Introduction

In our research projects, we develop a new drug delivery system which targets the brain, new imaging technology, and single cellular separation assay technology to elucidate the expression of brain functions in terms of morphology and cell structure, and to evaluate the mechanisms of expression of high-level brain functions such as memory and emotion, at the genetic, cellular, and organism levels. In addition, we are working on developing techniques with which we can artificially control such functions. Our aim is to apply this research to develop comprehensive therapies and diagnostic methods for brain disorders and to discover new drugs.
We have been working closely with industry, and, based on our experience, we are fully aware of the importance of basic research in medicine. It is true that basic medical research is the basis of modern medicine, however, at the same time, it is those who are involved in medical treatment who should decide the orientation of how to apply research results in the clinic. We would like to continue our research, with the aim of maintaining a balance between clinical and research aspects.

Research Projects

1. Elucidation of the mechanism of microglia in the regulation of higher brain function
   (1) Brain-specific migration of microglia, and its application in brain-targeted drug delivery
   (2) Microglial toxic changes in neural disorders
   (3) Control of higher brain functions by microglia and their subtypes
2. Development of “Tissue Penetrating Cell Technology” and “in vivo Imaging Methods”
   (1)Tissue penetrating cell analysis, drug targeting using these cells’ properties and application in disease treatment
   (2)Development of innovative bio-imaging methods
   - In vivo observation of gene expression using MRI for small animals
   - Bio-imaging using wide-spectrum near-infra red light sources - Bio-imaging of toxic transformation of microglia
   - Mass Spectrometry Imaging
   (3)Controlling cell activation using light
3. Altered decision-making in neuropsychiatric disorders
   Decision-making is a key activity of everyday life. Consequently, disturbances in the ability to make appropriate decisions or anticipate their possible consequences can result in massive social, medical, and financial problems. Impaired decision-making is recognized as a core problem in the neuropsychiatric disorders, and a better understanding of the mechanisms underlying impaired decision-making should provide insights leading to successful treatments for these diseases. Recently, we have demonstrated that GABAergic interneurons in the insular cortex are involved in altered decision-making in animal model of addiction. GABA receptors might be targeted by novel treatments for impaired decision-making in patients with neuropsychiatric or addiction disorders. We would like to consider roots of risky decisions in further research.

Faculty Members

Faculty	Position	Department
Makoto Sawada	Professor	RIEM, Division of Brain Function
Kenji Ono	Assistant Professor	RIEM, Division of Brain Function
Hiromi Suzuki	Assistant Professor	RIEM, Division of Brain Function
Hiroyuki Mizoguchi	Lecturer	RIEM, Research Center for Next-Generation Drug Development
Koich Oishi	Research Assistant Professor	RIEM, Research Center for Next-Generation Drug Development

Bibliography

• 2016

  1. Kawahara K, Hirata H, Ohbuchi K, Nishi K, Maeda A, Kuniyasu A, Yamada D, Maeda T, Tsuji A, Sawada M, Nakayama H. The novel monoclonal antibody 9F5 reveals expression of a fragment of GPNMB/osteoactivin processed by furin-like protease(s) in a subpopulation of microglia in neonatal rat brain. Glia, 2016; 64: 1938-1961.
  2. Takagishi Y, Katanosaka K, Mizoguchi H, Murata Y. Disrupted axon-glia interactions at the paranode in myelinated nerves cause axonal degeneration and neuronal cell death in the aged Caspr mutant mouse shambling. Neurobiology of Aging, 2016; 43: 34-46.
  3. Matsumoto T, Takahashi N, Kojima T, Yoshioka Y, Ishikawa J, Furukawa K, Ono K, Sawada M, Ishiguro N, Yamamoto A. Soluble Siglec-9 suppresses arthritis in a collagen-induced arthritis mouse model and inhibits M1 activation of RAW264.7 macrophages. Arthritis research & therapy, 2016; 18: 133.
  4. Fujisawa H, Sugimura Y, Takagi H, Mizoguchi H, Takeuchi H, Izumida H, Nakashima K, Ochiai H, Takeuchi S, Kiyota A, Fukumoto K, Iwama S, Takagishi Y, Hayashi Y, Arima H, Komatsu Y, Murata Y, Oiso Y. Chronic hyponatremia causes neurologic and psychologic impairments. Journal of the American Society of Nephrology, 2016; 27: 766-780.

• 2015

  1. Biju V, Hamada M, Ono K, Sugino S, Ohnishi T, Shibu ES, Yamamura S, Sawada M, Nakanishi S, Shigeri Y, Wakida SI. Nanoparticles speckled by ready-to-conjugate lanthanide complexes for multimodal imaging. Nanoscale, 2015; 7: 14829-14837.
  2. Mizoguchi H, Katahira K, Inutsuka A, Fukumoto K, Nakamura A, Wang T, Nagai T, Sato J, Sawada M, Ohira H, Yamanaka A, Yamada K. Insular neural system controls decision-making in healthy and methamphetamine-treated rats. Proceedings of the National Academy of Sciences of the United States of America, 2015; 112: E3930-3939.
  3. Sumida M, Hane M, Yabe U, Shimoda Y, Pearce OM, Kiso M, Miyagi T, Sawada M, Varki A, Kitajima K, Sato C. Rapid trimming of cell surface polySia by exovesicular sialidase triggers release of preexisting surface neurotrophin. The Journal of Biological Chemistry, 2015; 290: 13202-13214.
  4. Hatano K, Sekimata K, Yamada T, Abe J, Ito K, Ogawa M, Magata Y, Toyohara J, Ishiwata K, Biggio G, Serra M, Laquintana V, Denora N, Latrofa A, Trapani G, Liso G, Suzuki H, Sawada M, Nomura M, Toyama H.　 Radiosynthesis and in vivo evaluation of two imidazopyridineacetamides, [11C]CB184 and [ 11C]CB190, as a PET tracer for 18 kDa translocator protein: direct comparison with [ 11C](R)-PK11195. Annals of nuclear medicine, 2015; 29: 325-335.

• 2014

  1. Yukawa H, Nakagawa S, Yoshizumi Y, Watanabe M, Saito H, Miyamoto Y, Noguchi H, Oishi K, Ono K, Sawada M, Kato I, Onoshima D, Obayashi M, Hayashi Y, Kaji N, Ishikawa T, Hayashi S, Baba Y. Novel positively charged nanoparticle labeling for in vivo imaging of adipose tissue-derived stem cells. PLoS One, 2014; 9: e110142.
  2. Suzuki H, Ono K, Sawada M. Protective effect of INI-0602, a gap junction inhibitor, on dopaminergic neurodegeneration of mice with unilateral 6-hydroxydopamine injection. Journal of Neural Transmission, 2014; 121: 1349-1355.
  3. Mouri A, Hoshino Y, Narusawa S, Ikegami K, Mizoguchi H, Murata Y, Yoshimura T, Nabeshima T. Thyrotoropin receptor knockout changes monoaminergic neuronal system and produces methylphenidate-sensitive emotional and cognitive dysfunction. Psychoneuroendocrinology, 2014; 48: 147-161.
  4. Doi Y, Takeuchi H, Mizoguchi H, Fukumoto K, Horiuchi H, Jin S, Kawanokuchi J, Parajuli B, Sonobe Y, Mizuno T, Suzumura A. Granulocyte-colony stimulating factor attenuates oligomeric amyloid beta neurotoxicity by activation of neprilysin. PLoS One, 2014; 9: e103458.
  5. Fukumoto K, Mizoguchi H, Takeuchi H, Horiuchi H, Kawanokuchi J, Jin S, Mizuno T, Suzumura A. Fingolimod increases brain-derived neurotrophic factor levels and ameliorates amyloid beta-induced memory impairment. Behavioural Brain Research, 2014; 268: 88-93.
  6. Ono K, Suzuki H, Higa M, Tabata K, Sawada M. Glutamate release from astrocyte cell-line GL261 via alterations in the intracellular ion environment. Journal of Neural Transmission, 121: 245-257.

• 2013

  1. Sakai H, Li G, Hino Y, Moriura Y, KawawakiI J, Sawada M, Kuno M. Increases in intracellular pH facilitate endocytosis and decrease availability of voltage-gated proton channels in osteoclasts and microglia. The Journal of Physiology, 2013; 591: 5851-5866.
  2. Hori K, Matsuura T, Mori T, Kuno M, Sawada M, Nishikawa K. The effect of lipid emulsion on intracellular bupivacaine as a mechanism of lipid resuscitation: an electrophysiological study using voltage-gated proton channels. Anesthesia and analgesia, 2013; 117: 1293-1301.
  3. Shibu ES, Ono K, Sugino S, Nishioka A, Yasuda A, Shigeri Y, Wakida SI, Sawada M, Biju V. Photouncaging nanoparticles for MRI and fluorescence imaging in vitro and in vivo. American Chemical Society Nano, 2013; 7: 9851-9859.
  4. Shibu ES, Sugino S, Ono K, Saito H, Nishioka A, Yamamura S, Sawada M, Nosaka Y, Biju V. Singlet-oxygen-sensitizing near- infrared- fluorescent multimodal nanoparticles. Angewandte Chemie-International Edition, 2013; 52: 10559-10563.
  5. Mizoguchi H, Yamada K. Roles of matrix metalloproteinases and their targets in epileptogenesis and seizures. Clinical Psychopharmacology and Neuroscience, 2013; 11: 45-52.
  6. Ibi D, Nagai T, Nakajima A, Mizoguchi H, Kawase T, Tsuboi D, Kano S, Sato Y, Hayakawa M, Lange U C, Adams DJ, Surani MA, Satoh T, Sawa A, Kaibuchi K, Nabeshima T, Yamada K. Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice. Glia, 2013; 61: 679-693.
  7. Oishi K, Miyamoto Y, Saito H, Murase K, Ono K, Sawada M, Watanabe M, Noguchi Y, Fujiwara T, Hayashi S, Noguchi H. In vivo imaging of transplanted islets labeled with a novel cationic nanoparticle. PLoS One, 2013; 8: e57046.

• 2012

  1. Takuma K, Mizoguchi H, Funatsu Y, Kitahara Y, Ibi D, Kamei H, Matsuda T, Koike K, Inoue M, Nagai T, Yamada K. Placental extract improves hippocampal neuronal loss and fear memory impairment resulting from chronic restraint stress in ovariectomized mice. Journal of Pharmacological Sciences, 2012; 120: 89-97.
  2. Oishi K, Noguchi H, Saito H, Yukawa H, Miyamoto Y, Ono K, Murase K, Sawada M, Hayashi S. Novel positive-charged nanoparticles for efficient magnetic resonance imaging of islet transplantation. Cell Medicine, 2012; 3: 43-49.
  3. Nakamoto K, Kawasaki S, Kobori T, Fujita-Hamabe W, Mizoguchi H, Yamada K, Nabeshima T, Tokuyama S. Involvement of matrix metalloproteinase-9 in the development of morphine tolerance. European Journal of Pharmacology, 2012; 683: 86-92.
  4. Takuma K, Mizoguchi H, Funatsu Y, Hoshina Y, Himeno Y, Fukuzaki E, Kitahara Y, Arai S, Ibi D, Kamei H, Matsuda T, Koike K, Inoue M, Nagai T, Yamada K. Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice. Neuroscience, 2012; 207: 261-273.
  5. Sakai A, Takasu K, Sawada M, Suzuki H. Hemokinin-1 gene expression is upregulated in microglia activated by lipopolysaccharide through NFkB and p38 MAPK signaling pathways. PLoS One, 2012; 7: e32268.
  6. Matsuura T, Mori T, Hasaka M, Kuno M, Kawawaki J, Nishikawa K, Narahashi T, Sawada M, Asada A. Inhibition of voltage-gated proton channels by local anaesthetics in GMI-R1 rat microglia. The Journal of Physiology, 2012; 590: 827-844.

Research Keywords

microglia、 disease model mice、 MRI probe for brain functions、 optical imaging、 mass spectrometry imaging、 single cell analysis

Private Page

see following web site:

http://www.riem.nagoya-u.ac.jp/4/brain/