大脳辺縁系における情動・記憶・免疫系の相互干渉機構の解明

2000 Fiscal Year Annual Research Report

• Project/Area Number: 12210009
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (C)
• Research Institution: Toyama Medical and Pharmaceutical University
• Principal Investigator: 小野 武年 富山医科薬科大学, 医学部, 教授 (50019577)
• Co-Investigator(Kenkyū-buntansha): 倉知 正佳 富山医科薬科大学, 医学部, 教授 (80019603) ; 村口 篤 富山医科薬科大学, 医学部, 教授 (20174287) ; 西条 寿夫 富山医科薬科大学, 医学部, 教授 (00189284) ; 大谷 修 富山医科薬科大学, 医学部, 教授 (90127548) ; 許 南浩 富山医科薬科大学, 医学部, 教授 (70173573)
• Keywords: 情動 / 記憶 / 認知 / 免疫 / 大脳辺縁系 / ニューロン活動 / サイトカイン / 行動

Research Abstract

I.行動神経科学・神経生理学的研究:物体,場所,空間の認知・学習を行なっているラットの前頭葉眼窩皮質-視床下部系ニューロンの応答様式を解析した結果、これらニューロンの応答性と行動発現との間に有意な相関が認められ、これらの領域が嗜好性や動機的側面に基づく行動選択に重要な役割を果していることが明らかになった。また、免疫サイトカインであるIL-1βの視床下部における遺伝子発現はストレス負荷時の行動異常ならびに内分泌免疫機能の障害に関与することを行動神経科学的および分子生物学的に明らかにした。
II神経解剖学的研究:情動と記憶の相互作用に関与しているモノアミン系およびコリン作動線維の連絡様式をラットを用いて解析した結果、扁桃体基底外側核では、ノルアドレナリン(NA)作動性入力がコリン(ACh)作動性神経系に非対称性(興奮性)シナプスで結合し、一方ACh作動性神経系はNA作動性神経系に対称性(抑制性)および非対称性(興奮性)シナプスで結合することなどを神経解剖学的に明らかにした。
III.分子遺伝学的研究:1)遺伝子発現ベクター[弱毒βH1(HSV)ウイルス]を用いて,中枢神経系(脊髄前角細胞)に外来遺伝子を長期的に導入可能であることを検証した、2)末梢組織構築の変化に関連して発現する新規遺伝子(Calmin)が、海馬体、視床、線条体、小脳に特異的に発現することを明らかにした。3)胸腺細胞株に発現しているmRNAをPCRサブトラクション法で検索し、脳免疫関連遺伝子の一つであるグリア細胞由来神経栄養因子(GDNF)受容体が未熟胸腺細胞に発現していることを明らかにした。
IV.臨床的研究:記憶の組織化の脳内機構を明らかにするため,健常者と分裂病患者について,脳体積と記憶課題遂行中の局所脳血流および代謝活動との関連をMRI,SPECT,MRS等を用いて解析した。その結果、1)分裂病患者では、健常者と比較してMRSにおける神経細胞密度の指標が左側下前頭回で有意に低く、2)健常者では、単語のカテゴリー化の指標と左右の下前頭回の神経細胞密度に正の相関がみられたが、分裂病患者ではそのような相関が認められないことが判明した。

Research Products

• [Publications] Yonemori,M.,Nishijo,H.,Uwano,T.,Tamura,R.,Furuta,I.,Kawasaki,M.,Takashima,Y.and Ono,T.: "Orbital cortex neuronal responses during an odor-based conditioned associative task in rats."Neuroscience. 95. 691-703 (2000)
• [Publications] Tanebe,K.,Nishijo,H.,Muraguchi,A.and Ono,T.: "Effects of chronic stress on hypothalamic interleukin-1β, interleukin-2, and gonadotropin-releasing hormone gene expression in ovariectomized rats."J.Neuroendocrinol.. 12. 13-21 (2000)
• [Publications] Tamura,R.,Nakada,Y.,Nishijo,H.,Miyake,N.and Ono,T.: "Ameliorative effects of tamolarizine on place learning impairment induced by transient forebrain ischemia in rats."Brain Res.. 853. 81-92 (2000)
• [Publications] Nishijo,H.,Ono,T.,Uwano,T.,Kondoh,T.and Torii,K.: "Hypothalamic and amygdalar neuronal responses to various tastant solutions during ingestive behavior in rats."J.Nutrition. 130. 9545-9595 (2000)
• [Publications] Kondoh,T.,Mori,M.,Ono,T.and Torii,K.: "Mechanisms of umami taste preference and aversion in rats."J.Nutrition. 130. 9665-9705 (2000)
• [Publications] Gejo,R.,Kawaguchi,Y.,Kondoh,T.,Tabuchi,E.,Matsui,H.,Torii,K.,Ono,T.and Kimura,T.: "Magnetic resonance imaging and histologic evidence of postoperative back muscle injury in rats."Spine. 25. 941-946 (2000)
• [Publications] Yamamura,J.,Kageyama,S.,Uwano,T.,Kurokawa,M.,Imakita,M.and Shiraki,K.: "Long-term gene expression in the anterior horn motor neurons after intramuscular inoculation of a live herpes simplex virus vector."Gene Therapy. 7. 934-941 (2000)
• [Publications] Zhong,Y.M.,Nishijo,H.,Uwano,T.,Tamura,R.,Kawanishi,K.and Ono,T.: "Red ginseng ameliorated place navigation deficits in young rats with hippocampal lesions and aged rats."Physiol.Behav.. 69. 511-525 (2000)
• [Publications] Ono,T.,Nishijo,H.and Nishino,H.: "Functional role of the limbic system and basal ganglia in motivated behaviors."J.Neurol.. 247. 23-32 (2000)
• [Publications] Martin,P.D.and Ono,T.: "Effects of reward anticipation,reward presentation, and spatial parameters on the firing of single neurons recorded in the subiculum and nucleus accumbens of freely moving rats."Behav.Brain Res.. 116. 23-38 (2000)
• [Publications] 小野武年,西条寿夫,上野照子,鐘咏梅: "老齢ラットの場所学習障害に対する非サポニン分画の改善効果."The GINSENG REVIEW. 28. 30-39 (2000)
• [Publications] 梅野克身,永嶋義直,高倉大匡,矢田幸博,堀悦郎,小野武年,西条寿夫: "暗算負荷中の呼吸循環動態および脳波の線形解析."自律神経. 37. 572-579 (2000)
• [Publications] Kataoka,K.,Takata,Y.,Nakajima,A.,Saito,S.and Huh,N.: "A carcinoembryonic antigen family cDNA from mouse placenta encoding a protein with a rare domain composition."Placenta. 21(7). 610-614 (2000)
• [Publications] Nakajima,A.,Kataoka,K.,Takata,Y.and Huh,N.: "Cathepsin-6, a novel cysteine proteinase showing homology with and co-localized expression with cathepsin J/P in the labyrinthine layer of mouse placenta."Biochem.J.. 349. 689-692 (2000)
• [Publications] Takata,S.,Ohtani,O.and Watanabe,Y.: "Lectin binding patterns in rat nasal-associated lymphoid tissue (NALT) and the influence of various types of lectin on particle uptake in NALT."Arch.Histol.Cytol.. 63(4). 305-312 (2000)
• [Publications] Ohtani,O.and Ohtani,Y.: "A corrosion casting/scanning electron microscope method that simul-taneously demonstrates clear outlines of endothelial cells and three-dimensional vascular organization."Arch.Histol.Cytol.. 63(5). 425-429 (2000)
• [Publications] Kamiyama,T.,Sato,H.,Takahara,T.,Kageyama,S.and Shiraki,K.: "Novel immunogenicity of Oka varicella vaccine vector expressing hepatitis B surface antigen."J.Infect.Dis.. 181. 1158-1161 (2000)
• [Publications] Takasaki,I.,Andoh,T.,Shiraki,K.and Kuraishi,Y.: "Allodynia and hyperalgesia induced by herpes simplex virus type-1 infection in mice."Pain. 86. 95-101 (2000)
• [Publications] Ida,M.,Kageyama,S.,Sato,H.,Kamiyama,T.,Toyomoto,T.,Ozaki,T.,Kajita,Y.,Morohashi,M.and Shiaki,K.: "Characterization of acyclovir susceptibility and genetic stability of varicella-zoster viruses isolated during acyclovir therapy."J.Dermatol.Sci.. 23. 63-72 (2000)
• [Publications] Imakita,M.,Shiraki,K.,Yutani,C.and Ishibashi-Ueda,H.: "Pneumonia caused by rhinovirus."Clin.Infect.Dis.. 30. 611-612 (2000)
• [Publications] Tsuji,T.,Shiraki,K.,Sato,H.,Yue-Mea,J.,Honma,Y.,Yoshikawa,T.and Asano,Y.: "Humoral immunoresponse to varicella-zoster virus pernasally coadministered with Escherichia coli enterotoxin in mice."Vaccine. 18. 2049-2054 (2000)
• [Publications] Yamamura,J.,Kageyama,S.,Uwano,T.,Kurokawa,M.and Shiraki,K.: "Long-term gene expression in the anterior horn motor neurons after intramuscular inoculation of a live herpes simplex virus vector."Gene Therapy. 7. 934-941 (2000)
• [Publications] Kageyama,S.,Maniar,J.K.,Iwasaki,M.,Zhang,J.,Saple,D.G.,Tsuchie,H.,Tanabe-Tochikura,A.,Taniguchi,K.,Shiraki,K.,and Kurimura,T.: "Seronegative HIV-2 carriers in India."Int.J.STD AIDS. 11. 31-37 (2000)
• [Publications] Kageyama,S.,Kurokawa,M.and Shiraki,K.: "Extract of Prunella vulgaris spikes inhibits HIV replication at reverse-transcription in vitro and can be absorbed from intestine in vivo."Antiviral Chem.Chemother. 11. 157-164 (2000)
• [Publications] Takasaki,I.,Andoh,T.,Nitta,M.,Takahata,H.,Nemoto,H.,Shiraki,K.,Nojima,H.and Kuraishi,Y.: "Pharmacological and immunohistochemical characterization of mouse model of acute herpetic pain."Jpn.J.Pharmacol.. 83. 319-326 (2000)
• [Publications] Sasaki,K.,Asano,Y.,Honma,Y.,Kamiya,N.,Imamura,S.,Ichinose,Y.,Yokochi,T.,Shiraki,K.and Tsuji,T.: "Adjuvant action of Escherichia coli enterotoxin for delayed-type hypersensitivity to Oka vaccine virus on pernasal co-administration in mice."Vaccine. 18. 2049-2054 (2000)
• [Publications] Hasegawa,T.,Kawana,T.,Okuda,T.,Tsukada,T.,Horii,M.and Shiraki,K.: "Analysis of herpes simplex virus isolated from the genital lesions since 1977 in Japan."J.Med.Virol.. 63. 57-63 (2001)
• [Publications] Sasaki,K.,Asano,Y.,Honma,Y.,Kamiya,N.,Hnada,T.,Ichinose,Y.,Yokochi,T.,Shiraki,K.and Tsuji,T.: "Adjuvant action of Escherichia coli enterotoxin for delayed type hypersensitivity to Oka varicella virus on pernasal co-administration in mice."Vaccine. 19. 931-936 (2001)
• [Publications] Yokoyama,T.,Ayabe,S.,Miyagi,H.,Sugano,T.,Otsu,A.,Sato,H.,kageyama,S.,Fujii,T.and Shiraki,K.: "Varicella-zoster virus gH : gL contains a structure reactive with the anti-human gamma chain of IgG near the glycosylation site."J.Gen.Virol.. 82. 331-334 (2001)
• [Publications] Shiraki,K.,Sato,H.,Yoshida,Y.,Yamamura,J.,Tsurita,M.,Kurokawa,M.and Kageyama,S.: "Construction of Oka varicella vaccine expressing human immunodeficiency virus env antigen."J.Med.Virol.. (in press). (2001)
• [Publications] KTakasaki,I.,Andoh,T.,Nojima,H.,Shiraki,K.and Kuraishi,Y.: "Gabapentin antinociception in mice with acute herpetic pain induced by herpes simplex virus infection."J.Pharmacol.Exp.Therapeut.. (in press). (2001)
• [Publications] Kurokawa,M.,Hozumi,T.,Tsurita,M.,Kadota,S.,Namba,T.and Shiraki,K.: "Biological characterization of eugeniin as an anti-herpes simplex virus type 1 compound in vitro and in vivo."J.Pharmacol.Exp.Therapeut.. (in press). (2001)
• [Publications] Kamiya,N.,Asano,Y.,Yoshino,J.,Sasaki,K.,Honma,Y.,Kawase H.,Yokochi,T.,Shiraki,K.and Tsuji,T.: "Long-term persistence of cellular immunity to Oka vaccine virus induced by pernasal co-administration with Escherichia coli enterotoxin in mice."Vaccine. (in press). (2001)
• [Publications] Fujishiro,Y.,Kishi,H.,Matsuda,T.,Fuse,H.and Muraguchi,A.: "Lactate dehydrogenase A-dependent surface expression of immature thymocyte antigen-1; an implication for a novel trafficking function of lactate dehydrogenase-A during T cell development."Eur.J.Immunol.. 30(2). 516-524 (2000)
• [Publications] Matsuda,T.,Yamamoto,T.,Kishi,H.,Yoshimura,A.and Muraguchi,A.: "SOCS-1 can suppress CD3ζ-and Syk-mediated NF-AT activation in a non-lymphoid cell line."FEB S Letters.. 472. 235-240 (2000)
• [Publications] Kawakami,T.,Nagata,T.,A.Muraguchi,A.and Nishimura,T.: "Alteration of protein composition in mouse thymocytes by signals through T-cell receptor."Electrophoresis.. 21. 1846-1852 (2000)
• [Publications] Kishi,H.,Wei,X.-C.,Jin,Z.-X.,Fujishiro,Y.,Nagata,T.,Matsuda,T.and Muraguchi,A.: "Lineage-specific regulation of the murine RAG-2 promoter : GATA-3 in T cells and Pax-5 in B cells."Blood.. 95. 3845-3852 (2000)
• [Publications] Nagata,T.,Kishi,H.,Liu,Q.-L.,Yoshino,T.,Matsuda,T.,Jin,Z.-X.,Murayama,K.,Tsukada,K.and Muraguchi,A.: "Possible involvement of cyclophilin B and caspase-activated deoxyribonuclease in the induction of chromosomal DNA degradation in TCR-stimulated thymocytes."J.Immunol.. 165. 4281-4289 (2000)
• [Publications] Junicho,A.,Matsuda,T.,Yamamoto,T.,Kishi,H.,Korkmaz,K.,Saatcioglu,F.,Fuse H.,and Muraguchi,A.: "Protein inhibitor of activated STAT3 regulates androgen receptor signaling in postate carcinoma cells."Biochem.Biophys.Res.Commun.. 278. 9-13 (2000)
• [Publications] Yamamoto,T.,Matsuda,T.,Junicho,A.,Kishi,H.,Saatcioglu,F.,and Muraguchi,A.: "Cross-talk between signal transducer and activator of transcription3 and estrogen receptorsignaling."FEB S Letters.. 486. 143-148 (2000)
• [Publications] Kurachi,M.,Sumiyoshi,T.,Shibata,R.,Sun,Y-J.,Uehara,T.,Tanii,Y.,and Suzuki,M.: "Changes in limbic dopamine metabolism following quinolinic acid lesions of the left entorhinal cortex in rats."Psychiatry Clin Neurosci.. 54. 83-89 (2000)
• [Publications] Uehara,T.,Tanii,Y.,Sumiyoshi,T.and Kurachi,M.: "Neonatal lesions of the left entorhinal cortex affect dopamine metabolism in the rat brain."Brain Res.. 860. 77-86 (2000)
• [Publications] 田村了以,小野武年: "情動."Clin.Neurosci.. 18. 910-911 (2000)
• [Publications] Kuroki,T.,Ikuta,T.,Kashiwagi,M.,Kawabe,S.,Ohta,M.,Huh,N.,Mizuno,K.,Ohno,S.,Yamada,E.,Chida,K.: "Cholesterol sulfate, an activator of protein kinase C mediating squamous cell differentiation. (a review)"Mutat.Res.. 62. 189-195 (2000)
• [Publications] 井上貴央,大谷修,村上宅郎: "走査電子顕微鏡."電子顕微鏡. 35. 132-135 (2000)
• [Publications] 長田拓哉,岸裕幸,松田正,村口篤: "胸腺T細胞のアポトーシス誘導とその制御."臨床免疫. 34. 424-433 (2000)
• [Publications] 倉知正佳,黒川賢造: "症状評価尺度の有用性とその問題点."精神科治療学. 15. 23-26 (2000)
• [Publications] 倉知正佳: "診断法の展望."Schizophr Frontier. 1. 12-17 (2000)
• [Publications] Nohara,S.,Suzuki,M.,Kurachi,M.,Yamashita,I.Matsui,M.,Seto,H.,and Saitoh,O.: "Neural correlates of memory organization deficits in schizophrenia-a single photon emission computed tomography study with 99mTc-ECD during a verbal learning task-."Schizophr.Res.. 42. 209-222 (2000)
• [Publications] Kurokawa,K.,Nakamura,K.,Hagino,H.,Yotsutsuji.T.,Yamashita,I.,Suzuki,M.,Sumiyoshi,T.,Matsui,M.and Kurachi,M.: "Ventricular Enlargement in Schizophrenic Patients with Prodromal Symptoms of Obsessive-Compulsive Disorder."Psychiatry Res.Neuroimaging. 99. 83-91 (2000)
• [Publications] Sumiyoshi,T.,Kurachi,M.,Kurokawa,K.,Yotsutsuji,T.,Uehara,T.,Itoh,H.and Saitoh,O.: "Plasma homovanillic acid in the prodromal phase of schizophrenia."Biol.Psychiatry. 47. 428-433 (2000)
• [Publications] Sumiyoshi,T.,Matsui,M.,Yamashita,I.,Nohara,S.,Uehara T.,Kurachi,M.and Meltzer,H.Y.: "Effect of adjunctive therapy with serotonin1A agonist tandospirone on memory functions in schizophrenia."J.Clin.Psychopharmacol.. 20. 386-388 (2000)
• [Publications] Sumiyoshi,T.,Kurachi,M.and Itoh,H.: "Schizophrenia and plasma homovanillic acid in response of plasma homovanillic acid to mental stress : methodological considerations."Neuropsychopharmacology. 23. 347-349 (2000)
• [Publications] 山下委希子,松井三枝,倉知正佳: "記憶の体制化を測る単語記憶検査の作成."精神医学. 42. 1279-1284 (2000)
• [Publications] 鈴木道雄,萩野宏文,野原茂,高橋努,山下委希子,倉知正佳: "アルツハイマー病の早期臨床診断における問題点."老年精神医学. 11. 1210-1219 (2000)
• [Publications] Tamura R,Kondoh T,Ono T,Nishijo H,Torii,K: "Altered activity of lateral and medial hypothalamic neurons in rats during discrimination of conditioned cue tone stimuli in repeated cold stress."J.Neurophysiol.. 84. 2844-2858 (2000)
• [Publications] Nakada Y,Tamura R,Kimura T,Uwano T,Nishijo H,Ono T.: "Ameliorative effects of a cognitive enhancer, T-588, on place learning deficits induced by transient forebrain ischemia in rats."Physiol.Behav.. (in press). (2000)
• [Publications] Nishimura FT,Fukunaga T,Nishijo H,Ono T,Kajiura H,Yokomukai Y: "EEG spectral characteristics after alcohol ingestion in Japanese men with aldehyde dehydrogenase-2 genetic variations : Comparison with peripheral changes."Alcoholism : Clinical and Experimental Research. (in press). (2000)
• [Publications] Tamura,R.and Ono,T.: "Neural substrate for spatial memory in the monkey hippocampus. In Neuroscientific Basis of Dementia, by C.Tanaka, Y.Ihara and P.L.McGeer (Eds.)"Birkhauser Verlag Basel : Switzerland. 43-49 (2001)
• [Publications] 田村了以,小野武年: "多連ガラス微小電極法.脳科学大事典(甘利俊一,外山敬介編集)I.総論8.脳の研究手法8.3"朝倉書店:東京. 75-79 (2000)
• [Publications] 田村了以,小野武年: "海馬体.脳科学大事典(甘利俊一,外山敬介編集)II.脳のシステム2.記憶と学習2.6"朝倉書店:東京. 187-195 (2000)
• [Publications] 西条寿夫,小野武年: "摂食行動.脳科学大事典(甘利俊一,外山敬介編集)II.脳のシステム4.行動,情動4.1本能行動,4.1.1"朝倉書店:東京. 234-244 (2000)
• [Publications] 西条寿夫,小野武年: "快・不快情動行動.脳科学大事典(甘利俊一,外山敬介編集)II.脳のシステム4.行動,情動4.2"朝倉書店:東京. 261-273 (2000)
• [Publications] 田村了以,小野武年: "脳幹.脳科学大事典(甘利俊一,外山敬介編集)II.脳のシステム4.行動,情動4.3行動の機能局在,4.3.1"朝倉書店:東京. 274-280 (2000)
• [Publications] 西条寿夫,小野武年: "辺縁系.脳科学大事典(甘利俊一,外山敬介編集)II.脳のシステム4.行動,情動4.3行動の機能局在,4.3.2"朝倉書店:東京. 281-292 (2000)
• [Publications] 小野武年: "うま味認知の脳内機構.グルタミン酸の科学-うま味から神経伝達まで(栗原堅三,小野武年,渡辺明治,林裕造 共著)第3章"講談社サイエンティフィック:東京. 49-92 (2000)
• [Publications] 小野武年: "脳における神経伝達物質としてのグルタミン酸.グルタミン酸の科学-うま味から神経伝達まで(栗原堅三,小野武年,渡辺明治,林裕造 共著)第4章"講談社サイエンティフィック:東京. 93-112 (2000)
• [Publications] 西条寿夫,小野武年: "自己定位と現実感.バーチャルリアリティの基礎1人工現実感の基礎"培風館:東京. 174-187 (2000)
• [Publications] 小野武年,西条寿夫,上野照子: "紅蔘の中枢神経作用に関する神経生理学的および行動学的研究.薬用人蔘2000(熊谷朗監修)"共立出版:東京. 66-82 (2000)
• [Publications] 大谷修,堀尾嘉幸: "カラー図解 人体の正常構造と機能 II循環器"日本医事新報社:東京. 1-102 (2000)
• [Publications] 大谷修: "SEM試料作製法.「電子顕微鏡 基礎技術と応用2000〜凍結技法で広がる超微の世界〜J.第11回電顕サマースクール実行委員会編"学際企画:東京. 78-87 (2000)
• [Publications] 大谷修: "線維成分観察法.「走査電子顕微鏡」日本電子顕微鏡学会関東支部編"共立出版:東京. 197-200 (2000)
• [Publications] 倉知正佳,鈴木道雄,齋藤治 編著: "神経科精神科卒後研修マニュアル.-疾患別治療ガイドライン"星和書店. 1-198 (2000)
• [Publications] 鈴木道雄,倉知正佳: "精神疾患への画像診断の応用.III.精神分裂病,C.SPECT,「臨床精神医学講座」,松下正明総編集,第S10巻,精神科臨床における画像診断"中山書店. 410-428 (2000)
• [Publications] 大谷修: "鋳型法.「走査電子顕微鏡」日本電子顕微鏡学会関東支部編"共立出版:東京. 204-209 (2000)
• [Publications] 倉知正佳: "精神疾患の動向.今日の治療指針.多賀須幸男,尾形悦郎総編集"医学書院. 265 (2000)