Researchers Database

inutuka ayumu

    DivisionofBrainandNeurophysiology,DepartmentofPhysiology Research Associate
Last Updated :2021/11/23

Researcher Information

Degree

  • Ph.D.(Kyoto University)

J-Global ID

Research Interests

  • Neuropeptides   AAV vector   Nanobody   Oxytocin   DREADDs   orexin   LC-PolScope   Cytoskeleton   Hypothalamus   Optogenetics   Sleep   

Research Areas

  • Life sciences / Neuroscience - general
  • Life sciences / Neuroscience - general

Academic & Professional Experience

  • 2015/06 - Today  Jichi Medical University生理学講座Assistant Professor
  • 2015/04 - 2015/05  Research Institute of Environmental Medicine, Nagoya UniversityDesignated Assistant Professor
  • 2012/04 - 2015/03  Nagoya UniversityPostdoctoral research fellow
  • 2010/04 - 2012/03  Graduate School of Medical and Dental SciencePostdoctoral research fellow

Education

  • 2007/04 - 2010/03  Kyoto University  Graduate School of Science
  • 2005/04 - 2007/03  Kyoto University  Graduate School of Science
  • 2001/04 - 2005/03  Kyoto University  Department of Science

Association Memberships

  • PHYSIOLOGICAL SOCIETY OF JAPAN   Society for Neuroscience   THE JAPAN NEUROSCIENCE SOCIETY   Japan Neuroendocrine Society   

Published Papers

  • Naoki Usui, Masahide Yoshida, Yuki Takayanagi, Naranbat Nasanbuyan, Ayumu Inutsuka, Hiroshi Kurosu, Hiroaki Mizukami, Yoshiyuki Mori, Makoto Kuro-O, Tatsushi Onaka
    Journal of neuroendocrinology e13026  2021/08 [Refereed]
     
    Fibroblast growth factor 21 (FGF21) modulates energy metabolism and neuroendocrine stress responses. FGF21 synthesis is increased after environmental or metabolic challenges. Detailed roles of FGF21 in the control of behavioural disturbances under stressful conditions remain to be clarified. Here, we examined the roles of FGF21 in the control of behavioural changes after social defeat stress in male rodents. Central administration of FGF21 increased the number of tyrosine hydroxylase-positive catecholaminergic cells expressing c-Fos protein, an activity marker of neurones, in the nucleus tractus solitarius and area postrema. Double in situ hybridisation showed that some catecholaminergic neurones in the dorsal medulla oblongata expressed β-Klotho, an essential co-receptor for FGF21, in male mice. Social defeat stress increased FGF21 concentrations in the plasma of male mice. FGF21-deficient male mice showed social avoidance in a social avoidance test with C57BL/6J mice (background strain of FGF21-deficient mice) and augmented immobility behaviour in a forced swimming test after social defeat stress. On the other hand, overexpression of FGF21 by adeno-associated virus vectors did not significantly change behaviours either in wild-type male mice or FGF21-deficient male mice. The present data are consistent with the view that endogenous FGF21, possibly during the developmental period, has an inhibitory action on stress-induced depression-like behaviour in male rodents.
  • Yoshihide Sehara, Yuka Hayashi, Kenji Ohba, Ryosuke Uchibori, Masashi Urabe, Ayumu Inutsuka, Kuniko Shimazaki, Kensuke Kawai, Hiroaki Mizukami
    Human Gene Therapy 1043-0342 2021/08 [Refereed]
  • Makiya Matsumoto, Masahide Yoshida, Buddhini Wimarsha Jayathilake, Ayumu Inutsuka, Katsuhiko Nishimori, Yuki Takayanagi, Tatsushi Onaka
    Journal of Neuroendocrinology 0953-8194 2021/05 [Refereed]
  • Yoko Kato, Harumi Katsumata, Ayumu Inutsuka, Akihiro Yamanaka, Tatsushi Onaka, Shiro Minami, Chitose Orikasa
    Scientific reports 11 (1) 3348 - 3348 2021/02 [Refereed]
     
    Multiple sequential actions, performed during parental behaviors, are essential elements of reproduction in mammalian species. We showed that neurons expressing melanin concentrating hormone (MCH) in the lateral hypothalamic area (LHA) are more active in rodents of both sexes when exhibiting parental nursing behavior. Genetic ablation of the LHA-MCH neurons impaired maternal nursing. The post-birth survival rate was lower in pups born to female mice with congenitally ablated MCH neurons under control of tet-off system, exhibiting reduced crouching behavior. Virgin female and male mice with ablated MCH neurons were less interested in pups and maternal care. Chemogenetic and optogenetic stimulation of LHA-MCH neurons induced parental nursing in virgin female and male mice. LHA-MCH GABAergic neurons project fibres to the paraventricular hypothalamic nucleus (PVN) neurons. Optogenetic stimulation of PVN induces nursing crouching behavior along with increasing plasma oxytocin levels. The hypothalamic MCH neural relays play important functional roles in parental nursing behavior in female and male mice.
  • Ayumu Inutsuka, Daisuke Ino, Tatsushi Onaka
    Peptides 136 170456 - 170456 2020/11 [Refereed][Not invited]
     
    During a stress response, various neuropeptides are secreted in a spatiotemporally coordinated way in the brain and in the periphery. For a precise understanding of peptide functions in a stress response, it is important to investigate when and where they are released, how they diffuse, and how they are broken down in the brain. In the past two decades, genetically encoded fluorescent calcium indicators have greatly advanced our knowledge of the functions of specific neuronal activity in regulation of behavioral changes and physiological responses during stress. Recently, various kinds of structural information on G-protein-coupled receptors (GPCRs) for neuropeptides have been revealed. Genetically encoded fluorescent sensors have been developed for detection of neurotransmitters by making use of conformational changes induced by ligand binding. In this review, we summarize the recent and upcoming advances of techniques for detection of neuropeptides and then present several open questions that will be solved by application of recent or upcoming technical advances in detection of neuropeptides in vivo.
  • 尾仲 達史, Nasanbuyan Naranbat, Jayathilake Buddhini Wimarsha, 吉田 匡秀, 高柳 友紀, 犬束 歩
    日本内分泌学会雑誌 (一社)日本内分泌学会 96 (1) 133 - 133 0029-0661 2020/08
  • Ayumu Inutsuka, Norihiro Kimizuka, Natsuki Takanohashi, Hisashi Yakabu, Tatsushi Onaka
    Biochemical and biophysical research communications 522 (1) 138 - 143 0006-291X 2020/01 [Refereed][Not invited]
     
    Optical manipulations are widely used to analyze neuronal functions in vivo. Blue light is frequently used to activate channelrhodopsins or LOV domains, although the degrees of its absorption and scattering are higher than those of longer wavelength light. High spatial resolution of optical manipulation is easily achieved in vitro, while the light is unevenly scattered and absorbed in tissues due to many factors. It is difficult to spatially measure a blue light transmission area in vivo. Here, we propose a genetic method to visualize blue light transmission in the brain and other organs using light-induced nuclear translocation of fluorescent proteins with a LOV domain. A light-inducible nuclear localization signal (LINuS) consists of a LOV2 domain fused with a nuclear localization signal (NLS). We confirmed that blue light illumination induced reversible translocation of NES-tdTomato-LINuS from the cytosol to the nucleus within 30 min in HEK293 cells. By employing a PHP.eb capsid that can penetrate the blood-brain barrier, retro-orbital sinus injection of adeno-associated virus (AAV) vectors induced scattered expression of nuclear export signal (NES)-tdTomato-LINuS in the brain. We confirmed that 30-min transcranial blue light illumination induced nuclear translocation of NES-tdTomato-LINuS in the cortex, the hippocampus, and even the paraventricular nucleus of the thalamus. We also found that mice exposed to blue light in a shaved abdominal area exhibited a substantial increase in nuclear translocation in the ventral surface lobe of the liver. These results provide a simple way to obtain useful information on light transmission in tissues without any transgenic animals or skillful procedures.
  • Srikanta Chowdhury, Chi Jung Hung, Shuntaro Izawa, Ayumu Inutsuka, Meiko Kawamura, Takashi Kawashima, Haruhiko Bito, Itaru Imayoshi, Manabu Abe, Kenji Sakimura, Akihiro Yamanaka
    eLife 8 2019/06 [Refereed][Not invited]
     
    Uninterrupted arousal is important for survival during threatening situations. Activation of orexin/hypocretin neurons is implicated in sustained arousal. However, orexin neurons produce and release orexin as well as several co-transmitters including dynorphin and glutamate. To disambiguate orexin-dependent and -independent physiological functions of orexin neurons, we generated a novel Orexin-flippase (Flp) knock-in mouse line. Crossing with Flp-reporter or Cre-expressing mice showed gene expression exclusively in orexin neurons. Histological studies confirmed that orexin was knock-out in homozygous mice. Orexin neurons without orexin showed altered electrophysiological properties, as well as received decreased glutamatergic inputs. Selective chemogenetic activation revealed that both orexin and co-transmitters functioned to increase wakefulness, however, orexin was indispensable to promote sustained arousal. Surprisingly, such activation increased the total time spent in cataplexy. Taken together, orexin is essential to maintain basic membrane properties and input-output computation of orexin neurons, as well as to exert awake-sustaining aptitude of orexin neurons.
  • Sho Matsui, Tsutomu Sasaki, Daisuke Kohno, Keisuke Yaku, Ayumu Inutsuka, Hiromi Yokota-Hashimoto, Osamu Kikuchi, Takayoshi Suga, Masaki Kobayashi, Akihiro Yamanaka, Akihiro Harada, Takashi Nakagawa, Tatsushi Onaka, Tadahiro Kitamura
    Nature communications 9 (1) 4604 - 4604 2018/11 [Refereed][Not invited]
     
    Diet affects health through ingested calories and macronutrients, and macronutrient balance affects health span. The mechanisms regulating macronutrient-based diet choices are poorly understood. Previous studies had shown that NAD-dependent deacetylase sirtuin-1 (SIRT1) in part influences the health-promoting effects of caloric restriction by boosting fat use in peripheral tissues. Here, we show that neuronal SIRT1 shifts diet choice from sucrose to fat in mice, matching the peripheral metabolic shift. SIRT1-mediated suppression of simple sugar preference requires oxytocin signalling, and SIRT1 in oxytocin neurons drives this effect. The hepatokine FGF21 acts as an endocrine signal to oxytocin neurons, promoting neuronal activation and Oxt transcription and suppressing the simple sugar preference. SIRT1 promotes FGF21 signalling in oxytocin neurons and stimulates Oxt transcription through NRF2. Thus, neuronal SIRT1 contributes to the homeostatic regulation of macronutrient-based diet selection in mice.
  • Takefumi Kikusui, Mayu Kajita, Natsumi Otsuka, Tatsuya Hattori, Kanako Kumazawa, Akiyuki Watarai, Miho Nagasawa, Ayumu Inutsuka, Akihiro Yamanaka, Naoki Matsuo, Herbert E. Covington, Kazutaka Mogi
    Behavioural Brain Research 346 96 - 104 0166-4328 2018/07 [Refereed][Not invited]
  • Thannickal TC, John J, Shan L, Swaab DF, Wu MF, Ramanathan L, McGregor R, Chew KT, Cornford M, Yamanaka A, Inutsuka A, Fronczek R, Lammers GJ, Worley PF, Siegel JM
    Science translational medicine 10 (447) 1946-6234 2018/06 [Refereed][Not invited]
  • Naranbat Nasanbuyan, Masahide Yoshida, Yuki Takayanagi, Ayumu Inutsuka, Katsuhiko Nishimori, Akihiro Yamanaka, Tatsushi Onaka
    Endocrinology 159 (2) 763 - 775 0013-7227 2018/02 [Refereed][Not invited]
     
    Social stress has deteriorating effects on various psychiatric diseases. In animal models, exposure to socially dominant conspecifics (i.e., social defeat stress) evokes a species-specific defeat posture via unknown mechanisms. Oxytocin neurons have been shown to be activated by stressful stimuli and to have prosocial and anxiolytic actions. The roles of oxytocin during social defeat stress remain unclear. Expression of c-Fos, a marker of neuronal activation, in oxytocin neurons and in oxytocin receptor‒expressing neurons was investigated in mice. The projection of oxytocin neurons was examined with an anterograde viral tracer, which induces selective expression of membrane-targeted palmitoylated green fluorescent protein in oxytocin neurons. Defensive behaviors during double exposure to social defeat stress in oxytocin receptor‒deficient mice were analyzed. After social defeat stress, expression of c-Fos protein was increased in oxytocin neurons of the bed nucleus of the stria terminalis, supraoptic nucleus, and paraventricular hypothalamic nucleus. Expression of c-Fos protein was also increased in oxytocin receptor‒expressing neurons of brain regions, including the ventrolateral part of the ventromedial hypothalamus and ventrolateral periaqueductal gray. Projecting fibers from paraventricular hypothalamic oxytocin neurons were found in the ventrolateral part of the ventromedial hypothalamus and in the ventrolateral periaqueductal gray. Oxytocin receptor‒deficient mice showed reduced defeat posture during the second social defeat stress. These findings suggest that social defeat stress activates oxytocin-oxytocin receptor systems, and the findings are consistent with the view that activation of the oxytocin receptor in brain regions, including the ventrolateral part of the ventromedial hypothalamus and the ventrolateral periaqueductal gray, facilitates social defeat posture.
  • Ayumu Inutsuka, Akira Yamashita, Srikanta Chowdhury, Junichi Nakai, Masamichi Ohkura, Toru Taguchi, Akihiro Yamanaka
    SCIENTIFIC REPORTS 6 29480  2045-2322 2016/07 [Refereed][Not invited]
     
    The level of wakefulness is one of the major factors affecting nociception and pain. Stress-induced analgesia supports an animal's survival via prompt defensive responses against predators or competitors. Previous studies have shown the pharmacological effects of orexin peptides on analgesia. However, orexin neurons contain not only orexin but also other co-transmitters such as dynorphin, neurotensin and glutamate. Thus, the physiological importance of orexin neuronal activity in nociception is unknown. Here we show that adult-stage selective ablation of orexin neurons enhances pain-related behaviors, while pharmacogenetic activation of orexin neurons induces analgesia. Additionally, we found correlative activation of orexin neurons during nociception using fiber photometry recordings of orexin neurons in conscious animals. These findings suggest an integrative role for orexin neurons in nociceptive perception and pain regulation.
  • D. Miyamoto, D. Hirai, C. C. A. Fung, A. Inutsuka, M. Odagawa, T. Suzuki, R. Boehringer, C. Adaikkan, C. Matsubara, N. Matsuki, T. Fukai, T. J. McHugh, A. Yamanaka, M. Murayama
    SCIENCE 352 (6291) 1315 - 1318 0036-8075 2016/06 [Refereed][Not invited]
     
    During tactile perception, long-range intracortical top-down axonal projections are essential for processing sensory information. Whether these projections regulate sleep-dependent long-termmemory consolidation is unknown. We altered top-down inputs fromhigher-order cortex to sensory cortex during sleep and examined the consolidation of memories acquired earlier during awake texture perception. Mice learned novel textures and consolidated them during sleep. Within the first hour of non-rapid eye movement (NREM) sleep, optogenetic inhibition of top-down projecting axons fromsecondary motor cortex (M2) to primary somatosensory cortex (S1) impaired sleep-dependent reactivation of S1 neurons and memory consolidation. In NREM sleep and sleep-deprivation states, closed-loop asynchronous or synchronous M2-S1 coactivation, respectively, reduced or prolonged memory retention. Top-down cortical information flow in NREM sleep is thus required for perceptual memory consolidation.
  • Hiroyuki Mizoguchi, Kentaro Katahira, Ayumu Inutsuka, Kazuya Fukumoto, Akihiro Nakamura, Tian Wang, Taku Nagai, Jun Sato, Makoto Sawada, Hideki Ohira, Akihiro Yamanaka, Kiyofumi Yamada
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 112 (29) E3930 - E3939 0027-8424 2015/07 [Refereed][Not invited]
     
    Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making.
  • Satoshi Manita, Takayuki Suzuki, Chihiro Homma, Takashi Matsumoto, Maya Odagawa, Kazuyuki Yamada, Keisuke Ota, Chie Matsubara, Ayumu Inutsuka, Masaaki Sato, Masamichi Ohkura, Akihiro Yamanaka, Yuchio Yanagawa, Junichi Nakai, Yasunori Hayashi, Matthew E. Larkum, Masanori Murayama
    NEURON 86 (5) 1304 - 1316 0896-6273 2015/06 [Refereed][Not invited]
     
    A fundamental issue in cortical processing of sensory information is whether top-down control circuits from higher brain areas to primary sensory areas not only modulate but actively engage in perception. Here, we report the identification of a neural circuit for top-down control in the mouse somatosensory system. The circuit consisted of a long-range reciprocal projection between M2 secondary motor cortex and S1 primary somatosensory cortex. In vivo physiological recordings revealed that sensory stimulation induced sequential S1 to M2 followed by M2 to S1 neural activity. The top-down projection from M2 to S1 initiated dendritic spikes and persistent firing of S1 layer 5 (L5) neurons. Optogenetic inhibition of M2 input to S1 decreased L5 firing and the accurate perception of tactile surfaces. These findings demonstrate that recurrent input to sensory areas is essential for accurate perception and provide a physiological model for one type of top-down control circuit.
  • Hideaki E. Kato, Motoshi Kamiya, Seiya Sugo, Jumpei Ito, Reiya Taniguchi, Ayaka Orito, Kunio Hirata, Ayumu Inutsuka, Akihiro Yamanaka, Andres D. Maturana, Ryuichiro Ishitani, Yuki Sudo, Shigehiko Hayashi, Osamu Nureki
    NATURE COMMUNICATIONS 6 7177  2041-1723 2015/05 [Refereed][Not invited]
     
    Microbial opsins with a bound chromophore function as photosensitive ion transporters and have been employed in optogenetics for the optical control of neuronal activity. Molecular engineering has been utilized to create colour variants for the functional augmentation of optogenetics tools, but was limited by the complexity of the protein-chromophore interactions. Here we report the development of blue-shifted colour variants by rational design at atomic resolution, achieved through accurate hybrid molecular simulations, electrophysiology and X-ray crystallography. The molecular simulation models and the crystal structure reveal the precisely designed conformational changes of the chromophore induced by combinatory mutations that shrink its p-conjugated system which, together with electrostatic tuning, produce large blue shifts of the absorption spectra by maximally 100 nm, while maintaining photosensitive ion transport activities. The design principle we elaborate is applicable to other microbial opsins, and clarifies the underlying molecular mechanism of the blue-shifted action spectra of microbial opsins recently isolated from natural sources.
  • Tadahiro Nagaoka, Ayumu Inutsuka, Khadiza Begum, Khandakar Musabbir bin Hafiz, Masashi Kishi
    SCIENTIFIC REPORTS 4 6940  2045-2322 2014/11 [Refereed][Not invited]
     
    E-cadherin belongs to the classic cadherin subfamily of calcium-dependent cell adhesion molecules and is crucial for the formation and function of epithelial adherens junctions. In this study, we demonstrate that Vangl2, a vertebrate regulator of planar cell polarity (PCP), controls E-cadherin in epithelial cells. E-cadherin co-immunoprecipitates with Vangl2 from embryonic kidney extracts, and this association is also observed in transfected fibroblasts. Vangl2 enhances the internalization of E-cadherin when overexpressed. Conversely, the quantitative ratio of E-cadherin exposed to the cell surface is increased in cultured renal epithelial cells derived from Vangl2(Lpt/1) mutant mice. Interestingly, Vangl2 is also internalized through protein traffic involving Rab5-and Dynamin-dependent endocytosis. Taken together with recent reports regarding the transport of Frizzled3, MMP14 and nephrin, these results suggest that one of the molecular functions of Vangl2 is to enhance the internalization of specific plasma membrane proteins with broad selectivity. This function may be involved in the control of intercellular PCP signalling or in the PCP-related rearrangement of cell adhesions.
  • Ayumu Inutsuka, Azusa Inui, Sawako Tabuchi, Tomomi Tsunematsu, Michael Lazarus, Akihiro Yamanaka
    NEUROPHARMACOLOGY 85 451 - 460 0028-3908 2014/10 [Refereed][Not invited]
     
    Orexin neurons in the hypothalamus regulate energy homeostasis by coordinating various physiological responses. Past studies have shown the role of the orexin peptide itself; however, orexin neurons contain not only orexin but also other neurotransmitters such as glutamate and dynorphin. In this study, we examined the physiological role of orexin neurons in feeding behavior and metabolism by pharmacogenetic activation and chronic ablation. We generated novel orexin-Cre mice and utilized Cre-dependent adeno-associated virus vectors to express Gq-coupled modified GPCR, hM3Dq or diphtheria toxin fragment A in orexin neurons. By intraperitoneal injection of clozapine-N oxide in orexin-Cre mice expressing hM3Dq in orexin neurons, we could selectively manipulate the activity of orexin neurons. Pharmacogenetic stimulation of orexin neurons simultaneously increased locomotive activity, food intake, water intake and the respiratory exchange ratio (RER). Elevation of blood glucose levels and RER persisted even after locomotion and feeding behaviors returned to basal levels. Accordantly, 83% ablation of orexin neurons resulted in decreased food and water intake, while 70% ablation had almost no effect on these parameters. Our results indicate that orexin neurons play an integral role in regulation of both feeding behavior and metabolism. This regulation is so robust that greater than 80% of orexin neurons were ablated before significant changes in feeding behavior emerged. (C) 2014 The Authors. Published by Elsevier Ltd.
  • Tomomi Tsunematsu, Takafumi Ueno, Sawako Tabuchi, Ayumu Inutsuka, Kenji F. Tanaka, Hidetoshi Hasuwa, Thomas S. Kilduff, Akira Terao, Akihiro Yamanaka
    JOURNAL OF NEUROSCIENCE 34 (20) 6896 - 6909 0270-6474 2014/05 [Refereed][Not invited]
     
    Melanin-concentrating hormone (MCH) is a neuropeptide produced in neurons sparsely distributed in the lateral hypothalamic area. Recent studies have reported that MCH neurons are active during rapid eye movement (REM) sleep, but their physiological role in the regulation of sleep/wakefulness is not fully understood. To determine the physiological role of MCH neurons, newly developed transgenic mouse strains that enable manipulation of the activity and fate of MCH neurons in vivo were generated using the recently developed knockin-mediated enhanced gene expression by improved tetracycline-controlled gene induction system. The activity of these cells was controlled by optogenetics by expressing channelrhodopsin2 (E123T/T159C) or archaerhodopsin-T in MCH neurons. Acute optogenetic activation of MCH neurons at 10 Hz induced transitions from non-REM (NREM) to REM sleep and increased REM sleep time in conjunction with decreased NREM sleep. Activation of MCH neurons while mice were in NREM sleep induced REM sleep, but activation during wakefulness was ineffective. Acute optogenetic silencing of MCH neurons using archaerhodopsin-T had no effect on any vigilance states. Temporally controlled ablation of MCH neurons by cell-specific expression of diphtheria toxin A increased wakefulness and decreased NREM sleep duration without affecting REM sleep. Together, these results indicate that acute activation of MCH neurons is sufficient, but not necessary, to trigger the transition from NREM to REM sleep and that MCH neurons also play a role in the initiation and maintenance of NREM sleep.
  • Tadahiro Nagaoka, Riuko Ohashi, Ayumu Inutsuka, Seiko Sakai, Nobuyoshi Fujisawa, Minesuke Yokoyama, Yina H. Huang, Michihiro Igarashi, Masashi Kishi
    CELL REPORTS 6 (5) 916 - 927 2211-1247 2014/03 [Refereed][Not invited]
     
    Although regulators of the Wnt/planar cell polarity (PCP) pathway are widely expressed in vertebrate nervous systems, their roles at synapses are unknown. Here, we show that Vangl2 is a postsynaptic factor crucial for synaptogenesis and that it coprecipitates with N-cadherin and PSD-95 from synapse-rich brain extracts. Vangl2 directly binds N-cadherin and enhances its internalization in a Rab5-dependent manner. This physical and functional interaction is suppressed by beta-catenin, which binds the same intracellular region of N-cadherin as Vangl2. In hippocampal neurons expressing reduced Vangl2 levels, dendritic spine formation as well as synaptic marker clustering is significantly impaired. Furthermore, Prickle2, another postsynaptic PCP component, inhibits the N-cadherin-Vangl2 interaction and is required for normal spine formation. These results demonstrate direct control of classic cadherin by PCP factors; this control may play a central role in the precise formation and maturation of cell-cell adhesions at the synapse.
  • Ayumu Inutsuka, Akihiro Yamanaka
    Nagoya Journal of Medical Science 75 (1-2) 29 - 36 0027-7622 2013 [Refereed][Not invited]
     
    Orexins, also known as hypocretins, are neuropeptides that are exclusively expressed by neurons in the lateral hypothalamic area. Although originally recognized as regulators of feeding behavior, orexins are now mainly regarded as key modulators of the sleep/wakefulness cycle. In addition, anatomical studies of neural networks and analyses of transgenic mice have revealed integrated roles for orexin neurons in the coordination of emotion, energy homeostasis, and the reward system. A functional link between the limbic system and orexin neurons may be important for increasing vigilance in response to emotional stimuli. These findings suggest that orexin neurons relay information about an organism's environment to maintain the proper amount of sleep and wakefulness in animals.
  • Ayumu Inutsuka, Akihiro Yamanaka
    Frontiers in Endocrinology 4 18  1664-2392 2013 [Refereed][Not invited]
     
    The hypothalamus monitors body homeostasis and regulates various behaviors such as feeding, thermogenesis, and sleeping. Orexins (also known as hypocretins) were identified as endogenous ligands for two orphan G-protein-coupled receptors in the lateral hypothalamic area. They were initially recognized as regulators of feeding behavior, but they are mainly regarded as key modulators of the sleep/wakefulness cycle. Orexins activate orexin neurons, monoaminergic and cholinergic neurons in the hypothalamus/brainstem regions, to maintain a long, consolidated awake period. Anatomical studies of neural projections from/to orexin neurons and phenotypic characterization of transgenic mice revealed various roles for orexin neurons in the coordination of emotion, energy homeostasis, reward system, and arousal. For example, orexin neurons are regulated by peripheral metabolic cues, including ghrelin, leptin, and glucose concentration. This suggests that they may provide a link between energy homeostasis and arousal states. A link between the limbic system and orexin neurons might be important for increasing vigilance during emotional stimuli. Orexins are also involved in reward systems and the mechanisms of drug addiction. These findings suggest that orexin neurons sense the outer and inner environment of the body and maintain the proper wakefulness level of animals for survival. This review discusses the mechanism by which orexins maintain sleep/wakefulness states and how this mechanism relates to other systems that regulate emotion, reward, and energy homeostasis. © 2013 Inutsuka and Yamanaka.
  • Yasumasa Kuroda, Masaaki Kitada, Shohei Wakao, Kouki Nishikawa, Yukihiro Tanimura, Hideki Makinoshima, Makoto Goda, Hideo Akashi, Ayumu Inutsuka, Akira Niwa, Taeko Shigemoto, Yoko Nabeshima, Tatsutoshi Nakahata, Yo-ichi Nabeshima, Yoshinori Fujiyoshi, Mari Dezawa
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107 (19) 8639 - 8643 0027-8424 2010/05 [Refereed][Not invited]
     
    We found adult human stem cells that can generate, from a single cell, cells with the characteristics of the three germ layers. The cells are stress-tolerant and can be isolated from cultured skin fibroblasts or bone marrow stromal cells, or directly from bone marrow aspirates. These cells can self-renew; form characteristic cell clusters in suspension culture that express a set of genes associated with pluripotency; and can differentiate into endodermal, ectodermal, and mesodermal cells both in vitro and in vivo. When transplanted into immunodeficient mice by local or i.v. injection, the cells integrated into damaged skin, muscle, or liver and differentiated into cytokeratin 14-, dystrophin-, or albumin-positive cells in the respective tissues. Furthermore, they can be efficiently isolated as SSEA-3(+) cells. Unlike authentic ES cells, their proliferation activity is not very high and they do not form teratomas in immunodeficient mouse testes. Thus, nontumorigenic stem cells with the ability to generate the multiple cell types of the three germ layers can be obtained through easily accessible adult human mesenchymal cells without introducing exogenous genes. These unique cells will be beneficial for cell-based therapy and biomedical research.
  • Ayumu Inutsuka, Makoto Goda, Yoshinori Fujiyoshi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 390 (4) 1160 - 1166 0006-291X 2009/12 [Refereed][Not invited]
     
    Calyculin A (CL-A), a toxin isolated from the marine sponge Discodermia calyx, is a strong inhibitor of protein phosphatase 1 (PP1) and 2A (PP2A). Although CL-A is known to induce rapid neurite retraction in developing neurons, the cytoskeletal dynamics of this retraction have remained unclear. Here, we investigated the cytoskeletal dynamics during CL-A-induced neurite retraction in cultured rat hippocampal neurons, using fluorescence microscopy as well as polarized light microscopy, which can visualize the polymerization state of the cytoskeleton in living cells. We observed that MTs were bent while maintaining their polymerization state during the neurite retraction. In addition, we also found that: CL-A still induced neurite retraction when MTs were depolymerized by nocodazole or stabilized by paclitaxel. These results imply a mechanism other than depolymerization of MTs for CL-A-induced neurite retraction. Our pharmacological studies showed that blebbistatin and cytochalasin D, an inhibitor of myosin 11 and a depolymerizer of actin, strongly inhibited CL-A-induced neurite retraction. Based on all these findings, we propose that CL-A generates strong contractile forces by actomyosin to induce rapid neurite retraction independently from MT depolymerization. (C) 2009 Elsevier Inc. All rights reserved.

Books etc

  • 脳科学辞典 (視床下部の項目)
    犬束歩, 山中章弘 (Joint work)
    2019/02 
    DOI:10.14931/bsd.1033
  • jikkenigaku
    Ayumu Inutsuka (ContributorHow to use DREADDs for manipulation of neuronal activity in vivo)
    YODOSHA 2018/08 9784758125116
  • Clinical Neuroscience Vol.35 No.5 (2017-5)
    Ayumu Inutsuka, Yuki Takayanagi, Masahide Yoshida, Tatsushi Onaka (Contributor分子から迫る神経薬理学: オキシトシン受容体の機能)
    中外医学社 2017/05
  • 三品 昌美 (Contributor15章:食欲、肥満)
    化学同人 2015/04 4759815198 291 
    15章:食欲、肥満
  • 米田 悦啓, 岡村 康司, 金井 好克, 西田 幸二 (Contributor時間単位のリズム)
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