エストロゲン受容体を介した行動調節の脳内分子機構の解析

• Project/Area Number: 20022005
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: University of Tsukuba
• Principal Investigator: 小川 園子 University of Tsukuba, 大学院・人間総合科学研究科, 教授 (50396610)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥8,000,000 (Direct Cost: ¥8,000,000); Fiscal Year 2009: ¥4,000,000 (Direct Cost: ¥4,000,000); Fiscal Year 2008: ¥4,000,000 (Direct Cost: ¥4,000,000)
• Keywords: エストロゲン / RNA干渉法 / 遺伝子欠損マウス / 活動性 / 不安・情動性 / 視床下部 / 動機付け / 社会的認知

Research Abstract

我々はこれまでに、脳内での局と分子生物学的特性が確立している2種類のエストログン受容体(ER)、アルファ(ER-α)とベータ(ER-β)の各々の遺伝子の欠損マウスの行動解析を進め、2種のERが行動の制御に果たす役割の違いについて明らかにしてきた。本研究では、アデノ随伴ウイルス(AAV)を用いて脳内のERの発現を領域特異的に操作したマウスの行動解析を通して、ER-αが脳内のどの領域において、エストロゲンによる行動の制御に関わっているのかを特定することを目指した。ER-αのsiRNAを組み込んだAAV(AAV.siER-α)あるいはコントロールAAV(AAV.siLuc)を、雄マウス(C57BL/6マウス)の視床下部腹内側核に両側性に投与したところ、ホームケージ回転車およびオープンフィールド活動量が大きく低下した。特に、組織学的検索により腹内側核の腹外側部でのER-αの発現がほぼ完全に消失していることが確認されたマウスにおいて、活動量の最も顕著な低下が見られた。さらに、エストロゲンによる活動の促進効果が全く見られないことが報告されているER-α欠損マウスにおいて、腹内側核腹外側部へのER-α遺伝子の再導入を試みたところ、部分的ではあるが回転車活動量レベルに回復が見られることが確かめられた。一方、内側視索前野にAAV.siER-αを投与したマウスでは、雄タイプの性行動は大きく低下したものの、攻撃行動や活動量には変化が見られなかった。この結果は、雄性ステロイドホルモンであるテストステロンは酵素アロマテースによりエストラジオールに変換された後、視床下部腹内側核のER-αに作用して活動性を亢進し、内側視索前野のER-αに作用して雄の性行動の生起を促進することを示唆する。本研究で確立した手法を用いて、行動制御の基盤となる脳内機構の解明に向けた研究が推進されることが期待される。

Research Products

• [Journal Article] The role of the estrogen receptor alpha in the medial amygdala and ventromedial nucleus of the hypothalamus in social recognition, anxiety and aggression (2010)
  • Author(s): Spiteri T, Musatov S, Ogawa S, Ribeiro A, Pfaff DW, Agmo A
  • Journal Title: Behavioural Brain Research Epub(Feb23)
  • Peer Reviewed
• [Journal Article] Estrogen-Induced Sexual Incentive Motivation, Proceptivity and Receptivity Depend on a Functional Estrogen Receptor alpha in the Ventromedial Nucleus of the Hypothalamus but Not in the Amygdala (2010)
  • Author(s): Spiteri T, Musatov S, Ogawa S, Ribeiro A, Pfaff DW, Agmo A
  • Journal Title: Neuroendocrinology 91 Pages: 142-154
  • Peer Reviewed
• [Journal Article] Estrogen receptor-alpha in the bed nucleus of the stria terminalis regulates social affiliation in male prairie voles(Microtus ochrogaster) (2010)
  • Author(s): Lei K, Cushing BS, Musatov S, Ogawa S, Kramer KM
  • Journal Title: PloS One 5
  • Peer Reviewed
• [Journal Article] Litter environment affects behavior and brain metabolic activity of adult knockout mice (2009)
  • Author(s): Crews U, Rushworth D, Gonzalez-Lima F, Ogawa S
  • Journal Title: Frontiers in Behavioral Neuroscience 3
  • Peer Reviewed
• [Journal Article] Effect of ER-beta gene disruption on estrogenic regulation of anxiety in female mice (2009)
  • Author(s): Tomihara K, Soga T, Nomura M, Korach KS, Gustafsson JA, Pfaff DW, Ogawa S
  • Journal Title: Physiology and Behavior 96 Pages: 300-306
  • Peer Reviewed
• [Journal Article] Divergent effects of estradiol and the estrogen receptor-alpha agonist PPT on eating and activation of PVN CRH neurons in ovariectomized rats and mice (2009)
  • Author(s): Thammacharoen S, Geary N, Lutz TA, Ogawa S, Asarian L
  • Journal Title: Brain Research 1268 Pages: 88-96
  • Peer Reviewed
• [Journal Article] induction of progesterone receptors in the locus coeruleus in female mice (2009)
  • Author(s): K, Pfaff D, Anselmo-Franci JA, Ogawa S
  • Journal Title: Endocrine 36 Pages: 169-177
  • Peer Reviewed
• [Journal Article] 攻撃行動の性差 (2009)
  • Author(s): 小川園子
  • Journal Title: Clinical Neuroscience 27 Pages: 1116-1117
• [Journal Article] Estrogen receptors in the medial amygdala inhibit the expression of male prosocial behavior (2008)
  • Author(s): Cushing, B.S., Perry, A., Musatov, S., Ogawa, S. and Papademetriou E.
  • Journal Title: Journal of Neuroscience 28 Pages: 10399-10403
  • Peer Reviewed
• [Journal Article] Estrogen receptors α and β mediate different aspects of the facilitatory effects of female cues on male risk taking (2008)
  • Author(s): Kavaliers, M., Devidze, N., Choleris, E., Fudge, M., Gustafsson, Korach, K. S., Pfaff, D. W., and Ogawa, S.
  • Journal Title: Psychoneuroendocrinology 33 Pages: 634-642
  • Peer Reviewed
• [Journal Article] Hormonal regulation of prolactin cell development in the fetal pituitary gland of the mouse (2008)
  • Author(s): Ogasawara, K., Nogami, H., Tsuda, M.C. Gustafsson, j.-Å., Korach, K.S., Ogawa, S.,
  • Journal Title: Endocrinology 150 Pages: 1061-1068
  • NAID: 120007138396
  • Peer Reviewed
• [Journal Article] Effect of ER-β gene disruption on estrogenic regulation of anxiety in femalemice (2008)
  • Author(s): Tomihara, K., Soga, T., Nomura, M., Korach, K.S., Gustafsson, J-A, Pfaff, D.W., and Ogawa, S.
  • Journal Title: Physiology and Behavior 96 Pages: 300-306
  • Peer Reviewed
• [Presentation] 攻撃行動の性差 (2010)
  • Author(s): 小川園子
  • Organizer: 日本性差医学・医療学会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2010-02-20
• [Presentation] エストロゲンによる行動調節の神経内分泌基盤 (2009)
  • Author(s): 小川園子
  • Organizer: 第37回自律神経研究会特別講演
  • Place of Presentation: 東京
  • Year and Date: 2009-12-05
• [Presentation] Neuroendocrine Bases of Socio-Sexual and Emotional Behavior (2009)
  • Author(s): 小川園子
  • Organizer: IBRO Associate School of Neuroscience
  • Place of Presentation: Pennag, Malaysia(マレーシア)
  • Year and Date: 2009-12-03
• [Presentation] Neuroendocrine Bases of Socio-Sexual and Emotional Behavior (2009)
  • Author(s): 小川園子
  • Organizer: China Animal Behavior Conference
  • Place of Presentation: Hefei, China(中華人民共和国)
  • Year and Date: 2009-11-02
• [Presentation] 思春期のステロイドホルモン環境が情動・社会行動に及ぼす影響 (2009)
  • Author(s): 柏村実生, 津田夢芽子, Hood KD, Sisk CL, 坂本敏郎, 小川園
  • Organizer: 日本動物心理学会
  • Place of Presentation: 岐阜
  • Year and Date: 2009-09-27
• [Presentation] 思春期に折る雄マウスの攻撃行動の発動・維持に及は仔期母仔分離経験の影響 (2009)
  • Author(s): 棚原友季, 津田夢芽子, 小川園子
  • Organizer: 日本動物心理学会
  • Place of Presentation: 岐阜
  • Year and Date: 2009-09-27
• [Presentation] マウスの情動・社会行動制御に果たす周生期エストロゲヒ刺激の役割 (2009)
  • Author(s): 小川園子
  • Organizer: 日本動物心理学会
  • Place of Presentation: 岐阜
  • Year and Date: 2009-09-25
• [Presentation] Short-and long-term estrogen depletions produce sex dependent changes in food intake and body weight (2009)
  • Author(s): Nakata M, Kobayashi M, Sano K, Tsuda MC, Toda K, Vasudevan N, Ogawa S
  • Organizer: 日本神経科学会
  • Place of Presentation: 愛知
  • Year and Date: 2009-09-17
• [Presentation] Neonatal maternal separation(MS)disrupts the onset and maintenance of aggressive behavior in pubertal male mice (2009)
  • Author(s): Tsuda MC, Tanahara Y, Nagata K, Ogawa S
  • Organizer: 日本神経科学会
  • Place of Presentation: 愛知
  • Year and Date: 2009-09-17
• [Presentation] Neonatal maternal separation disrupts the peri-pubertal onset of aggression in male mice (2009)
  • Author(s): Tsuda MC, Tanahara, Y, Nagata K., Ogawa S
  • Organizer: The 13th Annual Meeting of Society for Behavioral Neuroendocrinology
  • Place of Presentation: Fast Lansing, USA(アメリカ)
  • Year and Date: 2009-06-26
• [Presentation] Anxiety and exploratory behaviors and social interactions in mice selectively bred for aggressiveness (2008)
  • Author(s): Uchimura, T. , Fukushi, A. , Tsuda, M. C. , Sano, K. , Kashimura, M. , Higo, S. , Hood K. E. , Tsukahara, S. , Vasudevan, N. , Ogawa, S.
  • Organizer: The 38th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Washington DC, USA.
  • Year and Date: 2008-11-18
• [Presentation] Neuronally expressed estrogen receptor-α (ER α) is required for the estrogen (E) -induced increase in running wheel activity in male mice (2008)
  • Author(s): Watai, K. , Tsuda, M. C. , Sano, K. , Uchimura, T. , Wintermantel, T. M. , Elzer, J. , Schutz, G. , Vasudevan, N. , Musatov, S , Ogawa, S.
  • Organizer: The 38th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Washington DC, USA.
  • Year and Date: 2008-11-18
• [Presentation] Role of estrogen receptor beta and sexual experience in the regulation of female sexual behavior in mice (2008)
  • Author(s): Xiao, K. , Tsuda, M.C. , Yamada, K., Ogawa, S.
  • Organizer: The 38th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Washington DC, USA.
  • Year and Date: 2008-11-18
• [Presentation] Increased expression of ER α in the bed nucleus of the-stria terminalis alters social behavior (2008)
  • Author(s): Lei, K. , Kramer, K. M. , Musatov, S. , Ogawa, S. , Cushing, B. S.
  • Organizer: The 38th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Washington DC, USA.
  • Year and Date: 2008-11-17
• [Presentation] Effect of neonatal estrogen administration on sexually dimorphic behaviors in estrogen receptor β knockout female mice (2008)
  • Author(s): Tsuda, M.C., Xiao, K., Ogawa, S.
  • Organizer: The 38th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Washington DC, USA.
  • Year and Date: 2008-11-17
• [Presentation] Behavioral Neuroendocrine Bases of KIZUNA Formation. (2008)
  • Author(s): Ogawa, S.
  • Organizer: 日本学術振興会二国間交流事業 : 都市化社会に代表される社会の変容が脳の健全な成育におよぼす影響についての二国間研究
  • Place of Presentation: 筑波大学
  • Year and Date: 2008-10-24
• [Presentation] 情動・社会行動を司る脳の働き・ホルモンの働き (2008)
  • Author(s): 小川園子
  • Organizer: 日本心理学会第72回大会・シンポジウム「こころに作用するホルモン」
  • Place of Presentation: 北海道大学
  • Year and Date: 2008-09-19
• [Presentation] Neuroendocrine Bases of Sex Differences in Emotional Behavior (2008)
  • Author(s): Ogawa, S. and Tsukahara, S.
  • Organizer: International Symposium for Gonad and Brain Sex Differentiation
  • Place of Presentation: JALリゾート・シーホークホテル福岡
  • Year and Date: 2008-09-16
• [Presentation] Role of Two Types of Estrogen Receptors in the Regulation of Mouse (2008)
  • Author(s): Ogawa, S.
  • Organizer: US-apan Symposium on " Brain and Steroid" , Gifu, Japan, September,2008, (日米科学技術協力事業「日米脳ステロイドシンポジウム2008」)
  • Place of Presentation: 岐阜県長良川国際会議場
  • Year and Date: 2008-09-11
• [Presentation] Neuronally expressed estrogen receptor- α (ER α) is critical for the estrogen (E) -induced rise in running wheel activity in male mice (2008)
  • Author(s): Ogawa, Sano, K., Tsuda, MC., Uchimura, T., Watai, K., Wintermental, T.M., Schutz, G., and Vasudevan, N.
  • Organizer: The 12th Annual Meeting of Society for Behavioral Neuroendocrinology
  • Place of Presentation: 3roningen, The Netherlands
  • Year and Date: 2008-07-09
• [Presentation] Establishment of sex differences in the developing rodent brain : Isit ER alpha or ER beta (2008)
  • Author(s): Schwarz, J.M., Nugent, B.M., Tsuda, M.C., Watai, K., Ogawa, S., McCarthy, M.M.
  • Organizer: The 2nd Annual Meeting of the Organization for the Study of Sex Differences
  • Place of Presentation: New Orleans, USA.
  • Year and Date: 2008-06-05