similar to Duchenne muscular dystrophy (DMD) with respect to clinical features and muscle pathology, except for its mode of inheritance, slightly later onset in most cases, less frequent cardiac involvement, absence of mental impairment, and slightly slower progression. The four sarcoglycan subunits (α-, β-, γ-, and δ-SG) of the sarcoglycan complex (SGC) have been shown in four respective forms of SGP.
    To analyze the physiological roles of the individual subunits of SGC and elucidate the pathogenetic mechanisms of muscle hypertrophy and degeneration, we generated γ-SG-deficient (GSG-/-) mice by gene targeting. The limb, shoulder, and pelvic muscles of the GSG-/- mice exhibited progressive muscle hypertrophy and weakness with age, and findings were similar to those seen in other mouse models for limb girdle and DMD.While calf muscle hypertrophy is a striking diagnostic finding in DMD and SGP, its pathogenetic mechanism remains unknown. We found that the number of muscle fibers in tibialis anterior muscle increased with age, and most of the fibers in the hypertrophic muscle were centrally nucleated regenerating fibers. Fiber branching was seen in hypertrophied muscle. Therefore, muscle hypertrophy may represent a consequence of extensive fiber branching and an increase of muscle fibers. Muscle hypertrophy is not due to fibrous and fat tissue replacement, as has been shown to be the case in the so-called pseudohypertrophy in muscle diseases in humans. The muscle pathology became more "dystrophic" in mice over one year of age when there was a marked variation in fiber size with interstitial fibrosis.

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  • 導入オンコジーンの体細胞突然変異によって起こる個体発癌の研究

    Grant number:04152116

    1992

    System name:科学研究費助成事業

    Research category:がん特別研究

    Awarding organization:日本学術振興会

    勝木 元也, 笹岡 俊邦, 貞野 宏之, 谷口 俊一郎

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    Grant amount:\10000000 ( Direct Cost: \10000000 )

    がんは遺伝子の変異が原因で起る細胞の異常増殖であることが最近益々明らかにされつつある。しかし、ヒトのがん細胞の解析からだけでは、いつ、どこで,どの遺伝子に,どのような変異が起こるかを実験的に検証することはできない。そこで特定の遺伝子に注目したトランスジェニックマウスやジーンターゲッティングマウスの作成とその解析が重要となる。
    本研究は、ヒトのがん細胞から最も頻繁に活性型が見出されるras群遺伝子のうち、H-ras遺伝子導入マウスおよびがん抑制遺伝子p53のジーンターゲッティングマウスの作成とその解析を行った。
    rasマウスにはアルキル化剤MNUやDMBAの投与によって短期間に高頻度の個体発がんが認められる。これらの化学物質が体細胞突然変異を導入遺伝子にひき起こすことが原因で組織特異的発がんが起こることが確認された。X線照射や、キノリン,ヘテロサイクリックアミンなどに対しては有意に高い発がんは認められなかった。
    p53遺伝子ターゲッティングマウスは、キメラマウスの段階で自然発がんが頻発した。その種類は多様で、悪性リンパ腫,テラトーマ,肉腫血管肉腫,その他生後1日〜6ヶ月の間にES細胞由来の細胞から生ずることが確認された。この結果は他の研究者と著しく異なっている。その原因は未解明であるが,第1はES細胞の遺伝的背景が異なっていること。第2は、欠失させている領域が、われわれの方がはるかに大きいことなどが考えられる。
    以上の結果、個体発がんを遺伝子変異を分子生物学的に直接解析しながら個体レベルで研究できるシステムが確立したものと考えられる。

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Teaching Experience (researchmap)

  • バイオメディカルサイエンス

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Teaching Experience

  • 人体の構造と機能I(生理学)

    2024
    Institution name:新潟大学

  • 統合臨床医学

    2020
    -
    2023
    Institution name:新潟大学

  • バイオメディカルサイエンス

    2014
    Institution name:新潟大学